Accolate

Leukotriene Receptor Antagonists (LTRAs)

Oral Administration

Administer zafirlukast on an empty stomach. Take at least 1 hour before or 2 hours after meals. The bioavailability of zafirlukast is substantially decreased when taken with food.
Zafirlukast is for chronic administration; continue therapy even during symptom-free periods.
Patients should be advised not to stop taking or decrease the use of other asthma treatments when starting zafirlukast unless otherwise directed by their health care prescriber.

Severe

hepatic failure / Delayed / 0-1.0
agranulocytosis / Delayed / 0-1.0
suicidal ideation / Delayed / 0-1.0
vasculitis / Delayed / 0-1.0
eosinophilic pneumonia / Delayed / 0-1.0
Churg-Strauss syndrome / Delayed / 0-1.0
angioedema / Rapid / Incidence not known
seizures / Delayed / Incidence not known

Moderate

hepatitis / Delayed / 0-1.0
eosinophilia / Delayed / 0-1.0
jaundice / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
depression / Delayed / Incidence not known
hallucinations / Early / Incidence not known
dyspnea / Early / Incidence not known
chest pain (unspecified) / Early / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
clastogenesis / Delayed / Incidence not known

Mild

headache / Early / 4.5-12.9
infection / Delayed / 3.5-3.5
nausea / Early / 1.8-3.1
diarrhea / Early / 1.8-2.8
asthenia / Delayed / 1.8-1.8
abdominal pain / Early / 1.8-1.8
myalgia / Early / 1.6-1.6
dizziness / Early / 1.6-1.6
fever / Early / 1.6-1.6
back pain / Delayed / 1.5-1.5
vomiting / Early / 1.5-1.5
dyspepsia / Early / 1.3-1.3
ecchymosis / Delayed / 0-1.0
pharyngitis / Delayed / Incidence not known
arthralgia / Delayed / Incidence not known
weakness / Early / Incidence not known
pruritus / Rapid / Incidence not known
lethargy / Early / Incidence not known
fatigue / Early / Incidence not known
rash / Early / Incidence not known
vesicular rash / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
insomnia / Early / Incidence not known
tremor / Early / Incidence not known
agitation / Early / Incidence not known
anxiety / Delayed / Incidence not known
malaise / Early / Incidence not known
irritability / Delayed / Incidence not known
restlessness / Early / Incidence not known
sinusitis / Delayed / Incidence not known

Accolate

Rx

Leukotriene receptor antagonist (LTRA)
Used for add-on asthma maintenance therapy in adult and pediatric patients 5 years and older; off-label use for allergic rhinitis and exercise-induced bronchospasm
Inhibits some CYP hepatic enzymes, which may lead to drug interactions; associated with rare hepatic toxicity

For asthma maintenance treatment. Oral dosage Adults

20 mg PO twice daily.

Children and Adolescents 12 to 17 years

20 mg PO twice daily.

Children 5 to 11 years

10 mg PO twice daily. 

For exercise-induced bronchospasm prophylaxis†. Oral dosage Adults

20 mg PO twice daily is the recommended dosing for controller therapy. Take at least 2 hours before exercise to have maximal prophylactic effect.[56291] Higher doses have been studied but may increase the risk of hepatotoxicity or other side effects.

Children and Adolescents 12 years and older

Efficacy data are limited. 20 mg PO twice daily is the recommended dosing for controller therapy.[56291] Other regimens have been studied. Zafirlukast 5 to 40 mg PO as a single dose given 4 hours before an exercise challenge was studied in a double-blind, crossover study of 40 children 6 to 14 years old. Some experts recommend administration at least 2 hours before exercise for best effect.[56291]

Children 5 to 11 years

Efficacy data are limited. 10 mg PO twice daily is the recommended dosing for controller therapy. [56291] Other regimens have been studied. Zafirlukast 5 to 40 mg PO as a single dose given 4 hours before an exercise challenge was studied in a double-blind, crossover study of 40 children 6 to 14 years old. Some experts recommend administration at least 2 hours before exercise for best effect.[56291]

For the treatment of allergic rhinitis†. Oral dosage Adults

20 mg PO twice daily is the usual dose. The data for zafirlukast in the treatment of allergic rhinitis are limited, especially compared to the more extensive clinical study data available for montelukast. Rhinitis guidelines suggest that an LTRA not be used for initial treatment of allergic rhinitis due to reduced efficacy when compared to other agents. However, in patients with allergic rhinitis and comorbid asthma, an LTRA could be an option after weighing the benefits of LTRA monotherapy versus an inhaled corticosteroid for asthma and an antihistamine or intranasal corticosteroid for allergic rhinitis.

†Indicates off-label use

Hepatic Impairment

Use is contraindicated in patients with hepatic impairment including hepatic cirrhosis as drug exposure is increased (see Contraindications).

Renal Impairment

It appears that no dosage adjustments are needed, zafirlukast is not significantly eliminated via the renal route.

Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Acetaminophen; Aspirin: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Acetaminophen; Aspirin; Diphenhydramine: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with zafirlukast may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and 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 reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of zafirlukast could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If zafirlukast is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Zafirlukast is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of zafirlukast is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like zafirlukast 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 in patients also receiving a CYP2D6 inhibitor. If zafirlukast 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; Ibuprofen: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of zafirlukast is necessary. If zafirlukast 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 zafirlukast 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 zafirlukast 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.
Alfentanil: (Moderate) Alfentanil is metabolized by the cytochrome P450 3A4 isoenzyme. Drugs that inhibit CYP3A4, such as zafirlukast, may decrease systemic clearance of alfentanil leading to increased or prolonged effects. Close monitoring for oversedation and respiratory depression is warranted if a CYP3A4 inhibitor is used with alfentanil.
Alogliptin; Pioglitazone: (Moderate) It is possible that an increase in the exposure of pioglitazone may occur when coadministered with drugs that inhibit CYP2C8 such as montelukast and zafirlukast. Although montelukast or zafirlukast administered with pioglitazone in vivo did not significantly increase pioglitazone concentrations, patients should be monitored for changes in glycemic control if any of these CYP2C8 inhibitors are coadministered with pioglitazone.
Alosetron: (Minor) Alosetron is metabolized by hepatic cytochrome P450 enzymes CYP2C9, CYP3A4 and CYP1A2. Inhibitors of these enzymes, such as zafirlukast, may decrease the clearance of alosetron and increase the systemic exposure of alosetron. Clinically, increased systemic exposure to alosetron may cause or worsen constipation, which might lead to serious adverse effects.
Alprazolam: (Major) Avoid coadministration of alprazolam and zafirlukast 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 zafirlukast, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and zafirlukast 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%.
Amlodipine: (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
Amlodipine; Atorvastatin: (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
Amlodipine; Benazepril: (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
Amlodipine; Celecoxib: (Minor) Celecoxib is a substrate of the cytochrome P450 2C9 isoenzyme. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 such as zafirlukast should be done with caution. (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
Amlodipine; Olmesartan: (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
Amlodipine; Valsartan: (Minor) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan. (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Minor) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan. (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Clarithromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when clarithromycin is added concurrently.
Aprepitant, Fosaprepitant: (Minor) Use caution if zafirlukast and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of zafirlukast. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Zafirlukast is a CYP2C9 substrate and aprepitant is a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant. When a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy (another CYP2C9 substrate), a 34% decrease in S-warfarin trough concentrations was noted, accompanied by a 14% decrease in the INR at five days after completion of aprepitant. Zafirlukast is also a weak in vitro CYP3A4 inhibitor 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: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of zafirlukast. Patients receiving both a CYP2D6 inhibitor plus zafirlukast may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; zafirlukast is a weak CYP3A inhibitor.
Artemether; Lumefantrine: (Moderate) Zafirlukast is a inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Zafirlukast is a inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
Asciminib: (Moderate) Monitor for an increase in zafirlukast-related adverse reactions if concomitant use of asciminib 200 mg twice daily is necessary. Concomitant use may increase zafirlukast exposure. Zafirlukast is a CYP2C9 substrate and asciminib 200 mg twice daily is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor increased the exposure of zafirlukast by approximately 58%. An interaction is not expected with asciminib doses less than 200 mg twice daily.
Aspirin, ASA: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Aspirin, ASA; Butalbital; Caffeine: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Aspirin, ASA; Caffeine: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Aspirin, ASA; Carisoprodol: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Aspirin, ASA; Carisoprodol; Codeine: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Aspirin, ASA; Dipyridamole: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Aspirin, ASA; Omeprazole: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of zafirlukast is necessary. If zafirlukast 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 zafirlukast 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 zafirlukast 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. (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Atazanavir: (Moderate) Zafirlukast is a CYP3A4 inhibitor, and serum concentrations of atazanavir, a CYP3A4 substrate, may increase with coadministration. Coadminister these drugs with caution due to the potential for atazanavir toxicity.
Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with zafirlukast as there is a potential for elevated concentrations of cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; cobicistat is a CYP3A4 substrate. (Moderate) Zafirlukast is a CYP3A4 inhibitor, and serum concentrations of atazanavir, a CYP3A4 substrate, may increase with coadministration. Coadminister these drugs with caution due to the potential for atazanavir toxicity.
Avanafil: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including zafirlukast, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
Bendamustine: (Major) Consider the use of an alternative therapy if zafirlukast treatment is needed in patients receiving bendamustine. Zafirlukast may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and zafirlukast is a CYP1A2 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with zafirlukast 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 zafirlukast 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 zafirlukast 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. Zafirlukast is a weak in vitro inhibitor of CYP3A4.
