Tasigna

Browse PDR's full list of drug information

Tasigna

Classes

Small Molecule Antineoplastic Breakpoint Cluster Region-Abelson (BCR-ABL) Inhibitors

Administration

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

Oral Administration

Take nilotinib on an empty stomach; no food should be consumed for at least 1 hour after the dose is taken or for at least 2 hours before the dose is taken.
For twice daily dosing, separate doses by approximately 12 hours.
In pediatric patients, dose should be rounded to the nearest 50 mg dose (maximum single dose, 400 mg); different strength capsules may need to be combined to make the dose.
Do not drink grapefruit juice during treatment.
Take H2-blockers 10 hours before taking nilotinib or 2 hours after; separate the nilotinib dose from antacids by at least 2 hours.
If a dose is missed, take the next scheduled dose at the regular time; do not take 2 doses at the same time.

Oral Solid Formulations

Swallow capsules whole with water.

Extemporaneous Compounding-Oral

For patients unable to swallow capsules, capsule contents may be dispersed in 1 teaspoonful (5 mL) of applesauce.
Take the mixture immediately or within 15 minutes; do not store for future use.

Adverse Reactions
Severe

thrombocytopenia / Delayed / 10.0-42.0
neutropenia / Delayed / 12.0-42.0
anemia / Delayed / 4.0-27.0
hypophosphatemia / Delayed / 8.0-17.0
hyperbilirubinemia / Delayed / 4.0-16.0
hyperglycemia / Delayed / 6.0-12.0
pancytopenia / Delayed / 1.0-10.0
atrial flutter / Early / 1.0-10.0
eczema vaccinatum / Delayed / 1.0-10.0
exfoliative dermatitis / Delayed / 1.0-10.0
elevated hepatic enzymes / Delayed / 1.0-10.0
pancreatitis / Delayed / 1.0-10.0
hyperkalemia / Delayed / 1.0-10.0
ocular hemorrhage / Delayed / 1.0-10.0
hypokalemia / Delayed / 0-9.0
hyponatremia / Delayed / 0-7.0
GI bleeding / Delayed / 0-5.0
hypocalcemia / Delayed / 0-5.0
hypoalbuminemia / Delayed / 3.0-4.0
fluid retention / Delayed / 3.9-3.9
abdominal pain / Early / 0-3.0
diarrhea / Early / 1.0-3.0
headache / Early / 1.0-3.0
fatigue / Early / 0-3.0
nausea / Early / 0-2.0
hypertension / Early / 0-2.0
dyspnea / Early / 2.0-2.0
rash / Early / 0-2.0
back pain / Delayed / 0-2.0
arthralgia / Delayed / 0-2.0
myalgia / Early / 0-2.0
bone pain / Delayed / 0-2.0
fever / Early / 0-2.0
bleeding / Early / 0-1.8
vomiting / Early / 0-1.0
dyspepsia / Early / 0-1.0
anorexia / Delayed / 0-1.0
constipation / Delayed / 0-1.0
pulmonary edema / Early / 0.1-1.0
pleural effusion / Delayed / 0.1-1.0
pericardial effusion / Delayed / 0.1-1.0
peripheral edema / Delayed / 0-1.0
cyanosis / Early / 0.1-1.0
hypertensive crisis / Early / 0.1-1.0
myocardial infarction / Delayed / 0.1-1.0
heart failure / Delayed / 0.1-1.0
cough / Rapid / 0-1.0
pruritus / Rapid / 0-1.0
night sweats / Early / 0-1.0
angioedema / Rapid / 0-1.0
pharyngitis / Delayed / 0-1.0
infection / Delayed / 0-1.0
musculoskeletal pain / Early / 0-1.0
dizziness / Early / 0-1.0
stroke / Early / 0.1-1.0
intracranial bleeding / Delayed / 0.1-1.0
visual impairment / Early / 0.1-1.0
insomnia / Early / 1.0-1.0
asthenia / Delayed / 0-1.0
ascites / Delayed / 0-0.7
enterocolitis / Delayed / 0-0.1
peptic ulcer / Delayed / 0-0.1
GI perforation / Delayed / 0-0.1
hearing loss / Delayed / 0-0.1
pericarditis / Delayed / 0-0.1
thrombosis / Delayed / 0-0.1
pulmonary hypertension / Delayed / 0-0.1
skin atrophy / Delayed / 0-0.1
erythema nodosum / Delayed / 0-0.1
erythema multiforme / Delayed / 0-0.1
cerebral edema / Early / 0-0.1
optic neuritis / Delayed / 0-0.1
retroperitoneal bleeding / Delayed / 0-0.1
hematemesis / Delayed / 0-0.1
renal failure (unspecified) / Delayed / 0-0.1
papilledema / Delayed / 0-0.1
atrial fibrillation / Early / Incidence not known
bradycardia / Rapid / Incidence not known
AV block / Early / Incidence not known
thrombotic microangiopathy / Delayed / Incidence not known
alopecia / Delayed / Incidence not known
tumor lysis syndrome (TLS) / Delayed / Incidence not known

Moderate

leukopenia / Delayed / 1.0-54.0
lymphopenia / Delayed / 1.0-36.0
hypercholesterolemia / Delayed / 1.0-28.0
hypertriglyceridemia / Delayed / 1.0-12.0
eosinophilia / Delayed / 1.0-10.0
QT prolongation / Rapid / 1.0-10.0
chest pain (unspecified) / Early / 1.0-10.0
sinus tachycardia / Rapid / 1.0-10.0
dysphonia / Delayed / 1.0-10.0
erythema / Early / 1.0-10.0
flank pain / Delayed / 1.0-10.0
peripheral neuropathy / Delayed / 1.0-10.0
hyperamylasemia / Delayed / 1.0-10.0
diabetes mellitus / Delayed / 1.0-10.0
hypercalcemia / Delayed / 1.0-10.0
hyperphosphatemia / Delayed / 1.0-10.0
hypomagnesemia / Delayed / 1.0-10.0
hyperlipidemia / Delayed / 1.0-10.0
conjunctivitis / Delayed / 1.0-10.0
depression / Delayed / 1.0-10.0
growth inhibition / Delayed / 0-9.0
oral ulceration / Delayed / 0.1-1.0
stomatitis / Delayed / 0.1-1.0
gastritis / Delayed / 0.1-1.0
melena / Delayed / 0.1-1.0
hypothyroidism / Delayed / 0.1-1.0
hyperthyroidism / Delayed / 0.1-1.0
jaundice / Delayed / 0.1-1.0
hepatitis / Delayed / 0.1-1.0
candidiasis / Delayed / 0.1-1.0
hyperesthesia / Delayed / 0.1-1.0
migraine / Early / 0.1-1.0
hematoma / Early / 0.1-1.0
dysuria / Early / 0.1-1.0
gout / Delayed / 0.1-1.0
dehydration / Delayed / 0.1-1.0
conjunctival hyperemia / Early / 0-1.0
hyperemia / Delayed / 0.1-1.0
photopsia / Delayed / 0.1-1.0
blurred vision / Early / 0.1-1.0
impotence (erectile dysfunction) / Delayed / 0.1-1.0
thrombocytosis / Delayed / 0-0.1
esophagitis / Delayed / 0-0.1
hemorrhoids / Delayed / 0-0.1
hypotension / Rapid / 0-0.1
wheezing / Rapid / 0-0.1
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-0.1
skin ulcer / Delayed / 0-0.1
psoriasis / Delayed / 0-0.1
cholestasis / Delayed / 0-0.1
hepatomegaly / Delayed / 0-0.1
hypoglycemia / Early / 0-0.1
urinary incontinence / Early / 0-0.1
hematuria / Delayed / 0-0.1
hyperuricemia / Delayed / 0-0.1
photophobia / Early / 0-0.1
blepharitis / Early / 0-0.1
amnesia / Delayed / 0-0.1
dysphoria / Early / 0-0.1
confusion / Early / 0-0.1
edema / Delayed / Incidence not known
palpitations / Early / Incidence not known
angina / Early / Incidence not known

Mild

influenza / Delayed / 13.0-13.0
xerosis / Delayed / 12.0-12.0
dysgeusia / Early / 1.0-10.0
flatulence / Early / 1.0-10.0
vertigo / Early / 1.0-10.0
epistaxis / Delayed / 1.0-10.0
weight gain / Delayed / 1.0-10.0
weight loss / Delayed / 1.0-10.0
hyperhidrosis / Delayed / 1.0-10.0
acne vulgaris / Delayed / 1.0-10.0
flushing / Rapid / 1.0-10.0
urticaria / Rapid / 1.0-10.0
folliculitis / Delayed / 1.0-10.0
weakness / Early / 1.0-10.0
hypoesthesia / Delayed / 1.0-10.0
paresthesias / Delayed / 1.0-10.0
increased urinary frequency / Early / 1.0-10.0
xerophthalmia / Early / 1.0-10.0
ocular pruritus / Rapid / 1.0-10.0
anxiety / Delayed / 1.0-10.0
malaise / Early / 1.0-10.0
gastroesophageal reflux / Delayed / 0.1-1.0
xerostomia / Early / 0.1-1.0
throat irritation / Early / 0.1-1.0
ecchymosis / Delayed / 0.1-1.0
tremor / Early / 0.1-1.0
syncope / Early / 0.1-1.0
urinary urgency / Early / 0.1-1.0
nocturia / Early / 0.1-1.0
appetite stimulation / Delayed / 0.1-1.0
blepharedema / Early / 1.0-1.0
ocular irritation / Rapid / 0.1-1.0
gynecomastia / Delayed / 0.1-1.0
mastalgia / Delayed / 0.1-1.0
chills / Rapid / 0.1-1.0
leukocytosis / Delayed / 0-0.1
gingivitis / Delayed / 0-0.1
otalgia / Early / 0-0.1
tinnitus / Delayed / 0-0.1
skin hyperpigmentation / Delayed / 0-0.1
hyperkeratosis / Delayed / 0-0.1
photosensitivity / Delayed / 0-0.1
petechiae / Delayed / 0-0.1
skin discoloration / Delayed / 0-0.1
restless legs syndrome (RLS) / Delayed / 0-0.1
lethargy / Early / 0-0.1
dysesthesia / Delayed / 0-0.1
ocular pain / Early / 0-0.1
diplopia / Early / 0-0.1
menorrhagia / Delayed / 0-0.1

Boxed Warning
Angina, apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, geriatric, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, mortality, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

Concentration-dependent QT prolongation and prolonged cardiac ventricular repolarization possibly leading to sudden cardiac death and mortality have been reported with nilotinib use; QT prolongation increases the risk of torsade de pointes. Use nilotinib with caution in patients with a history of cardiac arrhythmias; patients with unstable angina and significant bradycardia were excluded from clinical trials. Nilotinib use is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Avoid concomitant use of nilotinib with other medication known to prolong the QT interval or that are strong CYP3A4 inhibitors as coadministration with these agents may increase the risk of a significantly prolonged QT interval. Evaluate electrolytes at baseline and monitor periodically during therapy. Correct electrolyte abnormalities prior to starting nilotinib. Obtain an electrocardiogram at baseline, after 7 days on therapy, after dose adjustments, and periodically as clinically indicated. Hold nilotinib therapy in patients who develop a QTc more than 480 milliseconds; a dosage adjustment and/or therapy discontinuation may be necessary. Use nilotinib with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Common Brand Names

