Alectinib

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

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). For all patients with hepatic impairment, appropriate monitoring (e.g. markers of liver function) is advised.

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, alectinib should be withheld and resumed at a reduced dose, or permanently discontinued.

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.

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 alectinib is co-administered with P-gp substrates (e.g., digoxin, dabigatran etexilate, topotecan, sirolimus, everolimus, nilotinib and lapatinib), appropriate monitoring is recommended.

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 C_max and AUC_inf by 1.18 and 1.75-fold respectively, and reduced M4 C_max and AUC_inf by 71% and 25% respectively. The effect on the combined exposure of alectinib and M4 was minor, reducing C_max by 7% and increasing AUC_inf 1.36-fold. Based on the effects on the combined exposure of alectinib and M4, no dose adjustments are required when alectinib 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).

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 C_max, and AUC_inf by 51% and 73% respectively and increased M4 C_max and AUC_inf 2.20 and 1.79-fold respectively. The effect on the combined exposure of alectinib and M4 was minor, reducing C_max and AUC_inf by 4% and 18%, respectively. Based on the effects on the combined exposure of alectinib and M4, no dose adjustments are required when alectinib 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)).

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.

Female patients, who become pregnant while taking alectinib or during the 3 months following the last dose of alectinib must contact their doctor and should be advised of the potential harm to the foetus.

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 alectinib.

Women of childbearing potential/Contraception

Women of childbearing potential must be advised to avoid pregnancy while on alectinib. Female patients of child-bearing potential receiving alectinib must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of alectinib.

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.

Alectinib 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 alectinib.

Summary of the safety profile

The data described below reflect exposure to alectinib in 533 patients with resected or advanced ALK-positive NSCLC. These patients received alectinib 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).

In BO40336 (ALINA; N=128), the median duration of exposure to alectinib was 23.9 months. In BO28984 (ALEX; N=152) the median duration of exposure to alectinib was 28.1 months, In the phase II clinical trials (NP28761, NP28673; N=253), the median duration of exposure to alectinib 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

The table below lists the ADRs occurring in patients who received alectinib across clinical trials (BO40336, BO28984, NP28761, NP28673).

The ADRs listed in the table below 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.

ADRs reported in alectinib clinical trials (BO40336, BO28984, NP28761, NP28673; N=533):

^* 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 alectinib, 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 alectinib 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.

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 alectinib 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 alectinib 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 alectinib treatment. Grade 3 or 4 ALT or AST elevations were each observed in 5% of patients receiving alectinib 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 alectinib 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 alectinib treatment. In the phase III clinical trial BO28984, Grade 3 or 4 bilirubin elevations occurred in 3.9% of patients receiving alectinib 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 alectinib clinical trials.

Patients should be monitored for liver function including ALT, AST, and total bilirubin.

Bradycardia

Cases of bradycardia (11.1%) of Grade 1 or 2 have been reported in patients treated with alectinib across clinical trials. No patients had events of Grade 3 severity. There were 102 of 521 patients (19.6%) treated with alectinib, 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 alectinib had post-dose heart rate values below 50 bpm versus 21% of patients treated with crizotinib.

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 alectinib 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 alectinib treatment due to these adverse events were required for nine patients (1.7%); alectinib 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 alectinib. 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 alectinib 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 alectinib and 3.3% of patients receiving crizotinib.

Haemolytic anaemia

Haemolytic anaemia has been observed in 3.1% of patients treated with alectinib in the clinical trial setting. These cases were Grade 1 or 2 (non-serious) and did not lead to treatment discontinuation.

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 alectinib 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.