Xalkori

Treatment with XALKORI should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. 1 for information on assays used in the clinical studies). ALK-positive NSCLC, ROS1-positive NSCLC, ALK-positive ALCL or ALK-positive IMT status should be established prior to initiation of crizotinib therapy.

4). Posology Adult patients with ALK-positive or ROS1-positive advanced NSCLC The recommended dose schedule of crizotinib is 250 mg twice daily (500 mg daily) taken continuously. Paediatric patients with ALK-positive ALCL or ALK-positive IMT The recommended starting dose schedule of crizotinib in paediatric patients is based on body surface area (BSA).

The recommended dosage of crizotinib for paediatric patients with ALCL or IMT is 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. 34 m2 is provided in Table 1. If needed, attain the desired dose by combining different strengths of crizotinib capsules.

Table 1. 70 m2 500 mg (2 × 250 mg capsule) 1000 mg * Refers to the XALKORI 200 mg and 250 mg hard capsules. 34 m2, refer to Table 2. 34 m2, the granules in capsules for opening formulation of XALKORI should be used. 34 m2 is provided in Table 2.

The granules are encapsulated into 3 dosage strengths: 20 mg, 50 mg and 150 mg crizotinib. If needed, attain the desired dose by combining different strengths of crizotinib granules in capsules for opening. No more than 4 capsules will be required for a single dose (see Table 2).

Table 2. 33 m2 350 mg (1 × 50 mg + 2 × 150 mg) 700 mg * Refers to the 20 mg, 50 mg and 150 mg crizotinib granules in capsules for opening. 38 m2 has not been established. 34 m2, refer to Table 1. Administer crizotinib to paediatric patients under adult supervision.

Dose adjustments Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. Adult patients with ALK-positive or ROS1-positive advanced NSCLC In 1722 adult patients treated with crizotinib with either ALK-positive or ROS1-positive NSCLC across clinical studies, the most frequent adverse reactions (≥3%) associated with dosing interruptions were neutropenia, elevated transaminases, vomiting, and nausea.

The most frequent adverse reactions (≥3%) associated with dose reductions were elevated transaminases and neutropenia. If dose reduction is necessary for patients treated with crizotinib 250 mg orally twice daily, then the dose of crizotinib should be reduced as below.

1). These patients received a starting oral dose of 250 mg taken twice daily continuously. In Study 1014, the median duration of study treatment was 47 weeks for patients in the crizotinib arm (N=171); the median duration of treatment was 23 weeks for patients who crossed over from the chemotherapy arm to receive crizotinib treatment (N=109).

In Study 1007, the median duration of study treatment was 48 weeks for patients in the crizotinib arm (N=172). For ALK-positive NSCLC patients in Studies 1001 (N=154) and 1005 (N=1063), the median duration of treatment was 57 and 45 weeks, respectively.

For ROS1-positive NSCLC patients in Study 1001 (N=53), the median duration of treatment was 101 weeks. 4). The most common adverse reactions (≥25%) in patients with either ALK-positive or ROS1-positive NSCLC were vision disorder, nausea, diarrhoea, vomiting, oedema, constipation, elevated transaminases, fatigue, decreased appetite, dizziness and neuropathy.

The most frequent adverse reactions (≥3%, all-causality frequency) associated with dosing interruptions were neutropenia (11%), elevated transaminases (7%), vomiting (5%) and nausea (4%). The most frequent adverse reactions (≥3%, all-causality frequency) associated with dose reductions were elevated transaminases (4%) and neutropenia (3%).

All-causality adverse events associated with permanent treatment discontinuation occurred in 302 (18%) patients of which the most frequent (≥1%) were ILD (1%) and elevated transaminases (1%). 1). 18 The adverse reactions listed in Table 9 are presented by system organ class and frequency categories, defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 9. Adverse reactions reported in crizotinib clinical studies of NSCLC (N=1722) System organ class Very common Common Uncommon Blood and lymphatic system disorders Neutropaeniaa (22%) Anaemiab (15%) Leukopeniac (15%) Metabolism and nutrition disorders Decreased appetite (30%) Hypophosphataemia (6%) Nervous system disorders Neuropathyd (25%) Dysgeusia (21%) Eye disorders Vision disordere (63%) Cardiac disorders Dizzinessf (26%) Bradycardiag (13%) Cardiac failureh (1%) Electrocardiogram QT prolonged (4%) Syncope (3%) Respiratory, thoracic and mediastinal disorders Interstitial lung diseasei (3%) Gastrointestinal disorders Vomiting (51%) Diarrhoea (54%) Nausea (57%) Constipation (43%) Abdominal painj (21%) Oesophagitisk (2%) Dyspepsia (8%) Gastrointestinal perforationl (<1%) Hepatobiliary disorders Elevated transaminasesm (32%) Blood alkaline phosphatase increased (7%) Hepatic failure (<1%) Skin and subcutaneous tissue disorders Rash (13%) Photosensitivity (<1%) Renal and urinary disorders Renal cystn (3%) Blood creatinine increasedo (8%) Acute renal failure (<1%) Renal failure (<1%) General disorders and administration site conditions Oedemap (47%) Fatigue (30%) Investigations Blood testosterone decreasedq (2%) Blood creatine phosphokinase increased (<1%)* Event terms that represent the same medical concept or condition were grouped together and reported as a single adverse drug reaction in Table 9.

Assessment of ALK and ROS1 status When assessing either ALK or ROS1 status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations. 8). Liver function tests including ALT, AST, and total bilirubin should be monitored once a week during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for Grades 2, 3 or 4 elevations.

2. Interstitial lung disease/pneumonitis Severe, life-threatening or fatal ILD/pneumonitis can occur in patients treated with crizotinib. Patients with pulmonary symptoms indicative of ILD/pneumonitis should be monitored. Crizotinib treatment should be withheld if ILD/pneumonitis is suspected.

Drug-induced ILD/pneumonitis should be considered in the differential diagnosis of patients with ILD-like conditions such as: pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonitis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), alveolitis, lung infiltration, pneumonia, pulmonary oedema, chronic obstructive pulmonary disease, pleural effusion, aspiration pneumonia, bronchitis, obliterative bronchiolitis and bronchiectasis.

8). , Torsade de Pointes) or sudden death. The benefits and potential risks of crizotinib should be considered before beginning therapy in patients with pre-existing bradycardia, who have a history of or predisposition for 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. , 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 at the beginning of treatment in case of vomiting, diarrhoea, dehydration or impaired renal function.

1.