Alecensa

Treatment with Alecensa should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. A validated ALK assay is necessary for the selection of ALK-positive NSCLC patients. ALK-positive NSCLC status should be established prior to initiation of Alecensa therapy.

Posology The recommended dose of Alecensa is 600 mg (four 150 mg capsules) taken twice daily with food (total daily dose of 1200 mg). Patients with underlying severe hepatic impairment (Child-Pugh C) should receive a starting dose of 450 mg taken twice daily with food (total daily dose of 900 mg).

3 Duration of treatment Adjuvant treatment of resected NSCLC Treatment with Alecensa should be continued until disease recurrence, unacceptable toxicity or for 2 years. Treatment of advanced NSCLC Treatment with Alecensa should be continued until disease progression or unacceptable toxicity.

Delayed or missed doses If a planned dose of Alecensa is missed, patients can make up that dose unless the next dose is due within 6 hours. Patients should not take two doses at the same time to make up for a missed dose. If vomiting occurs after taking a dose of Alecensa, patients should take the next dose at the scheduled time.

Dose adjustments Management of adverse events may require dose reduction, temporary interruption, or discontinuation of treatment with Alecensa. The dose of Alecensa should be reduced in steps of 150 mg twice daily based on tolerability.

Alecensa treatment should be permanently discontinued if patients are unable to tolerate the 300 mg twice daily dose. Dose modification advice is provided in Tables 1 and 2 below. 8) CTCAE grade Alecensa treatment ILD/pneumonitis of any severity grade Immediately interrupt and permanently discontinue Alecensa if no other potential causes of ILD/pneumonitis have been identified.

ALT or AST elevation of > 5 times ULN with total bilirubin  2 times ULN Temporarily withhold until recovery to baseline or ≤ 3 times ULN, then resume at reduced dose (see Table 1). ALT or AST elevation of > 3 times ULN with total bilirubin elevation > 2 times ULN in the absence of cholestasis or haemolysis Permanently discontinue Alecensa.

Bradycardiaa Grade 2 or Grade 3 (symptomatic, may be severe and medically significant, medical intervention indicated) Temporarily withhold until recovery to  Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm. Evaluate concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive medicinal products.

Summary of the safety profile The data described below reflect exposure to Alecensa in 533 patients with resected or advanced ALK-positive NSCLC. These patients received Alecensa at the recommended dose of 600 mg twice daily in pivotal clinical trials for adjuvant treatment of resected NSCLC (BO40336, ALINA) or for treatment of advanced NSCLC (BO28984, ALEX; NP28761; NP28673).

1 for further information on clinical trial participants. 9 months. 1 months. 2 months. The most common adverse drug reactions (ADRs) (≥ 20 %) were constipation, myalgia, oedema, increased bilirubin, increased AST, anaemia, rash and increased ALT.

Tabulated list of adverse drug reactions Table 3 lists the ADRs occurring in patients who received Alecensa across clinical trials (BO40336, BO28984, NP28761, NP28673). The ADRs listed in Table 3 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).

Within each system organ class, undesirable effects are presented in order of decreasing frequency and severity. Within the same frequency and severity grouping, undesirable effects are presented in order of decreasing seriousness. Table 3 ADRs reported in Alecensa clinical trials (BO40336, BO28984, NP28761, NP28673; N = 533) System organ class ADRs (MedDRA) Alecensa N = 533 Frequency category (all grades) Frequency category (grades 3-4) Blood and lymphatic system disorders Anaemia1) Very common Common Haemolytic anaemia2) Common -* Nervous system disorders Dysgeusia3) Common Uncommon Eye disorders Vision disorders4) Common -* Cardiac disorders Bradycardia5) Very common -* Respiratory, thoracic and mediastinal disorders Interstitial lung disease / pneumonitis Common Uncommon Gastrointestinal disorders Diarrhoea Very common Common Vomiting Very common Uncommon Constipation Very common Uncommon Nausea Very common Uncommon Stomatitis6) Common Uncommon Hepatobiliary disorders Increased AST Very common Common Increased ALT Very common Common Increased bilirubin7) Very common Common Increased alkaline phosphatase Very Common Uncommon Drug-induced liver injury8) Uncommon Uncommon Skin and subcutaneous tissue disorders Rash9) Very common Common Photosensitivity Common Uncommon 10 System organ class ADRs (MedDRA) Alecensa N = 533 Frequency category (all grades) Frequency category (grades 3-4) Musculoskeletal and connective tissues disorders Myalgia10) Very common Uncommon Increased blood creatine phosphokinase Very common Common Renal and urinary disorders Blood creatinine increased Very common Uncommon** Acute kidney injury Common Uncommon** General disorders and administration site conditions Oedema11) Very common Uncommon Investigations Weight increased Very common Uncommon Metabolism and Nutrition Disorders Hyperuricaemia12) Common -* *No Grade 3-4 ADRs were observed.

4. Renal impairment No dose adjustment is required in patients with mild or moderate renal impairment. Alecensa has not been studied in patients with severe renal impairment. 2). 2). There are no available data on patients over 80 years of age.

Paediatric population The safety and efficacy of Alecensa in children and adolescents below 18 years of age have not been established. No data are available. e. 9123 kg. There are no available data on patients with body weight above 130 kg.

Method of administration Alecensa is for oral use. The hard capsules should be swallowed whole, and must not be opened or dissolved. 2). 1. 8). Patients should be monitored for pulmonary symptoms indicative of pneumonitis. 2). 8). The majority of these events occurred during the first 3 months of treatment.

In the pivotal Alecensa clinical trials it was reported that three patients with Grade 3-4 AST/ALT elevations had drug induced liver injury. Concurrent elevations in ALT or AST greater than or equal 3 times the ULN and total bilirubin greater than or equal 2 times the ULN, with normal alkaline phosphatase, occurred in one patient treated in Alecensa clinical trials.

Liver function, including ALT, AST, and total bilirubin should be monitored at baseline and then every 2 weeks during the first 3 months of treatment. Thereafter, monitoring should be performed periodically, since events may occur later than 3 months, with more frequent testing in patients who develop aminotransferase and bilirubin elevations.

2). 8). 8). Median time to Grade ≥ 3 CPK elevation was 15 days across clinical trials (BO40336, BO28984, NP28761, NP28673). Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. CPK levels should be assessed every two weeks for the first month of treatment and as clinically indicated in patients reporting symptoms.

2). 8). Heart rate and blood pressure should be monitored as clinically indicated. 2). 5, ‘P-gp substrates’ and ‘BCRP substrates’). 8). If haemoglobin concentration is below 10 g/dL and haemolytic anaemia is suspected, Alecensa should be withheld and appropriate laboratory testing should be initiated.

1.