Bosentan: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes by zafirlukast may increase the plasma concentration of bosentan. Monitor for potential adverse effects of bosentan during coadministration with zafirlukast. Excessive bosentan dosage may result in hypotension or elevated hepatic enzymes.
Bromocriptine: (Minor) Bromocriptine is a cytochrome P450 3A4 substrate. In theory, inhibitors of this isoenzyme like zafirlukast may decrease the metabolism of bromocriptine.
Bupivacaine; Lidocaine: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as lidocaine.
Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with zafirlukast is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and zafirlukast is a weak CYP2C9 inhibitor.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and zafirlukast can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when zafirlukast is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping zafirlukast, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If zafirlukast is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and zafirlukast is a CYP3A inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and zafirlukast can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when zafirlukast is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping zafirlukast, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If zafirlukast is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and zafirlukast is a CYP3A inhibitor.
Buspirone: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as buspirone.
Butalbital; Aspirin; Caffeine; Codeine: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering zafirlukast with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Cannabidiol: (Moderate) Consider a dose reduction of zafirlukast as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Increased zafirlukast exposure is possible. Zafirlukast is a CYP2C9 substrate. In vitro data predicts inhibition of CYP2C9 by cannabidiol potentially resulting in clinically significant interactions.
Carbamazepine: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as carbamazepine.
Celecoxib: (Minor) Celecoxib is a substrate of the cytochrome P450 2C9 isoenzyme. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 such as zafirlukast should be done with caution.
Celecoxib; Tramadol: (Minor) Celecoxib is a substrate of the cytochrome P450 2C9 isoenzyme. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 such as zafirlukast should be done with caution.
Chlordiazepoxide: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as chlordiazepoxide.
Chlordiazepoxide; Amitriptyline: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as chlordiazepoxide.
Chlordiazepoxide; Clidinium: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as chlordiazepoxide.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with zafirlukast may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and 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 reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of zafirlukast could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If zafirlukast is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Zafirlukast is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of zafirlukast is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like zafirlukast 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 in patients also receiving a CYP2D6 inhibitor. If zafirlukast 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.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
Cilostazol: (Moderate) Cilostazol is extensively metabolized by the cytochrome P450 CYP3A4 hepatic isoenzyme and metabolism may be inhibited by zafirlukast, an inhibitor of CYP3A4.
Cisapride: (Contraindicated) Post-marketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death, when known and potent inhibitors of CYP3A4 are coadministered with cisapride. Zafirlukast may have the potential to inhibit the metabolism of cisapride through CYP3A4 and thus, is essentially considered contraindicated for use with cisapride.
Clarithromycin: (Moderate) Clarithromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when clarithromycin is added concurrently.
Clonazepam: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as clonazepam.
Clorazepate: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as clorazepate.
Clozapine: (Moderate) Caution is advisable during concurrent use of zafirlukast and clozapine. Zafirlukast is an inhibitor of CYP3A4 and CYP1A2, two of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 or CYP1A2 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: (Moderate) Caution is warranted when cobicistat is administered with zafirlukast as there is a potential for elevated concentrations of cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; cobicistat is a CYP3A4 substrate.
Cobimetinib: (Moderate) If concurrent use of cobimetinib and zafirlukast is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and zafirlukast is a weak inhibitor of CYP3A. 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.
Conjugated Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Corticosteroids: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as corticosteroids.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with zafirlukast is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 substrate and zafirlukast is a weak CYP3A4 inhibitor.
Dapagliflozin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and zafirlukast are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as zafirlukast.
Darifenacin: (Moderate) Zafirlukast inhibits CYP3A4 and may increase the serum concentration of darifenacin, a CYP3A4 substrate.
Darunavir: (Moderate) Caution is warranted when darunavir is administered with zafirlukast as there is a potential for elevated concentrations of darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; darunavir is a CYP3A4 substrate.
Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with zafirlukast as there is a potential for elevated concentrations of cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; cobicistat is a CYP3A4 substrate. (Moderate) Caution is warranted when darunavir is administered with zafirlukast as there is a potential for elevated concentrations of darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; darunavir is a CYP3A4 substrate.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with zafirlukast as there is a potential for elevated concentrations of cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; cobicistat is a CYP3A4 substrate. (Moderate) Caution is warranted when darunavir is administered with zafirlukast as there is a potential for elevated concentrations of darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; darunavir is a CYP3A4 substrate.
Dextromethorphan; Quinidine: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as quinidine.
