Ranexa

Anti-anginal Agents, other

NOTE: Do NOT use ranolazine to relieve an acute angina episode. Ranolazine is a maintenance medication for angina and it must be administered on a regularly scheduled basis to reduce the symptoms of chronic stable angina.
 

Oral Administration

Administer with or without meals.
Limit grapefruit juice and the ingestion of grapefruit-containing products during ranolazine administration.

Oral Solid Formulations

Extended-Release Tablets (e.g., Ranexa)
Extended-release tablets should be swallowed whole; do not crush, break, cut, or chew.
 
Extended-Release Oral Granules (e.g., Aspruzyo Sprinkle Extended-Release Granules)
Avoid concurrent use with alcohol. Alcohol causes a rapid release of ranolazine from the extended-release granules and may increase the risk of adverse events.
Administration with soft foods (e.g., applesauce and yogurt):
Sprinkle granules on 1 tablespoonful (15 mL) of soft food and have the patient swallow immediately. Do not prepare dose in advance.
Do not crush or chew the granules.
Administration via nasogastric or gastric tube:
Nasogastric (NG) tube: Open the sachet and empty intact granules into a cathete tip syringe. Add 50 mL of water to the syringe. Gently shake the syringe for approximately 15 seconds. Promptly administer through a 12-French or larger NG-tube. Ensure no granules are left in the syringe. If needed, rinse with approximately 15 mL of additional water.
Gastronomy/Gastric (G) tube: Open the sachet and empty intact granules into a cathete tip syringe. Add 30 mL of water to the syringe. Gently shake the syringe for approximately 15 seconds. Promptly administer through a 12-French or larger G-tube. Rinse with 20 mL of water in the syringe. Ensure no granules are left in the syringe. If needed, rinse with approximately 15 mL of additional water.

Severe

bradycardia / Rapid / 0.5-4.0
azotemia / Delayed / 0-0.5
renal failure / Delayed / 0-0.5
pancytopenia / Delayed / 0-0.5
pulmonary fibrosis / Delayed / 0-0.5
angioedema / Rapid / 0-0.5

Moderate

constipation / Delayed / 4.5-4.5
confusion / Early / 0.5-4.0
peripheral edema / Delayed / 0.5-4.0
palpitations / Early / 0.5-4.0
hypotension / Rapid / 0.5-4.0
orthostatic hypotension / Delayed / 0.5-4.0
blurred vision / Early / 0.5-4.0
hematuria / Delayed / 0.5-4.0
dyspnea / Early / 0.5-4.0
leukopenia / Delayed / 0-0.5
eosinophilia / Delayed / 0-0.5
thrombocytopenia / Delayed / 0-0.5
myoclonia / Delayed / Incidence not known
hallucinations / Early / Incidence not known
QT prolongation / Rapid / Incidence not known
hypoglycemia / Early / Incidence not known
urinary retention / Early / Incidence not known
dysuria / Early / Incidence not known

Mild

dizziness / Early / 6.2-6.2
headache / Early / 5.5-5.5
nausea / Early / 4.4-4.4
syncope / Early / 0.5-4.0
asthenia / Delayed / 0.5-4.0
tinnitus / Delayed / 0.5-4.0
vertigo / Early / 0.5-4.0
dyspepsia / Early / 0.5-4.0
xerostomia / Early / 0.5-4.0
abdominal pain / Early / 0.5-4.0
vomiting / Early / 0.5-4.0
anorexia / Delayed / 0.5-4.0
hyperhidrosis / Delayed / 0.5-4.0
paresthesias / Delayed / 0-0.5
hypoesthesia / Delayed / 0-0.5
tremor / Early / 0-0.5
urine discoloration / Early / 0-0.5
rash / Early / Incidence not known
pruritus / Rapid / Incidence not known

ASPRUZYO, Ranexa

Rx

Oral antianginal, piperazine derivative
Used for chronic angina in adults
Contraindicated in patients with liver cirrhosis or taking CYP3A inducers or strong CYP3A inhibitors; ranolazine causes dose-related QT prolongation

For the treatment of chronic angina. Oral dosage Adults

500 mg PO twice daily. May increase dose to 1,000 mg PO twice daily if needed. Max: 1,000 mg PO twice daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of acute coronary syndromes in patients with acute myocardial infarction, NSTEMI†. Intravenous† and Oral dosage

NOTE: The IV formulation is not available in the US.

Adults

Dosage not established. Within 48 hours of ischemic symptoms, patients were randomized to ranolazine 200 mg IV bolus over 1 hour then 80 mg/hour IV infusion for 12 to 96 hours followed by 1,000 mg PO twice daily or placebo. There was no significant difference in the primary efficacy endpoint of composite cardiovascular death, myocardial infarction, or recurrent ischemia.

For the treatment of acute coronary syndromes in patients with unstable angina†. Intravenous† and Oral dosage

NOTE: The IV formulation is not available in the US.

Adults

Dosage not established. Within 48 hours of ischemic symptoms, patients were randomized to ranolazine 200 mg IV bolus over 1 hour then 80 mg/hour IV infusion for 12 to 96 hours followed by 1,000 mg PO twice daily or placebo. There was no significant difference in the primary efficacy endpoint of composite cardiovascular death, myocardial infarction, or recurrent ischemia.

†Indicates off-label use

Hepatic Impairment

Ranolazine is contraindicated in patients with hepatic cirrhosis (regardless of Child-Pugh class), due to a greatly increased risk for QT prolongation.

Renal Impairment

No specific dosage adjustments are recommended. Periodic monitoring of renal function is recommended in patients with moderate to severe renal impairment (CrCl less than 60 mL/minute). Ranolazine should be discontinued if acute renal failure develops.
 
Intermittent hemodialysis
Use has not been assessed. Since ranolazine is about 62% bound to plasma proteins, hemodialysis is unlikely to be effective in clearing ranolazine.

