XALKORI® Prescribing information

XALKORI® (crizotinib) Prescribing Information:

Please refer to the Summary of Product Characteristics (SmPC) before prescribing XALKORI 200 mg or 250 mg hard capsules.

Presentation: Hard capsules containing 200 mg or 250 mg crizotinib.

Indications: As monotherapy for first-line treatment of adults with anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC), treatment of adults with previously treated ALK-positive advanced NSCLC and the treatment of adults with ROS1-positive advanced NSCLC.

Dosage: Therapy should be initiated and supervised by a physician experienced in the administration of anti-cancer medicinal products.  An accurate and validated assay for either ALK or ROS1 is necessary for the selection of patients for treatment with crizotinib (see SmPC section 5.1). Either ALK-positive or ROS1-positive NSCLC status should be established prior to initiation of crizotinib. Assessment should be performed by laboratories with demonstrated proficiency in the specific technology being utilised (see SmPC section 4.4). The recommended dose of crizotinib is 250 mg taken orally (twice daily) with or without food, continuously. Capsules should be swallowed whole preferably with water, and should not be crushed, dissolved, or opened. Grapefruit or grapefruit juice should be avoided since it may increase crizotinib plasma concentration (see SmPC section 4.2); St. John’s wort should be avoided since it may decrease crizotinib plasma concentration (see SmPC section 4.5). Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose reduction is necessary for patients treated with crizotinib 250 mg orally twice daily, then the first dose reduction is to crizotinib 200 mg taken orally twice daily. If second dose reduction is necessary, then the dose should be reduced to 250 mg taken once daily. Permanently discontinue if patient is unable to tolerate 250 mg taken orally once daily. For dose reduction guidelines for haematologic and non-haematologic toxicities, refer to SmPC section 4.2. Treatment with crizotinib should be used with caution in patients with hepatic impairment see SmPC sections 4.2, 4.4, 4.8 and 5.2). No starting dose adjustment of crizotinib is recommended for patients with mild hepatic impairment (either AST > Upper Limit of Normal (ULN) and total bilirubin ≤ULN or any AST and total bilirubin >ULN but £1.5 × ULN). The starting crizotinib dose for patients with moderate hepatic impairment (any AST and total bilirubin >1.5 × ULN and £3 × ULN) is recommended to be 200 mg twice daily. The starting crizotinib dose for patients with severe hepatic impairment (any AST and total bilirubin >3 × ULN) is recommended to be 250 mg once daily (see SmPC section 5.2). No starting dose adjustment is recommended for patients with mild (60≤ creatinine clearance [CLcr] < 90 mL/min) or moderate (30≤ CLcr <60 mL/min) renal impairment. Crizotinib plasma concentrations may be increased in patients with severe renal impairment (CLcr <30 mL/min). Crizotinib starting dose should be adjusted to 250 mg once daily in patients with severe renal impairment, not requiring peritoneal dialysis or haemodialysis, and may be increased to 200 mg twice daily based on individual safety and tolerability, after at least 4 weeks of treatment (refer to SmPC sections 4.2, 4.4 and 5.2). In the elderly population, no starting dose adjustment is required (see SmPC sections 5.1 and 5.2). The safety and efficacy of crizotinib in paediatric patients has not been established.Contraindications: Hypersensitivity to the active substance or to any of the excipients (see SmPC section 6.1).

