ALECENSA Hard capsule Ref.[6109] Active ingredients: Alectinib

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 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 14 days across clinical trials (NP28761, NP28673, BO28984).

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’).

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) sun screen and lip balm (SPF ≥50) to help protect against potential sunburn.

Women of child-bearing potential

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 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.

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 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 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 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 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-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

P-gp substrates

In vitro, alectinib and its major active metabolite M4 are inhibitors of the efflux transporter P-glycoprotein (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.

BCRP substrates

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 Alecensa is co-administered with BCRP substrates (e.g., methotrexate, mitoxantrone, topotecan and lapatinib), appropriate monitoring is recommended.

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 PXR regulated enzymes apart from CYP3A4 cannot be completely excluded. The effectiveness of concomitant administration of oral contraceptives may be reduced.

Women of childbearing potential/contraception

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

Pregnancy

There are no or limited amount of data from the use of Alecensa in pregnant women. Based on its mechanism of action, Alecensa 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 3 months following the last dose of Alecensa must contact their doctor and should be advised of the potential harm to the foetus.

Breast-feeding

It is unknown whether alectinib and 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 Alecensa. No adverse effects on male and female reproductive organs were observed in general toxicology studies (see section 5.3).

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).

Summary of the safety profile

The data described below reflect exposure to Alecensa in 405 patients with ALK-positive advanced NSCLC who participated in one randomised Phase III clinical trial (BO28984) and in two single-arm phase II clinical trials (NP28761, NP28673). These patients were treated with the recommended dose of 600 mg twice daily. In the phase II clinical trials (NP28761, NP28673; N=253), the median duration of exposure to Alecensa was 11 months. In BO28984 (ALEX; N=152) the median duration of exposure to Alecensa was 17.9 months, whereas the median duration of exposure to crizotinib was 10.7 months.

The most common adverse drug reactions (ADRs) (≥20%) were constipation (35%), oedema (30%, including oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital oedema, face oedema and localised oedema), and myalgia (28%, including myalgia and musculoskeletal pain).

Tabulated list of adverse drug reactions

Table 3 lists the ADRs occurring in patients who received Alecensa across two phase II clinical trials (NP28761, NP28673) and one phase III clinical trial (BO28984; ALEX), and during post-marketing.

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.

Table 3. ADRs reported in Alecensa clinical trials (NP28761, NP28673. BO28984; N=405) and during post-marketing:

* Includes one Grade 5 event
** Increased alkaline phosphatase was reported in the post-marketing period and in pivotal phase II and phase III clinical trials.
¹ includes cases of anaemia and haemoglobin decreased
² includes cases of dysgeusia and hypogeusia
³ includes cases of blurred vision, visual impairment, vitreous floaters, reduced visual acuity, asthenopia, and diplopia
⁴ includes cases of bradycardia and sinus bradycardia
⁵ includes cases of stomatitis and mouth ulceration
⁶ includes cases of blood bilirubin increased, hyperbilirubinaemia and bilirubin conjugated increased
⁷ 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
⁸ includes cases of rash, rash maculopapular, dermatitis acneiform, erythema, rash generalised, rash papular, rash pruritic, rash macular and exfoliative rash
⁹ includes cases of myalgia and musculoskeletal pain
¹⁰ includes cases of oedema peripheral, oedema, generalised oedema, eyelid oedema, periorbital oedema, face oedema and localised oedema

Description of selected adverse drug reactions

The safety profile of Alecensa was generally consistent across the pivotal phase III clinical trial BO28984 (ALEX) and phase II trials (NP28761, NP28673).

Interstitial lung disease (ILD) / pneumonitis

Severe ILD/pneumonitis occurred in patients treated with Alecensa. Across clinical trials (NP28761, NP28673. BO28984), 1 out of 405 patients treated with Alecensa (0.2%) had a Grade 3 ILD. This event led to withdrawal from Alecensa treatment. 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 (NP28761, NP28673. BO28984) two patients with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by liver biopsy. In addition, one patient experienced a Grade 4 adverse event of drug-induced liver injury. Two of these cases led to withdrawal from Alecensa treatment. Adverse reactions of increased AST and ALT levels (15% and 14% respectively) were reported in patients treated with Alecensa across clinical trials (NP28761, NP28673. BO28984). The majority of these events were of Grade 1 and 2 intensity, and events of Grade ≥3 were reported in 3.7% and 3.7% of the patients, 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 1.5% and 3.0% of the patients, respectively) or dose reduction (2.2% and 1.2%, respectively). In 1.2% 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 each observed in 5% of patients receiving Alecensa versus 15% and 11% of patients receiving crizotinib in the phase III clinical trial BO28984.

Adverse reactions of bilirubin elevations were reported in 18% of the patients treated with Alecensa across clinical trials (NP28761, NP28673. BO28984). The majority of the events were of Grade 1 and 2 intensity; Grade 3 events were reported in 3.2% 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 5.2% 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 3.3% 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 (8.9%) of Grade 1 or 2 have been reported in patients treated with Alecensa across clinical trials (NP28761, NP28673. BO28984). No patients had events of Grade ≥3 severity. There were 66 of 365 patients (18%) treated with Alecensa who had post-dose heart rate values below 50 beats per minutes (bpm). In the phase III clinical trial BO28984 15% of patients treated with Alecensa had post-dose heart rate values below 50 bpm versus 20% 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 (28%) including myalgia events (22%) and musculoskeletal pain (7.4%) have been reported in patients treated with Alecensa across clinical trials (NP28761, NP28673. BO28984). The majority of events were Grades 1 or 2 and three patients (0.7%) had a Grade 3 event. Dose modifications of Alecensa treatment due to these adverse events were only required for two patients (0.5%); Alecensa treatment was not withdrawn due to these events of myalgia. Elevations of CPK occurred in 43% of 362 patients with CPK laboratory data available across clinical trials (NP28761, NP28673. BO28984) with Alecensa. The incidence of Grade 3 elevations of CPK was 3.7%. Median time to Grade 3 CPK elevation was 14 days across trials (NP28761, NP28673. BO28984). Dose modifications for elevation of CPK occurred in 3.2% of patients; withdrawal from Alecensa treatment did not occur due to CPK elevations. Severe myalgia has not been reported in the clinical trial BO28984. Grade 3 elevation of CPK was reported for 2.6% of patients receiving Alecensa and 1.3% of patients receiving crizotinib; and median time to Grade 3 CPK elevation was 27.5 days and 369 days, respectively, in the pivotal phase III clinical trial BO28984 (ALEX).

Gastrointestinal effects

Constipation (35%), nausea (19%), diarrhoea (16%) and vomiting (11%) were the most commonly reported gastrointestinal (GI) reactions. Most of these events were of mild or moderate severity; Grade 3 events were reported for diarrhea (0.7%), nausea (0.5%), and vomiting (0.2%). These events did not lead to withdrawal from Alecensa treatment. Median time to onset for constipation, nausea, diarrhea, and/or vomiting events across clinical trials (NP28761, NP28673. BO28984) was 21 days. The events declined in frequency after the first month of treatment. In the phase III clinical trial BO28984, one patient (0.2%) experienced a Grade 4 event of nausea in the Alecensa arm and the incidence of Grade 3 and 4 events for 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 national reporting system listed in Appendix V.

Not applicable.