Abarelix: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval such as abarelix.
Abrocitinib: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with abrocitinib is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; abrocitinib is a P-gp inhibitor.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with ranolazine may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of ranolazine could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ranolazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Ranolazine is a moderate inhibitor of CYP2D6 and a weak inhibitor of CYP3A4. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with ranolazine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of ranolazine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If ranolazine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ranolazine is a moderate inhibitor of CYP2D6.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like ranolazine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If ranolazine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. If ranolazine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like ranolazine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ranolazine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Contraindicated) Coadministration of ranolazine with adagrasib is contraindicated as concurrent use may increase ranolazine exposure. Concomitant use also increases the risk for QT/QTc prolongation and torsade de pointes (TdP). Ranolazine is a CYP3A and P-gp substrate, adagrasib is a strong CYP3A and P-gp inhibitor, and both medications have been associated with QT interval prolongation. Coadministration of another strong CYP3A inhibitor increased ranolazine exposure by 220%.
Afatinib: (Moderate) If the concomitant use of ranolazine and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of ranolazine. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and ranolazine is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. If ranolazine is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ranolazine can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If ranolazine is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alfuzosin: (Moderate) Use caution when administering alfuzosin with ranolazine due to the potential for QT prolongation. Alfuzosin may prolong the QT interval in a dose-dependent manner. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Alogliptin; Metformin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Alprazolam: (Major) Avoid coadministration of alprazolam and ranolazine due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ranolazine, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and ranolazine is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amiodarone: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with amiodarone is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A and P-gp substrate and amiodarone is a moderate CYP3A inhibitor and inhibitor of P-gp. Coadministration with another moderate CYP3A inhibitor increased plasma levels of ranolazine by 50% to 130%.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with ranolazine. Amisulpride causes dose- and concentration- dependent QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Amlodipine; Atorvastatin: (Moderate) Ranolazine inhibits CYP3A isoenzymes and P-glycoprotein transport. Although not studied, ranolazine may theoretically increase plasma concentrations of CYP3A4 and/or P-glycoprotein substrates such as atorvastatin. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including clarithromycin. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Furthermore, clarithromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include ranolazine.
Apalutamide: (Contraindicated) The concomitant use of apalutamide with ranolazine is contraindicated due to decreased plasma concentrations of ranolazine resulting in decreased efficacy. Apalutamide is a strong CYP3A4 inducer and ranolazine is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inducer decreased the plasma concentrations of ranolazine by approximately 95%.
Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with ranolazine since concurrent use may increase the risk of QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Aprepitant, Fosaprepitant: (Major) The dose of ranolazine should be limited to 500 mg PO twice daily when coadministered with moderate CYP3A4 inhibitors, such as a multi-day regimen of aprepitant. Monitor for an increase in ranolazine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Ranolazine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of ranolazine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Ranolazine is also a weak in vitro CYP3A4 inhibitor in vitro and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
Aripiprazole: (Major) Concomitant use of aripiprazole and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients and increases aripiprazole exposure and risk for side effects. An aripiprazole dosage reduction is necessary; management recommendations vary by aripiprazole dosage form. For aripiprazole oral dosage forms, administer a quarter of the usual dose. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 200 mg/month or from 300 mg to 160 mg/month. Additionally, consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. Aripiprazole is CYP2D6 and CYP3A substrate, ranolazine is a moderate CYP2D6 and weak CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. (Moderate) Concomitant use of aripiprazole and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported.
Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and ranolazine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased ranolazine concentrations. Additionally, artemether; lumefantrine is a substrate and ranolazine is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased artemether; lumefantrine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval such as ranolazine should be avoided. Consider ECG monitoring if ranolazine must be used with or after artemether; lumefantrine treatment.
Asenapine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the time of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, such as asenapine, Coadministration may result in additive QT prolongation. In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, potentially leading to adverse reactions, such as QT prolongation. Asenapine is a CYP3A4 substrate that also has a possible risk for QT prolongation and TdP and should be used cautiously with ranolazine.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with ranolazine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of ranolazine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If ranolazine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ranolazine is a moderate inhibitor of CYP2D6.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. If ranolazine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like ranolazine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ranolazine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Coadministration of ranolazine and atazanavir; cobicistat is contraindicated. A dose reduction may be required if ranolazine is coadminsitered with atazanavir alone. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Ranolazine is metabolized mainly by CYP3A. Although not specifically mentioned by the manufacturer, atazanavir is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently.
Atazanavir; Cobicistat: (Contraindicated) Concomitant use of ranolazine with cobicistat is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-gp. Coadministration of another strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%. Serum concentrations of cobicistat could also be increased as ranolazine is a CYP3A4 and CYP2D6 inhibitor, and cobicistat is a CYP3A4 and CYP2D6 substrate. (Major) Coadministration of ranolazine and atazanavir; cobicistat is contraindicated. A dose reduction may be required if ranolazine is coadminsitered with atazanavir alone. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Ranolazine is metabolized mainly by CYP3A. Although not specifically mentioned by the manufacturer, atazanavir is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently.
Atomoxetine: (Moderate) Concomitant use of atomoxetine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Atorvastatin: (Moderate) Ranolazine inhibits CYP3A isoenzymes and P-glycoprotein transport. Although not studied, ranolazine may theoretically increase plasma concentrations of CYP3A4 and/or P-glycoprotein substrates such as atorvastatin. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
Atorvastatin; Ezetimibe: (Moderate) Ranolazine inhibits CYP3A isoenzymes and P-glycoprotein transport. Although not studied, ranolazine may theoretically increase plasma concentrations of CYP3A4 and/or P-glycoprotein substrates such as atorvastatin. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
Azithromycin: (Major) Concomitant use of ranolazine and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Barbiturates: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including barbiturates. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
Bedaquiline: (Major) Caution is advised when administering bedaquiline concurrently with ranolazine. Ranolazine may inhibit the CYP3A4 metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with ranolazine may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of ranolazine in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If ranolazine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Ranolazine is an in vitro inhibitor of CYP3A4 and CYP2D6.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking ranolazine. Additionally, limit the dose of ranolazine to 500 mg twice daily. Concurrent use may increase the exposure of both berotralstat and ranolazine. Berotralstat is a P-gp substrate and P-gp and moderate CYP3A4 inhibitor; ranolazine is a CYP3A4 and P-gp substrate and P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving ranolazine. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving ranolazine. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; ranolazine inhibits P-gp.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bosentan: (Moderate) Coadministration of ranolazine with CYP3A enzyme inducers such as bosentan may result in a decreased metabolism of ranolazine. Monitor antianginal response to ranolazine closely during initiation of bosentan.
Brentuximab vedotin: (Minor) Concomitant administration of brentuximab vedotin and ranolazine, a P-glycoprotein inhibitor, may increase exposure of monomethyl auristatin E (MMAE), a P-glycoprotein substrate. MMAE is one of the 3 components released from brentuximab vedotin. If co-administration is necessary, monitor patients for adverse reactions.
Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Ranolazine and/or its metabolites are moderate inhibitors of CYP2D6. If ranolazine is used in combination with brexpiprazole and a moderate to strong CYP3A4 inhibitor, the brexpiprazole dose should be reduced and the patient should be carefully monitored for brexpiprazole-related adverse reactions. It should be noted that no dosage adjustment is needed in patients taking a CYP2D6 inhibitor who are receiving brexpiprazole as adjunct treatment for major depressive disorder because CYP2D6 considerations are already factored into general dosing recommendations.
Brigatinib: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with brigatinib is necessary. Ranolazine is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
Brimonidine; Timolol: (Moderate) Timolol is metabolized by CYP2D6 isoenzymes. Ranolazine, a CYP2D6 inhibitor, could theoretically impair timolol metabolism. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
Bupivacaine; Lidocaine: (Major) Ranolazine is an inhibitor of the cytochrome P450 (CYP) isoenzyme 3A, and lidocaine is a substrate for this pathway. Thus, ranolazine may theoretically reduce lidocaine clearance. If concurrent therapy with ranolazine is necessary, administer lidocaine parenteral infusions with caution and monitor lidocaine serum concentrations.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bupropion: (Moderate) Bupropion inhibits CYP2D6. Coadministration of bupropion with medications that are metabolized by CYP2D6, like ranolazine, may result in increased ranolazine plasma concentrations if bupropion is added.
Bupropion; Naltrexone: (Moderate) Bupropion inhibits CYP2D6. Coadministration of bupropion with medications that are metabolized by CYP2D6, like ranolazine, may result in increased ranolazine plasma concentrations if bupropion is added.
Buspirone: (Moderate) Although data are not available, CYP3A4 inhibitors, such as ranolazine, may decrease systemic clearance of buspirone leading to increased or prolonged effects. If buspirone is to be administered concurrently with significant CYP3A4 inhibitors, a low dose of buspirone (i.e., 2.5 mg PO twice daily) is recommended initially. Subsequent dosage adjustments should be based on clinical response.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with ranolazine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of ranolazine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If ranolazine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ranolazine is a moderate inhibitor of CYP2D6.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with ranolazine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of ranolazine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If ranolazine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ranolazine is a moderate inhibitor of CYP2D6.
Cabotegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with ranolazine as concurrent use may increase the risk of QT prolongation; rilpivirine exposure may also increase. Rilpivirine is a CYP3A4 substrate; supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Ranolazine is a moderate CYP3A4 inhibitor that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation.
Cabozantinib: (Minor) Monitor for an increase in ranolazine-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of ranolazine may be necessary. Ranolazine is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
Canagliflozin; Metformin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Cannabidiol: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with cannabidiol is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; cannabidiol is a P-gp inhibitor.
Capmatinib: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with capmatinib is necessary; a dose adjustment of ranolazine may be necessary. Ranolazine is a P-glycoprotein (P-gp) substrate. Capmatinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates.
Carbamazepine: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including carbamazepine. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy. In addition, carbamazepine may increase the absorption of ranolazine via induction of P-glycoprotein transport.
Carvedilol: (Moderate) Inhibitors of CYP2D6, like ranolazine, may inhibit the hepatic oxidative metabolism of carvedilol.
Celecoxib; Tramadol: (Moderate) As ranolazine is a weak to moderate CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Cenobamate: (Contraindicated) Coadministration of ranolazine with cenobamate is contraindicated due to decreased ranolazine exposure and efficacy. Ranolazine is a CYP3A4 substrate; cenobamate is a moderate CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the plasma concentrations of ranolazine by approximately 95%.
Ceritinib: (Contraindicated) Coadministration of ranolazine with ceritinib is contraindicated due to increased plasma concentrations of ranolazine; QT prolongation may also occur. Ranolazine is a CYP3A4 substrate that is associated with dose- and plasma concentration-dependent increases in the QTc interval. Ceritinib is a strong CYP3A4 inhibitor that also causes concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased ranolazine exposure by 220%.
Chlordiazepoxide: (Moderate) CYP3A4 inhibitors like ranolazine may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chlordiazepoxide; Amitriptyline: (Moderate) CYP3A4 inhibitors like ranolazine may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chlordiazepoxide; Clidinium: (Moderate) CYP3A4 inhibitors like ranolazine may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Chloroquine: (Major) Avoid coadministration of chloroquine with ranolazine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with ranolazine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of ranolazine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If ranolazine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ranolazine is a moderate inhibitor of CYP2D6.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with ranolazine may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of ranolazine could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ranolazine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Ranolazine is a moderate inhibitor of CYP2D6 and a weak inhibitor of CYP3A4. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like ranolazine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If ranolazine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpromazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval, such as chlorpromazine. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Chlorpromazine is a known CYP2D6 inhibitor; coadministration with ranolazine may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects.
Cilostazol: (Moderate) Ranolazine inhibits CYP3A isoenzymes and may theoretically increase plasma concentrations of CYP3A4 substrates, like cilostazol, potentially leading to adverse reactions.
Cimetidine: (Moderate) Coadminister ranolazine and cimetidine with caution. Cimetidine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Cimetidine also is a CYP2D6 and CYP3A4 inhibitor, and ranolazine is a substrate for these enzymes; however, coadministration of cimetidine does not increase the plasma concentrations of ranolazine in healthy volunteers.
Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Cisapride: (Contraindicated) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Because of the potential for TdP, use of ranolazine with cisapride is contraindicated. In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, such as cisapride, potentially leading to adverse reactions.
Citalopram: (Major) Citalopram causes dose-dependent QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with citalopram include ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Citalopram is a known CYP2D6 inhibitor; coadministration may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended.
Clarithromycin: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including clarithromycin. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Furthermore, clarithromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
Clofazimine: (Major) Concomitant use of clofazimine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Clonazepam: (Moderate) CYP3A4 inhibitors, like ranolazine, may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity.
Clorazepate: (Moderate) CYP3A4 inhibitors, like ranolazine, may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity.
Clozapine: (Major) Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation such as ranolazine. Additionally, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates, such as clozapine. Elevated plasma concentrations of clozapine may increase the risk for QT prolongation, torsade de pointes (TdP), sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Cobicistat: (Contraindicated) Concomitant use of ranolazine with cobicistat is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-gp. Coadministration of another strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%. Serum concentrations of cobicistat could also be increased as ranolazine is a CYP3A4 and CYP2D6 inhibitor, and cobicistat is a CYP3A4 and CYP2D6 substrate.
Cobimetinib: (Moderate) If concurrent use of cobimetinib and ranolazine is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) substrate; in vitro, ranolazine is a weak inhibitor of CYP3A and a moderate P-gp inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Codeine: (Moderate) Concomitant use of codeine with ranolazine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of ranolazine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If ranolazine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ranolazine is a moderate inhibitor of CYP2D6.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with ranolazine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of ranolazine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If ranolazine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ranolazine is a moderate inhibitor of CYP2D6.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with ranolazine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of ranolazine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If ranolazine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ranolazine is a moderate inhibitor of CYP2D6.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with ranolazine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of ranolazine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If ranolazine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ranolazine is a moderate inhibitor of CYP2D6. (Moderate) Concomitant use of promethazine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with ranolazine may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of ranolazine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If ranolazine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ranolazine is a moderate inhibitor of CYP2D6. (Moderate) Concomitant use of promethazine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Colchicine: (Major) Avoid concomitant use of colchicine and ranolazine due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and ranolazine is a P-gp inhibitor.
Conivaptan: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with conivaptan is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor. Coadministration with another moderate CYP3A inhibitor increased plasma levels of ranolazine by 50% to 130%.
Crizotinib: (Major) Avoid coadministration of crizotinib with ranolazine due to the risk of QT prolongation. If concomitant use is unavoidable, limit the dose of ranolazine to 500 mg twice daily and monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Ranolazine is a CYP3A4 substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Coadministration with other moderate CYP3A4 inhibitors increased ranolazine exposure by 50% to 130%.
Cyclosporine: (Contraindicated) Cyclosporine inhibits the cytochrome P450 3A4 (CYP3A4) isoenzyme. Moderate or potent CYP3A4 inhibitors are contraindicated for use with ranolazine, a CYP3A4 substrate. Inhibition of ranolazine metabolism by cyclosporine could lead to increased ranolazine plasma concentrations. In addition, ranolazine is a substrate of P-glycoprotein (P-gp); inhibitors of P-gp may increase the absorption of ranolazine and should be coadministered with caution. When possible, it is prudent to avoid coadministration of ranolazine with cyclosporine due to the potential for increased plasma concentrations of ranolazine, which may result in QT prolongation and increase the risk for proarrhythmias. If necessary to coadminister these drugs, it is prudent to monitor the individual patient response to ranolazine therapy closely, including an evaluation of the ECG effects and antianginal benefits during coadministration.
Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ranolazine, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like ranolazine in patients with CrCl less than 50 mL/minute. When dabigatran is