Tasigna

Dea Class

Rx

Description

BCR-ABL tyrosine kinase inhibitor
Used in certain types of Philadelphia chromosome-positive chronic myelogenous leukemia
May cause QT prolongation; sudden death has been reported

Dosage And Indications
For the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).
NOTE: Nilotinib has been designated an orphan drug by the FDA for the treatment of CML.
For the treatment of chronic phase Ph+CML in patients resistant or intolerant to prior therapy that included imatinib. Oral dosage Adults

400 mg orally twice daily (approximately 12 hours apart) on an empty stomach. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Temporary interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Patients who have received nilotinib for a minimum of 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation. If nilotinib is discontinued, patients must be frequently monitored by a FDA-authorized test to detect possible loss of remission; re-initiation of therapy may be necessary. At a minimum follow-up of 24 months, treatment with nilotinib resulted in a major cytogenic response rate (primary end point) of 59% in patients with Ph+CML in a multicenter, single-arm trial (n = 321). Of the 126 patients with chronic phase Ph+CML who received nilotinib following prior imatinib therapy and entered the treatment-free remission (TFR) phase after achieving a sustained molecular response (MR4.5) during consolidation with nilotinib in an open-label, multicenter, single-arm trial (ENESTop trial; n = 163), 52 patients (41.3%) were still in TFR and 36 patients (28.6%) had remained continuously in MR4.5 at the time of the data cut-off (follow-up of 5 years). Of 59 patients who entered the treatment re-initiating phase after loss of MMR, 98.3% and 93.2% of these patients achieved a MMR and MR4.5, respectively. At data cut-off, 31 of 59 patients (52.5%) were still in the re-initiation phase. The 5-year progression-free survival and overall survival rates were both 95.9% in this study.

For the treatment of newly diagnosed chronic phase Ph+CML. Oral dosage Adults

300 mg orally twice daily (approximately 12 hours apart) on an empty stomach. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Temporary interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Patients who have received nilotinib for a minimum of 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation. If nilotinib is discontinued, patients must be frequently monitored by a FDA-authorized test to detect possible loss of remission; re-initiation of therapy may be necessary. The primary end point of major molecular response (MMR) rate at 12 months was significantly improved with nilotinib 300 mg twice daily (44%) and nilotinib 400 mg twice daily (43%) compared with imatinib 400 mg once daily (22%; p less than 0.001 for both comparisons) in patients with newly diagnosed chronic phase Ph+CML in a multicenter, randomized, phase 3 trial (the ENESTnd trial; n = 846). Additionally, the 12-month complete cytogenetic response rates were significantly higher for nilotinib (600 mg/day, 80%; 800 mg/day, 78%) compared with imatinib (65%; p less than 0.001 for both comparisons). At a minimum follow-up of 10 years, the overall cumulative MMR rate continued to be higher for nilotinib (600 mg/day, 77.7%; 800 mg/day, 80.1%) compared with imatinib (62.5%). The estimated 10-year progression-free survival rates were 86.2% (hazard ratio [HR] = 1.08; 95% CI, 0.67 to 1.74) and 89.9% (HR = 0.74; 95% CI, 0.44 to 1.25) in the nilotinib 600 mg/day and 800 mg/day arms, respectively, compared with the 87.2% in the imatinib arm. The estimated 10-year overall survival rates were 87.6% (HR = 1.07; 95% CI, 0.64 to 1.76) and 90.3% (HR = 0.79; 95% CI, 0.46 to 1.36) in the nilotinib 600 mg/day and 800 mg/day arms, respectively, compared with the 88.3% in the imatinib arm. Of the 190 patients with newly diagnosed chronic phase Ph+CML who entered the treatment-free remission (TFR) phase after achieving a MR4.5 during consolidation with nilotinib in an open-label, single-arm trial (the ENESTfreedom trial; n = 215), 79 patients (41.6%) continued to have at least a MMR and 76 patients (40%) remained in MR4.5 at the time of the 5-year data cut-off (median follow-up of 75.9 weeks; range, 7.6 to 303 weeks). Of 91 patients who entered the treatment re-initiating phase after loss of MMR, 98.9% and 92.3% of these patients achieved a MMR and MR4.5, respectively. At data cut-off, 44 of 91 patients (48.4%) were still in the re-initiation phase.

Adolescents and Children

230 mg/m2 orally twice daily (approximately 12 hours apart) on an empty stomach until disease progression or unacceptable toxicity. Round the dose to the nearest 50 mg to a maximum single dose of 400 mg. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Temporary interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. The cumulative major molecular response (MMR; defined as BCR-ABL/ABL of 0.1% IS or less) rate was 76% by cycle 66 in a cohort of pediatric patients aged 2 to less than 18 years with newly diagnosed chronic phase Ph+CML (n = 25) who received nilotinib therapy in an open-label, single-arm, multicenter trial. The median time to first MMR was 5.6 months (range, 2.7 to 16.6 months). Additionally, 44% of patients had a sustained molecular response (defined as a 4.5-log reduction in BCR-ABL transcripts or a BCR-ABL/ABL of 0.0032% IS or less) by cycle 66. At a median follow-up time of 51.9 months, 3 patients had a confirmed loss of MMR.

For the treatment of accelerated phase Ph+CML in patients resistant or intolerant to prior therapy that included imatinib. Oral dosage Adults

400 mg orally twice daily (approximately 12 hours apart) on an empty stomach. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Temporary interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. At a minimum follow-up of 24 months, treatment with nilotinib resulted in a hematologic response rate (primary end point) of 55% in patients with accelerated phase Ph+CML in a multicenter, single-arm trial (n = 137).

For the treatment of chronic phase Ph+CML or accelerated phase Ph+CML in patients resistant or intolerant to prior tyrosine-kinase inhibitor therapy. Oral dosage Adolescents and Children

230 mg/m2 orally twice daily (approximately 12 hours apart) on an empty stomach until disease progression or unacceptable toxicity. Round the dose to the nearest 50 mg to a maximum single dose of 400 mg. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Temporary interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. In a pooled analysis from 2 open-label, single-arm, multi-center studies, the cumulative major molecular response (MMR; defined as BCR-ABL/ABL of 0.1% IS or less) rate was 60.6% at the end of cycle 66 in pediatric patients aged 2 to less than 18 years with imatinib or dasatinib resistant or intolerant chronic phase Ph+CML (n = 44) who received nilotinib therapy. The median time to first MMR was 2.8 months (range, 0 to 11.3 months). Additionally, 12.1% of patients had a sustained molecular response (defined as a 4.5-log reduction in BCR-ABL transcripts or a BCR-ABL/ABL of 0.0032% IS or less) by cycle 66. At a median follow-up time of 60.5 months, no patient had experienced a confirmed loss of MMR and 1 patient progressed to accelerated/blast phase CML at 10.1 months from starting nilotinib treatment. Efficacy in pediatric patients 1 year of age or older with resistant or intolerant accelerated phase Ph+CML is based on data from an adequate and well-controlled single-arm study in adults and from safety data from 2 studies in pediatric patients with chronic phase Ph+CML.

Dosing Considerations
Hepatic Impairment

Baseline Hepatic Impairment (adults only)
Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML)
Any hepatic impairment: Initiate nilotinib at 200 mg PO twice daily. Escalate dosage to the recommended dosage of 300 mg twice daily based on individual patient tolerability.
Resistant or intolerant Ph+ CML
Mild or Moderate hepatic impairment (Child-Pugh class A or B): Initiate nilotinib at 300 mg PO twice daily. Escalate dosage to the recommended dosage of 400 mg twice daily based on individual patient tolerability.
Severe hepatic impairment (Child-Pugh class C): Initiate nilotinib at 200 mg PO twice daily. Escalate dosage to 300 mg twice daily and then to the recommended dosage of 400 mg twice daily based on individual patient tolerability.
 
Dosage Adjustments due to Treatment-Related Toxicity
Adults
Grade 3 or higher elevated bilirubin or transaminase levels: Hold nilotinib therapy. Once toxicity is resolved to grade 1 or less, resume nilotinib at 400 mg PO once daily.
Pediatric Patients
Grade 2 or higher elevated bilirubin level OR grade 3 or higher transaminase levels: Hold nilotinib therapy. Once toxicity is resolved to grade 1 or less, resume nilotinib at 230 mg/m2 PO once daily if previous dosage was nilotinib 230 mg/m2 PO twice daily. Discontinue therapy in pediatric patients who were receiving a previous dose of nilotinib 230 mg/m2 PO once daily and recovery to grade 1 or less takes longer than 28 days.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Drug Interactions

Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with nilotinib is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with nilotinib. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with nilotinib 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 nilotinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Nilotinib is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with nilotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nilotinib is a moderate inhibitor of CYP3A4.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of nilotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nilotinib 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 nilotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of nilotinib is necessary. If nilotinib 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 moderate inhibitor like nilotinib 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 nilotinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Major) Avoid the concomitant use of nilotinib and adagrasib due to the potential for increased nilotinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is required, reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. If adagrasib is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A, adagrasib is a strong inhibitor of CYP3A, and both medications have been associated with QT interval prolongation.
Alfentanil: (Major) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and alfentanil, a CYP3A4 substrate with a narrow therapeutic range, may result in increased alfentanil levels. Monitor for oversedation, respiratory depression, and hypotension. An alfentanil dose reduction may be necessary if these drugs are used together.
Alfuzosin: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as alfuzosin. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and alfuzosin is a substrate of CYP3A4; administering these drugs together may result in increased alfuzosin levels. If the use of alfuzosin is necessary, hold nilotinib therapy. If these drugs are used together, consider an alfuzosin dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Alprazolam: (Major) Avoid coadministration of alprazolam and nilotinib 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 nilotinib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
Aluminum Hydroxide: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Amiodarone: (Major) Avoid the concomitant use of nilotinib with amiodarone as significant prolongation of the QT interval may occur. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Sudden deaths and QT prolongation have been reported with nilotinib therapy. Both amiodarone and nilotinib are moderate inhibitors and substrates of CYP3A4; therefore, levels of either agent may be increased resulting in increased toxicity.
Amisulpride: (Major) Avoid the concomitant use of nilotinib and amisulpride; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Amisulpride causes dose- and concentration- dependent QT prolongation.
Amlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
Amlodipine; Atorvastatin: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required. (Moderate) Monitor for evidence of myopathy if atorvastatin is coadministered with nilotinib. Concurrent use may result in increased atorvastatin exposure. Nilotinib is a moderate CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate.
Amlodipine; Benazepril: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
Amlodipine; Celecoxib: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
Amlodipine; Olmesartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
Amlodipine; Valsartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the concomitant use of nilotinib and clarithromycin; significant prolongation of the QT interval and torsade de pointes (TdP) may occur. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Clarithromycin is associated with an established risk for QT prolongation and TdP. If therapy with clarithromycin is necessary, interrupt nilotinib therapy if possible. Monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in adult patients with resistant or intolerant Ph+ CML or to 200 mg once daily in adult patients with newly diagnosed Ph+ CML. If clarithromycin is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and clarithromycin is a strong inhibitor of CYP3A4. (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Amphotericin B lipid complex (ABLC): (Moderate) Administration of amphotericin B [lipid complex (ABLC), cholesteryl sulfate complex (ABCD), and liposomal (LAmB)] with antineoplastic agents may increase the potential for nephrotoxicity, bronchospasm, and hypotension. Amphotericin B-induced hypokalemia can result in interactions with other drugs.
Amphotericin B liposomal (LAmB): (Moderate) Administration of amphotericin B [lipid complex (ABLC), cholesteryl sulfate complex (ABCD), and liposomal (LAmB)] with antineoplastic agents may increase the potential for nephrotoxicity, bronchospasm, and hypotension. Amphotericin B-induced hypokalemia can result in interactions with other drugs.
Amphotericin B: (Moderate) Administration of amphotericin B [lipid complex (ABLC), cholesteryl sulfate complex (ABCD), and liposomal (LAmB)] with antineoplastic agents may increase the potential for nephrotoxicity, bronchospasm, and hypotension. Amphotericin B-induced hypokalemia can result in interactions with other drugs.
Anagrelide: (Major) Avoid the concomitant use of nilotinib with anagrelide as significant prolongation of the QT interval may occur. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Sudden deaths and QT prolongation have been reported with nilotinib therapy.
Antacids: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Apalutamide: (Major) Avoid the concomitant use of nilotinib and apalutamide; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and apalutamide is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Apomorphine: (Major) Avoid the concomitant use of nilotinib and other drugs with a known potential to prolong the QT interval such as apomorphine; significant prolongation of the QT interval may occur. Sudden death and QT interval prolongation have been reported in patients who received nilotinib therapy. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of nilotinib with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased nilotinib exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in nilotinib- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Nilotinib is a moderate 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. Nilotinib is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may additionally increase plasma concentrations of nilotinib. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) Avoid concomitant use aripiprazole and nilotinib, if possible, especially in patients with risk factors for torsade de pointes (TdP). If concomitant use is necessary, patients receiving both a CYP2D6 inhibitor plus nilotinib may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use increases the risk for QT/QTc prolongation and TdP and may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate, nilotinib is a moderate CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Arsenic Trioxide: (Major) Avoid the concomitant use of nilotinib and arsenic trioxide; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Torsade de pointes, QT prolongation, and complete atrioventricular block have occurred with arsenic trioxide use.
Artemether; Lumefantrine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as artemether; lumefantrine. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and artemether; lumefantrine is a substrate of CYP3A4; administering these drugs together may result in increased artemether; lumefantrine levels. If the use of artemether; lumefantrine is necessary, hold nilotinib therapy. If these drugs are used together, consider an artemether; lumefantrine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Asenapine: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as asenapine, is not advised; nilotinib prolongs the QT interval. Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as asenapine. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and asenapine is a substrate of CYP3A4; administering these drugs together may result in increased asenapine levels. If the use of asenapine is necessary, hold nilotinib therapy. If these drugs are used together, consider an asenapine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with nilotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nilotinib is a moderate inhibitor of CYP3A4.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Aspirin, ASA; Omeprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of nilotinib is necessary. If nilotinib 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 moderate inhibitor like nilotinib 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 nilotinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Avoid the concomitant use of nilotinib and atazanavir. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If atazanavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and atazanavir is a strong inhibitor of CYP3A4.
Atazanavir; Cobicistat: (Major) Avoid the concomitant use of nilotinib and atazanavir. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If atazanavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and atazanavir is a strong inhibitor of CYP3A4. (Major) Avoid the concomitant use of nilotinib and cobicistat. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If cobicistat is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and cobicistat is a substrate and a strong inhibitor of CYP3A4.
Atomoxetine: (Major) Concomitant use of atomoxetine and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Atorvastatin: (Moderate) Monitor for evidence of myopathy if atorvastatin is coadministered with nilotinib. Concurrent use may result in increased atorvastatin exposure. Nilotinib is a moderate CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate.
Atorvastatin; Ezetimibe: (Moderate) Monitor for evidence of myopathy if atorvastatin is coadministered with nilotinib. Concurrent use may result in increased atorvastatin exposure. Nilotinib is a moderate CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate.
Avapritinib: (Major) Avoid coadministration of avapritinib with nilotinib due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Azithromycin: (Major) Concomitant use of azithromycin and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bedaquiline: (Major) Avoid the concomitant use of nilotinib with bedaquiline as significant prolongation of the QT interval may occur. Bedaquiline has been reported to prolong the QT interval. Sudden deaths and QT prolongation have also been reported with nilotinib therapy.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with nilotinib 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 nilotinib 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 nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Nilotinib is an inhibitor of CYP3A4 and CYP2D6.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Nilotinib is a moderate inhibitor of CYP3A4. If nilotinib is used in combination with brexpiprazole and a moderate to strong CYP2D6 inhibitor, the brexpiprazole dose should be adjusted and the patient should be carefully monitored for brexpiprazole-related adverse reactions. A reduction of the brexpiprazole dose to 25% of the usual dose is also recommended in patients who are poor metabolizers of CYP2D6 and are receiving a moderate CYP3A4 inhibitor.
Brigatinib: (Major) Avoid coadministration of brigatinib with nilotinib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of nilotinib, resume the brigatinib dose that was tolerated prior to initiation of nilotinib. Brigatinib is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of nilotinib. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; nilotinib is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
Bupivacaine; Lidocaine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Systemic lidocaine has been established to have a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a moderate CYP3A4 inhibitor and lidocaine is a CYP3A4 substrate; administering these drugs together may result in increased lidocaine levels. If the use of lidocaine is required, hold nilotinib therapy. If the use of nilotinib and lidocaine cannot be avoided, a lidocaine dose reduction may be necessary; close monitoring of the QT interval is recommended.
Buprenorphine: (Major) Buprenorphine should be avoided in combination with nitlotinib. Nilotinib prolongs the QT interval; coadministration with a drug that prolongs the QT interval is not advised. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, the plasma concentrations of buprenorphine, a CYP3A4 substrate, may be increased when administered concurrently with nilotinib, a CYP3A4 inhibitor, further increasing the risk of toxicity. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Buprenorphine; Naloxone: (Major) Buprenorphine should be avoided in combination with nitlotinib. Nilotinib prolongs the QT interval; coadministration with a drug that prolongs the QT interval is not advised. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, the plasma concentrations of buprenorphine, a CYP3A4 substrate, may be increased when administered concurrently with nilotinib, a CYP3A4 inhibitor, further increasing the risk of toxicity. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
Buspirone: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and buspirone, a CYP3A4 substrate, may result in increased buspirone levels. A buspirone dose reduction may be necessary if these drugs are used together.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with nilotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nilotinib is a moderate inhibitor of CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with nilotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nilotinib is a moderate inhibitor of CYP3A4.
Cabotegravir; Rilpivirine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as rilpivirine. Nilotinib is a moderate inhibitor of CYP3A4 and rilpivirine is a substrate of CYP3A4; administering these drugs together may result in increased rilpivirine levels. If the use of rilpivirine is necessary, hold nilotinib therapy. If these drugs are used together, consider a rilpivirine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Calcium Carbonate: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose. (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Calcium Carbonate; Simethicone: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Calcium; Vitamin D: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Carbamazepine: (Major) Avoid the concomitant use of nilotinib and carbamazepine; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and carbamazepine is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Cariprazine: (Moderate) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4 and may reduce the hepatic metabolism of CYP3A4 substrates, although the impact of moderate CYP3A4 inhibitors on cariprazine metabolism has not been studied. Monitoring for adverse effects, such as CNS effects and extrapyramidal symptoms, is advisable during coadministration.
Celecoxib; Tramadol: (Major) The concomitant use of nilotinib and tramadol may reduce the clearance of tramadol and increase the risk for serious adverse events including seizures and serotonin syndrome. If coadministration of these drugs is required, consider reducing the dose of tramadol and monitor patients for signs of toxicity. Nilotinib is a moderate CYP3A4 inhibitor and tramadol is a CYP3A4 substrate.
Ceritinib: (Major) Avoid the concomitant use of nilotinib and ceritinib due to increased plasma concentrations of nilotinib which may result in QT prolongation. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. Periodically monitor electrolytes as well. If ceritinib is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and ceritinib is a strong inhibitor of CYP3A4. Concentration-dependent QT prolongation has been reported with ceritinib therapy. Sudden death and QT interval prolongation have occurred in patients who received nilotinib treatment.
Chloramphenicol: (Major) Avoid the concomitant use of nilotinib and chloramphenicol. If therapy with chloramphenicol is necessary, interrupt nilotinib therapy if possible. Monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If chloramphenicol is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and chloramphenicol is a strong inhibitor of CYP3A4.
Chloroquine: (Major) Avoid coadministration of chloroquine with nilotinib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with nilotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nilotinib is a moderate inhibitor of CYP3A4.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with nilotinib 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 nilotinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Nilotinib is a moderate 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 nilotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nilotinib 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 nilotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpromazine: (Major) Avoid the concomitant use of nilotinib and chlorpromazine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Chlorpromazine is associated with an established risk of QT prolongation and torsade de pointes.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cilostazol: (Moderate) Concomitant use of nilotinib, an moderate CYP3A4 inhibitor, and cilostazol, a CYP3A4 substrate, may result in increased cilostazol levels. A cilostazol dose reduction may be necessary if these drugs are used together.
Cimetidine: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
Ciprofloxacin: (Major) Concomitant use of ciprofloxacin and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) Nilotinib prolongs the QT interval. Because of the potential for torsade de pointes (TdP), use of cisapride with nilotinib is contraindicated.
Citalopram: (Major) Concomitant use of citalopram and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clarithromycin: (Major) Avoid the concomitant use of nilotinib and clarithromycin; significant prolongation of the QT interval and torsade de pointes (TdP) may occur. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Clarithromycin is associated with an established risk for QT prolongation and TdP. If therapy with clarithromycin is necessary, interrupt nilotinib therapy if possible. Monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in adult patients with resistant or intolerant Ph+ CML or to 200 mg once daily in adult patients with newly diagnosed Ph+ CML. If clarithromycin is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and clarithromycin is a strong inhibitor of CYP3A4.
Clofazimine: (Major) Concomitant use of clofazimine and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clonazepam: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and clonazepam, a CYP3A4 substrate, may result in increased clonazepam levels. A clonazepam dose reduction may be necessary if these drugs are used together.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. In addition, coadministration of clozapine and nilotinib may result in increased risk of QT prolongation.
Cobicistat: (Major) Avoid the concomitant use of nilotinib and cobicistat. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If cobicistat is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and cobicistat is a substrate and a strong inhibitor of CYP3A4.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with nilotinib due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate and nilotinib is a moderate inhibitor of CYP3A. 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.
Codeine: (Moderate) Concomitant use of codeine with nilotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nilotinib is a moderate inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with nilotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nilotinib is a moderate inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with nilotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nilotinib is a moderate inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with nilotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nilotinib is a moderate inhibitor of CYP3A4. (Moderate) Concomitant use of promethazine and nilotinib may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with nilotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nilotinib is a moderate inhibitor of CYP3A4. (Moderate) Concomitant use of promethazine and nilotinib may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Conside

r taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Colchicine: (Major) Avoid concomitant use of colchicine and nilotinib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Crizotinib: (Major) Avoid coadministration of crizotinib with nilotinib due to the risk of QT prolongation; exposure to crizotinib may also increase. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy; nilotinib is also a moderate CYP3A4 inhibitor. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation.
Cyclosporine: (Major) Concomitant use of nilotinib, a substrate and inhibitor of CYP3A4, and cyclosporine, a CYP3A4 substrate and inhibitor with a narrow therapeutic range, may result in increased nilotinib and/or cyclosporine levels. A dose reduction of either agent may be necessary if these drugs are used together; monitor patients for nilotinib and cyclosporine toxicity (e.g., cyclosporine concentrations to help avoid graft failure or drug-related toxicity and QT interval prolongation).
Danazol: (Moderate) Concomitant use of nilotinib, a substrate and moderate CYP3A4 inhibitor, and danazol, 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.
Dapsone: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and dapsone, a CYP3A4 substrate, may result in increased dapsone levels. A dapsone dose reduction may be necessary if these drugs are used together.
Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with nilotinib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Darunavir: (Major) Avoid the concomitant use of nilotinib and darunavir; increased plasma concentrations of either drug may occur. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If darunavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and darunavir is a sensitive substrate and strong inhibitor of CYP3A4.
Darunavir; Cobicistat: (Major) Avoid the concomitant use of nilotinib and cobicistat. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If cobicistat is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and cobicistat is a substrate and a strong inhibitor of CYP3A4. (Major) Avoid the concomitant use of nilotinib and darunavir; increased plasma concentrations of either drug may occur. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If darunavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and darunavir is a sensitive substrate and strong inhibitor of CYP3A4.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid the concomitant use of nilotinib and cobicistat. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If cobicistat is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and cobicistat is a substrate and a strong inhibitor of CYP3A4. (Major) Avoid the concomitant use of nilotinib and darunavir; increased plasma concentrations of either drug may occur. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If darunavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and darunavir is a sensitive substrate and strong inhibitor of CYP3A4.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with nilotinib. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; nilotinib is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Degarelix: (Major) Avoid the concomitant use of nilotinib and degarelix; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval.
Delavirdine: (Major) Avoid the concomitant use of nilotinib and delavirdine. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If delavirdine is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and delavirdine is a strong inhibitor of CYP3A4.
Desflurane: (Major) Avoid the concomitant use of nilotinib and halogenated anesthetics; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, fatal cases of torsade de pointes have been reported with halogenated anesthetic use.
Deutetrabenazine: (Major) Avoid administration of nilotinib with other drugs with a known potential to prolong the QT interval. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexlansoprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Quinidine: (Major) Avoid coadministration of nilotinib with quinidine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of quinidine may be increased resulting in an increase in quinidine-related adverse reactions. Nilotinib is a moderate CYP3A4 inhibitor. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Quinidine is a CYP3A4 substrate that has also been associated with QT prolongation and torsade de pointes (TdP).
Dienogest; Estradiol valerate: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with nilotinib is necessary; also monitor for nilotinib-related side effects. Nilotinib and diltiazem are both substrates of and inhibitors of CYP3A4. Elevations of diltiazem plasma levels resulting in clinically significant interactions have been reported with other moderate CYP3A4 inhibitors. Increased nilotinib concentrations may increase the risk for treatment-related side effects.
Disopyramide: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Disopyramide has been established to have a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and disopyramide is a substrate of CYP3A4; administering these drugs together may result in increased disopyramide levels. If the use of disopyramide is necessary, hold nilotinib therapy. If these drugs are used together, consider a disopyramide dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Docetaxel: (Major) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and docetaxel, a CYP3A4 substrate, may result in increased docetaxel levels. A docetaxel dose reduction may be necessary if these drugs are used together.
Dofetilide: (Major) Coadministration of dofetilide and nilotinib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Dolasetron: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as dolasetron. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Dolasetron has also been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals. Concomitant use may increase the risk for QT prolongation.
Dolutegravir; Rilpivirine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as rilpivirine. Nilotinib is a moderate inhibitor of CYP3A4 and rilpivirine is a substrate of CYP3A4; administering these drugs together may result in increased rilpivirine levels. If the use of rilpivirine is necessary, hold nilotinib therapy. If these drugs are used together, consider a rilpivirine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Donepezil: (Major) Avoid coadministration of nilotinib with donepezil due to an increased risk for QT prolongation and torsade de pointes (TdP). Donepezil has been associated with QT prolongation and TdP in case reports. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Donepezil; Memantine: (Major) Avoid coadministration of nilotinib with donepezil due to an increased risk for QT prolongation and torsade de pointes (TdP). Donepezil has been associated with QT prolongation and TdP in case reports. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Doxorubicin Liposomal: (Major) Avoid coadministration of nilotinib with doxorubicin due to the risk of increased doxorubicin exposure. Nilotinib is a moderate CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4; clinically significant interactions have been reported with other CYP3A4 inhibitors, resulting in increased concentration and clinical effect of doxorubicin.
Doxorubicin: (Major) Avoid coadministration of nilotinib with doxorubicin due to the risk of increased doxorubicin exposure. Nilotinib is a moderate CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4; clinically significant interactions have been reported with other CYP3A4 inhibitors, resulting in increased concentration and clinical effect of doxorubicin.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with nilotinib 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; nilotinib is a moderate inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Contraindicated) Concomitant use of dronedarone and nilotinib is contraindicated. Nilotinib prolongs the QT interval. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Avoid coadministration of nilotinib with droperidol due to an increased risk for QT prolongation and torsade de pointes (TdP). Droperidol administration is associated with an established risk for QT prolongation and TdP. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Drospirenone; Estradiol: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
Duvelisib: (Moderate) Monitor for increased toxicity of duvelisib if coadministered with nilotinib. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; nilotinib is a moderate CYP3A inhibitor.
Efavirenz: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as efavirenz, is not advised; nilotinib prolongs the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. In addition, concomitant use of nilotinib, a substrate and an inhibitor of CYP3A4, and efavirenz, a substrate and inducer of CYP3A4, may result in decreased nilotinib plasma concentrations and/or increased efavirenz concentrations. Selecting an alternate agent with less potential for CYP3A4 induction should be considered. Closely monitor patients if these drugs are used together; increasing the nilotinib dosage will most likely not account for the loss of exposure based on the nonlinear pharmacokinetics of nilotinib.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as efavirenz, is not advised; nilotinib prolongs the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. In addition, concomitant use of nilotinib, a substrate and an inhibitor of CYP3A4, and efavirenz, a substrate and inducer of CYP3A4, may result in decreased nilotinib plasma concentrations and/or increased efavirenz concentrations. Selecting an alternate agent with less potential for CYP3A4 induction should be considered. Closely monitor patients if these drugs are used together; increasing the nilotinib dosage will most likely not account for the loss of exposure based on the nonlinear pharmacokinetics of nilotinib.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as efavirenz, is not advised; nilotinib prolongs the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. In addition, concomitant use of nilotinib, a substrate and an inhibitor of CYP3A4, and efavirenz, a substrate and inducer of CYP3A4, may result in decreased nilotinib plasma concentrations and/or increased efavirenz concentrations. Selecting an alternate agent with less potential for CYP3A4 induction should be considered. Closely monitor patients if these drugs are used together; increasing the nilotinib dosage will most likely not account for the loss of exposure based on the nonlinear pharmacokinetics of nilotinib.
Elacestrant: (Major) Avoid concomitant use of elacestrant and nilotinib due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased elacestrant overall exposure by 2.3-fold.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with nilotinib may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nilotinib is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with nilotinib. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4, and nilotinib is a moderate CYP3A4 inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with nilotinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); nilotinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If nilotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to every other day in the morning when coadministered with nilotinib; omit the ivacaftor evening dose and administer in the morning every other day alternating with elexacaftor; tezacaftor; ivacaftor (i.e., recommended dose of elexacaftor; tezacaftor; ivacaftor on day 1 in the morning and recommended dose of ivacaftor on day 2 in the morning). Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; nilotinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 2.9-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2.1-fold, respectively.
Eliglustat: (Major) Avoid the concomitant use of nilotinib and eliglustat; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid the concomitant use of nilotinib and cobicistat. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If cobicistat is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and cobicistat is a substrate and a strong inhibitor of CYP3A4.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of nilotinib and cobicistat. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If cobicistat is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and cobicistat is a substrate and a strong inhibitor of CYP3A4.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as rilpivirine. Nilotinib is a moderate inhibitor of CYP3A4 and rilpivirine is a substrate of CYP3A4; administering these drugs together may result in increased rilpivirine levels. If the use of rilpivirine is necessary, hold nilotinib therapy. If these drugs are used together, consider a rilpivirine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as rilpivirine. Nilotinib is a moderate inhibitor of CYP3A4 and rilpivirine is a substrate of CYP3A4; administering these drugs together may result in increased rilpivirine levels. If the use of rilpivirine is necessary, hold nilotinib therapy. If these drugs are used together, consider a rilpivirine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Encorafenib: (Major) Avoid coadministration of encorafenib and nilotinib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of nilotinib. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If nilotinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of nilotinib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Entrectinib: (Major) Avoid coadministration of entrectinib with nilotinib due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If nilotinib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of nilotinib. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; nilotinib is a moderate CYP3A4 inhibitor that has been associated with sudden death and QT interval prolongation. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
Enzalutamide: (Major) Avoid the concomitant use of nilotinib and enzalutamide; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and enzalutamide is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Nilotinib is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Ergot alkaloids: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and ergot alkaloids (e.g., ergotamine, dihydroergotamine), CYP3A4 substrates with a narrow therapeutic range, may result in increased ergot alkaloid levels. Avoid co-use when possible; consider alternative therapy to the ergot medication. Be alert for symptoms of ergot toxicity if these drugs together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together.
Eribulin: (Major) Avoid the concomitant use of nilotinib and eribulin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, QT prolongation has occurred with eribulin use.
Erlotinib: (Moderate) Use caution if coadministration of erlotinib with nilotinib is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both nilotinib and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Nilotinib is a moderate CYP3A4 inhibitor in vitro. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with nilotinib may also increase erlotinib exposure.
Erythromycin: (Major) Concomitant use of nilotinib and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Escitalopram: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as escitalopram. Nilotinib is a moderate inhibitor of CYP3A4 and escitalopram is a substrate of CYP3A4; administering these drugs together may result in increased escitalopram levels. If the use of escitalopram is necessary, hold nilotinib therapy. If these drugs are used together, consider an escitalopram dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Esomeprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Estazolam: (Major) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and estazolam, a CYP3A4 substrate, may result in increased estazolam levels. A estazolam dose reduction may be necessary if these drugs are used together.
Estradiol: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
Estradiol; Levonorgestrel: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
Estradiol; Norethindrone: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
Estradiol; Norgestimate: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
Estradiol; Progesterone: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
Ethosuximide: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and ethosuximide, a CYP3A4 substrate, may result in increased ethosuximide levels. A ethosuximide dose reduction may be necessary if these drugs are used together.
Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as nilotinib may increase the serum concentration of etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as nilotinib may increase the serum concentration of etonogestrel.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with nilotinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Nilotinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
Famotidine: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of nilotinib is necessary. If nilotinib 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 nilotinib 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 nilotinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finasteride; Tadalafil: (Moderate) Concomitant use of nilotinib, an moderate CYP3A4 inhibitor, and tadalafil, a CYP3A4 substrate, may result in increased tadalafil levels. A tadalafil dose reduction may be necessary if these drugs are used together.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or nilotinib; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
Fingolimod: (Major) Avoid the concomitant use of nilotinib and fingolimod; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Concomitant use of flecainide and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as nilotinib, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
Fluconazole: (Contraindicated) Due to the risk of life-threatening arrhythmias such as torsade de pointes (TdP), coadministration of fluconazole with drugs that both prolong the QT interval and are CYP3A4 substrates, like nilotinib, is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additonally, fluconazole is an inhibitor of CYP3A4. Coadministration may result in elevated plasma concentrations of nilotinib, causing an increased risk for adverse events such as QT prolongation.
Fluoxetine: (Major) Concomitant use of nilotinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluphenazine: (Minor) QT interval prolongation may be additive if nilotinib and fluphenazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Flurazepam: (Major) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and flurazepam, a CYP3A4 substrate, may result in increased flurazepam levels. A flurazepam dose reduction may be necessary if these drugs are used together.
