Adverse reactions : תופעות לוואי

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 pivotal 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, 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, anaemia, rash, increased bilirubin, increased ALT and increased AST.

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 <1/1000), 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                                              Alecensa ADRs (MedDRA)                                                  N=533
Frequency category                Frequency category
(all grades)                     (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 /
Common                              Uncommon pneumonitis
Gastrointestinal disorders
Diarrhoea                              Very common                            Uncommon Vomiting                               Very common                            Uncommon Constipation                           Very common                            Uncommon Nausea                                 Very common                            Uncommon 6)
Stomatitis                                Common                              Uncommon Hepatobiliary disorders
Increased AST                          Very common                             Common Increased ALT                          Very common                             Common Increased bilirubin7)                  Very common                             Common Increased alkaline
Very Common                            Uncommon phosphatase
8)
Drug-induced liver injury                Uncommon                             Uncommon Skin and subcutaneous tissue disorders
Rash9)                                 Very common                             Common Photosensitivity                          Common                              Uncommon 

System organ class                                                    Alecensa ADRs (MedDRA)                                                        N=533 Frequency category                           Frequency category
(all grades)                               (grades 3-4)
Musculoskeletal and connective tissues disorders
Myalgia10)                              Very common                                   Uncommon Increased blood creatine
Very common                                    Common phosphokinase
Renal and urinary disorders
Acute kidney injury                      Uncommon                                    Uncommon** Blood creatinine increased                Common                                     Uncommon** General disorders and administration site conditions
Oedema 11)                              Very common                                   Uncommon Investigations
Weight increased                        Very common                                   Uncommon Metabolism and Nutrition Disorders
Hyperuricaemia 12)                          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 and 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 acneiform, erythema, rash generalised, 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

Interstitial lung disease (ILD) / pneumonitis
Across clinical trials, ILD/pneumonitis occurred in 1.3% of patients treated with Alecensa, 0.4% of these cases were Grade 3 and treatment discontinuations due to ILD/pneumonitis occurred in 0.9% of patients. 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 (22.7% and 20.1% 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 1.1%
and 1.3% of the patients, AST and ALT elevations, respectively, led to withdrawal from Alecensa treatment. Grade 3 or 4 ALT or AST elevations were each observed in 5% of patients receiving Alecensa versus 16% and 11% of patients receiving crizotinib in the phase III clinical trial BO28984.

Adverse reactions of bilirubin elevations were reported in 25.1% 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 3.4% 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 7.7% of patients, bilirubin elevations led to dose modifications and in 1.5% 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 3.9% 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 (11.1%) 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 15% of patients treated with Alecensa had post-dose heart rate values below 50 bpm versus 21% 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 (34.9%) including myalgia events (24.0%), arthralgia (16.1%), and musculoskeletal pain (0.9%) 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 55.6% 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 5.3% 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 3.9% of patients receiving Alecensa and 3.3% 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 (see sections 4.2 and 4.4).

Gastrointestinal effects
Constipation (38.6%), nausea (17.4%), diarrhoea (17.4%) and vomiting (12.0%) 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 (0.9%), nausea (0.4%), vomiting (0.2%), and constipation (0.4%). 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, diarrhoea and constipation were reported in one patient each (0.7%) in the alectinib arm and the incidence of Grade 3 and 4 events of nausea, diarrhoea and vomiting was 3.3%, 2.0% and 3.3%, 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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/