used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with ranolazine, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Daclatasvir: (Moderate) Systemic exposure of ranolazine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of ranolazine; monitor patients for potential adverse effects.
Dapagliflozin; Metformin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Darunavir: (Contraindicated) Coadministration of darunavir with ranolazine is contraindicated due to the potential for elevated ranolazine concentrations and the potential for serious and life threatening reactions, such as cardiac arrhythmias. Ranolazine is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of a strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%.
Darunavir; Cobicistat: (Contraindicated) Coadministration of darunavir with ranolazine is contraindicated due to the potential for elevated ranolazine concentrations and the potential for serious and life threatening reactions, such as cardiac arrhythmias. Ranolazine is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of a strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%. (Contraindicated) Concomitant use of ranolazine with cobicistat is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-gp. Coadministration of another strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%. Serum concentrations of cobicistat could also be increased as ranolazine is a CYP3A4 and CYP2D6 inhibitor, and cobicistat is a CYP3A4 and CYP2D6 substrate.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Coadministration of darunavir with ranolazine is contraindicated due to the potential for elevated ranolazine concentrations and the potential for serious and life threatening reactions, such as cardiac arrhythmias. Ranolazine is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of a strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%. (Contraindicated) Concomitant use of ranolazine with cobicistat is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-gp. Coadministration of another strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%. Serum concentrations of cobicistat could also be increased as ranolazine is a CYP3A4 and CYP2D6 inhibitor, and cobicistat is a CYP3A4 and CYP2D6 substrate.
Dasatinib: (Moderate) Monitor for evidence of QT prolongation during concurrent use of dasatinib and ranolazine. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving ranolazine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Delavirdine: (Contraindicated) Ranolazine is metabolized mainly by CYP3A, and is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors, such as delavirdine. In addition, ranolazine is metabolized to a lesser extent by CYP2D6; delavirdine is a known CYP2D6 inhibitor. Concurrent administration may result in an increase in ranolazine concentrations.
Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ranolazine. Halogenated anesthetics can prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Desogestrel; Ethinyl Estradiol: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Deutetrabenazine: (Moderate) The risk of QT prolongation may be increased with coadministration of deutetrabenazine and ranolazine. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Dextromethorphan; Bupropion: (Moderate) Bupropion inhibits CYP2D6. Coadministration of bupropion with medications that are metabolized by CYP2D6, like ranolazine, may result in increased ranolazine plasma concentrations if bupropion is added.
Dextromethorphan; Quinidine: (Contraindicated) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include ranolazine.
Diazepam: (Moderate) CYP3A4 inhibitors, like ranolazine, may reduce the metabolism of diazepam and increase the potential for benzodiazepine toxicity.
Digoxin: (Major) In vitro studies suggest that ranolazine is a P-glycoprotein inhibitor. Ranolazine increases digoxin concentrations by 1.5-fold in healthy volunteers receiving ranolazine (1000 mg PO twice daily) and digoxin (0.125 mg PO once daily). Measure serum digoxin concentrations before initiating ranolazine. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. In contrast, digoxin does not increase the plasma concentrations of ranolazine. No dose adjustment of ranolazine is required for patients treated with digoxin.
Diltiazem: (Major) The dose of ranolazine, a CYP3A4 substrate, should be limited to 500 mg PO twice daily when coadministered with diltiazem, a moderate CYP3A inhibitor. Diltiazem (180 to 360 mg daily) causes dose-dependent increases in the average steady-state concentrations of ranolazine by about 2-fold.
Disopyramide: (Major) Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP). Disopyramide is a substrate for CYP3A4. Life-threatening interactions have been reported with the coadministration of disopyramide with clarithromycin and erythromycin, both have a possible risk for QT prolongation and TdP and inhibit CYP3A4. The coadministration of disopyramide and CYP3A4 inhibitors may result in a potentially fatal interaction. Drugs with a possible risk for QT prolongation and TdP that are also inhibitors of CYP3A4 that should be used cautiously with disopyramide include ranolazine.
Dofetilide: (Major) Coadministration of dofetilide and ranolazine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Dolasetron: (Moderate) Administer dolasetron with caution in combination with ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with ranolazine as concurrent use may increase the risk of QT prolongation; rilpivirine exposure may also increase. Rilpivirine is a CYP3A4 substrate; supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Ranolazine is a moderate CYP3A4 inhibitor that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation.
Donepezil: (Moderate) Use donepezil with caution in combination with ranolazine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with ranolazine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Dorzolamide; Timolol: (Moderate) Timolol is metabolized by CYP2D6 isoenzymes. Ranolazine, a CYP2D6 inhibitor, could theoretically impair timolol metabolism. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, including ranolazine, may inhibit the conversion of doxercalciferol to its active metabolite and result in decreased efficacy of doxercalciferol.
Doxorubicin Liposomal: (Major) Avoid coadministration of ranolazine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4, CYP2D6, and P-gp. Concurrent use of CYP3A4, CYP2D6, or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of ranolazine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4, CYP2D6, and P-gp. Concurrent use of CYP3A4, CYP2D6, or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with ranolazine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; ranolazine is a weak inhibitor of CYP3A4 in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Contraindicated) Concomitant use of dronedarone and ranolazine is contraindicated due to the risk of QT prolongation. Both dronedarone and ranolazine prolong the QT-interval in a dose-related manner. In addition, coadministration of dronedarone and ranolazine may result in elevated plasma concentrations of both drugs, further increasing the risk of QT prolongation and torsade de pointes (TdP). Dronedarone and ranolazine are both substrates and inhibitors of CYP3A. In addition, ranolazine is a substrate of P-glycoprotein (P-gp), and dronedarone is a P-gp inhibitor.
Droperidol: (Major) Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. If coadministration is necessary, ranolazine should be used cautiously with drugs that prolong the QT interval, such as droperidol. In addition, droperidol is a substrate for CYP3A4 and P-glycoprotein (P-gp). Ranolazine is an inhibitor of CYP3A4 and P-gp. Concurrent administration of ranolazine and droperdol may result in increased droperidol concentrations.
Drospirenone; Ethinyl Estradiol: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of ranolazine. Tamsulosin is extensively metabolized by CYP2D6 and CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Therefore, concomitant use with drugs that inhibit both CYP2D6 and CYP3A4, such as ranolazine, should be avoided.
Duvelisib: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with duvelisib is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A4 substrate and duvelisib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased plasma levels of ranolazine by 100%.
Edoxaban: (Moderate) Coadministration of edoxaban and ranolazine may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and in vitro data indicate ranolazine is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ranolazine; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
Efavirenz: (Contraindicated) Do not use ranolazine in combination with CYP3A inducers like efavirenz as ranolazine exposure and therapeutic response may be decreased; additive effects on the QT interval are also possible. Efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Ranolazine is a CYP3A substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Although the effect of moderate inducers is not reported by the ranolazine manufacturer, coadministration with a strong CYP3A inducer decreased the ranolazine plasma concentrations by 95%.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Do not use ranolazine in combination with CYP3A inducers like efavirenz as ranolazine exposure and therapeutic response may be decreased; additive effects on the QT interval are also possible. Efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Ranolazine is a CYP3A substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Although the effect of moderate inducers is not reported by the ranolazine manufacturer, coadministration with a strong CYP3A inducer decreased the ranolazine plasma concentrations by 95%. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Contraindicated) Do not use ranolazine in combination with CYP3A inducers like efavirenz as ranolazine exposure and therapeutic response may be decreased; additive effects on the QT interval are also possible. Efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Ranolazine is a CYP3A substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Although the effect of moderate inducers is not reported by the ranolazine manufacturer, coadministration with a strong CYP3A inducer decreased the ranolazine plasma concentrations by 95%. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Elacestrant: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with elacestrant is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; elacestrant is a P-gp inhibitor.
Elagolix: (Contraindicated) Coadministration of elagolix and ranolazine is contraindicated. Concurrent use may decrease elagolix exposure resulting in reduced therapeutic response. Ranolazine is a CYP3A4 substrate; elagolix is a weak to moderate CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the plasma concentrations of ranolazine by approximately 95%.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Coadministration of elagolix and ranolazine is contraindicated. Concurrent use may decrease elagolix exposure resulting in reduced therapeutic response. Ranolazine is a CYP3A4 substrate; elagolix is a weak to moderate CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the plasma concentrations of ranolazine by approximately 95%.
Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with ranolazine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ranolazine is a substrate and mild inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Eliglustat: (Major) Coadminister ranolazine and eliglustat with caution. Based on in vitro pharmacokinetic data, coadministration is not recommended in CYP2D6 poor metabolizers (PMs) and a dosage reduction of eliglustat to 84 mg PO once daily is required in extensive or intermediate CYP2D6 metabolizers (EMs or IMs). In addition, coadministration of eliglustat with both ranolazine and a strong or moderate CYP3A inhibitor is contraindicated in all patients. Both eliglustat and ranolazine can independently prolong the QT interval, and coadministration increases this risk. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. In vitro data indicate ranolazine is a CYP2D6 and P-glycoprotein (P-gp) substrate, as well as a weak inhibitor of CYP3A and moderate inhibitor of CYP2D6. Eliglustat is a CYP2D6 and CYP3A substrate and CYP2D6 and P-gp inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of ranolazine and eliglustat may result in additive effects on the QT interval and, potentially, increased plasma concentrations of one or both drugs, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). For coadministration with P-gp substrates and CYP2D6 substrates, eliglustat's product labeling recommends monitoring therapeutic drug concentrations of the P-gp substrate, if possible, or consideration of a dosage reduction and titrating to clinical effect.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Concomitant use of ranolazine with cobicistat is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-gp. Coadministration of another strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%. Serum concentrations of cobicistat could also be increased as ranolazine is a CYP3A4 and CYP2D6 inhibitor, and cobicistat is a CYP3A4 and CYP2D6 substrate.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concomitant use of ranolazine with cobicistat is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-gp. Coadministration of another strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%. Serum concentrations of cobicistat could also be increased as ranolazine is a CYP3A4 and CYP2D6 inhibitor, and cobicistat is a CYP3A4 and CYP2D6 substrate. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Empagliflozin; Linagliptin; Metformin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Empagliflozin; Metformin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering rilpivirine with ranolazine as concurrent use may increase the risk of QT prolongation; rilpivirine exposure may also increase. Rilpivirine is a CYP3A4 substrate; supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Ranolazine is a moderate CYP3A4 inhibitor that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering rilpivirine with ranolazine as concurrent use may increase the risk of QT prolongation; rilpivirine exposure may also increase. Rilpivirine is a CYP3A4 substrate; supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Ranolazine is a moderate CYP3A4 inhibitor that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Enasidenib: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with enasidenib is necessary; a dose adjustment of ranolazine may be necessary. Ranolazine is a P-gp substrate. Enasidenib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates.
Encorafenib: (Major) Avoid coadministration of encorafenib and ranolazine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Entrectinib: (Major) Avoid coadministration of entrectinib with ranolazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Enzalutamide: (Contraindicated) The concomitant use of enzalutamide with ranolazine is contraindicated due to decreased plasma concentrations of ranolazine resulting in decreased efficacy. Enzalutamide is a strong CYP3A4 inducer and ranolazine is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inducer decreased the plasma concentrations of ranolazine by approximately 95%.
Ergot alkaloids: (Major) In vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, such as ergot alkaloids, potentially leading to adverse reactions.
Eribulin: (Major) Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval, such as ranolazine, must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Ertugliflozin; Metformin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Erythromycin: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval, such as erythromycin. Furthermore, the dose of ranolazine, a CYP3A4 and P-glycoprotein substrate, should be limited to 500 mg PO twice daily when coadministered with erythromycin, a moderate CYP3A inhibitor. Furthermore, erythromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
Escitalopram: (Moderate) Concomitant use of escitalopram and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Eslicarbazepine: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers. In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Although not specifically mentioned by the manufacturer, coadministration of ranolazine with eslicarbazepine may result in decreased ranolazine plasma concentrations and decreased efficacy.
Estazolam: (Moderate) CYP3A4 inhibitors, like ranolazine, may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
Ethanol: (Major) Advise patients taking ranolazine extended-release oral granules to avoid alcohol ingestion; alcohol may cause a rapid-release of medication that can cause serious side effects, including QT prolongation.
