4.1. Therapeutic indications

Adjuvant Treatment of Resected Non-Small Cell Lung Cancer

Alecensa as monotherapy is indicated as adjuvant treatment for adult patients with Stage IB (tumours ≥4cm) to IIIA (7th edition of the UICC/AJCC-staging system) anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) following complete tumour resection

Treatment of Advanced Non-Small Cell Lung Cancer

Alecensa as monotherapy is indicated for the first-line treatment of adult patients with ALK-positive advanced NSCLC.

Alecensa as monotherapy is indicated for the treatment of adult patients with ALK‑positive advanced NSCLC previously treated with crizotinib.

4.2. Posology and method of administration

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).

Duration of treatment

Adjuvant Treatment of Resected Non-Small Cell Lung Cancer

Treatment with Alecensa should be continued until disease recurrence, unacceptable toxicity or for 2 years.

Treatment of Advanced Non-Small Cell Lung Cancer

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.

Table 1 Dose reduction schedule

Dose reduction schedule

Dose level

Dose

600 mg twice daily

First dose reduction

450 mg twice daily

Second dose reduction

300 mg twice daily

Table 2 Dose modification advice for specified Adverse Drug Reactions (see sections 4.4 and 4.8)

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.

If a contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to ≤ Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm.

If no contributing concomitant medicinal product is identified, or if contributing concomitant medicinal products are not discontinued or dose modified, resume at reduced dose (see Table 1) upon recovery to ≤ Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm.

Bradycardiaa Grade 4 (life-threatening consequences, urgent intervention indicated)

Permanently discontinue if no contributing concomitant medicinal product is identified.

If a contributing concomitant medicinal product is identified and discontinued, or its dose is adjusted, resume at reduced dose (see Table 1) upon recovery to ≤ Grade 1 (asymptomatic) bradycardia or to a heart rate of ≥ 60 bpm, with frequent monitoring as clinically indicated.

Permanently discontinue in case of recurrence.

CPK elevation > 5 times ULN

Temporarily withhold until recovery to baseline or to ≤ 2.5 times ULN, then resume at the same dose.

CPK elevation > 10 times ULN or second occurrence of CPK elevation of > 5 times ULN

Temporarily withhold until recovery to baseline or to ≤ 2.5 times ULN, then resume at reduced dose as per Table 1.

Haemolytic anaemia with haemoglobin of < 10 g/dL (Grade ≥ 2)

Temporarily withhold until resolution, then resume at reduced dose (see Table 1).

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; CTCAE = NCI Common Terminology Criteria for Adverse Events; ILD = interstitial lung disease; ULN = upper limit of normal

a Heart rate less than 60 beats per minute (bpm).

Special populations

Hepatic impairment

No starting dose adjustment is required in patients with underlying mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Patients with underlying severe hepatic impairment (Child-Pugh C) should receive a starting dose of 450 mg taken twice daily (total dose of 900 mg) (see section 5.2). For all patients with hepatic impairment, appropriate monitoring (e.g. markers of liver function) is advised, see section 4.4.

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. However, since alectinib elimination via the kidney is negligible, no dose adjustment is required in patients with severe renal impairment (see section 5.2).

Elderly (≥ 65 years)

The limited data on the safety and efficacy of Alecensa in patients aged 65 years and older do not suggest that a dose adjustment is required in elderly patients (see section 5.2). 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.

Extreme body weight (> 130 kg)

Although pharmacokinetic (PK) simulations for Alecensa do not indicate a low exposure in patients with extreme body weight (i.e. >130 kg), alectinib is widely distributed and clinical studies for alectinib enrolled patients within a range of body weights of 36.9-123 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. They must be taken with food (see section 5.2).

4.3. Contraindications

Hypersensitivity to alectinib or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Interstitial lung disease (ILD)/pneumonitis

Cases of ILD/pneumonitis have been reported in clinical trials with Alecensa (see section 4.8). Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Alecensa should be immediately interrupted in patients diagnosed with ILD/pneumonitis and should be permanently discontinued if no other potential causes of ILD/pneumonitis have been identified (see section 4.2).