Warnings and Precautions: Drug induced hepatotoxicity (including cases with fatal outcome) has been reported (see SmPC section 4.8). Monitor liver function tests including ALT, AST, and total bilirubin once a week during the first 2 months of treatment then once a month and as clinically indicated with more frequent testing for Grades 2, 3 or 4 elevations. For patients who develop transaminase elevations see SmPC section 4.2. Severe, life-threatening, and/or fatal interstitial lung disease (ILD)/pneumonitis has been reported. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Withhold crizotinib treatment if ILD/pneumonitis is suspected. Drug-induced ILD/pneumonitis should be considered in the differential diagnosis of patients with ILD-like conditions (e.g. pulmonary oedema, pneumonitis etc.). Other potential causes of ILD/pneumonitis should be excluded, and crizotinib should be permanently discontinued in patients diagnosed with treatment-related ILD/pneumonitis (see SmPC sections 4.2 and 4.8). QTc prolongation, which may lead to an increased risk for ventricular tachyarrhythmias (e.g., Torsade de Pointes) or sudden death, has been observed in clinical studies (see SmPC sections 4.8 and 5.2). The benefits and potential risks should be considered before beginning crizotinib in patients with pre-existing bradycardia, who have a history of or predisposition to QTc prolongation, who are taking antiarrhythmics or other medicinal products that are known to prolong QT interval and in patients with relevant pre‑existing cardiac disease and/or electrolyte disturbances. Crizotinib should be administered with caution in these patients and periodic monitoring of electrocardiograms (ECG), electrolytes and renal function is required. ECG and electrolytes (e.g., calcium, magnesium, potassium) should be obtained as close as possible prior to the first dose and periodic monitoring with ECGs and electrolytes is recommended, especially in case of vomiting, diarrhoea, dehydration or impaired renal function. Correct electrolytes as necessary. If QTc increases by ≥60 msec from baseline but QTc is <500 msec, crizotinib should be withheld and cardiologist advice should be sought. If QTc increases to ≥500 msec, cardiologist advice must be immediately sought (see SmPC sections 4.2, 4.8 and 5.2). All-causality bradycardia was reported in clinical studies in 13% of patients treated with crizotinib. Symptomatic bradycardia (e.g., syncope, dizziness and hypotension) can occur in patients receiving crizotinib. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after start of treatment. Avoid using crizotinib in combination with other bradycardic agents (e.g., beta-blockers, non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, clonidine, digoxin) to the extent possible, due to the increased risk of symptomatic bradycardia. Monitor heart rate and blood pressure regularly. Dose modification is not required in cases of asymptomatic bradycardia. For management of patients who develop symptomatic bradycardia, refer to SmPC sections 4.2 and 4.8. In clinical studies with crizotinib and during post marketing surveillance, severe, life-threatening, or fatal adverse reactions of cardiac failure were reported (see SmPC section 4.8). Patients with or without pre-existing cardiac disorders, receiving crizotinib, should be monitored for signs and symptoms of heart failure (dyspnoea, oedema, rapid weight gain from fluid retention). Dosing interruption, dose reduction, or discontinuation should be considered as appropriate if such symptoms are observed. In clinical studies with crizotinib in patients with either ALK-positive or ROS1-positive NSCLC Grade 3 or 4 neutropenia has been very commonly (12%) reported. Grade 3 or 4 leukopenia has been commonly (3%) reported (see SmPC section 4.8) and less than 0.5% of patients experienced febrile neutropenia. Complete blood counts should be monitored as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs (see SmPC section 4.2). In clinical studies with crizotinib, events of gastrointestinal perforations were reported with reports of fatal cases during post-marketing use (see SmPC section 4.8). Crizotinib should be used with caution in patients at risk for gastrointestinal perforation (e.g., history of diverticulitis, metastases to the gastrointestinal tract, concomitant use of medicinal products with a recognised risk of gastrointestinal perforation). Crizotinib should be discontinued in patients who develop gastrointestinal perforation. Patients should be informed of the first signs of gastrointestinal perforations and advised to seek emergency medical attention in case of occurrence. Blood creatinine increase and creatinine clearance decreased were observed in patients in clinical studies with crizotinib. Renal failure and acute renal failure were reported in patients treated with crizotinib in clinical trials and during post marketing. Cases with fatal outcome, cases requiring hemodialysis and cases of grade 4 hyperkalemia were also observed. Monitoring of patients for renal function at baseline and during therapy with crizotinib is recommended, with particular attention to those who have risk factors or previous history of renal impairment (see SmPC section 4.8). In clinical studies with crizotinib with either ALK positive or ROS1 positive NSCLC, Grade 4 visual field defect with vision loss has been reported (0.2% patients). In patients with new onset of severe visual loss (best corrected visual acuity less than 6/60 in one or both eyes), crizotinib treatment should be discontinued (see SmPC section 4.2). Ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT) and other evaluations as appropriate for new onset of severe visual loss, should be performed. There is insufficient information to characterise the risks of resumption of crizotinib in patients with a severe visual loss. A decision to resume crizotinib should consider the potential benefit to the patient. Optic atrophy and optic nerve disorder have been reported as potential causes of vision loss. Ophthalmological evaluation is recommended if vision disorder persists or worsens in severity (see SmPC section 4.8).