Ethinyl Estradiol; Norelgestromin: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Ethinyl Estradiol; Norgestrel: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Ethosuximide: (Moderate) Ranolazine inhibits CYP3A isoenzymes and may theoretically increase the plasma concentrations of ethosuximide.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Etonogestrel; Ethinyl Estradiol: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Etravirine: (Moderate) Etravirine is a CYP3A4 inducer/substrate and a P-glycoprotein (PGP) inhibitor. Ranolazine is a CYP3A4 substrate/inhibitor and PGP substrate/inhibitor. Caution is warranted if these drugs are coadministered.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ranolazine is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and ranolazine is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Ezetimibe; Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking ranolazine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on ranolazine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of ranolazine and simvastatin against the potential risks. Ranolazine increases the simvastatin exposure by approximately 2-fold.
Fedratinib: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with fedratinib is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased plasma levels of ranolazine by 50% to 130%.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. If ranolazine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ranolazine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ranolazine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finasteride; Tadalafil: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Inhibitors of CYP3A4 may reduce tadalafil clearance. In theory, CYP3A4 inhibitors which may interact with tadalafil include ranolazine. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the 'as needed' dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the 'once-daily' dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or ranolazine; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and ranolazine is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with ranolazine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Flecainide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering ranolazine with flecainide. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Flecainide, a Class IC antiarrhythmic, is also associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6, and flecainide is a CYP2D6 substrate. Coadministration may result in elevated flecainide serum concentrations. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during concurrent treatment.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including ranolazine, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
Fluconazole: (Major) Limit the dose of ranolazine to 500 mg twice daily if administered with fluconazole as increased ranolazine exposure may occur; concurrent use may also increase the risk of QT prolongation. Ranolazine is a CYP3A4 substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Fluconazole is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Plasma levels of ranolazine were increased 50% to 130% when administered with moderate CYP3A4 inhibitors in drug interaction studies.
Fluoxetine: (Major) Use fluoxetine with caution in combination with ranolazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Additionally, monitor for adverse effects of fluoxetine during coadministration as ranolazine may increase the concentrations of fluoxetine. QT prolongation and TdP have been reported in patients treated with fluoxetine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Fluoxetine is a substrate of CYP2D6; ranolazine is a moderate inhibitor of CYP2D6.
Fluphenazine: (Minor) Use ranolazine with caution in combination with fluphenazine as concurrent use may increase the risk of QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Flurazepam: (Moderate) CYP3A4 inhibitors, like ranolazine, may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity.
Fluvoxamine: (Major) According to the manufacturer of ranolazine, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving moderate CYP3A inhibitors. Ranolazine is a primary substrate of CYP3A and fluvoxamine is a moderate CYP3A4 inhibitor. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Fosamprenavir: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with fosamprenavir is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased plasma levels of ranolazine by 50% to 130%.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as ranolazine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosphenytoin: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers. Although not specifically mentioned by the manufacturer, coadministration of ranolazine with a CYP3A enzyme inducer such as fosphenytoin may result in decreased ranolazine plasma concentrations and decreased efficacy.
Fostamatinib: (Moderate) Monitor for ranolazine toxicities that may require ranolazine dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a P-gp substrate may increase the concentration of the P-gp substrate. Fostamatinib is a P-gp inhibitor; ranolazine is a substrate for P-gp. Coadministration of fostamatinib with another P-gp substrate increased the P-gp substrate AUC by 37% and Cmax by 70%.
Fostemsavir: (Moderate) Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, such as fostemsavir, concurrent use may result in additive QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Futibatinib: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with futibatinib is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; futibatinib is a P-gp inhibitor.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ranolazine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and ranolazine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Gemifloxacin: (Moderate) Gemifloxacin should be used cautiously with ranolazine as concurrent use may increase the risk of QT prolongation. Gemifloxacin may prolong the QT interval in some patients. The maximal change in QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and ranolazine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and ranolazine is necessary. Gilteritinib has been associated with QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Monitor for an increase in ranolazine-related adverse reactions if coadministration with gilteritinib is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; gilteritinib is a P-gp inhibitor.
Glasdegib: (Major) Avoid coadministration of glasdegib with ranolazine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and ranolazine as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and ranolazine are both substrates and inhibitors of P-glycoprotein (P-gp). (Moderate) Caution is advised with the coadministration of pibrentasvir and ranolazine as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Both pibrentasvir and ranolazine are substrates and inhibitors of P-glycoprotein (P-gp).
Glipizide; Metformin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Glyburide; Metformin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving ranolazine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Granisetron: (Moderate) Use granisetron with caution in combination with ranolazine due to the risk of QT prolongation. Granisetron has been associated with QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Grapefruit juice: (Major) Patients should limit intake of grapefruit juice during ranolazine treatment and avoid grapefruit-containing products and grapefruit juice if possible. If ingestion of grapefruit juice is not avoidable, limit the dose of ranolazine to 500 mg PO twice daily. Grapefruit juice is a CYP3A inhibitor. Ranolazine is a CYP3A4 and P-gp substrate; coadministration is expected to increase ranolazine plasma concentrations/exposure and may increase the risk for side effects, such as QT prolongation.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like ranolazine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If ranolazine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ranolazine. Halogenated anesthetics can prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Haloperidol: (Moderate) Caution is advisable when combining haloperidol concurrently with ranolazine as concurrent use may increase the risk of QT prolongation and increase haloperidol-related adverse effects. Haloperidol is a CYP2D6 substrate that has been associated with QT prolongation and torsade de pointes (TdP). Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Ranolazine is a CYP2D6 inhibitor associated with dose- and plasma concentration-related increases in the QTc interval. Mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP2D6 inhibitors.
Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving ranolazine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like ranolazine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If ranolazine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like ranolazine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If ranolazine is discontinued, hydrocodone plasma conce ntrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like ranolazine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If ranolazine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like ranolazine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If ranolazine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydroxychloroquine: (Major) Concomitant use of ranolazine and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Moderate) Concomitant use of hydroxyzine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. If ranolazine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like ranolazine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ranolazine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ibutilide: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, such as ibutilide, coadministration may result in additive QT prolongation. Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Idelalisib: (Contraindicated) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with ranolazine, a CYP3A substrate, as ranolazine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Iloperidone: (Major) Avoid coadministration of iloperidone and ranolazine. Iloperidone has been associated with QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Imatinib: (Contraindicated) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors. Inhibition of ranolazine metabolism could lead to increased ranolazine plasma concentrations and associated QTc prolongation. Although not specifically mentioned by the manufacturer of ranolazine, imatinib, STI-571 is known to be a strong inhibitor of CYP3A4. In addition, ranolazine is metabolized to a lesser extent by CYP2D6; imatinib, STI-571 is a known CYP2D6 inhibitor.
Indinavir: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including indinavir. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes. In addition, ranolazine may increase the absorption of indinavir via inhibition of P-glycoprotein transport.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with ranolazine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Isavuconazonium: (Major) The dose of ranolazine, a CYP3A4 and P-glycoprotein (P-gp) substrate, should be limited to 500 mg PO twice daily when coadministered with isavuconazonium. Isavuconazole, the active moiety of isavuconazonium is a moderate inhibitor of CYP3A4 and an inhibitor of P-gp. Inhibition of ranolazine CYP3A4 metabolism could lead to increased ranolazine plasma concentrations. Serum concentrations of isavuconazole may also be increased as ranolazine is a CYP3A4 inhibitor, while isavuconazole is a sensitive substrate of CYP3A4.
Isoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ranolazine. Halogenated anesthetics can prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including rifampin. Ranolazine also is a substrate for CYP2D6 and P-glycoprotein. Rifampin potently induces cytochrome P450 enzymes, including CYP3A isoenzymes, and is also an inducer of P-glycoprotein transport. Rifampin (600 mg daily) decreases the plasma concentration of ranolazine (1000 mg twice daily) by approximately 95%, likely due to induction of CYP3A and P-glycoprotein.
Isoniazid, INH; Rifampin: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including rifampin. Ranolazine also is a substrate for CYP2D6 and P-glycoprotein. Rifampin potently induces cytochrome P450 enzymes, including CYP3A isoenzymes, and is also an inducer of P-glycoprotein transport. Rifampin (600 mg daily) decreases the plasma concentration of ranolazine (1000 mg twice daily) by approximately 95%, likely due to induction of CYP3A and P-glycoprotein.
Istradefylline: (Moderate) Monitor for ranolazine-related adverse reactions and titrate according to clinical response if coadministration of istradefylline is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a P-gp substrate; istradefylline is a P-gp inhibitor.
Itraconazole: (Contraindicated) Ranolazine is contraindicated for use during and for 2 weeks after itraconazole therapy. Inhibition of ranolazine CYP3A metabolism by itraconazole could lead to increased ranolazine plasma concentrations, prolonged QTc prolongation, and possibly torsade de pointes.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with ranolazine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of ranolazine is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and ranolazine is a weak CYP3A inhibitor.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and ranolazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of ranolazine, further increasing the risk for adverse effects. Ranolazine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased ranolazine exposure by 220%.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including clarithromycin. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Furthermore, clarithromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
Lapatinib: (Major) Monitor for an increase in treatment-related adverse reactions if coadministration with ranolazine is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate/inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Ranolazine is also a P-gp substrate/inhibitor that is also associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors.
Lasmiditan: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with lasmiditan is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; lasmiditan is a P-gp inhibitor.
Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of ranolazine and ledipasvir; sofosbuvir. Both ledipasvir and ranolazine are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
Lefamulin: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with oral lefamulin is necessary. Coadministration may increase the exposure of ranolazine. Additionally, monitor for lefamulin-related adverse effects as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Ranolazine is a CYP3A4 substrate and P-gp inhibitor and oral lefamulin is CYP3A4 and P-gp substrate and moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased plasma levels of ranolazine by 50% to 130%.
Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with ranolazine as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; ranolazine is a weak CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Lenacapavir: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with lenacapavir is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A and P-gp substrate and lenacapavir is a moderate CYP3A and P-gp inhibitor. Coadministration with another moderate CYP3A inhibitor increased plasma levels of ranolazine by 50% to 130%.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with ranolazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Letermovir: (Major) Limit the maximum dose of ranolazine to 500 mg twice daily if coadministered with letermovir. Concurrent use is contraindicated if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. A clinically relevant increase in the plasma concentration of ranolazine may occur if given with letermovir. Ranolazine is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with another strong CYP3A inhibitor increased ranolazine plasma concentrations by 220%. When given with another moderate CYP3A inhibitor, ranolazine plasma concentrations increased by 50% to 130%.
Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving ranolazine as concurrent use may increase the risk of QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Androgen deprivation therapy may prolong the QT/QTc interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving ranolazine as concurrent use may increase the risk of QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Androgen deprivation therapy may prolong the QT/QTc interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Levofloxacin: (Moderate) Concomitant use of levofloxacin and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and ranolazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of ranolazine, further increasing the risk for adverse effects. Ranolazine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased ranolazine exposure by 220%.