Diazepam: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as diazepam.
Diclofenac: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as diclofenac.
Diclofenac; Misoprostol: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as diclofenac.
Dienogest; Estradiol valerate: (Minor) As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Diltiazem: (Minor) Zafirlukast and zileuton are respiratory antiinflammatory agents which can theoretically inhibit CYP3A4 metabolism of calcium-channel blockers, CYP3A4 substrates.
Diphenhydramine; Ibuprofen: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
Disopyramide: (Moderate) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of disopyramide.
Dofetilide: (Major) Zafirlukast, a CYP 3A4 inhibitor, may increase plasma dofetilide concentrations with potential for dofetilide toxicity.
Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering zafirlukast with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as zafirlukast, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
Doxorubicin Liposomal: (Major) In vitro, zafirlukast is a CYP3A4 inhibitor; doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of zafirlukast and doxorubicin if possible. If not possible, closely monitor increased side effects of doxorubicin, including myelosuppression and cardiotoxicity.
Doxorubicin: (Major) In vitro, zafirlukast is a CYP3A4 inhibitor; doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of zafirlukast and doxorubicin if possible. If not possible, closely monitor increased side effects of doxorubicin, including myelosuppression and cardiotoxicity.
Dronabinol: (Major) Use caution if coadministration of dronabinol with zafirlukast 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; zafirlukast is a moderate inhibitor of CYP2C9 and a weak 3A4 inhibitor in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Moderate) Dronedarone and zafirlukast should be coadministered with caution. Dronedarone is metabolized by CYP3A. Zafirlukast is an inhibitor of CYP3A4. Concomitant use of dronedarone with zafirlukast may increase dronedarone concentrations.
Drospirenone; Estradiol: (Minor) As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as zafirlukast. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
Elagolix; Estradiol; Norethindrone acetate: (Minor) As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with zafirlukast may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Zafirlukast is a mild inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of zafirlukast and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of zafirlukast and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily. Zafirlukast is a weak CYP3A4 inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration with CYP3A4 inhibitors, such as zafirlukast, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP2C8. The significance of administering inhibitors of CYP2C8, such as zafirlukast, on the systemic exposure of eltrombopag has not been established. Monitor patients for signs of eltrombopag toxicity if these drugs are coadministered.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with zafirlukast as there is a potential for elevated concentrations of cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; cobicistat is a CYP3A4 substrate.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with zafirlukast as there is a potential for elevated concentrations of cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; cobicistat is a CYP3A4 substrate.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering zafirlukast with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Close clinical monitoring is advised when administering zafirlukast with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Erlotinib: (Major) Avoid coadministration of erlotinib with zafirlukast if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. Zafirlukast is a CYP3A4 and CYP1A2 inhibitor. Coadministration with a moderate CYP3A4/CYP1A2 inhibitor increased erlotinib exposure by 39% and increased the erlotinib Cmax by 17%.
Erythromycin: (Moderate) Erythromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when erythromycin is added concurrently.
Estazolam: (Moderate) Zafirlukast is a CYP3A4 inhibitor and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Estradiol: (Minor) As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Levonorgestrel: (Minor) As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Norethindrone: (Minor) As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Norgestimate: (Minor) As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Progesterone: (Minor) As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estropipate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as zafirlukast may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Ezetimibe; Simvastatin: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as simvastatin.
Felodipine: (Minor) Zafirlukast is a CYP3A4 inhibitors which theoretically may decrease hepatic clearance and enhance oral bioavailability of felodipine, a CYP3A4 substrate.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of zafirlukast is necessary. If zafirlukast 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 zafirlukast 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 zafirlukast 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.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including zafirlukast, 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.
Flurazepam: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as flurazepam.
Fluvastatin: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as fluvastatin.
Food: (Major) Because the bioavailability of zafirlukast is substantially decreased when taken with food, take zafirlukast on an empty stomach at least 1 hour before or 2 hours after meals.
Fosphenytoin: (Minor) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 especially those drugs with narrow therapeutic ranges. Employ appropriate clinical monitoring. Drugs primarily metabolized by CYP2C9 include phenytoin or fosphenytoin. Dosage reduction of fosphenytoin may be warranted.
Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like zafirlukast. Monitor serum glucose concentrations if glimepiride is coadministered with zafirlukast. Dosage adjustments may be necessary.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of zafirlukast is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like zafirlukast 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 in patients also receiving a CYP2D6 inhibitor. If zafirlukast 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.