Hepatotoxicity

Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 5 times the upper limit of normal (ULN) as well as bilirubin elevations of more than 3 times the ULN occurred in patients in pivotal clinical trials with Alecensa (see section 4.8). 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. Based on the severity of the adverse drug reaction, Alecensa should be withheld and resumed at a reduced dose, or permanently discontinued as described in Table 2 (see section 4.2).

Severe myalgia and creatine phosphokinase (CPK) elevation

Myalgia or musculoskeletal pain was reported in patients in pivotal trials with Alecensa, including Grade 3 events (see section 4.8).

Elevations of CPK occurred in pivotal trials with Alecensa, including Grade 3 events (see section 4.8). 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. Based on the severity of the CPK elevation, Alecensa should be withheld, then resumed or dose reduced (see section 4.2).

Bradycardia

Symptomatic bradycardia can occur with Alecensa (see section 4.8). Heart rate and blood pressure should be monitored as clinically indicated. Dose modification is not required in case of asymptomatic bradycardia (see section 4.2). If patients experience symptomatic bradycardia or life-threatening events, concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive medicinal products should be evaluated and Alecensa treatment should be adjusted as described in Table 2 (see sections 4.2 and 4.5, 'P-gp substrates' and 'BCRP substrates').

Haemolytic anaemia

Haemolytic anaemia has been reported with Alecensa (see section 4.8). If haemoglobin concentration is below 10 g/dL and haemolytic anaemia is suspected, Alecensa should be withheld and appropriate laboratory testing should be initiated. If haemolytic anaemia is confirmed, Alecensa should be resumed at a reduced dose upon resolution as described in Table 2 (see section 4.2).

Gastrointestinal perforation

Cases of gastrointestinal perforations have been reported in patients at increased risk (e.g., history of diverticulitis, metastases to the gastrointestinal tract, concomitant use of medicinal product with a recognised risk of gastrointestinal perforation) treated with alectinib. Discontinuation of Alecensa in patients who develop gastrointestinal perforation should be considered. Patients should be informed of the signs and symptoms of gastrointestinal perforations and advised to consult rapidly in case of occurrence.

Photosensitivity

Photosensitivity to sunlight has been reported with Alecensa administration (see section 4.8). Patients should be advised to avoid prolonged sun exposure while taking Alecensa, and for at least 7 days after discontinuation of treatment. Patients should also be advised to use a broad‑spectrum Ultraviolet A (UVA)/ Ultraviolet B (UVB) sunscreen and lip balm (sun protection factor [SPF] ≥50) to help protect against potential sunburn.

Embryo-foetal toxicity

Alecensa may cause foetal harm when administered to a pregnant woman. Female patients of child‑bearing potential receiving Alecensa, must use highly effective contraceptive methods during treatment and for at least 5 weeks following the last dose of Alecensa (see sections 4.5, 4.6 and 5.3). Male patients with female partners of child-bearing potential must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of Alecensa (see sections 4.6 and 5.3).

Lactose intolerance

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, a congenital lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium content

This medicinal product contains 48 mg sodium per daily dose (1200 mg), equivalent to 2.4 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on alectinib

Based on in vitro data, CYP3A4 is the primary enzyme mediating the metabolism of both alectinib and its major active metabolite M4, and CYP3A contributes to 40 % - 50 % of total hepatic metabolism. M4 has shown similar in vitro potency and activity against ALK.

CYP3A inducers

Co-administration of multiple oral doses of 600 mg rifampicin once daily, a strong CYP3A inducer, with a single oral dose of 600 mg alectinib reduced alectinib Cmax, and AUCinf by 51 % and 73 % respectively and increased M4 Cmax and AUCinf 2.20 and 1.79-fold respectively. The effect on the combined exposure of alectinib and M4 was minor, reducing Cmax and AUCinf by 4 % and 18 %, respectively. Based on the effects on the combined exposure of alectinib and M4, no dose adjustments are required when Alecensa is co-administered with CYP3A inducers. Appropriate monitoring is recommended for patients taking concomitant strong CYP3A inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John's Wort (Hypericum perforatum)).