Levonorgestrel; Ethinyl Estradiol: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Lidocaine: (Major) Ranolazine is an inhibitor of the cytochrome P450 (CYP) isoenzyme 3A, and lidocaine is a substrate for this pathway. Thus, ranolazine may theoretically reduce lidocaine clearance. If concurrent therapy with ranolazine is necessary, administer lidocaine parenteral infusions with caution and monitor lidocaine serum concentrations.
Lidocaine; Epinephrine: (Major) Ranolazine is an inhibitor of the cytochrome P450 (CYP) isoenzyme 3A, and lidocaine is a substrate for this pathway. Thus, ranolazine may theoretically reduce lidocaine clearance. If concurrent therapy with ranolazine is necessary, administer lidocaine parenteral infusions with caution and monitor lidocaine serum concentrations.
Lidocaine; Prilocaine: (Major) Ranolazine is an inhibitor of the cytochrome P450 (CYP) isoenzyme 3A, and lidocaine is a substrate for this pathway. Thus, ranolazine may theoretically reduce lidocaine clearance. If concurrent therapy with ranolazine is necessary, administer lidocaine parenteral infusions with caution and monitor lidocaine serum concentrations.
Linagliptin; Metformin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Lithium: (Moderate) Concomitant use of lithium and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Lofexidine: (Moderate) Monitor the ECG for QT prolongation during concurrent use of lofexidine and ranolazine. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Lomitapide: (Major) Concomitant use of lomitapide and ranolazine may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Ranolazine is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors. In addition, concomitant use may result in increased serum concentrations of ranolazine. According to the manufacturer of lomitapide, dose reduction of ranolazine should be considered during concurrent use. Lomitapide is an inhibitor of P-glycoprotein (P-gp) and ranolazine is a P-gp substrate.
Lonafarnib: (Contraindicated) Concomitant use of lonafarnib and ranolazine is contraindicated and may increase the exposure and risk of adverse effects from both drugs. If concomitant use is necessary, reduce to or continue lonafarnib at a dosage of 115 mg/m2. Ranolazine is a CYP3A4 and P-gp substrate and weak CYP3A4 inhibitor; lonafarnib is a sensitive CYP3A4 substrate and P-gp and strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased ranolazine exposure by 220%.
Loperamide: (Moderate) Concomitant use of loperamide and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a P-gp substrate and ranolazine is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Concomitant use of loperamide and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a P-gp substrate and ranolazine is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Contraindicated) Coadministration of lopinavir; ritonavir with ranolazine is contraindicated due to the potential for additive QT prolongation. Ranolazine is highly dependent on CYP3A for clearance and is associated with dose- and plasma concentration-related increases in the QTc interval. Lopinavir; ritonavir is a potent CYP3A inhibitor and is also associated with QT prolongation. (Contraindicated) Concomitant use of ranolazine with ritonavir is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; ritonavir is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-gp. Coadministration of another strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%.
Lorlatinib: (Contraindicated) The concomitant use of lorlatinib with ranolazine is contraindicated due to decreased plasma concentrations of ranolazine resulting in decreased efficacy. Lorlatinib is a moderate CYP3A4 inducer and ranolazine is a CYP3A4 substrate.
Lovastatin: (Moderate) Carefully weigh the benefits of combined use of ranolazine and lovastatin against the potential risks. Lovastatin exposure may increase resulting in increased risk of myopathy/rhabdomyolysis. Although FDA-approved labeling for ranolazine and lovastatin do not provide specific dose adjustments, guidelines recommend limiting the dose of lovastatin to 20 mg/day if combined with ranolazine. Lovastatin is a CYP3A4 substrate; ranolazine is a weak CYP3A4 inhibitor.
Lumacaftor; Ivacaftor: (Contraindicated) Concomitant use of lumacaftor; ivacaftor and ranolazine is contraindicated. Ranolazine is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of ranolazine through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Regardless, FDA-approved labeling for ranolazine contraindicates its use with CYP3A inducers. Rifampin, another strong CYP3A inducer, decreases the plasma concentrations of ranolazine by approximately 95%; however, this interaction may also be influenced by rifampin's induction of P-gp transport.
Lumacaftor; Ivacaftor: (Contraindicated) Concomitant use of lumacaftor; ivacaftor and ranolazine is contraindicated. Ranolazine is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp). Lumacaftor is a strong CYP3A inducer; in vitro data also suggest lumacaftor; ivacaftor may induce and/or inhibit P-gp. Although induction of ranolazine through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Regardless, FDA-approved labeling for ranolazine contraindicates its use with CYP3A inducers. Rifampin, another strong CYP3A inducer, decreases the plasma concentrations of ranolazine by approximately 95%; however, this interaction may also be influenced by rifampin's induction of P-gp transport.
Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, concurrent use of CYP3A4 inhibitors, such as ranolazine, can theoretically lead to an increased risk of lurasidone-related adverse reactions.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as ranolazine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Maprotiline: (Major) Ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates, such as maprotiline, and could lead to toxicity for drugs that have a narrow therapeutic range. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration. In addition, maprotiline is associated with QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval. The need to coadminister maprotiline with ranolazine should be done with a careful assessment of risk versus benefit; consider alternative therapy to maprotiline.
Maraviroc: (Moderate) Use caution and careful monitoring with the coadministration of maraviroc and ranolazine as increased maraviroc concentrations may occur. Maraviroc is a substrate of P-glycoprotein (P-gp) and CYP3A; ranolazine is an inhibitor of P-gp and a weak in vitro inhibitor of CYP3A. The effects of P-gp on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
Maribavir: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with maribavir is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; maribavir is a P-gp inhibitor.
Mavacamten: (Contraindicated) Coadministration of ranolazine with mavacamten is contraindicated due to decreased ranolazine exposure and efficacy. Additionally, concomitant use may increase the risk of left ventricular systolic dysfunction and heart failure symptoms. Ranolazine is a CYP3A substrate; mavacamten is a moderate CYP3A inducer.
Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving ranolazine; exposure to both drugs may also be increased. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, mefloquine is metabolized by CYP3A4 and P-glycoprotein (P-gp) and is a P-gp inhibitor. Ranolazine is an inhibitor of CYP3A4 and P-gp and is a substrate for P-gp. Concurrent use may increase the serum concentrations of mefloquine and/or ranolazine, further increasing the risk for QT prolongation.
Metformin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Metformin; Repaglinide: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance. (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Ranolazine is a mild inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
Metformin; Rosiglitazone: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Metformin; Saxagliptin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Metformin; Sitagliptin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. At high doses, methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses averaging approximately 400 mg/day. In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with inhibitors of these enzymes may result in increased serum concentrations of methadone. Drugs with a possible risk for QT prolongation and TdP that inhibit CYP3A4, CYP2D6, and P-gp that should be used cautiously with methadone include ranolazine.
Methamphetamine: (Major) Ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates, such as methamphetamine, and could lead to toxicity for drugs that have a narrow therapeutic range. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; ranolazine is a CYP2D6 inhibitor.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; ranolazine is a CYP2D6 inhibitor.
Metronidazole: (Moderate) Concomitant use of metronidazole and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Mexiletine: (Moderate) Mexiletine is significantly metabolized by CYP2D6 isoenzymes. Moderate CYP2D6 inhibitors, like ranolazine, could impair mexiletine metabolism and increase mexiletine concentrations and the risk for mexiletine-related side effects. Monitor for changes in heart rate and rhythm, as well as gastrointestinal and neurologic tolerance.
Midazolam: (Moderate) In vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates with a narrow therapeutic index, such as midazolam, potentially leading to adverse reactions. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent.
Midostaurin: (Major) The concomitant use of midostaurin and ranolazine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Additionally, ranolazine increased the QTc interval compared with placebo in a clinical trial.
Mifepristone: (Major) Avoid use together if possible. Both drugs may prolong the QT interval and may increase the risk for arrhythmia. If use together is necessary, limit the ranolazine dosage to 500 mg PO twice daily. Monitor for ranolazine-related adverse reactions such as dizziness, headache, constipation, and nausea. Limit the mifepristone to the lowest effective dose to reduce QT prolongation risk. Ranolazine is metabolized mainly by CYP3A4 and to an extent by P-glycoprotein (P-gp) and mifepristone is known to inhibit CYP3A4 and may also inhibit P-glycoprotein (P-gp); use together is expected to increase ranolazine concentrations. Due to the slow elimination of mifepristone from the body, drug interactions that occur may be prolonged.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as ranolazine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
Mirtazapine: (Moderate) Concomitant use of mirtazapine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Mitapivat: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with mitapivat is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; mitapivat is a P-gp inhibitor.
Mitotane: (Contraindicated) The concomitant use of mitotane with ranolazine is contraindicated due to decreased ranolazine exposure and efficacy. Mitotane is a strong CYP3A4 inducer and ranolazine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ranolazine.
Mobocertinib: (Major) Concomitant use of mobocertinib and ranolazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Moxifloxacin: (Major) Prolongation of the QT interval has been reported with administration of moxifloxacin. Post-marketing surveillance has identified very rare cases of ventricular arrhythmias including torsade de pointes (TdP), usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded. According to the manufacturer, moxifloxacin should be avoided in patients taking drugs that can result in prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP include ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions and consider dose reduction of naldemedine if coadministered with ranolazine. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; ranolazine is a moderate P-gp inhibitor in vitro.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and ranolazine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and ranolazine is a weak CYP3A and P-gp inhibitor.
Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with ranolazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as ranolazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with ranolazine. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as ranolazine, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
Nefazodone: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including nefazodone. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes.
Nelfinavir: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including nelfinavir. Ranolazine is associated with dose and plasma concentration-related increases in the QTc interval. Coadministration with nelfinavir may increase the plasma concentrations of ranolazine, thus increasing the risk of drug toxicity and proarrhythmic effects. In addition, nelfinavir may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
Neratinib: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with neratinib is necessary and titrate the dose of ranolazine based on clinical response. Concomitant use may increase ranolazine exposure. Ranolazine is a P-glycoprotein (P-gp) substrate. Neratinib is a P-gp inhibitor.
Netupitant, Fosnetupitant; Palonosetron: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as ranolazine. The plasma concentrations of ranolazine can increase when co-administered with netupitant, which is a moderate CYP3A4 inhibitor; the inhibitory effect on CYP3A4 can last for multiple days. This might increase the risk for ranolazine-related side effects, such as QT prolongation. Ranolazine is a mild CYP3A4 inhibitor and a CYP2D6 inhbitior, but should not have significant effect on netupitant or palonosetron. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. Co-administration of single dose netupitant 600 mg and palonosetron 1.5 mg had no significant effects on the QTc interval.
Niacin; Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking ranolazine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on ranolazine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of ranolazine and simvastatin against the potential risks. Ranolazine increases the simvastatin exposure by approximately 2-fold.
Nicardipine: (Major) Coadministration of ranolazine with nicardipine may lead to an increase in serum levels of ranolazine.
Nilotinib: (Major) Avoid coadministration of nilotinib with ranolazine due to an increased risk for QT prolongation. Additionally, the systemic exposure of ranolazine may be increased resulting in an increase in treatment-related adverse reactions. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Ranolazine is a CYP3A4 substrate that has also been associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ranolazine, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. In vitro, ranolazine is a moderate inhibitor of P-gp and a mild CYP3A4 inhibitor; nintedanib is a P-gp substrate as well as a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
Nirmatrelvir; Ritonavir: (Contraindicated) Concomitant use of ranolazine with ritonavir is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; ritonavir is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-gp. Coadministration of another strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%. (Contraindicated) Concomitant use of ritonavir-boosted nirmatrelvir and ranolazine is contraindicated. Consider temporary discontinuation of ranolazine during treatment with ritonavir-boosted nirmatrelvir and for at least 2 to 3 days after treatment completion; if not feasible, consider alternative COVID-19 therapy. Coadministration may increase ranolazine exposure resulting in increased toxicity. Ranolazine is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with ranolazine due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and ranolazine is a weak CYP3A4 inhibitor.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Norethindrone; Ethinyl Estradiol: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Norgestimate; Ethinyl Estradiol: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Ofloxacin: (Moderate) Concomitant use of ofloxacin and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Olanzapine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include olanzapine.
Olanzapine; Fluoxetine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include olanzapine. (Major) Use fluoxetine with caution in combination with ranolazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Additionally, monitor for adverse effects of fluoxetine during coadministration as ranolazine may increase the concentrations of fluoxetine. QT prolongation and TdP have been reported in patients treated with fluoxetine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Fluoxetine is a substrate of CYP2D6; ranolazine is a moderate inhibitor of CYP2D6.