Fluvoxamine: (Major) Avoid administration of nilotinib with other drugs with a known potential to prolong the QT interval, such as fluvoxamine. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. QT prolongation and torsade de pointes (TdP) have been reported during fluvoxamine post-marketing use.
Food: (Contraindicated) Do not administer Nilotinib with food. Nilotinib needs to be taken at least 1 hour before a meal or 2 hours after a meal. Food increases the bioavailability of nilotinib. Increased nilotinib serum concentrations may occur if the drug is taken with food, possibly resulting in QT porlongation, palpitations, torsade de pointes (TdP) and/or myelotoxicity.
Fosamprenavir: (Moderate) Monitor for increased fosamprenavir toxicity if coadministered with nilotinib. Concurrent use may increase the plasma concentrations of fosamprenavir. Fosamprenavir is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor.
Foscarnet: (Major) Avoid the concomitant use of nilotinib and foscarnet; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes.
Fosphenytoin: (Major) Avoid the concomitant use of nilotinib and fosphenytoin; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and fosphenytoin is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Fostemsavir: (Major) Avoid administration of nilotinib with other drugs with a known potential to prolong the QT interval. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Major) Avoid the concomitant use of nilotinib and gemifloxacin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Avoid the concomitant use of nilotinib and gemtuzumab ozogamicin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin.
Gilteritinib: (Major) Avoid concomitant use of nilotinib with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Glasdegib: (Major) Avoid administration of nilotinib with glasdegib due to the potential for additive QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
Goserelin: (Major) Avoid administration of nilotinib with goserelin due to the risk of QT interval prolongation. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
Granisetron: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as granisetron. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and granisetron is a substrate of CYP3A4; administering these drugs together may result in increased granisetron levels. If the use of granisetron is necessary, hold nilotinib therapy. If these drugs are used together, consider a granisetron dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Grapefruit juice: (Major) Avoid the use of nilotinib with grapefruit, grapefruit juice, or grapefruit products. The AUC value of nilotinib increased by 1.3-fold when nilotinib was administered with a single intake of double-strength grapefruit juice.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of nilotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nilotinib 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 nilotinib 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.
Guanfacine: (Major) Nilotinib may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon nilotinib discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and nilotinib is a moderate CYP3A4 inhibitor.
H2-blockers: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
Halogenated Anesthetics: (Major) Avoid the concomitant use of nilotinib and halogenated anesthetics; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, fatal cases of torsade de pointes have been reported with halogenated anesthetic use.
Haloperidol: (Major) Avoid administration of nilotinib with other drugs with a known potential to prolong the QT interval, such as haloperidol. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Major) Avoid administration of nilotinib with histrelin due to the risk of QT interval prolongation. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of nilotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nilotinib 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 nilotinib 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 nilotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nilotinib 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 nilotinib 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 nilotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nilotinib 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 nilotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of nilotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like nilotinib 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 nilotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydroxychloroquine: (Major) Concomitant use of nilotinib and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of nilotinib and hydroxyzine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ibrutinib: (Major) If ibrutinib is coadministered with nilotinib, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if nilotinib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Ibuprofen; Famotidine: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of nilotinib is necessary. If nilotinib 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 moderate inhibitor like nilotinib 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 nilotinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ibutilide: (Major) Avoid the concomitant use of nilotinib and ibutilide; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Ibutilide administration can cause QT prolongation and torsades de pointes; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Idelalisib: (Major) Avoid the concomitant use of nilotinib and idelalisib. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If idelalisib is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and idelalisib is a strong inhibitor of CYP3A4.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with nilotinib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Nilotinib is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Avoid the concomitant use of nilotinib and iloperidone; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, iloperidone has been associated with QT prolongation.
Imatinib: (Major) The concomitant use of nilotinib and imatinib resulted in increased levels of both drugs in a phase I study. Both nilotinib and imatinib are a substrates and moderate inhibitors of CYP3A4. Following the administration of nilotinib 400 mg twice daily in combination with imatinib 400 mg once daily or imatinib 400 mg twice daily in a phase I study, the AUC values were increased by 30 to 50% for nilotinib and by about 20% for imatinib. These agents may be used together; monitor patients for nilotinib or imatinib toxicity including QT interval prolongation.
Indinavir: (Major) Avoid the concomitant use of nilotinib and indinavir; increased plasma concentrations of either drug may occur. If coadministration is required, reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. Additionally, monitor patients closely for prolongation of the QT interval and for adverse reactions associated with nilotinib or indinavir. If indinavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and indinavir is a sensitive substrate and strong inhibitor of CYP3A4.
Infigratinib: (Major) Avoid concomitant use of infigratinib and nilotinib. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with nilotinib due to the potential for additive QT prolongation and risk of torsade de pointes. If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment; closely monitor for evidence of QT prolongation during concurrent use. Inotuzumab has been associated with QT interval prolongation. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy.
Isoflurane: (Major) Avoid the concomitant use of nilotinib and halogenated anesthetics; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, fatal cases of torsade de pointes have been reported with halogenated anesthetic use.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of nilotinib and rifampin; significantly decreased nilotinib exposure was observed in a drug interaction study. Coadministration of these drugs may lead to reduced nilotinib efficacy. Nilotinib is a CYPA4 substrate and rifampin is a strong CYP3A4 inducer. In a drug interaction study, the AUC value of nilotinib was decreased by about 80% following the addition of rifampicin/rifampin 600 mg once daily for 12 days.
Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of nilotinib and rifampin; significantly decreased nilotinib exposure was observed in a drug interaction study. Coadministration of these drugs may lead to reduced nilotinib efficacy. Nilotinib is a CYPA4 substrate and rifampin is a strong CYP3A4 inducer. In a drug interaction study, the AUC value of nilotinib was decreased by about 80% following the addition of rifampicin/rifampin 600 mg once daily for 12 days.
Itraconazole: (Major) Avoid nilotinib use during and for 2 weeks after discontinuation of itraconazole. If use of itraconazole is necessary, hold nilotinib therapy. Consider a nilotinib dose reduction (to nilotinib 200 mg PO once daily in adult patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in adult patients with resistant or intolerant Ph+ CML); close monitoring of the QT interval is recommended. If itraconazole is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period. Taking these drugs together may increase concentrations of nilotinib and itraconazole and could result in additive effects on the QT interval. Nilotinib is a substrate and moderate inhibitor of CYP3A4. Itraconazole is a substrate and strong inhibitor of CYP3A4.
Ivabradine: (Major) Avoid coadministration of ivabradine and nilotinib as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; nilotinib inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
Ivacaftor: (Major) If nilotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with nilotinib due to increased plasma concentrations of ivosidenib and QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of nilotinib is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor.
Ketoconazole: (Major) Avoid the concomitant use of nilotinib and ketoconazole due to the potential for additive effects on the QT interval and increased exposure to nilotinib; ketoconazole concentrations may also be increased. Nilotinib is a substrate and moderate inhibitor of CYP3A4. Ketoconazole is a substrate and strong inhibitor of CYP3A4. If the use of a strong CYP3A4 inhibitor like ketoconazole is necessary, hold nilotinib therap y. If the use of nilotinib and ketoconazole cannot be avoided, consider a nilotinib dose reduction (to nilotinib 200 mg PO once daily in adult patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in adult patients with resistant or intolerant Ph+ CML); close monitoring of the QT interval is recommended. If ketoconazole is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period. Concurrent use of nilotinib and ketoconazole 400 mg once daily for 6 days led to an approximate 3-fold increase in the nilotinib AUC.
Lansoprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid the concomitant use of nilotinib and clarithromycin; significant prolongation of the QT interval and torsade de pointes (TdP) may occur. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Clarithromycin is associated with an established risk for QT prolongation and TdP. If therapy with clarithromycin is necessary, interrupt nilotinib therapy if possible. Monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in adult patients with resistant or intolerant Ph+ CML or to 200 mg once daily in adult patients with newly diagnosed Ph+ CML. If clarithromycin is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and clarithromycin is a strong inhibitor of CYP3A4. (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Lapatinib: (Major) Avoid administration of nilotinib with lapatinib due to the risk of QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
Larotrectinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with nilotinib is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Lefamulin: (Major) Avoid coadministration of lefamulin with nilotinib as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Nilotinib is a moderate CYP3A4 inhibitor that has been associated with sudden death and QT interval prolongation in patients who received therapy.
Lemborexant: (Major) Avoid coadministration of lemborexant and nilotinib as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with nilotinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Letermovir: (Moderate) Coadministration of letermovir and nilotinib may increase nilotinib exposure. Avoid this combination if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. If the use of letermovir with cyclosporine is necessary, interrupt nilotinib therapy. If the use of nilotinib with letermovir and cyclosporine cannot be avoided, consider a nilotinib dose reduction (to nilotinib 200 mg PO once daily in adult patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in adult patients with resistant or intolerant Ph+ CML); close monitoring of the QT interval is recommended. If letermovir with cyclosporine is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period. Nilotinib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide: (Major) Avoid administration of nilotinib with leuprolide due to the risk of QT interval prolongation. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Avoid administration of nilotinib with leuprolide due to the risk of QT interval prolongation. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Levamlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
Levofloxacin: (Major) Concomitant use of levofloxacin and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Major) Avoid the concomitant use of nilotinib and ketoconazole due to the potential for additive effects on the QT interval and increased exposure to nilotinib; ketoconazole concentrations may also be increased. Nilotinib is a substrate and moderate inhibitor of CYP3A4. Ketoconazole is a substrate and strong inhibitor of CYP3A4. If the use of a strong CYP3A4 inhibitor like ketoconazole is necessary, hold nilotinib therapy. If the use of nilotinib and ketoconazole cannot be avoided, consider a nilotinib dose reduction (to nilotinib 200 mg PO once daily in adult patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in adult patients with resistant or intolerant Ph+ CML); close monitoring of the QT interval is recommended. If ketoconazole is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period. Concurrent use of nilotinib and ketoconazole 400 mg once daily for 6 days led to an approximate 3-fold increase in the nilotinib AUC.
Lidocaine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Systemic lidocaine has been established to have a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a moderate CYP3A4 inhibitor and lidocaine is a CYP3A4 substrate; administering these drugs together may result in increased lidocaine levels. If the use of lidocaine is required, hold nilotinib therapy. If the use of nilotinib and lidocaine cannot be avoided, a lidocaine dose reduction may be necessary; close monitoring of the QT interval is recommended.
Lidocaine; Epinephrine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Systemic lidocaine has been established to have a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a moderate CYP3A4 inhibitor and lidocaine is a CYP3A4 substrate; administering these drugs together may result in increased lidocaine levels. If the use of lidocaine is required, hold nilotinib therapy. If the use of nilotinib and lidocaine cannot be avoided, a lidocaine dose reduction may be necessary; close monitoring of the QT interval is recommended.
Lidocaine; Prilocaine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Systemic lidocaine has been established to have a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a moderate CYP3A4 inhibitor and lidocaine is a CYP3A4 substrate; administering these drugs together may result in increased lidocaine levels. If the use of lidocaine is required, hold nilotinib therapy. If the use of nilotinib and lidocaine cannot be avoided, a lidocaine dose reduction may be necessary; close monitoring of the QT interval is recommended.
Lithium: (Major) Concomitant use of lithium and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Lofexidine: (Major) Avoid the concomitant use of nilotinib and lofexidine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes.
Lomitapide: (Contraindicated) Concomitant use of nilotinib and lomitapide is contraindicated due to increased lomitapide exposure. If treatment with nilotinib is unavoidable, lomitapide should be stopped during the course of treatment. Lomitapide is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Although concomitant use of moderate CYP3A4 inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use based on the 27-fold increase in exposure observed with coadministration of a strong CYP3A4 inhibitor.
Lonafarnib: (Contraindicated) Concomitant use of lonafarnib and nilotinib is contraindicated and may increase the exposure and risk of adverse effects from both drugs. If concomitant use is necessary, reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML and monitor closely for QT prolongation. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; nilotinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor.
Loperamide: (Major) Loperamide should be avoided in combination with nilotinib. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Nilotinib also prolongs the QT interval and the manufacturer advises against use with other drugs that prolong the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation.
Loperamide; Simethicone: (Major) Loperamide should be avoided in combination with nilotinib. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Nilotinib also prolongs the QT interval and the manufacturer advises against use with other drugs that prolong the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with nilotinib due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. (Major) Avoid the concomitant use of nilotinib and ritonavir. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If ritonavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and ritonavir is a substrate and a strong inhibitor of CYP3A4.
Lovastatin: (Moderate) Concomitant use of nilotinib and lovastatin may result in increased lovastatin levels. A lovastatin dose reduction may be necessary if these drugs are used together. Be alert for symptoms of statin-induced myopathy. Lovastatin is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor.
Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of nilotinib and lumacaftor; ivacaftor because significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%. (Major) If nilotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of nilotinib and lumacaftor; ivacaftor because significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use of nilotinib is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased lumateperone exposure by approximately 2-fold.
Lurasidone: (Major) Nilotinib is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of these medications may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and nilotinib due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as nilotinib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Nilotinib also prolongs the QT interval.
Magnesium Hydroxide: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Maprotiline: (Major) Avoid the concomitant use of nilotinib and maprotiline; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
Mavacamten: (Major) Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting nilotinib therapy. Avoid initiation of nilotinib in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable nilotinib therapy. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a moderate CYP3A inhibitor increased mavacamten overall exposure by 15% in CYP2C19 normal and intermediate metabolizers; concomitant use in poor metabolizers is predicted to increase mavacamten exposure by up to 55%.
Mefloquine: (Major) Avoid the concomitant use of nilotinib with mefloquine due to an increased risk for QT prolongation. Systemic exposure of mefloquine may also be increased resulting in increase in treatment-related adverse reactions. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Mefloquine is a CYP3A4 substrate. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
Methadone: (Major) Avoid coadministration of nilotinib with methadone due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of methadone may also be increased resulting in an increase in methadone-related adverse reactions including respiratory depression and sedation. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Methadone is a CYP3A4 substrate that has also been associated with an increased risk of QT prolongation and TdP, especially at higher doses (greater than 200 mg per day but averaging approximately 400 mg per day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
Metronidazole: (Major) Concomitant use of metronidazole and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midazolam: (Major) The concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and midazolam, a CYP3A4 substrate, resulted in a 2.6-fold increase in the systemic midazolam exposure in patients with chronic myelogenous leukemia. Consider a midazolam dose reduction if these drugs are used together.
Midostaurin: (Major) Avoid the concomitant use of nilotinib and midostaurin; significant prolongation of the QT interval may occur. If concomitant use is required, consider ECG monitoring. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
Mifepristone: (Major) Avoid the concomitant use of nilotinib and mifepristone; significant prolongation of the QT interval may occur. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Mifepristone has been associated with dose-dependent prolongation of the QT interval. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. If coadministration is required, monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in adult patients with resistant or intolerant Ph+ CML or to 200 mg once daily in adult patients with newly diagnosed Ph+ CML. If mifepristone is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and mifepristone is a strong inhibitor of CYP3A4.
Mirtazapine: (Major) Concomitant use of nilotinib and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with nilotinib and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold.
Mitotane: (Major) Avoid the concomitant use of nilotinib and mitotane; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYP3A substrate and mitotane is a strong CYP3A inducer. In a drug interaction study, coadministration with another strong CYP3A inducer decreased nilotinib exposure by approximately 80%.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and nilotinib; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase mobocertinib exposure and the risk for mobocertinib-related adverse reactions. Mobocertinib is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
Moxifloxacin: (Major) Avoid the concomitant use of nilotinib and moxifloxacin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including torsade de pointes, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with nilotinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor.
Naloxegol: (Major) Avoid concomitant administration of naloxegol and nilotinib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with nilotinib is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of nilotinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor.
Naproxen; Esomeprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Nefazodone: (Major) Avoid the concomitant use of nilotinib and nefazodone. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If nefazodone is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and nefazodone is a strong inhibitor of CYP3A4.
Nelfinavir: (Major) Avoid the concomitant use of nilotinib and nelfinavir. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If nelfinavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and nelfinavir is a strong inhibitor of CYP3A4.
Neratinib: (Major) Avoid concomitant use of nilotinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
Nirmatrelvir; Ritonavir: (Major) Avoid the concomitant use of nilotinib and ritonavir. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If ritonavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and ritonavir is a substrate and a strong inhibitor of CYP3A4.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with nilotinib 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 nilotinib is a moderate CYP3A4 inhibitor.
Nizatidine: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
Ofloxacin: (Major) Concomitant use of ofloxacin and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine; Fluoxetine: (Major) Concomitant use of nilotinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olaparib: (Major) Avoid coadministration of olaparib with nilotinib due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after nilotinib is discontinued. Olaparib is a CYP3A substrate and nilotinib is a moderate CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the AUC by 121%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and nilotinib is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and nilotinib may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If nilotinib is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and nilotinib. If concomitant use is necessary, decrease omaveloxolone dose to 100 mg once daily; additional dosage reductions may be necessary. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased omaveloxolone overall exposure by 1.25-fold.
Omeprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Omeprazole; Sodium Bicarbonate: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time. (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Ondansetron: (Major) Avoid coadministration of nilotinib with ondansetron due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of ondansetron may also be increased resulting in an increase in ondansetron-related adverse reactions. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Ondansetron is a CYP3A4 substrate that has also been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
Osilodrostat: (Major) Avoid the concomitant use of nilotinib and osilodrostat; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid the concomitant use of nilotinib and osimertinib; significant prolongation of the QT interval may occur. If concomitant use is unavoidable, closely monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
Oxaliplatin: (Major) Avoid coadministration of nilotinib with oxaliplatin due to the risk of QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of nilotinib is necessary. If nilotinib 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 moderate inhibitor like nilotinib 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 nilotinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking nilotinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Pacritinib: (Major) Avoid concurrent use of pacritinib with nilotinib due to the risk of increased pacritinib exposure which increases the risk of adverse reactions. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor.
Palovarotene: (Major) Avoid concomitant use of palovarotene and nilotinib due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. If concomitant use is necessary, decrease the palovarotene dose by half. Palovarotene is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold.
Panobinostat: (Major) The co-administration of panobinostat with nilotinib is not recommended; QT prolongation has been reported with both agents. Nilotinib is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of nilotinib and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of panobinostat toxicity such as cardiac arrhythmias, diarrhea, bleeding, infection, and hepatotoxicity. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Pantoprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Paricalcitol: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and paricalcitol, a CYP3A4 substrate, may result in increased paricalcitol levels. A paricalcitol dose reduction may be necessary if these drugs are used together.
Pasireotide: (Major) Avoid the concomitant use of nilotinib and pasireotide; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. QT prolongation has occurred with therapeutic and subtherapeutic doses of pasireotide.
Pazopanib: (Major) Avoid the concomitant use of nilotinib with pazopanib due to an increased risk for QT prolongation. Pazopanib has been reported to prolong the QT interval. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and nilotinib due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If nilotinib is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of nilotinib. Pemigatinib is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
Pentamidine: (Major) Avoid the concomitant use of nilotinib and pentamidine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Systemic pentamidine has been associated with QT prolongation.
Perindopril; Amlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
Perphenazine: (Minor) QT interval prolongation may be additive if nilotinib and perphenazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (Minor) QT interval prolongation may be additive if nilotinib and perphenazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and nilotinib due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If nilotinib is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of nilotinib. Pexidartinib is a CYP3A substrate; nilotinib is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased pexidartinib overall exposure by 67%.
Phenobarbital: (Major) Avoid the concomitant use of nilotinib and phenobarbital; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and phenobarbital is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of nilotinib and phenobarbital; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and phenobarbital is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Phenytoin: (Major) Avoid the concomitant use of nilotinib and phenytoin; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and phenytoin is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Pimavanserin: (Major) Avoid the concomitant use of nilotinib and pimavanserin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Pimavanserin may also cause QT prolongation.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of nilotinib with pimozide is contraindicated.
Pitolisant: (Major) Avoid coadministration of pitolisant with nilotinib as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking nilotinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Posaconazole: (Contraindicated) The concurrent use of posaconazole and nilotinib is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of nilotinib. These drugs used in combination may result in elevated nilotinib plasma concentrations, causing an increased risk for nilotinib-related adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP.
Pralsetinib: (Major) Avoid concomitant use of nilotinib with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of pralsetinib by 71%.
Primaquine: (Major) Avoid the concomitant use of nilotinib and primaquine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Primaquine has the potential to prolong the QT interval.
Primidone: (Major) Avoid the concomitant use of nilotinib and primidone; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and primidone is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and nilotinib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Procainamide: (Major) Avoid the concomitant use of nilotinib and procainamide; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes.
Prochlorperazine: (Minor) QT interval prolongation may be additive if nilotinib and prochlorperazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Prochlorperazine is associated with a possible risk for QT prolongation.
Promethazine: (Moderate) Concomitant use of promethazine and nilotinib may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Promethazine; Dextromethorphan: (Moderate) Concomitant use of promethazine and nilotinib may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Promethazine; Phenylephrine: (Moderate) Concomitant use of promethazine and nilotinib may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Propafenone: (Major) Concomitant use of propafenone and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Proton pump inhibitors: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Quazepam: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and quazepam, a CYP3A4 substrate, may result in increased quazepam levels. A quazepam dose reduction may be necessary if these drugs are used together.
Quetiapine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as quetiapine. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and quetiapine is a substrate of CYP3A4; administering these drugs together may result in increased quetiapine levels. If the use of quetiapine is necessary, hold nilotinib therapy. If these drugs are used together, consider a quetiapine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Quinidine: (Major) Avoid coadministration of nilotinib with quinidine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of quinidine may be increased resulting in an increase in quinidine-related adverse reactions. Nilotinib is a moderate CYP3A4 inhibitor. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Quinidine is a CYP3A4 substrate that has also been associated with QT prolongation and torsade de pointes (TdP).
Quinine: (Major) Avoid the concomitant use of nilotinib and quinine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Quizartinib: (Major) Concomitant use of quizartinib and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Rabeprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
Ranitidine: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
Ranolazine: (Major) Avoid coadministration of nilotinib with ranolazine due to an increased risk for QT prolongation. Additionally, the systemic exposure of ranolazine may be increased resulting in an increase in treatment-related adverse reactions. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Ranolazine is a CYP3A4 substrate that has also been associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Relugolix: (Major) Avoid administration of nilotinib with other drugs with a known potential to prolong the QT interval such as relugolix. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid administration of nilotinib with other drugs with a known potential to prolong the QT interval such as relugolix. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
Ribociclib: (Major) Avoid coadministration of ribociclib with nilotinib due to an increased risk for QT prolongation. Additionally, the systemic exposure of nilotinib may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Nilotinib is a CYP3A4 substrate that has also been associated with QT prolongation and sudden death. Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with nilotinib due to an increased risk for QT prolongation. Additionally, the systemic exposure of nilotinib may be increased resulting in an increase in treatment-related adverse reactions . Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Nilotinib is a CYP3A4 substrate that has also been associated with QT prolongation and sudden death. Concomitant use may increase the risk for QT prolongation.
Rifampin: (Major) Avoid the concomitant use of nilotinib and rifampin; significantly decreased nilotinib exposure was observed in a drug interaction study. Coadministration of these drugs may lead to reduced nilotinib efficacy. Nilotinib is a CYPA4 substrate and rifampin is a strong CYP3A4 inducer. In a drug interaction study, the AUC value of nilotinib was decreased by about 80% following the addition of rifampicin/rifampin 600 mg once daily for 12 days.
Rifapentine: (Major) Avoid the concomitant use of nilotinib and rifapentine; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and rifapentine is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Rilpivirine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as rilpivirine. Nilotinib is a moderate inhibitor of CYP3A4 and rilpivirine is a substrate of CYP3A4; administering these drugs together may result in increased rilpivirine levels. If the use of rilpivirine is necessary, hold nilotinib therapy. If these drugs are used together, consider a rilpivirine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with nilotinib; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor.
Risperidone: (Major) Avoid the concomitant use of nilotinib and risperidone; significant prolongation of the QT interval may occur. If coadministration is required and the patient has risk factors for cardiac disease or arrhythmias, careful monitoring is recommended. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Risperidone has been associated with a possible risk for QT prolongation and/or TdP. Reports of QT prolongation and TdP during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting.
Ritonavir: (Major) Avoid the concomitant use of nilotinib and ritonavir. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If ritonavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and ritonavir is a substrate and a strong inhibitor of CYP3A4.