CYP3A inhibitors

Co-administration of multiple oral doses of 400 mg posaconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 300 mg alectinib increased alectinib exposure Cmax and AUCinf by 1.18 and 1.75-fold respectively, and reduced M4 Cmax and AUCinf by 71 % and 25 % respectively.The effect on the combined exposure of alectinib and M4 was minor, reducing Cmax by 7 % and increasing AUCinf 1.36-fold. Based on the effects on the combined exposure of alectinib and M4, no dose adjustments are required when Alecensa is co-administered with CYP3A inhibitors. Appropriate monitoring is recommended for patients taking concomitant strong CYP3A inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole nefazodone, grapefruit or Seville oranges).

Medicinal products that increase gastric pH

Multiple doses of esomeprazole, a proton pump inhibitor, 40 mg once daily, demonstrated no clinically relevant effect on the combined exposure of alectinib and M4. Therefore, no dose adjustments are required when Alecensa is co-administered with proton pump inhibitors or other medicinal products which raise gastric pH (e.g. H2 receptor antagonists or antacids).

Effect of transporters on alectinib disposition

M4 is a substrate of P-glycoprotein (P-gp). As alectinib inhibits P-gp, it is not expected that co-medication with P-gp inhibitors has a relevant effect on M4 exposure.

Effects of alectinib on other medicinal products

CYP substrates

In vitro, alectinib and M4 show weak time-dependent inhibition of CYP3A4, and alectinib exhibits a weak induction potential of CYP3A4 and CYP2B6 at clinical concentrations.

Multiple doses of 600 mg alectinib had no influence on the exposure of midazolam (2 mg), a sensitive CYP3A substrate. Therefore, no dose adjustment is required for co-administered CYP3A substrates.

A risk for induction of CYP2B6 and pregnane X receptor (PXR) regulated enzymes apart from CYP3A4 cannot be completely excluded. The effectiveness of concomitant administration of oral contraceptives may be reduced.

P-gp substrates

In vitro, alectinib and its major active metabolite M4 are inhibitors of the efflux transporter P-gp. Therefore, alectinib and M4 may have the potential to increase plasma concentrations of co-administered substrates of P-gp. When Alecensa is co-administered with P-gp substrates (e.g., digoxin, dabigatran etexilate, topotecan, sirolimus, everolimus, nilotinib and lapatinib), appropriate monitoring is recommended.

Breast cancer resistance protein (BCRP) substrates

In vitro, alectinib and M4 are inhibitors of the efflux transporter BCRP. Therefore, alectinib and M4 may have the potential to increase plasma concentrations of co‑administered substrates of BCRP. When Alecensa is co-administered with BCRP substrates (e.g., methotrexate, mitoxantrone, topotecan and lapatinib), appropriate monitoring is recommended.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of child-bearing potential must be advised to avoid pregnancy while on Alecensa (see section 4.4).

Contraception in female patients

Female patients of child-bearing potential receiving Alecensa must use highly effective contraceptive methods during treatment and for at least 5 weeks following the last dose of Alecensa (see sections 4.4 and 4.5).

Contraception in male patients

Male patients with female partners of child-bearing potential must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of Alecensa (see section 4.4).

Pregnancy

There are no or limited amount of data from the use of alectinib in pregnant women. Based on its mechanism of action, alectinib may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity (see section 5.3).

Female patients, who become pregnant while taking Alecensa or during the 5 weeks following the last dose of Alecensa must contact their doctor and should be advised of the potential harm to the foetus.

Male patients with female partners who become pregnant while the male patient is taking Alecensa, or during the 3 months following the last dose of Alecensa, must contact their doctor, and their female partner should seek medical advice due to the potential harm to the foetus based on its aneugenic potential (see section 5.3).

Breast-feeding

It is unknown whether alectinib and/or its metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded. Mothers should be advised against breast-feeding while receiving Alecensa.

Fertility

No fertility studies in animals have been performed to evaluate the effect of alectinib. No adverse effects on male and female reproductive organs were observed in general toxicology studies (see section 5.3).

4.7. Effects on ability to drive and use machines

Alecensa has minor influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience symptomatic bradycardia (e.g., syncope, dizziness, hypotension) or vision disorders while taking Alecensa (see section 4.8).