Olanzapine; Samidorphan: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include olanzapine.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and ranolazine is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and ranolazine may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If ranolazine is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP2D6 substrate and ranolazine is a moderate CYP2D6 inhibitor.
Omeprazole; Amoxicillin; Rifabutin: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including rifabutin. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
Ondansetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and ranolazine should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ondansetron is a substrate for CYP3A4 and CYP2D6 and P-glycoprotein (P-gp). Ranolazine is an inhibitor of CYP3A4 and CYP2D6 and P-gp. Concurrent administration of ranolazine and ondansetron may result in increased ondansetron concentrations.
Oritavancin: (Major) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers. Although not specifically mentioned by the manufacturer, coadministration of ranolazine with a CYP3A enzyme inducer such as oritavancin (a weak inducer) may result in decreased ranolazine plasma concentrations and decreased efficacy. Ranolazine is also a substrate of CYP2D6 and oritavancin is a weak CYP2D6 inducer.
Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with ranolazine as concurrent use may increase the risk of QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Osimertinib: (Major) Avoid coadministration of ranolazine with osimertinib if possible due to t he risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in ranolazine-related adverse reactions, periodically monitor ECGs for QT prolongation, and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Ranolazine is a P-glycoprotein (P-gp) substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration may result in additive QT prolongation. Concentration-dependent QTc prolongation also occurred during clinical trials of osimertinib, which is a P-gp inhibitor.
Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ranolazine with oxaliplatin is necessary as additive QT prolongation is possible; correct electrolyte abnormalities prior to administration of oxaliplatin. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. If ranolazine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like ranolazine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ranolazine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking ranolazine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Pacritinib: (Major) Concomitant use of ranolazine and pacritinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase ranolazine exposure and the risk for other ranolazine-related adverse effects; a dose adjustment of ranolazine may be necessary. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Ranolazine is a substrate of P-gp and pacritinib is a P-gp inhibitor.
Paliperidone: (Major) According to the manufacturer of paliperidone, the drug should be avoided in combination with agents known to prolong the QT interval. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1,000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Panobinostat: (Major) The co-administration of panobinostat with ranolazine is not recommended; QT prolongation has been reported with both agents. Ranolazine is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of ranolazine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of panobinostat toxicity such as cardiac arrhythmias, diarrhea, bleeding, infection, and hepatotoxicity. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Paricalcitol: (Moderate) Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates like paricalcitol, potentially leading to adverse reactions.
Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with ranolazine is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and ranolazine is a moderate CYP2D6 inhibitor.
Pasireotide: (Moderate) Use caution when using pasireotide in combination with ranolazine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib and ranolazine have been reported to prolong the QT interval. If pazopanib and ranolazine must be continued, closely monitor the patient for QT interval prolongation. In addition, pazopanib is a weak inhibitor of and substrate for CYP3A4 and a substrate for P-glycoprotein (P-gp). Ranolazine is a substrate for and an inhibitor of CYP3A4 and P-gp. Concurrent administration of ranolazine and pazopanib may result in increased pazopanib concentrations and/or increased ranolazine concentrations. Dose reduction of pazopanib should be considered when coadministration of pazopanib and ranolazine is necessary.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to ranolazine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while ranolazine is partially metabolized by the CYP2D6 isoenzyme.
Pentamidine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include pentamidine.
Perphenazine: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Coadministration of ranolazine with inhibitors of CYP2D6 may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects. Drugs that are CYP2D6 inhibitors that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include perphenazine.
Perphenazine; Amitriptyline: (Minor) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Coadministration of ranolazine with inhibitors of CYP2D6 may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects. Drugs that are CYP2D6 inhibitors that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include perphenazine.
Pexidartinib: (Contraindicated) Coadministration of ranolazine with pexidartinib is contraindicated due to decreased ranolazine exposure and efficacy. Ranolazine is a CYP3A4 substrate; pexidartinib is a moderate CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the plasma concentrations of ranolazine by approximately 95%.
Phenicol Derivatives: (Contraindicated) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors. Although not specifically mentioned by the manufacturer of ranolazine, chloramphenicol is known to be a strong inhibitor of CYP3A4. Inhibition of ranolazine metabolism could lead to increased ranolazine plasma concentrations and associated QTc prolongation. Do not use ranolazine with chloramphenicol due to the potential for reduced metabolism of ranolazine and the risk of QT prolongation.
Phenytoin: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including phenytoin. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
Pimavanserin: (Major) Pimavanserin should be avoided in combination with ranolazine. Pimavanserin may cause QT prolongation and ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of ranolazine with pimozide is contraindicated.
Pioglitazone; Metformin: (Major) Limit the dose of metformin to 1,700 mg/day in adults if coadministered with ranolazine 1,000 mg twice daily. Coadministration of metformin with ranolazine 1,000 mg twice daily results in increased exposure to metformin. There is potential for an increased risk for lactic acidosis, which is associated with high metformin concentrations. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily, as metformin exposure was not significantly increased with this lower dose of ranolazine. Ranolazine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). Consider the benefits and risks of concomitant use of ranolazine with metformin. Monitor blood sugar and for gastrointestinal side effects, and increase monitoring for a risk for lactic acidosis, including renal function and electrolytes/acid-base balance.
Pirtobrutinib: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with pirtobrutinib is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; pirtobrutinib is a P-gp inhibitor.
Pitolisant: (Major) Avoid coadministration of pitolisant with ranolazine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking ranolazine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Posaconazole: (Contraindicated) The concurrent use of posaconazole and ranolazine is contraindicated due to the risk of life-threatening arrhythmias such as torsades de pointes (TdP) and increased ranolazine exposure; posaconazole exposure may also be increased. Ranolazine is a CYP3A4 and P-gp substrate, and a P-gp inhibitor that is associated with dose- and plasma concentration-related increases in the QTc interval. Posaconazole is a strong CYP3A4 inhibitor and an inhibitor and substrate of P-gp that has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Plasma levels of ranolazine were increased by 220% when administered with a strong CYP3A4 inhibitor.
Pralsetinib: (Major) Avoid concomitant use of ranolazine with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and ranolazine is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Pretomanid: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with pretomanid is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; pretomanid is a P-gp inhibitor.
Primaquine: (Moderate) Exercise caution when administering primaquine in combination with ranolazine. Primaquine is associated with QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and ranolazine due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and ranolazine is a P-gp inhibitor.
Procainamide: (Major) Ranolazine should be used cautiously with procainamide. Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Prochlorperazine: (Minor) Use ranolazine with caution in combination with prochlorperazine as concurrent use may increase the risk of QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Promethazine: (Moderate) Concomitant use of promethazine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Promethazine; Dextromethorphan: (Moderate) Concomitant use of promethazine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Promethazine; Phenylephrine: (Moderate) Concomitant use of promethazine and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Propafenone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with ranolazine. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. In addition, ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Coadministration of ranolazine with inhibitors of CYP2D6, such as propafenone, may result in increased plasma concentrations of ranolazine. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministering CYP2D6 inhibitors. Until further data are available, it is prudent to cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects.
Propranolol: (Moderate) Propranolol is metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ranolazine, could theoretically impair propranolol metabolism. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Propranolol is metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ranolazine, could theoretically impair propranolol metabolism. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
Quazepam: (Moderate) CYP3A4 inhibitors, such as ranolazine, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
Quetiapine: (Major) Ranolazine may increase plasma concentrations of quetiapine through CYP3A4 inhibition. Avoid co-use if possible, as both drugs have been noted to cause QTc interval prolongation. If co-use is necessary, use the combination with caution. The manufacturer of quetiapine recommends a reduced dosage of quetiapine during concurrent administration of CYP3A4 inhibitors.
Quinidine: (Contraindicated) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include ranolazine.
Quinine: (Major) Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Avoid concurrent use of quinine with other drugs that prolong the QT, such as ranolazine. In addition, quinine is an inhibitor of both CYP3A4 and CYP2D6. Ranolazine is primarily metabolized by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Conversely, ranolazine is a P-glycoprotein (P-gp) and CYP3A inhibitor, and quinine is a substrate for P-gp and CYP3A. Ranolazine may theoretically increase plasma concentrations of quinine and increase the risk for adverse effects, such as QT prolongation.
Quizartinib: (Major) Concomitant use of quizartinib and ranolazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ranitidine: (Moderate) Coadminister ranolazine and ranitidine with caution. Ranitidine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the ranitidine dose may be necessary.
Red Yeast Rice: (Moderate) Since certain red yeast rice products (i.e., pre-2005 Cholestin formulations) contain lovastatin, clinicians should use red yeast rice cautiously in combination with drugs known to interact with lovastatin. CYP3A4 inhibitors have been shown to increase HMG-CoA reductase activity and potential for myopathy when coadministered with lovastatin. Because of these potential risks, red yeast rice is best avoided by patients taking CYP3A4 inhibitors. Examples of CYP3A4 inhibitors include ranolazine.
Relugolix: (Major) Avoid concomitant use of relugolix and oral ranolazine. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects; QT prolongation may also occur. If concomitant use is unavoidable, administer ranolazine at least six hours after relugolix and monitor for adverse reactions. Relugolix is a P-gp substrate that may prolong the QT/QTc interval. Ranolazine is a P-gp inhibitor that is associated with dose- and plasma concentration-related increases in the QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral ranolazine. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects; QT prolongation may also occur. If concomitant use is unavoidable, administer ranolazine at least six hours after relugolix and monitor for adverse reactions. Relugolix is a P-gp substrate that may prolong the QT/QTc interval. Ranolazine is a P-gp inhibitor that is associated with dose- and plasma concentration-related increases in the QTc interval.
Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Ranolazine is a mild inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
Ribociclib: (Contraindicated) Coadministration of ranolazine and ribociclib is contraindicated due to elevated ranolazine concentrations and the potential for serious and life threatening reactions, such as cardiac arrhythmias. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Ranolazine is a CYP3A4 substrate that has also been associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of a strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%.
Ribociclib; Letrozole: (Contraindicated) Coadministration of ranolazine and ribociclib is contraindicated due to elevated ranolazine concentrations and the potential for serious and life threatening reactions, such as cardiac arrhythmias. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Ranolazine is a CYP3A4 substrate that has also been associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of a strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%.
Rifabutin: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including rifabutin. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
Rifampin: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including rifampin. Ranolazine also is a substrate for CYP2D6 and P-glycoprotein. Rifampin potently induces cytochrome P450 enzymes, including CYP3A isoenzymes, and is also an inducer of P-glycoprotein transport. Rifampin (600 mg daily) decreases the plasma concentration of ranolazine (1000 mg twice daily) by approximately 95%, likely due to induction of CYP3A and P-glycoprotein.
Rifapentine: (Contraindicated) Coadministration of ranolazine with rifapentine is contraindicated due to decreased ranolazine exposure and efficacy. Ranolazine is a CYP3A4 substrate; rifapentine is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased the plasma concentrations of ranolazine by approximately 95%.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ranolazine is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ranolazine is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with ranolazine as concurrent use may increase the risk of QT prolongation; rilpivirine exposure may also increase. Rilpivirine is a CYP3A4 substrate; supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Ranolazine is a moderate CYP3A4 inhibitor that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with ranolazine; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and ranolazine is a P-gp inhibitor.
Risperidone: (Moderate) Use risperidone and ranolazine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation.
Ritlecitinib: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with ritlecitinib is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased plasma levels of ranolazine by 50% to 130%.
Ritonavir: (Contraindicated) Concomitant use of ranolazine with ritonavir is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; ritonavir is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-gp. Coadministration of another strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%.
