XALKORI

What it is

XALKORI (crizotinib) is supplied as hard gelatin capsules containing 200 mg or 250 mg of crizotinib.

Approved indications

— Treatment of patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). — Treatment of patients with ROS1-positive advanced non-small cell lung cancer (NSCLC).

Dosing overview

The recommended dose schedule of XALKORI is 250 mg taken orally twice daily. Treatment should continue as long as the patient is deriving clinical benefit from therapy. XALKORI may be taken with or without food. 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, the first dose reduction is XALKORI 200 mg taken orally twice daily, and the second dose reduction is XALKORI 250 mg taken orally once daily, with permanent discontinuation if unable to tolerate XALKORI 250 mg taken orally once daily. No starting dose adjustment is needed for patients with mild or moderate renal impairment. The crizotinib dose should be adjusted to 250 mg taken orally once daily in patients with severe renal impairment not requiring peritoneal dialysis or haemodialysis, with potential dose increase to 200 mg twice daily after at least 4 weeks of treatment based on individual safety and tolerability.

Key safety warnings

Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of 1722 patients treated with crizotinib across clinical trials. Concurrent elevations in ALT and/or AST ≥3×ULN and total bilirubin ≥2×ULN have been observed in less than 1% of patients. Transaminase elevations generally occurred within the first 2 months of treatment, with median time to onset of increased Grade 1 or 2 transaminases being 23 days and Grade 3 or 4 transaminases being 43 days. Liver function tests including ALT, AST and total bilirubin should be monitored every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated. Crizotinib has been associated with severe, life-threatening or fatal interstitial lung disease (ILD)/pneumonitis in clinical trials with a frequency of 26 (2%) of 1722 patients treated with crizotinib. These cases generally occurred within 90 days (range 5 days to 790 days) after the initiation of treatment. Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis. Other potential causes of pneumonitis should be excluded. Crizotinib should be permanently discontinued in patients diagnosed with treatment-related ILD/pneumonitis. Automated machine-read QTc prolongation without accompanying arrhythmia has been observed. Crizotinib should be administered with caution to patients who have a history of or predisposition for QTc prolongation or who are taking medications that are known to prolong the QT interval. When using crizotinib in these patients, periodic monitoring with electrocardiograms and electrolytes should be considered. Bradycardia has been reported in clinical studies and it was usually asymptomatic. The full effect of crizotinib on pulse 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. Monthly monitoring of pulse rate and blood pressure is recommended. Severe, life-threatening or fatal adverse events of cardiac failure were reported in clinical studies and during post-marketing surveillance. Patients with or without pre-existing cardiac disorders receiving crizotinib should be monitored for signs and symptoms of heart failure. Dosing interruption, dose reduction or discontinuation should be considered as appropriate if such symptoms are observed. Crizotinib has been associated with neutropenia and, less commonly, febrile neutropenia. Dosing interruption is recommended in patients with Grade 3-4 neutropenia. Onset of neutropenia may occur after many months of exposure to crizotinib. 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 medications with a recognised risk of gastrointestinal perforation). Crizotinib should be discontinued in patients who develop gastrointestinal perforation. Patients should be informed of the signs of gastrointestinal perforation and be advised to consult their doctor immediately if these signs are experienced. In clinical studies with crizotinib in patients with either ALK-positive or ROS1-positive NSCLC (N=1722), Grade 4 visual field defect with vision loss has been reported in 4 (0.2%) patients. Optic atrophy and optic nerve disorder have been reported as potential causes of vision loss. 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.

Contraindications

Use of XALKORI is contraindicated in patients with hypersensitivity to crizotinib or to any of the excipients.

PBS listing

XALKORI 250 mg capsules and 200 mg capsules are listed on the PBS with 2 items each. Both strengths have authority required restrictions, with an ex-manufacturer price of A$6433.30.

Regulatory history

XALKORI crizotinib 250 mg and 200 mg capsules were first listed on the ARTG on 27 September 2013. An AusPAR was issued on 24 September 2013 for the indication of treatment of patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). In March 2017, PBAC recommended a change to remove the requirement for patients to be registered for the MES and to remove the restriction pertaining to grandfathered patients, as the MES concluded. In November 2017, PBAC recommended an amendment to the PBS listing to allow crizotinib to be used as first-line therapy for ALK-positive advanced NSCLC. In July 2018, PBAC recommended a new listing for Stage IIIB (locally advanced) or Stage IV (metastatic) NSCLC with a ROS1 gene rearrangement, acknowledging high unmet clinical need and cost-effectiveness at the proposed price.