Haloperidol: (Moderate) Zafirlukast is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and substrates or inhibitors of CYP3A4. Until more data are available, it is advisable to closely monitor for adverse events when these medications are co-administered.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of zafirlukast is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like zafirlukast 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 in patients also receiving a CYP2D6 inhibitor. If zafirlukast 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 zafirlukast is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like zafirlukast 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 in patients also receiving a CYP2D6 inhibitor. If zafirlukast 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; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of zafirlukast is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like zafirlukast 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 in patients also receiving a CYP2D6 inhibitor. If zafirlukast 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. (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of zafirlukast is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like zafirlukast 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 in patients also receiving a CYP2D6 inhibitor. If zafirlukast 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.
Ibuprofen: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
Ibuprofen; Famotidine: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of zafirlukast is necessary. If zafirlukast 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 zafirlukast 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 zafirlukast 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. (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
Ibuprofen; Pseudoephedrine: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as ibuprofen.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with zafirlukast may result in increased serum concentrations of isavuconazonium. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; zafirlukast is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isradipine: (Minor) Caution should be used when CYP3A4 inhibitors are co-administered with isradipine, a CYP3A4 substrates. This combination may reduce the metabolism and lead to increased effect of isradipine.
Ixabepilone: (Major) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of zafirlukast is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and zafirlukast is a weak CYP3A inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Clarithromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when clarithromycin is added concurrently.
Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with zafirlukast as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; zafirlukast is a weak CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Lesinurad: (Moderate) Use lesinurad and zafirlukast together with caution; zafirlukast may increase the systemic exposure of lesinurad. Zafirlukast is an inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
Lesinurad; Allopurinol: (Moderate) Use lesinurad and zafirlukast together with caution; zafirlukast may increase the systemic exposure of lesinurad. Zafirlukast is an inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
Levamlodipine: (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
Lidocaine: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as lidocaine.
Lidocaine; Epinephrine: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as lidocaine.
Lidocaine; Prilocaine: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as lidocaine.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and zafirlukast; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing zafirlukast. Lonafarnib is a sensitive CYP3A4 and CYP2C9 substrate and zafirlukast is a weak CYP3A4 and CYP2C9 inhibitor.
Lopinavir; Ritonavir: (Moderate) Concurrent administration of zafirlukast with ritonavir may result in elevated plasma concentrations of ritonavir. In vitro, zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4. Ritonavir is a substrate for CYP3A4. Caution and close monitoring are advised if these drugs are administered together.
Losartan: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as losartan.
Losartan; Hydrochlorothiazide, HCTZ: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as losartan.
Lovastatin: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as lovastatin.
Lumacaftor; Ivacaftor: (Minor) Although the clinical significance of this interaction is unknown, concurrent use of zafirlukast and lumacaftor; ivacaftor may alter zafirlukast exposure; caution and monitoring are advised if these drugs are used together. Zafirlukast is a substrate of CYP2C9. In vitro data suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C9. The net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear, but substrate exposure may be affected leading to decreased efficacy or increased or prolonged therapeutic effects and adverse events.
Lurasidone: (Major) Zafirlukast is a minor inhibitor of CYP3A4. Because lurasidone is primarily metabolized by CYP3A4, concurrent use of zafirlukast can theoretically lead to an increased risk of lurasidone-related adverse reactions.
Maraviroc: (Minor) Use caution if coadministration of maraviroc with zafirlukast is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and zafirlukast is a weak CYP3A4 inhibitor. Monitor for an increase in adverse effects with concomitant use.
Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Zafirlukast is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with zafirlukast is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and zafirlukast is a weak CYP2C9 inhibitor.
Metformin; Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Zafirlukast has been shown to be an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
Metformin; Rosiglitazone: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as rosiglitazone, especially those drugs with narrow therapeutic ranges.
Metformin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and zafirlukast are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as zafirlukast.
Methadone: (Moderate) The concurrent administration of methadone and inhibitors of cytochrome P450 3A4, such as zafirlukast, may result in increased concentrations of methadone. Inhibition of methadone metabolism can lead to toxicity including CNS adverse effects and potential for QT prolongation and torsades de pointes when high doses of methadone are used.
Methylergonovine: (Major) Zafirlukast is a significant CYP3A4 inhibitor. Coadministration of ergotamine with inhibitors of CYP3A4 may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
Midazolam: (Moderate) Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as zafirlukast, can potentiate the clinical effects of midazolam. Interactions of this type are most pronounced with oral midazolam.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of zafirlukast. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and zafirlukast is a weak CYP3A inhibitor.
Nateglinide: (Moderate) Monitor blood glucose and for hypoglycemia. In vitro data indicate that zafirlukast is a moderate to potent inhibitor of CYP2C9. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as nateglinide.
Nebivolol; Valsartan: (Minor) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan.
Niaci