Rivaroxaban: (Moderate) Patients with renal impairment (CrCl 15 to 79 mL/min) may be at an increased risk for rivaroxaban-related adverse effects such as bleeding and bruising if rivaroxaban and nilotinib are used together. The manufacturer of rivaroxaban recommends avoiding use of dual moderate CYP3A and P-gp inhibitors in patients with renal impairment. Nilotinib is a moderate CYP3A inhibitor however the extent to which it inhibits P-gp has not been fully elucidated. In a pharmacokinetic trial, coadministration with a combined moderate CYP3A4/P-gp inhibitor increased the AUC of rivaroxaban by 76% in patients with mild renal impairment (CrCl 50 to 79 mL/min) and by 99% in patients with moderate renal impairment (CrCl 30 to 49 mL/min) compared to patients with normal renal function (CrCl greater than 80 mL/min); similar trends in pharmacodynamic effects were also observed.
Romidepsin: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as romidepsin. Nilotinib is a moderate inhibitor of CYP3A4 and romidepsin is a substrate of CYP3A4; administering these drugs together may result in increased romidepsin levels. If the use of romidepsin is necessary, hold nilotinib therapy. If these drugs are used together, consider a romidepsin dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Saquinavir: (Contraindicated) The concurrent use of nilotinib and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsades de pointes (TdP). Both saquinavir boosted with ritonavir and nilotinib are inhibitors and substrates of the hepatic isoenzyme CYP3A4. This complex interaction may ultimately result in elevated plasma concentrations of both nilotinib and saquinavir, thus increasing the risk of drug toxicity and proarrhythmic effects.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Coadministration of segesterone, a CYP3A4 substrate and nilotinib, a moderate CYP3A4 inhibitor may increase the serum concentration of segesterone.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and nilotinib due to the risk of additive QT prolongation and increased selpercatinib exposure resulting in increased treatment-related adverse effects. If coadministration is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If nilotinib is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of nilotinib. Selpercatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; nilotinib is a moderate CYP3A4 inhibitor that has been associated with sudden death and QT interval prolongation. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase selpercatinib exposure by 60% to 99%.
Selumetinib: (Major) Avoid coadministration of selumetinib and nilotinib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If nilotinib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of nilotinib. Selumetinib is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Sertraline: (Major) Concomitant use of sertraline and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Avoid the concomitant use of nilotinib and halogenated anesthetics; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, fatal cases of torsade de pointes have been reported with halogenated anesthetic use.
Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with nilotinib is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving nilotinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Additionally, concomitant use of siponimod and nilotinib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of nilotinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Sodium Bicarbonate: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with nilotinib. Taking these medications together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Nilotinib is a moderate inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with nilotinib. Taking these medications together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Nilotinib is a moderate inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and nilotinib; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and nilotinib is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Sorafenib: (Major) Avoid coadministration of nilotinib with sorafenib due to the risk of QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Sorafenib has also been associated with QT prolongation.
Sotalol: (Major) Concomitant use of sotalol and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sparsentan: (Moderate) Monitor for an increase in sparsentan-related adverse effects if concomitant use with nilotinib is necessary. Concomitant use may increase sparsentan exposure. Sparsentan is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sparsentan overall exposure by 70%.
St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of nilotinib and St. John's Wort; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and St. John's Wort is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Sufentanil: (Major) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if nilotinib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of nilotinib is necessary. If nilotinib is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a moderate CYP3A4 inhibitor like nilotinib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If nilotinib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sunitinib: (Major) Avoid the concomitant use of nilotinib and sunitinib; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points.
Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with nilotinib. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the suvorexant AUC by 2-fold.
Tacrolimus: (Major) Nilotinib and tacrolimus both prolong the QT interval. Additionally, tacrolimus is metabolized by CYP3A4 and nilotinib inhibits this isoenzyme. Coadministration of nilotinib and a drug that prolongs the QT interval is not advised, as nilotinib prolongs the QT interval. If concurrent administration with tacrolimus is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. The manufacturer of tacrolimus advises reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as nilotinib. Tacrolimus concentrations and thus other adverse reactions may also be increased during concomitant administration.
Tadalafil: (Moderate) Concomitant use of nilotinib, an moderate CYP3A4 inhibitor, and tadalafil, a CYP3A4 substrate, may result in increased tadalafil levels. A tadalafil dose reduction may be necessary if these drugs are used together.
Tamoxifen: (Major) Concomitant use of tamoxifen and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and nilotinib. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as nilotinib, may increase exposure to tasimelteon with the potential for adverse reactions.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with nilotinib as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If nilotinib is discontinued, wait at least 3 half-lives of nilotinib before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telavancin: (Major) Avoid the concomitant use of nilotinib and telavancin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Telavancin has been associated with QT prolongation.
Telmisartan; Amlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
Teniposide: (Major) Concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and teniposide, a P-gp and CYP3A4 substrate with a narrow therapeutic range, may result in increased teniposide levels. A teniposide dose reduction may be necessary if these drugs are used together.
Tetrabenazine: (Major) Avoid the concomitant use of nilotinib and tetrabenazine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Tetrabenazine causes a small increase in the corrected QT interval.
Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with nilotinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); nilotinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If nilotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Thioridazine: (Contraindicated) Nilotinib prolongs the QT interval. Because of the potential for torsade de pointes, use of thioridazine with nilotinib is contraindicated.
Tipranavir: (Major) Avoid the concomitant use of nilotinib and tipranavir. If coadministration is required, reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. Additionally, monitor patients closely for prolongation of the QT interval and for adverse reactions associated with nilotinib or tipranavir. If tipranavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and tipranavir is a sensitive substrate and strong inhibitor of CYP3A4.
Tolterodine: (Major) Avoid coadministration of nilotinib with tolterodine due to an increased risk for QT prolongation. Systemic exposure of tolterodine may also be increased resulting in increase in treatment-related adverse reactions. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Tolterodine is a CYP3A4 substrate that has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Concomitant use may increase the risk for QT prolongation.
Tolvaptan: (Major) Avoid coadministration of nilotinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with nilotinib. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
Toremifene: (Major) Avoid coadministration of nilotinib with toremifene due to the risk of additive QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
Tramadol: (Major) The concomitant use of nilotinib and tramadol may reduce the clearance of tramadol and increase the risk for serious adverse events including seizures and serotonin syndrome. If coadministration of these drugs is required, consider reducing the dose of tramadol and monitor patients for signs of toxicity. Nilotinib is a moderate CYP3A4 inhibitor and tramadol is a CYP3A4 substrate.
Tramadol; Acetaminophen: (Major) The concomitant use of nilotinib and tramadol may reduce the clearance of tramadol and increase the risk for serious adverse events including seizures and serotonin syndrome. If coadministration of these drugs is required, consider reducing the dose of tramadol and monitor patients for signs of toxicity. Nilotinib is a moderate CYP3A4 inhibitor and tramadol is a CYP3A4 substrate.
Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with nilotinib is necessary; also monitor for nilotinib-related side effects. Nilotinib and verapamil are both substrates of and inhibitors of CYP3A4. Elevations of verapamil plasma levels resulting in clinically significant interactions have been reported with other moderate CYP3A4 inhibitors. Increased nilotinib concentrations may increase the risk for treatment-related side effects.
Trazodone: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Trazodone can prolong the QT interval at therapeutic doses, and torsade de pointes (TdP) has been reported with post-marketing use. Additionally, nilotinib is a moderate CYP3A4 inhibitor and trazodone is a CYP3A4 substrate; administering these drugs together may result in increased trazodone levels. If the use of trazodone is required, hold nilotinib therapy. If the use of nilotinib and trazodone cannot be avoided, a trazodone dose reduction may be necessary; close monitoring of the QT interval is recommended.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with nilotinib and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and nilotinib is a moderate CYP3A inhibitor.
Triclabendazole: (Major) Concomitant use of triclabendazole and nilotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trifluoperazine: (Minor) QT interval prolongation may be additive if nilotinib and trifluoperazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Trifluoperazine is associated with a possible risk of QT prolongation.
Triptorelin: (Major) Avoid administration of nilotinib with triptorelin due to the risk of QT interval prolongation. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
Tucatinib: (Major) Avoid the concomitant use of nilotinib and tucatinib. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If tucatinib is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and tucatinib is a strong inhibitor of CYP3A4.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with nilotinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
Vandetanib: (Major) Avoid coadministration of vandetanib with nilotinib due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
Vardenafil: (Major) Avoid the concomitant use of nilotinib with other agents known to prolong the QT interval, such as vardenafil. Sudden death and QT prolongation have occurred in patients receiving nilotinib therapy. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval. Also, nilotinib is a moderate CYP3A4 inhibitor and vardenafil is a primary CYP3A4 substrate; administering these drugs together may result in increased vardenafil concentrations. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold. Do not use vardenafil orally disintegrating tablets with nilotinib due to increased vardenafil exposure. If use of nilotinib and vardenafil oral tablets is required, do not exceed a single vardenafil oral tablet dose of 5 mg per 24-hour period.
Vemurafenib: (Major) Avoid coadministration of vemurafenib with nilotinib with vemurafenib due to the risk of QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Vemurafenib has also been associated with QT prolongation. Additive QT prolongation may occur.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with nilotinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of nilotinib. Venetoclax is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor.
Venlafaxine: (Major) Avoid coadministration of nilotinib with venlafaxine due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of venlafaxine may also be increased resulting in increase in treatment-related adverse reactions. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Venlafaxine is a CYP3A4 substrate that is also associated with a possible risk of QT prolongation; TdP has reported with postmarketing use. Concomitant use may increase the risk for QT prolongation.
Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with nilotinib is necessary; also monitor for nilotinib-related side effects. Nilotinib and verapamil are both substrates of and inhibitors of CYP3A4. Elevations of verapamil plasma levels resulting in clinically significant interactions have been reported with other moderate CYP3A4 inhibitors. Increased nilotinib concentrations may increase the risk for treatment-related side effects.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with nilotinib is necessary. Vinblastine is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
Vincristine Liposomal: (Moderate) Monitor for increased severity or earlier onset of vincristine-related adverse reactions (e.g., periipheral, autonomic and central neuropathy; low blood counts) if coadministration with nilotinib is necessary. Nilotinib may increase vincristine exposure. Vincristine is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor.
Vincristine: (Moderate) Monitor for increased severity or earlier onset of vincristine-related adverse reactions (e.g., periipheral, autonomic and central neuropathy; low blood counts) if coadministration with nilotinib is necessary. Nilotinib may increase vincristine exposure. Vincristine is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with nilotinib is necessary. Vinorelbine is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor.
Voclosporin: (Major) Avoid coadministration of voclosporin and nilotinib due to the risk of QT prolongation. Voclosporin exposure and the risk for voclosporin-related adverse effects may also be increased. If concomitant use is necessary, reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening. Voclosporin is a sensitive CYP3A4 substrate that is associated with QT prolongation at supratherapeutic doses. Nilotinib is a moderate CYP3A4 inhibitor that has been associated with sudden death and QT prolongation. Coadministration with moderate CYP3A4 inhibitors is predicted to increase voclosporin exposure by 3-fold.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of nilotinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of nilotinib reducing its efficacy.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of nilotinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of nilotinib reducing its efficacy. (Major) Avoid the concomitant use of nilotinib and clarithromycin; significant prolongation of the QT interval and torsade de pointes (TdP) may occur. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Clarithromycin is associated with an established risk for QT prolongation and TdP. If therapy with clarithromycin is necessary, interrupt nilotinib therapy if possible. Monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in adult patients with resistant or intolerant Ph+ CML or to 200 mg once daily in adult patients with newly diagnosed Ph+ CML. If clarithromycin is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and clarithromycin is a strong inhibitor of CYP3A4.
Voriconazole: (Major) Avoid the concomitant use of nilotinib and voriconazole; significant prolongation of the QT interval may occur. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Voriconazole has been associated with QT interval prolongation as well as rare cases of torsade de pointes. If therapy with voriconazole is necessary, interrupt nilotinib therapy if possible. Monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in adult patients with resistant or intolerant Ph+ CML or to 200 mg once daily in adult patients with newly diagnosed Ph+ CML. If voriconazole is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and voriconazole is a strong inhibitor of CYP3A4.
Vorinostat: (Major) Avoid the concomitant use of nilotinib and vorinotat; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Vorinostat therapy is associated with a risk of QT prolongation.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with nilotinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Nilotinib is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zafirlukast: (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.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with nilotinib. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of nilotinib, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A4 inhibitors.
Ziprasidone: (Contraindicated) Ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs, including nilotinib. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP). Nilotinib is is associated with concentration-dependent QT prolongation. Significant prolongation of the QT interval may occur when nilotinib is given with medications with a known potential to prolong the QT interval, including ziprasidone.
Zolpidem: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of nilotinib, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem when the drug is co-administered with some potent inhibitors of CYP3A4, such as azole antifungals. Concurrent administration of nilotinib and midazolam, a CYP3A4 substrate, increased midazolam exposure by 30%.