4.8. Undesirable effects

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 clinical trials for adjuvant treatment of resected NSCLC (BO40336 [ALINA]) or for treatment of advanced NSCLC (BO28984 [ALEX]; NP28761; NP28673). See Section 5.1 for further information on clinical trial participants.

In BO40336 (ALINA; N = 128), the median duration of exposure to Alecensa was 23.9 months. In BO28984 (ALEX; N = 152) the median duration of exposure to Alecensa was 28.1 months, whereas the median duration of exposure to crizotinib was 10.8 months.

In the phase II clinical trials (NP28761, NP28673; N = 253), the median duration of exposure to Alecensa was 11.2 months.

The most common adverse drug reactions (ADRs) (≥ 20%) were constipation, myalgia, oedema, increased bilirubin, increased ALT, 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

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.

** Includes one Grade 5 event (observed in the advanced NSCLC setting).

1) includes cases of anaemia, haemoglobin decreased, normochromic normocytic anaemia.

2) cases reported in study BO40336 (N=128).

3) includes cases of dysgeusia, hypogeusia, and taste disorder.

4) includes cases of blurred vision, visual impairment, vitreous floaters, reduced visual acuity, asthenopia, diplopia, photophobia, and photopsia.

5) includes cases of bradycardia and sinus bradycardia.

6) includes cases of stomatitis and mouth ulceration.

7) includes cases of blood bilirubin increased, hyperbilirubinaemia, bilirubin conjugated increased, and blood bilirubin unconjugated increased.

8) includes two patients with reported MedDRA term of drug-induced liver injury as well as one patient with reported Grade 4 increased AST and ALT who had documented drug-induced liver injury by liver biopsy.

9) includes cases of rash, rash maculopapular, dermatitis, dermatitis acneiform, erythema, rash papular, rash pruritic, rash macular, exfoliative rash, and rash erythematous.

10) includes cases of myalgia, musculoskeletal pain, and arthralgia.

11) includes cases of oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital oedema, face oedema, localised oedema, peripheral swelling, face swelling, lip swelling, swelling, joint swelling and eyelid swelling.

12) includes cases of hyperuricaemia and increased blood uric acid.

Description of selected adverse drug reactions

The safety profile of Alecensa was generally consistent across clinical trials in the resected (BO40336) and advanced (BO28984, NP28761, NP28673) NSCLC patient populations.

Interstitial lung disease (ILD) / pneumonitis

Across clinical trials, ILD/pneumonitis occurred in 1.7 % of patients treated with Alecensa. 0.4 % of these cases were Grade 3 and treatment discontinuations due to ILD/pneumonitis occurred in 1.1 % of patients, and in 0.4 % of patients, the event led to dose modifications. In the phase III clinical trial BO28984, Grade 3 or 4 ILD/pneumonitis was not observed in patients receiving Alecensa versus 2.0 % of patients receiving crizotinib. There were no fatal cases of ILD in any of the clinical trials. Patients should be monitored for pulmonary symptoms indicative of pneumonitis (see sections 4.2 and 4.4).

Hepatotoxicity

Across clinical trials, three patients had a documented drug-induced liver injury (including two patients with the reported term drug-induced liver injury and one patient with reported Grade 4 increased AST and ALT who had documented drug-induced liver injury by liver biopsy). Adverse reactions of increased AST and ALT levels (23.6 % and 20.5 % respectively) were reported in patients treated with Alecensa across clinical trials. The majority of these events were of Grade 1 and 2 intensity, and events of Grade ≥ 3 were reported in 3.0 % and 3.2 % of the patients for increased AST and ALT levels, respectively. The events generally occurred during the first 3 months of treatment, were usually transient and resolved upon temporary interruption of Alecensa treatment (reported for 2.3 % and 3.6 % of the patients, respectively) or dose reduction (1.7 % and 1.5 %, respectively). In 1.3 % and 1.5 % of the patients, AST and ALT elevations, respectively, led to withdrawal from Alecensa treatment. Grade 3 or 4 ALT or AST elevations were observed in 4.6 % and 5.3 % of patients receiving Alecensa versus 16.6 % and 10.6 % of patients receiving crizotinib in the phase III clinical trial BO28984.