Rivaroxaban: (Minor) The coadministration of rivaroxaban and ranolazine should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. Ranolazine is a combined mild CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
Rolapitant: (Major) Use caution if ranolazine and rolapitant are used concurrently, and monitor for ranolazine-related adverse effects. Ranolazine is a CYP2D6 and P-glycoprotein (P-gp) substrate and rolapitant is a CYP2D6 and P-gp inhibitor; the inhibitory effect of rolapitant on CYP2D6 lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with ranolazine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation.
Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as ranolazine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
Saquinavir: (Contraindicated) Concurrent use of ranolazine and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Both saquinavir boosted with ritonavir and ranolazine are inhibitors and substrates of the hepatic isoenzyme CYP3A4. Further, both ranolazine and saquinavir are substrates for P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. This complex interaction may ultimately result in elevated plasma concentrations of both ranolazine and saquinavir, thus increasing the risk of drug toxicity and proarrhythmic effects. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as ranolazine.
Segesterone Acetate; Ethinyl Estradiol: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, ethinyl estradiol is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, ranolazine may decrease the absorption of ethinyl estradiol via P-glycoprotein inhibition.
Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with ranolazine is necessary due to the risk of additive QT prolongation; ranolazine exposure may also increase, resulting in an increase in ranolazine-related adverse reactions. Consider a ranolazine dosage adjustment. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Ranolazine is a P-gp substrate; selpercatinib is a P-gp inhibitor.
Sertraline: (Moderate) Concomitant use of sertraline and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with ranolazine. Halogenated anesthetics can prolong the QT interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Sildenafil: (Moderate) Sildenafil is metabolized principally by the hepatic CYP3A4 (major route) and 2C9 (minor route) isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors. Population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors. CYP3A4 inhibitors include ranolazine.
Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking ranolazine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on ranolazine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of ranolazine and simvastatin against the potential risks. Ranolazine increases the simvastatin exposure by approximately 2-fold.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving ranolazine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ranolazine. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and ranolazine is a weak CYP3A and P-gp inhibitor.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with taurursodiol is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; taurursodiol is a P-gp inhibitor.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Sofosbuvir; Velpatasvir: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with velpatasvir is necessary; a dose adjustment of ranolazine may be necessary. Ranolazine is a P-gp substrate. Velpatasvir is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with velpatasvir is necessary; a dose adjustment of ranolazine may be necessary. Ranolazine is a P-gp substrate. Velpatasvir is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates. (Moderate) Plasma concentrations of ranolazine, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently.
Solifenacin: (Moderate) Use ranolazine with caution in combination with solifenacin as concurrent use may increase the risk of QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
Sorafenib: (Major) Avoid coadministration of sorafenib with ranolazine due to the risk of additive QT prolongation; the risk of ranolazine-related adverse reactions may also increase. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Ranolazine is a P-glycoprotein (P-gp) substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Sorafenib is a P-gp inhibitor that is also associated with QTc prolongation.
Sotalol: (Major) Concomitant use of sotalol and ranolazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotorasib: (Contraindicated) Coadministration of ranolazine with sotorasib is contraindicated. Concomitant use may have an unpredictable effect on ranolazine exposure resulting in decreased ranolazine efficacy or an increase in ranolazine-related adverse effects. Ranolazine is a CYP3A and P-gp substrate and sotorasib is a moderate CYP3A inducer and P-gp inhibitor. Ranolazine use is contraindicated with moderate CYP3A inducers.
Sparsentan: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with sparsentan is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; sparsentan is a P-gp inhibitor.
St. John's Wort, Hypericum perforatum: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including St. John's wort, Hypericum perforatum. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if ranolazine must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of ranolazine is necessary. If ranolazine is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like ranolazine can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If ranolazine is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with ranolazine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Sunitinib can prolong the QT interval.
Tacrolimus: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. The impact of coadministering ranolazine with other CYP3A4 substrates has not been studied. Ranolazine may theoretically increase plasma concentrations of CYP3A4 substrates, potentially leading to adverse reactions, such as QT prolongation. Drugs that are CYP3A4 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include tacrolimus.
Tadalafil: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Inhibitors of CYP3A4 may reduce tadalafil clearance. In theory, CYP3A4 inhibitors which may interact with tadalafil include ranolazine. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the 'as needed' dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the 'once-daily' dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with ranolazine is necessary. Talazoparib is a P-gp substrate and ranolazine is a P-gp inhibitor.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of ranolazine. Tamsulosin is extensively metabolized by CYP2D6 and CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Therefore, concomitant use with drugs that inhibit both CYP2D6 and CYP3A4, such as ranolazine, should be avoided.
Telavancin: (Moderate) Due to increased risk of QT interval prolongation and torsade de pointes (TdP), use caution if telavancin is administered with ranolazine. Telavancin has been associated with QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus- and ranolazine-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of both temsirolimus and ranolazine.
Tenofovir Alafenamide: (Minor) Close clinical monitoring is advised when administering ranolazine with tenofovir alafenamide due to an increased potential for adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Ranolazine is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Coadministration may result in increased tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Tepotinib: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with tepotinib is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; tepotinib is a P-gp inhibitor.
Terbinafine: (Moderate) Coadministration of terbinafine and ranolazine may result in increased plasma concentrations of ranolazine. Ranolazine is metabolized mainly by CYP3A and to a lesser extent by CYP2D6. Terbinafine is a known CYP2D6 inhibitor. Cautiously monitor the concurrent use of ranolazine and significant CYP2D6 inhibitors since potential increases in plasma concentrations of ranolazine may result in adverse effects. The manufacturer specifies that no dosage adjustment of ranolazine is necessary when coadministered with CYP2D6 inhibitors.
Tetrabenazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, such as tetrabenazine, coadministration of such drugs may result in additive QT prolongation. The manufacturer of tetrabenazine recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes and tetrabenazine is a substrate. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment.
Thioridazine: (Contraindicated) Coadministration is contraindicated. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Because of the potential for TdP, coadministration is contraindicated. Additionally, thioridazine is an inhibitor of CYP2D6, and ranolazine is metabolized, to a lesser extent, by CYP2D6. Thioridazine may increase the plasma concentrations of ranolazine.
Ticagrelor: (Moderate) Coadministration of ticagrelor and ranolazine may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and ranolazine is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
Timolol: (Moderate) Timolol is metabolized by CYP2D6 isoenzymes. Ranolazine, a CYP2D6 inhibitor, could theoretically impair timolol metabolism. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration.
Tipranavir: (Major) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Although not specifically mentioned by the manufacturer, tipranavir is known to inhibit CYP3A4. A reduction in the ranolazine dose may be prudent if these two agents are administered concurrently. In addition, tipranavir may decrease the absorption of ranolazine via P-glycoprotein induction.
Tolterodine: (Moderate) Use caution if ranolazine is administered with tolterodine as concurrent use may increase the risk of QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation.
Topotecan: (Major) Avoid coadministration of ranolazine with oral topotecan due to increased topotecan exposure; ranolazine may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ranolazine is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Toremifene: (Major) Avoid coadministration of ranolazine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Both drugs have been shown to prolong the QTc interval in a dose- and concentration-related manner. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Tramadol: (Moderate) As ranolazine is a weak to moderate CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Tramadol; Acetaminophen: (Moderate) As ranolazine is a weak to moderate CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Trandolapril; Verapamil: (Major) The dose of ranolazine, a CYP3A4 and P-glycoprotein substrate, should be limited to 500 mg PO twice daily when coadministered with verapamil, a moderate CYP3A inhibitor. Verapamil (120 mg three times daily) causes dose-dependent increases in the average steady-state concentrations of ranolazine by about 2-fold.
Trazodone: (Major) The manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. In addition, ranolazine could impair the metabolism of trazodone through inhibition of CYP3A, thereby increasing the risk of trazodone-related adverse effects, including QT prolongation.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with ranolazine and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and ranolazine is a weak CYP3A inhibitor.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and ranolazine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Tricyclic antidepressants: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include tricyclic antidepressants.
Trifluoperazine: (Minor) Use ranolazine with caution in combination with trifluoperazine as concurrent use may increase the risk of QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving ranolazine as concurrent use may increase the risk of QT prolongation. R anolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Androgen deprivation therapy may prolong the QT/QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Tucatinib: (Contraindicated) Coadministration of ranolazine with tucatinib is contraindicated as concurrent use may increase ranolazine exposure. Ranolazine is a CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of another strong CYP3A4 inhibitor increased ranolazine exposure by 220%.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with ranolazine. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 and P-gp substrate; ranolazine is a weak CYP3A4 inhibitor and a P-gp inhibitor.
Vandetanib: (Major) Avoid coadministration of vandetanib with ranolazine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Both drugs can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Vardenafil: (Major) Concomitant use of vardenafil and ranolazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as ranolazine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, ranolazine is a CYP2D6 substrate, a CYP3A4 substrate/inhibitor, and P-glycoprotein (PGP) substrate/inhibitor. Vemurafenib is a weak CYP2D6 inhibitor, a CYP3A4 substrate/inducer, and a PGP substrate/inhibitor. Altered concentrations of both drugs may occur with concomitant use; therefore, monitor the patient for toxicity and efficacy.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with ranolazine due to the potential for increased venetoclax exposure. Additionally, ranolazine exposure may be increased. Resume the original venetoclax dose 2 to 3 days after discontinuation of ranolazine. Both venetoclax and ranolazine are P-glycoprotein (P-gp) substrates and inhibitors. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Venlafaxine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include venlafaxine. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates, such as venlafaxine, and could lead to toxicity for drugs that have a narrow therapeutic range.
Verapamil: (Major) The dose of ranolazine, a CYP3A4 and P-glycoprotein substrate, should be limited to 500 mg PO twice daily when coadministered with verapamil, a moderate CYP3A inhibitor. Verapamil (120 mg three times daily) causes dose-dependent increases in the average steady-state concentrations of ranolazine by about 2-fold.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ranolazine is necessary. Vinorelbine is a CYP3A4 substrate and ranolazine is a weak CYP3A4 inhibitor.
Voclosporin: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with voclosporin is necessary and consider a ranolazine dosage reduction. Concomitant use may increase ranolazine exposure and the risk of QT prolongation. Ranolazine is a P-gp substrate that is associated with dose- and plasma concentration-related increases in the QTc interval; voclosporin is a P-gp inhibitor that has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including clarithromycin. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes. In addition, ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Furthermore, clarithromycin may decrease the absorption of ranolazine via inhibition of P-glycoprotein transport.
Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and ranolazine. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ranolazine, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors including voriconazole. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, QTc prolongation, and possibly torsade de pointes.
Vorinostat: (Moderate) Use ranolazine with caution in combination with vorinostat as concurrent use may increase the risk of QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Vorinostat therapy is associated with a risk of QT prolongation.
Voxelotor: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with voxelotor is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased plasma levels of ranolazine by 50% to 130%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with ranolazine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ranolazine is a weak CYP3A4 inhibitor and warfarin is a CYP3A4 substrate.
Zafirlukast: (Major) Coadministration of ranolazine with CYP3A4 inhibitors like zafirlukast could lead to an increase in ranolazine serum concentrations, with potential to result in QTc prolongation and torsade de pointes.
Ziprasidone: (Major) Concomitant use of ziprasidone and ranolazine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Zolpidem: (Moderate) In vitro studies indicate that ranolazine and its O-demethylated metabolite are inhibitors of CYP3A isoenzymes. In theory, ranolazine may inhibit zolpidem CYP3A4 metabolism, potentially leading to increased zolpidem plasma concentrations. Although not studied, excessive sedation and possible respiratory depression may occur.
Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ranolazine is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