n; Simvastatin: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as simvastatin.
Nicardipine: (Minor) Caution should be used when CYP3A4 inhibitors, such as zafirlukast are co-administered with nicardipine, a CYP3A4 substrate and inhibitor. Zafirlukast may inhibit the metabolism and increase the effect of nicardipine.
Nifedipine: (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease hepatic clearance and enhance oral bioavailability of nifedipine, a CYP3A4 substrate.
Nilotinib: (Major) The concomitant use of nilotinib, a substrate and inhibitor of CYP3A4, and zafirlukast, a CYP3A4 inhibitor, may result in increased nilotinib levels. Monitor patients for nilotinib toxicity (e.g., QT interval prolongation) if these drugs are used together.
Nimodipine: (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease hepatic metabolism of nimodipine, a CYP3A4 substrate.
Nirmatrelvir; Ritonavir: (Moderate) Concurrent administration of zafirlukast with ritonavir may result in elevated plasma concentrations of ritonavir. In vitro, zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4. Ritonavir is a substrate for CYP3A4. Caution and close monitoring are advised if these drugs are administered together.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with zafirlukast 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 zafirlukast is a CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
Oritavancin: (Moderate) Zafirlukast is metabolized by CYP2C9; oritavancin is a weak CYP2C9 inhibitor. Coadministration may result in elevated zafirlukast plasma concentrations. If these drugs are administered concurrently, monitor patients for zafirlukast toxicity such as headache, nausea, or diarrhea.
Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Inhibitors of the CYP3A4 enzyme, such as zafirlukast, may increase the serum concentrations of oxybutynin. The manufacturer recommends caution when oxybutynin is co-administered with CYP3A4 inhibitors.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of zafirlukast is necessary. If zafirlukast 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 zafirlukast 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 zafirlukast 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.
Paclitaxel: (Moderate) Published data indicate zafirlukast inhibits CYP2C8 rather potently. Until further data are available to confirm the absence of drug interactions, CYP2C8 metabolized drugs, such as paclitaxel, may require closer monitoring when used in conjunction with zafirlukast.
Paricalcitol: (Moderate) Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as zafirlukast. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
Pazopanib: (Moderate) Pazopanib is a substrate for CYP3A4 and CYP2C8. Zafirlukast is an inhibitor of CYP3A4 and CYP2C8. Concurrent administration may result in increased pazopanib concentrations. Dose reduction of pazopanib may be necessary when coadministration of pazopanib and zafirlukast is required.
Perindopril; Amlodipine: (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
Phenytoin: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as phenytoin.
Pimozide: (Contraindicated) Concurrent use of pimozide and zafirlukast should be avoided. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Zafirlukast is a strong inhibitor of CYP1A2 and a lesser inhibitor of CYP3A4. Increased pimozide concentrations may occur, and can lead to QT prolongation, ventricular arrhythmias, and sudden death. Consider alternatives to zafirlukast.
Pioglitazone: (Moderate) It is possible that an increase in the exposure of pioglitazone may occur when coadministered with drugs that inhibit CYP2C8 such as montelukast and zafirlukast. Although montelukast or zafirlukast administered with pioglitazone in vivo did not significantly increase pioglitazone concentrations, patients should be monitored for changes in glycemic control if any of these CYP2C8 inhibitors are coadministered with pioglitazone.
Pioglitazone; Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like zafirlukast. Monitor serum glucose concentrations if glimepiride is coadministered with zafirlukast. Dosage adjustments may be necessary. (Moderate) It is possible that an increase in the exposure of pioglitazone may occur when coadministered with drugs that inhibit CYP2C8 such as montelukast and zafirlukast. Although montelukast or zafirlukast administered with pioglitazone in vivo did not significantly increase pioglitazone concentrations, patients should be monitored for changes in glycemic control if any of these CYP2C8 inhibitors are coadministered with pioglitazone.
Pioglitazone; Metformin: (Moderate) It is possible that an increase in the exposure of pioglitazone may occur when coadministered with drugs that inhibit CYP2C8 such as montelukast and zafirlukast. Although montelukast or zafirlukast administered with pioglitazone in vivo did not significantly increase pioglitazone concentrations, patients should be monitored for changes in glycemic control if any of these CYP2C8 inhibitors are coadministered with pioglitazone.
Pirfenidone: (Major) Discontinue zafirlukast prior to beginning pirfenidone because it significantly increases exposure to pirfenidone. Zafirlukast is a moderate inhibitor of CYP1A2 and CYP2C9. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
Piroxicam: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as piroxicam.
Propafenone: (Moderate) In vitro data indicate that zafirlukast inhibits CYP3A4 at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, especially those drugs, like propafenone, with narrow therapeutic ranges.
Quazepam: (Moderate) Zafirlukast is a CYP3A4 inhibitor and may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
Quetiapine: (Moderate) Zafirlukast may inhibit the CYP3A4-mediated metabolism of quetiapine, leading to increased serum concentrations of quetiapine. The manufacturer of quetiapine recommends a reduced dosage during concurrent administration of CYP3A4 inhibitors.
Quinidine: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as quinidine.
Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as zafirlukast, may lead to increases in the serum concentrations of ramelteon.
Ranolazine: (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.
Rasagiline: (Major) Do not exceed a rasagiline dose of 0.5 mg once daily when coadministered with zafirlukast. Coadministration may result in increased rasagiline concentrations. Rasagiline is primarily metabolized by CYP1A2; zafirlukast is a strong CYP1A2 inhibitor. When rasagiline was administered with a strong CYP1A2 inhibitor, the AUC of rasagiline increased by 83%.
Relugolix; Estradiol; Norethindrone acetate: (Minor) As zarfirlukast inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Zafirlukast has been shown to be an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
Rilpivirine: (Moderate) Close clinical monitoring is advised when administering zafirlukast with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Riluzole: (Moderate) Coadministration of riluzole with zafirlukast may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and zafirlukast is a CYP1A2 inhibitor.