Adverse reactions of bilirubin elevations were reported in 25.9 % of the patients treated with Alecensa across clinical trials. The majority of the events were of Grade 1 and 2 intensity; Grade ≥ 3 events were reported in 3.9 % of the patients. The events generally occurred during the first 3 months of treatment, were usually transient and the majority resolved upon dose modification. In 8.3 % of patients, bilirubin elevations led to dose modifications and in 2.1 % of patients, bilirubin elevations led to withdrawal from Alecensa treatment. In the phase III clinical trial BO28984, Grade 3 or 4 bilirubin elevations occurred in 5.9 % of patients receiving Alecensa versus no patient receiving crizotinib.

Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in one patient (0.2 %) treated in Alecensa clinical trials.

Patients should be monitored for liver function including ALT, AST, and total bilirubin as outlined in section 4.4 and managed as recommended in section 4.2.

Bradycardia

Cases of bradycardia (11.3 %) of Grade 1 or 2 have been reported in patients treated with Alecensa across clinical trials. No patients had events of Grade ≥ 3 severity. There were 102 of 521 patients (19.6 %) treated with Alecensa, for whom serial ECGs were available, had post-dose heart rate values below 50 beats per minute (bpm). In the phase III clinical trial BO28984 12.4 % of patients treated with Alecensa had post-dose heart rate values below 50 bpm versus 17.6 % of patients treated with crizotinib. Patients who develop symptomatic bradycardia should be managed as recommended in sections 4.2 and 4.4. No case of bradycardia led to withdrawal from Alecensa treatment.

Severe myalgia and CPK elevations

Cases of myalgia (35.3 %) including myalgia events (24.2 %), arthralgia (16.3 %), and musculoskeletal pain (0.8 %) have been reported in patients treated with Alecensa across clinical trials. The majority of events were Grades 1 or 2 and five patients (0.9 %) had a Grade 3 event. Dose modifications of Alecensa treatment due to these adverse events were required for nine patients (1.7 %); Alecensa treatment was not withdrawn due to these events of myalgia. Elevations of CPK occurred in 56.2 % of 491 patients with CPK laboratory data available across clinical trials with Alecensa. The incidence of Grade ≥3 elevations of CPK was 5.5 %. Median time to Grade ≥3 CPK elevation was 15 days across trials. Dose modifications for elevation of CPK occurred in 5.4 % of patients; withdrawal from Alecensa treatment did not occur due to CPK elevations. In the clinical trial BO28984, severe arthralgia was reported in one patient (0.7 %) in the alectinib arm and in two patients (1.3 %) in the crizotinib arm. Grade ≥ 3 elevation of CPK was reported for 3.3 % of patients receiving Alecensa and 4.6 % of patients receiving crizotinib.

Haemolytic anaemia

Haemolytic anaemia has been observed in 3.1 % of patients treated with Alecensa in the clinical trial setting. These cases were Grade 1 or 2 (non-serious) and did not lead to treatment discontinuation. Cases of haemolytic anaemia have been reported in the post-marketing period. Out of the events with known outcome and known action taken with alectinib, the majority recovered or were recovering following a dose modification of alectinib; recovered outcomes without any dose modification have also been reported.

Gastrointestinal effects

Constipation (39.6 %), diarrhoea (18.8 %), nausea (17.6 %), and vomiting (12.4 %) were the most commonly reported gastrointestinal (GI) reactions. Most of these events were of mild or moderate severity; Grade 3 events were reported for diarrhoea (1.1 %), nausea (0.4 %), constipation (0.4 %), and vomiting (0.2 %). These events did not lead to withdrawal from Alecensa treatment. Median time to onset for constipation, nausea, diarrhoea, and/or vomiting events across clinical trials was 21 days. The events declined in frequency after the first month of treatment. In the phase III clinical trial BO28984, Grade 3 and 4 events of nausea and constipation were reported in one patient each (0.7 %), while diarrhoea was reported in 2 patients (1.3 %) in the alectinib arm; The incidence of Grade 3 and 4 events of nausea, vomiting and diarrhoea was 3.3 %, 3.3 % and 2.0 %, respectively, in the crizotinib arm.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Patients who experience overdose should be closely supervised and general supportive care instituted. There is no specific antidote for overdose with Alecensa.