ASPRUZYO Oral Gran: 500mg, 1000mg
Ranexa/Ranolazine Oral Tab ER: 500mg, 1000mg

Adults

2,000 mg/day PO.

Geriatric

2,000 mg/day PO.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

The mechanism of action of ranolazine's antianginal effects has not been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure product, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (INa). However, the relationship of this inhibition to angina symptoms is uncertain. Initially, the main anti-anginal effects of ranolazine were thought to be related to the actions of ranolazine to shift adenosine triphosphate (ATP) production away from fatty acid oxidation toward glycolysis. Recent evidence suggests ranolazine is an inhibitor of the late sodium current which results in a reduction of the intracellular sodium and calcium overload in ischemic cardiac myocytes. Ranolazine has been associated with a significant dose and concentration-related prolongation of the QT interval. These effects are believed to be caused by ranolazine and not by its metabolites. The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of I(Kr), which prolongs the ventricular action potential.
 
Ranolazine does not possess negative chronotropic or inotropic effects, and has had minimal effects on heart rate and blood pressure during clinical trials in patients with angina and CHF NYHA Class I or II, and also in a study of 85 patients with CHF NYHA Class III or IV. In contrast, traditional antianginal agents reduce myocardial oxygen demand by lowering blood pressure and/or heart rate. Heart rate and arterial pressure at rest and at peak exercise are unchanged after ranolazine (240 mg single dose). Given the absence of hemodynamic effects, this drug can be safely added to traditional antianginal therapy if there are no other significant drug interactions.
 
In addition to comparable antianginal efficacy for diabetic vs. nondiabetic patients, preliminary data suggest that ranolazine may have a slight benefit on hemoglobin A1C (A1C) values in diabetic patients. The mechanism of this effect is under investigation, but may be related to inhibition of glucagon secretion, preservation of pancreatic beta-cell function, and an increase in insulin secretion. Studies have demonstrated an A1C reduction of 0.5% to 0.6% in patients with diabetes and chronic angina receiving ranolazine therapy.

Ranolazine is administered orally. Ranolazine is approximately 62% bound to plasma proteins. Following absorption, ranolazine is rapidly and extensively metabolized within the liver and intestine by hepatic CYP450 isoenzymes; primarily CYP3A and to a lesser extent CYP2D6. Ranolazine is also a substrate of P-glycoprotein. Ranolazine is metabolized by numerous drug elimination pathways, forming an abundant number of metabolites (at least 12), with four main metabolites having exposure (AUC) at least 10% relative to the parent compound. Approximately 75% of an oral dose of ranolazine is excreted in urine; 25% is excreted in feces. Less than 5% is excreted unchanged in the urine and feces. The apparent terminal half-life of ranolazine is 7 hours for the extended-release tablets and a mean elimination half-life is 5.3 hours (range of 2 to 11 hours). Steady-state for the parent drug is generally achieved within 3 days of twice daily dosing. After dosing to steady-state with 500 mg to 1,500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about 5% to 33% that of ranolazine. The half-lives of the metabolites range from 6 to 22 hours. The pharmacologic activity of the metabolites has not been well characterized. The drug-induced QT prolonging effects are believed to be caused by ranolazine and not by its metabolites.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2D6, P-glycoprotein (P-gp), OCT2
In vitro studies indicate that ranolazine is a substrate of CYP3A and, to a lesser extent, of CYP2D6. It is also a P-gp substrate. In vitro studies indicate that ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A and moderate inhibitors of CYP2D6 and P-gp. Based on in vitro data, ranolazine is also a OCT2 inhibitor. Coadministration of ranolazine with either a CYP3A inducer or strong CYP3A inhibitor is contraindicated; reduced dosages needed when coadministered with a moderate CYP3A inhibitor. Dose adjustments may be needed for medications that are CYP3A, CYP2D6, and P-gp substrates, as well as, medications that are transported by OCT2 when coadministered with ranolazine. Coadministration of ranolazine with ketoconazole, a strong CYP3A inhibitor, and diltiazem, a moderate CYP3A inhibitor, resulted in a 200% and 130% increase in plasma ranolazine levels, respectively. Coadministration with simvastatin and cimetidine, weak CYP3A inhibitors, did not increase ranolazine levels in healthy volunteers. Plasma concentrations of ranolazine were decreased by approximately 95% when coadministered with a strong CYP3A inducer, rifampin. In subjects with type 2 diabetes mellitus, the exposure to metformin (an OCT2 substrate) was increased by 40% and 80% following administration of ranolazine 500 and 1,000 mg twice daily, respectively.

Oral Route

Following administration of an oral solution of radiolabeled ranolazine, 73% of the dose is systemically available as parent drug or metabolites. Compared to the oral solution, the relative bioavailability of ranolazine extended-release tablets or ranolazine extended-release granules is about 76%.
Due to extensive and rapid gut and liver metabolism, the systemic availability of ranolazine is highly variable. For example, at an oral dose of 1,000 mg twice daily the mean steady-state Cmax is 2600 ng/ml, with 95% of Cmax values ranging between 420 and 6,080 ng/mL. The variability has clinical relevance since ranolazine is associated with dose and plasma concentration-dependent increases in QTc prolongation. At steady-state, ranolazine Cmax and AUC increase slightly more than proportionally to dose, 2.2- and 2.4-fold or 120% and 140%, respectively, over the therapeutic range (500 to 1,000 mg PO twice daily). With twice daily dosing, the trough to peak ratio of the ranolazine plasma concentration is 0.3 to 0.6. The relationship between ranolazine plasma concentrations and QTc remains linear over a concentration range up to several-fold greater than the concentrations produced by the maximum recommended dosage (1,000 mg PO twice daily), and is not affected by changes in heart rate. Age, weight, gender, race, heart rate, NYHA heart failure Class I to IV, and diabetes have no significant effect on the relationship between ranolazine plasma concentration and the increase in QTc interval.
Extended-release tablets: After oral administration, peak plasma concentrations of ranolazine are attained within 2 to 5 hours. Food (high-fat breakfast) has no important effect on the Cmax or AUC.
Extended-release granules: After oral administration of ranolazine 100 mg, the median time to attain peak plasma concentrations (Tmax) was 10 hours (range of 2 to 16 hours) under fasting conditions and 4.5 to 6 hours under fed conditions. Compared to the fasted state, the AUC and Cmax were increased by 10% and 27%, respectively, when ranolazine was given 30 minutes after a high fat meal. Following administration with a low fate, low calorie meal, the AUC was increased by 6% and the Cmax by 48%.

Pregnancy

There are no data on the use of ranolazine during pregnancy to inform any drug-associated risks. Animal studies have shown fetal toxicity (decreased fetal weight and reduced ossification) and maternal weight loss at doses 4 times the maximum recommended human dose (MRHD). No adverse effects were observed when animals were administered doses equal to the MRHD.

There are no data regarding the presence of ranolazine in human milk, the effects on the breastfed infant, or the effects on milk production. Ranolazine is present in rat milk. Adult female rats were administered ranolazine from gestation through postnatal day 20. At maternally toxic doses, male and female pups exhibited increased mortality and decreased body weight, and female pups showed increased motor activity. The pups were potentially exposed to low amounts of ranolazine via maternal milk. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for ranolazine and any potential adverse effects on the breastfed infant from ranolazine or from the underlying maternal condition.