Riociguat: (Minor) It is possible that an increase in the exposure of riociguat may occur when coadministered with drugs that inhibit CYP2C8 such as zafirlukast. Although in vivo data has not substantiated clinically relavent interactions with CYP2C8 substrates, patients should be monitored for hypotension if zafirlukast is coadministered with riociguat.
Ritonavir: (Moderate) Concurrent administration of zafirlukast with ritonavir may result in elevated plasma concentrations of ritonavir. In vitro, zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4. Ritonavir is a substrate for CYP3A4. Caution and close monitoring are advised if these drugs are administered together.
Rivaroxaban: (Minor) Coadministration of rivaroxaban and zafirlukast may result in increases in rivaroxaban exposure and may increase bleeding risk. Zafirlukast is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4. Zafirlukast is an inhibitor of CYP3A4. Concurrent administration of romidepsin with an inhibitor of CYP3A4 may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
Rosiglitazone: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as rosiglitazone, especially those drugs with narrow therapeutic ranges.
Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as zafirlukast, 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.
Sacubitril; Valsartan: (Minor) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan.
Saquinavir: (Contraindicated) The concurrent use of saquinavir boosted with ritonavir and zafirlukast should be used cautiously due to the potential for life threatening arrhythmias such as torsades de pointes (TdP). Both saquinavir boosted with ritonavir and zafirlukast are inhibitors of CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation. The use of saquinavir/ritonavir with zafirlukast may result in increases in saquinavir plasma concentrations, which could cause adverse events such as life threatening cardiac arrhythmias (e.g., torsades de pointes [TdP]).
Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and zafirlukast are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as zafirlukast.
Sildenafil: (Moderate) Concomitant use of zafirlukast with sildenafil may increase sildenafil exposure. In vitro studies suggest zafirlukast inhibits CYP3A (weak) and CYP2C9 (moderate top potent). Sildenafil is cleared predominantly by CYP3A (major route) and CYP2C9 (minor route). Use caution and monitor patients for potential sildenafil-related side effects.
Silodosin: (Moderate) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. In theory, drugs that inhibit CYP3A4 such as zafirlukast may cause significant increases in silodosin plasma concentrations.
Simvastatin: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as simvastatin.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of zafirlukast. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and zafirlukast is a weak CYP3A inhibitor.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with zafirlukast. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Velpatasvir is a CYP3A4 substrate; zafirlukast is an inhibitor of CYP3A4.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with zafirlukast. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Velpatasvir is a CYP3A4 substrate; zafirlukast is an inhibitor of CYP3A4.
Solifenacin: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as solifenacin.
Suvorexant: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors and a maximum recommended dose of 10 mg/day. Zafirlukast is a moderate CYP3A4 inhibitor, and increased plasma concentrations of suvorexant are possible during concurrent use of these drugs.
Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP3A4 inhibitor such as zafirlukast. Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure; interactions with moderate CYP3A4 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
Telmisartan; Amlodipine: (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering zafirlukast. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP1A2, CYP2C8, CYP2C9, and CYP3A4; zafirlukast is an inhibitor of these enzymes. Monitor patients for adverse reactions if these drugs are coadministered.
Theophylline, Aminophylline: (Moderate) Increased theophylline levels with clinical signs and symptoms of toxicity after the addition of zafirlukast to an existing theophylline regimen have been reported. Monitor for signs and symptoms of toxicity, as well as serum aminophylline levels, when zafirlukast is used in combination with aminophylline. (Moderate) Increased theophylline levels with clinical signs and symptoms of toxicity after the addition of zafirlukast to an existing theophylline regimen have been reported. Monitor for signs and symptoms of toxicity, as well as serum theophylline levels, when zafirlukast is used in combination with theophylline.
Tolbutamide: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as tolbutamide.
Tolterodine: (Minor) Zafirlukast inhibits the CYP3A4 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as tolterodine.
Trandolapril; Verapamil: (Minor) Caution should be used when CYP3A4 inhibitors are co-administered with verapamil, a CYP3A4 substrate and inhibitor. This combination may cause reduced metabolism and increased effect of verapamil.
Triazolam: (Moderate) CYP3A4 inhibitors, such as zafirlukast, may reduce the metabolism of triazolam and increase the potential for benzodiazepine toxicity.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with zafirlukast. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; zafirlukast is a weak CYP3A4 inhibitor.
Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and zafirlukast is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
Valsartan: (Minor) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan.
Valsartan; Hydrochlorothiazide, HCTZ: (Minor) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP2C9 such as valsartan.
Verapamil: (Minor) Caution should be used when CYP3A4 inhibitors are co-administered with verapamil, a CYP3A4 substrate and inhibitor. This combination may cause reduced metabolism and increased effect of verapamil.
Vincristine Liposomal: (Major) Zafirlukast inhibits CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
Vincristine: (Major) Zafirlukast inhibits CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with zafirlukast is necessary. Vinorelbine is a CYP3A4 substrate and zafirlukast is a weak CYP3A4 inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Clarithromycin may decrease the bioavailability of zafirlukast. Be alert for decreased clinical response to zafirlukast when clarithromycin is added concurrently.
Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and zafirlukast. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with zafirlukast, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4 and CYP2C9, such as voriconazole.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with zafirlukast is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Zafirlukast is a weak CYP3A4/CYP2C9/CYP1A2 inhibitor and warfarin is a CYP3A4/CYP2C9/CYP1A2 substrate.

