XALKORI (crizotinib) Drug Interactions

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Overview

Crizotinib is a substrate and inhibitor of CYP3A and an inhibitor of CYP2B6. It is also a substrate and an inhibitor of P- glycoprotein (P-gp). The aqueous solubility of crizotinib is pH-dependent. Drug interactions were observed when crizotinib was co-administered with a strong CYP3A inhibitor, a strong CYP3A inducer, and a substrate of CYP3A. Drug interactions may occur when crizotinib is co-administered with other QTc-prolonging and heart rate-lowering drugs. The related findings and precautions are discussed further below.

Drug-Drug Interactions

Drugs That May Increase Crizotinib Plasma Concentrations

CYP3A Inhibitors

Crizotinib is predominantly metabolized by CYP3A. Co-administration of XALKORI with CYP3A inhibitors may increase crizotinib plasma concentrations. Co-administration of a single 150 mg oral dose of crizotinib in the presence of ketoconazole (200 mg twice daily), a strong CYP3A4 inhibitor, resulted in increases in crizotinib systemic exposure, with crizotinib AUCinf and Cmax values that were approximately 3.2‑fold and 1.4‑fold, respectively, to those seen when crizotinib was administered alone. Co-administration of XALKORI (250 mg once daily) with itraconazole (200 mg once daily), a strong CYP3A inhibitor, resulted in increases in crizotinib systemic exposure at steady-state. Steady-state AUCτ and Cmax were approximately 1.6-fold and 1.3-fold, respectively, to those observed when XALKORI was administered alone. The concomitant use of strong CYP3A inhibitors, including but not limited to, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole, should be avoided (see DOSAGE AND ADMINISTRATION section). Physiologically-based pharmacokinetic (PBPK) simulations predicted a 17% increase in crizotinib steady-state AUC after treatment with the moderate CYP3A inhibitors (diltiazem or verapamil). Caution should be exercised when moderate CYP3A inhibitors are co-administered.

Drugs That May Decrease Crizotinib Plasma Concentrations

CYP3A Inducers

Co-administration of crizotinib with CYP3A inducers may decrease crizotinib plasma concentrations. Co-administration of crizotinib (250 mg twice daily) with rifampin (600 mg once daily), a strong CYP3A inducer, resulted in 84% and 79% decreases in crizotinib steady-state AUCtau and Cmax, respectively, compared to when crizotinib was given alone. The concurrent use of strong CYP3A inducers, including but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s wort, should be avoided (see DOSAGE AND ADMINISTRATION section).

Agents That Increase Gastric pH

The aqueous solubility of crizotinib is pH-dependent, with high (less acidic) pH resulting in lower solubility. The ratio of adjusted geometric means (90% CI) of crizotinib total exposure (AUCinf) was 89.81% (79.05%, 102.03%), following administration of crizotinib 250 mg relative to crizotinib 250 mg and esomeprazole (40 mg once daily × 5 days). Based on the extent of the change in total exposure, starting dose adjustment is not required when crizotinib is co-administered with agents that increase gastric pH (such as proton pump inhibitors, H2 blockers, or antacids).

Drugs Whose Plasma Concentrations May Be Altered by Crizotinib

CYP3A Substrates

Crizotinib has been identified as an inhibitor of CYP3A both in vitro and in vivo. Crizotinib may increase plasma concentrations of co-administered CYP3A substrates. Following 28 days of crizotinib dosing at 250 mg taken twice daily in cancer patients, the oral midazolam AUCinf was 3.65-fold (90% CI: 2.63-5.07) those seen when midazolam was administered alone, suggesting that crizotinib is a moderate inhibitor of CYP3A.

Caution should be exercised in administering crizotinib in combination with drugs that are predominantly metabolized by CYP3A, particularly those CYP3A substrates that have narrow therapeutic indices, including but not limited to alfentanil, cyclosporine, fentanyl, quinidine, sirolimus, and tacrolimus. Co-administration of crizotinib should be avoided with CYP3A substrates that have narrow therapeutic indices and are associated with life-threatening arrhythmias, including but not limited to dihydroergotamine, ergotamine, and pimozide.

CYP2B6 Substrates

Crizotinib is an inhibitor of CYP2B6 in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of co-administered drugs that are predominantly metabolized by CYP2B6.

Other CYP Substrates

In vitro studies indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19 or CYP2D6.

In vitro studies in human hepatocytes indicated that clinical drug-drug interactions are unlikely to occur as a result of crizotinib-mediated induction of the metabolism of drugs that are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A (see DETAILED PHARMACOLOGY section).