How Supplied

Tasigna Oral Cap: 50mg, 150mg, 200mg

Maximum Dosage
Adults

800 mg/day PO.

Geriatric

800 mg/day PO.

Adolescents

230 mg/m2 twice daily, not to exceed 400 mg/dose.

Children

230 mg/m2 twice daily, not to exceed 400 mg/dose.

Infants

Safety and efficacy have not been established.

Mechanism Of Action

Mechanism of Action: Chronic myelogenous leukemia is a myeloproliferative disorder caused by the reciprocal translocation of chromosomes 9 and 22 (t 9,22), which is also known as the Philadelphia Chromosome. The Philadelphia Chromosome combines the breakpoint cluster region (BCR) of chromosome 22 and the active tyrosine kinase portion of the Abelson murine leukemia (ABL) gene from chromosome 9. Nilotinib is an oral tyrosine kinase inhibitor designed to selectively inhibit the BCR-ABL tyrosine kinase. Nilotinib is a competitive inhibitor at the ATP-binding site of BCR-ABL and prevents tyrosine phosphorylation of downstream intracellular signal transduction proteins. Like imatinib and dasatinib, nilotinib binds to an inactive portion of the ABL kinase domain and prevents the enzyme from converting to its catalytically active conformation. Blocking the tyrosine kinase prevents proliferation of BCR-ABL cells and induces apoptosis.Changes in the BCR-ABL protein such as point mutations and binding site conformation changes are a source of drug resistant disease. Nilotinib is active in 32 of 33 imatinib-resistant BCR-ABL mutant cell lines; the exception is the T315I mutation. Unlike imatinib and dasatinib, nilotinib is selective for ABL kinase over KIT and PDGF receptor kinases and the Src-family of kinases. In addition, nilotinib enhances binding site affinity by offering alternate binding groups while continuing to bind the inactive conformation binding site of the ABL tyrosine kinase. The increased kinase selectivity and binding site affinity make nilotinib 30 times more potent than imatinib in imatinib-sensitive CML cell lines and 3—7 times more potent in imatinib-resistant CML cell lines.

Pharmacokinetics

Nilotinib is administered orally. It is approximately 98% protein bound in serum; the blood to serum ratio is 0.68. Nilotinib is metabolized via oxidation by CYP3A4 (major) and CYP2C8 (minor) isoenzymes in the liver; no active metabolites have been identified. The elimination half-life of nilotinib is approximately 17 hours (coefficient of variation (CV), 69%) and the mean apparent clearance is about 29 L/hour (CV, 61%). Following a single radiolabeled nilotinib dose, 93% of the dose was eliminated mainly in the feces within 7 days, and parent drug accounted for 69% of the dose.
 
Affected cytochrome P450 isoenzymes and transporters: CYP3A4, CYP2C8, P-gp
Nilotinib is a moderately sensitive substrate of CYP3A4 and a moderate CYP3A4 inhibitor. Concomitant administration with strong CYP3A4 inhibitors or inducers may increase or decrease nilotinib concentrations significantly. In vitro, nilotinib is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, P-glycoprotein (P-gp) and UGT1A1 and induces CYP2B6 and CYP2C8. Additionally, nilotinib is a substrate and P-gp in vitro. Coadministration of nilotinib and warfarin, a CYP2C9 substrate, did not alter the pharmacokinetic parameters of warfarin in a single-dose drug interaction study.

Oral Route

The relative bioavailability of nilotinib capsules is approximately 50% compared with an oral drink solution. However, a single dose of two 200-mg nilotinib capsules (each dispersed in 1 teaspoon of applesauce and administered within 15 minutes) was bioequivalent to a single dose of two 200-mg intact capsules. The steady-state nilotinib exposure is dose-dependent and exhibits less than dose-proportional increases in systemic exposure at dosages higher than 400 mg once or twice daily. The increase in nilotinib exposure between the first dose and steady state is about 2-fold for daily dosing and 3.8-fold for twice daily dosing. The Tmax is reached at 3 hours after oral administration. Following the administration of nilotinib 400 mg PO twice daily, the steady-state mean Cmax and AUC(0-12 hr) values were 2,260 ng/mL (coefficient of variation (CV), 35%) and 18,000 ng X hour/mL (CV, 33%), respectively, in adults with resistant or intolerant chronic myelogenous leukemia (CML). Following the administration of nilotinib 300 mg PO twice daily, the steady-state mean Cmax and AUC(0-12 hr values were 1,540 ng/mL (CV, 48%) and 13,337 ng X hour/mL (CV, 46%), respectively, in adults with newly diagnosed CML. Steady-state concentrations are achieved by day 8.
 
Effect of Food: The bioavailability of nilotinib is significantly increased by food. The AUC value was increased 82% when nilotinib was taken 30 minutes prior to a high-fat meal (800 to 1,000 calories with 50% of total caloric content as fat) compared with the fasted state.

Pregnancy And Lactation
Pregnancy

Nilotinib may cause fetal harm when administered during pregnancy, based on its mechanism of action and animal studies. Females of reproductive potential should avoid pregnancy during and after treatment. Discuss the potential hazard to the fetus if nilotinib is used during pregnancy or if a patient becomes pregnant while taking this drug. In animals studies, embryo-fetal toxicities including skeletal variations (e.g., incomplete ossification, fused sternebra), cleft palate, and dilated ureters and small renal papilla were observed following nilotinib administration during organogenesis at doses that resulted in drug exposures approximately 0.5-times (rabbits) and 2-times (rats) the exposures achieved at the highest recommended human dose.

It is not known if nilotinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during nilotinib therapy and for 14 days after the last dose.