Drug Interactions: Coadministration of crizotinib with strong CYP3A inhibitors (including but not limited to atazanavir, ritonavir, cobicistat, itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, and erythromycin is expected to increase crizotinib plasma concentrations and should therefore be avoided unless the potential benefit to the patient outweighs the risk, in which case patients should be closely monitored for crizotinib adverse events (see SmPC section 4.4). Caution is recommended in case of coadministration of crizotinib with moderate CYP3A inhibitors. Coadministration of crizotinib with strong or moderate CYP3A inducers should be avoided (see SmPC section 4.5). The concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifampicin, and St. John’s wort, should be avoided (see section 4.4 of the SmPC). The effect of a moderate inducer including but not limited to efavirenz or rifabutin is not clearly established therefore, their combination with crizotinib should be also avoided (see SmPC section 4.4). Starting dose adjustment is not required when crizotinib is coadministered with agents that increase the gastric pH (such as proton-pump inhibitors, H2 blockers, or antacids). Coadministration of crizotinib with CYP3A substrates with narrow therapeutic indices, including but not limited to alfentanil, cisapride, cyclosporine, ergot derivatives, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus should be avoided (see section 4.4 of the SmPC). If the combination is needed, then close clinical monitoring should be exercised. Avoid using crizotinib in combination with other bradycardic agents, medicinal products that are known to prolong QT interval and/or antiarrhythmics. In vitro studies indicated that crizotinib is an inhibitor of CYP2B6. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are metabolised by CYP2B6 (e.g., bupropion, efavirenz). In vitro studies indicated that crizotinib may induce pregnane X receptor (PXR)- and constitutive androstane receptor (CAR)-regulated enzymes (e.g. CYP3A4, CYP2B6,  CYP2C8, CYP2C9, UGT1A1). However, there was no observed induction in vivo when crizotinib was coadministered with the CYP3A probe substrate midazolam. Caution should be exercised in administering crizotinib in combination with medicinal products that are predominantly metabolised by these enzymes. Effectiveness of concomitantly administered oral contraceptives may be reduced. In vitro studies indicated that crizotinib is a weak inhibitor of uridine diphosphate glucuronosyltransferase (UGT)1A1 and UGT2B7. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are metabolised predominantly by UGT1A1 (e.g. raltegravir, irinotecan) or UGT2B7 (e.g., morphine, naloxone). Based on an in vitro study, crizotinib is predicted to inhibit intestinal P-gp Therefore, administration of crizotinib with medicinal products that are substrates of P-gp (e.g. digoxin, dabigatran, colchicine, pravastatin) may increase their therapeutic effect and adverse reactions. Close clinical surveillance is recommended when crizotinib is administered with these medicinal products. Crizotinib is an inhibitor of OCT1 and OCT2 in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are substrates of OCT1 or OCT2 (metformin, procainamide). Prolonged QT interval has been observed with crizotinib. The concomitant use of crizotinib with medicinal products known to prolong QT interval or able to induce Torsades de pointes (e.g., class IA [quinidine, disopyramide] or class III [e.g., amiodarone, sotalol, dofetilide, ibutilide], methadone, cisapride, moxifloxacine, antipsychotics, etc.) should be carefully considered. A monitoring of the QT interval should be made in case of combinations of such medicinal products with crizotinib (see SmPC sections 4.2 and 4.4). Use crizotinib with caution due to the risk of excessive bradycardia when used in combination with other bradycardic agents (e.g. non‑dihydropyridine calcium channel blockers such as verapamil and diltiazem, beta-blockers, clonidine, guanfacine, digoxin, mefloquine, anticholinesterases, pilocarpine) (See SmPC section 4.2 and 4.4).

Pregnancy & Lactation: Women of childbearing potential should be advised to avoid becoming pregnant while receiving crizotinib. Crizotinib may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity (see SmPC section 5.3). Crizotinib should not be used during pregnancy unless the clinical condition of the mother requires treatment. Pregnant women, or patients becoming pregnant while receiving crizotinib, or treated male patients as partners of pregnant women, should be apprised of the potential hazard to the foetus. Because of the potential harm to the infant, mothers should be advised to avoid breast-feeding while receiving Crizotinib (See SmPC section 5.3). Adequate contraceptive methods should be used during therapy, and for at least 90 days after completing therapy (see SmPC section 4.5). Crizotinib may impair fertility (see SmPC section 5.3) and both men and women should seek advice on fertility preservation before treatment.

Driving and operating machinery: Caution should be exercised when driving or operating machines as patients may experience symptomatic bradycardia (e.g., syncope, dizziness, hypotension), vision disorder, or fatigue while taking crizotinib (see SmPC section 4.2, 4.4 and 4.8).

Side Effects: The most serious adverse reactions in patients with either ALK-positive or ROS1-positive advanced NSCLC were hepatotoxicity, ILD/pneumonitis, neutropenia and QT interval prolongation (see SmPC section 4.4). Very common adverse events (>1/10) are neutropenia, anaemia, leukopenia, decreased appetite, neuropathy, dysgeusia, vision disorder, dizziness, bradycardia,  diarrhoea, vomiting, nausea, constipation, abdominal pain, elevated transaminases, rash, oedema, fatigue. Commonly reported adverse events (>1/100 to <1/10), are hypophosphataemia, cardiac failure, electrocardiogram QT prolonged, syncope, interstitial lung disease, dyspepsia, oesophagitis, elevated blood alkaline phosphatase, renal cyst, blood creatinine increased, blood testosterone decreased. Uncommon side effects (>1/1000 to <1/100) are gastrointestinal perforation (<1%), hepatic failure (<1%), acute renal failure (<1%) and renal failure (<1%). Refer to SmPC for further information on side effects.

Legal Category: POM. Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium.  

Package quantities, Marketing Authorisation Numbers and Basic NHS Price: XALKORI 200mg, 60 capsules, EU/1/12/793/001 £4689; XALKORI 250mg, 60 capsules, EU/1/12/793/003 £4689.  

Further information is available on request from: Medical Information at Pfizer Limited, Walton Oaks, Dorking Road, Tadworth, Surrey, KT20 7NS, UK. Tel: +44 (0) 1304 616161

Adverse events should be reported.  Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. Adverse events should also be reported to Pfizer Medical Information on 01304 616161.

Last revised: 2/2019

Ref: XI 19_0 

PP-XLK-GBR-0993. March 2019