Co-administration with UGT Substrates

Crizotinib is identified as a competitive inhibitor of UGT enzyme isoforms UGT 1A1 and UGT2B7 in vitro with IC50 values IC50 5.3 µM and 6.9 µM, respectively. Therefore, crizotinib may have the potential to increase plasma concentrations of co-administered drugs that are metabolized predominantly by UGT1A1 (e.g., raltegravir, irinotecan) or UGT2B7 (e.g., morphine, naloxone) (see DETAILED PHARMACOLOGY).

P-gp Substrates

Crizotinib is an inhibitor of P-gp in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of co-administered drugs that are substrates of P-gp.

OCT Substrates

Crizotinib is an inhibitor of OCT1 (IC50 = 2.4µM) and OCT2 (IC50 = 0.22µM) in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of co-administered drugs that are substrates of OCT1 or OCT2 (see DETAILED PHARMACOLOGY).

Heart Rate-Lowering Drugs

Bradycardia has been reported in patients treated with XALKORI (see WARNINGS AND PRECAUTIONS, Cardiovascular & Monitoring and Laboratory Tests; ADVERSE REACTIONS, Electrocardiography and Haemodynamics). Avoid using crizotinib in combination with other bradycardic agents (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, cholinesterase inhibitors, and sphingosine-1 phosphate receptor modulators) (including but not limited to atenolol, verapamil, diltiazem, clonidine, digoxin to the extent possible, due to the increased risk of symptomatic bradycardia (syncope, dizziness, hypotension).

The concomitant use of XALKORI with QT interval-prolonging drugs should be avoided to the extent possible (see WARNINGS AND PRECAUTIONS, Cardiovascular & Monitoring and Laboratory Tests; ADVERSE REACTIONS, Electrocardiography and Haemodynamics). Drugs that have been associated with QT interval prolongation and/or Torsade de Pointes include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QT/QTc interval prolongation and/or Torsade de Pointes:

  • Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide)

  • Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide, dronedarone)

  • Class 1C antiarrhythmics (e.g., flecainide, propafenone)

  • antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone)

  • antidepressants (e.g., fluoxetine, citalopram, venlafaxine, tricyclic/tetracyclic antidepressants [e.g., amitriptyline, imipramine, maprotiline])

  • opioids (e.g., methadone)

  • macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, telithromycin, tacrolimus)

  • quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin)

  • pentamidine

  • antimalarials (e.g., quinine, chloroquine)

  • azole antifungals (e.g., ketoconazole, fluconazole, voriconazole)

  • domperidone

  • 5-hydroxytryptamine (5-HT)3 receptor antagonists (e.g., dolasetron, ondansetron)

  • tyrosine kinase inhibitors (e.g., sunitinib, nilotinib, lapatinib, vandetanib)

  • histone deacetylase inhibitors (e.g., vorinostat)

  • beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol)

Drugs that Affect Electrolytes

The use of XALKORI with drugs that can disrupt electrolyte levels should be avoided to the extent possible. Drugs that can disrupt electrolyte levels include, but are not limited to, the following:

  • loop, thiazide, and related diuretics
  • laxatives and enemas
  • amphotericin B
  • high-dose corticosteroids

The above list of potentially interacting drugs is not comprehensive. Current information sources should be consulted for newly approved drugs that decrease heart rate, prolong the QT/QTc interval, or decrease electrolytes, as well as for older drugs for which these effects have recently been established.

Drug-Food Interactions

Grapefruit has CYP3A4 inhibitory activity. Therefore, ingestion of grapefruit while on XALKORI (crizotinib) therapy may increase crizotinib plasma concentrations. Concomitant administration of XALKORI with grapefruit, grapefruit juice, products containing grapefruit extract, star fruit, pomegranate, Seville oranges, and other similar fruits that are known to inhibit CYP3A4 should be avoided.

Drug-Herb Interactions

St. John’s wort is a strong CYP3A4 inducer. Co-administration with XALKORI may decrease crizotinib plasma concentrations. Patients receiving XALKORI should not take St. John’s wort concomitantly.

Drug-Lifestyle Interactions

Vision disorder, that was considered related to treatment with XALKORI, most commonly visual impairment, photopsia, vision blurred, and vitreous floaters, was experienced by 1038 (62%) of 1669 patients across clinical trials. Caution should be exercised when driving or operating machinery by patients who experience vision disorder.