Accolate/Zafirlukast Oral Tab: 10mg, 20mg

Adults

40 mg/day PO.

Geriatric

40 mg/day PO.

Adolescents

40 mg/day PO.

Children

12 years: 40 mg/day PO.
5 to 11 years: 20 mg/day PO.
Less than 5 years: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Mechanism of Action: Zafirlukast is a potent, selective, and long-acting leukotriene receptor antagonist that exhibits antiinflammatory properties and mild bronchodilator effects. Zafirlukast selectively inhibits the binding of leukotriene types D4 (LTD4), and E4 (LTE4) and is 1000 to 10,000-fold more selective for leukotriene receptors (CysLT) than for alpha-receptors, beta-receptors, histamine receptors, or others. Leukotrienes are a group of arachidonic acid derivatives, created via the 5-lipoxygenase pathway, with the potential to mediate inflammatory events in asthma or other inflammatory diseases. The binding of cysteinyl leukotrienes to CysLT has been associated with asthma pathophysiology, including increased endothelial membrane permeability leading to airway edema, smooth muscle contraction, and enhanced secretion of thick, viscous mucus. When leukotriene receptors are blocked, there is a decrease in vascular leak and edema, mucus secretion, eosinophil chemotaxis and bronchial hyperresponsiveness. Blockage of the LTD4 receptors, in particular, results in bronchial relaxation. As monotherapy, zafirlukast appears to exhibit similar anti-inflammatory activity to cromolyn or nedocromil, but less than that of inhaled corticosteroids. The time to onset of zafirlukast-induced bronchodilator response is longer than that of beta-agonists and it is also less pronounced.In humans, zafirlukast inhibits inflammation and also inhibits bronchoconstriction mediated by various inhalational challenges, including: aspirin; cold-air; allergens like cat dander, ragweed and grass or mixed antigen exposures; sulfur dioxide; and exercise. In patients with asthma, the clinical outcomes (improvements in FEV1 or control of symptoms) resulting from the use of zafirlukast may exhibit large inter-patient variability.

Zafirlukast is administered orally and has also been studied as an inhalation. Systemically, protein-binding is greater than 99%. It is distributed to tissues to some degree; animal studies (rat) have demonstrated minimal distribution across the blood-brain-barrier. Zafirlukast is extensively metabolized; the hydroxylated metabolites are formed through the hepatic cytochrome P450 CYP2C9 isoenzyme. Hepatic impairment is expected to result in drug accumulation. Hydroxylated metabolites are excreted in the feces. Urinary excretion accounts for 10% of a dose, but the parent drug is not detected in the urine. The mean terminal elimination half-life in both normal controls and asthma patients is approximately 10 hours.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2C8, CYP2C9, CYP3A4
The significance of zafirlukast-mediated effects on cytochrome P450 isoenzymes is unclear. Zafirlukast has been shown in vitro to inhibit the activity of several hepatic cytochrome isoenzymes including CYP2C8 (potent inhibitor), CYP2C9 (moderate to potent inhibitor), and CYP3A4 (minor inhibitor) ; however, in vivo data do not substantiate clinically relevant interactions with 2C8 substrates. Pharmacokinetic alterations are reported when zafirlukast and known 2C9 and 3A4 substrates are used in combination. Furthermore, while in vitro and in vivo trial data are lacking, isolated reports of CYP1A2-metabolized medication toxicity following zafirlukast initiation have been published ; the mechanism of interaction is unknown. According to the manufacturer, zafirlukast is a substrate of the isoenzyme 2C9 in vitro. It should be used cautiously in patients stabilized on drugs metabolized by CYP1A2, CYP2C8, CYP2C9, and CYP3A4, particularly when such drugs have narrow therapeutic ranges, and in patients on medications that may affect CYP2C9 function.

Oral Route

Peak plasma concentrations of zafirlukast are observed within 3 hours after oral dosing. The absolute bioavailability of zafirlukast is unknown. Food reduces the bioavailability of zafirlukast by roughly 40% so it should be taken either 1 hour before or 2 hours after meals. In the treatment of asthma, the peak onset of action may be noted as soon as 1 day of therapy, and usually within 2 weeks. Pharmacodynamic studies showed protective effects of zafirlukast on inhaled LTD-4 for 12 to 24 hours after dosing.

Pregnancy

There are no adequate or controlled trials in pregnant women. Safe use during human pregnancy has not been established. Because animal studies are not always indicative of human response, use during pregnancy only if clearly needed. A risk-benefit assessment should be performed. No teratogenic effects were seen in cynomolgus monkeys at doses roughly 120 times the maximum recommended human daily dosage based on comparative drug AUCs. Higher dosages (roughly 410 times the maximum recommended human daily dosage) have resulted in maternal and/or fetal toxicity in this species. A no-effect dosage has not been established. The National Asthma Education and Prevention Program, Asthma and Pregnancy Working Group lists leukotriene receptor antagonists (LRTAs) as an alternative treatment option in the recommended stepwise management of asthma in pregnancy and lactation.

According to the manufacturer, zafirlukast is excreted into breast milk at concentrations equal to roughly 20% of maternal plasma levels. The manufacturer recommends against breast-feeding while on this medication. Nevertheless, the National Asthma Education and Prevention Program, Asthma and Pregnancy Working Group lists leukotriene receptor antagonists as an alternative treatment option in the recommended stepwise management of asthma in pregnancy and lactation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.