Chemical formula: C₃₀H₃₄N₄O₂ Molecular mass: 482.617 g/mol PubChem compound: 49806720
Alectinib interacts in the following cases:
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.
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.
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 alectinib is co-administered with P-gp substrates (e.g., digoxin, dabigatran etexilate, topotecan, sirolimus, everolimus, nilotinib and lapatinib), appropriate monitoring is recommended.
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.
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 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).
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.
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 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)).
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.
Cases of interstitial lung disease (ILD), pneumonitis have been reported in clinical trials with alectinib. Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Alectinib 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.
Symptomatic bradycardia can occur with alectinib. Heart rate and blood pressure should be monitored as clinically indicated. Dose modification is not required in case of asymptomatic bradycardia. 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 alectinib treatment should be adjusted as described in the following table.
Dose modification advice for specified Adverse Drug Reactions:
| CTCAE grade | Alectinib treatment |
|---|---|
| ILD/pneumonitis of any severity grade | Immediately interrupt and permanently discontinue alectinib if no other potential causes of ILD/pneumonitis have been identified. |
| ALT or AST elevation of Grade ≥3 (>5 times ULN) with total bilirubin ≤2 times ULN | Temporarily withhold until recovery to baseline or ≤ Grade 1 (≤3 times ULN), then resume at reduced dose. |
| ALT or AST elevation of Grade ≥2 (>3 times ULN) with total bilirubin elevation >2 times ULN in the absence of cholestasis or haemolysis | Permanently discontinue alectinib. |
| 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 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 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. |
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).
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 alectinib. The majority of these events occurred during the first 3 months of treatment. In the pivotal alectinib 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 alectinib 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, alectinib should be withheld and resumed at a reduced dose, or permanently discontinued as described in the following table.
Dose modification advice for specified Adverse Drug Reactions:
| CTCAE grade | Alectinib treatment |
|---|---|
| ILD/pneumonitis of any severity grade | Immediately interrupt and permanently discontinue alectinib if no other potential causes of ILD/pneumonitis have been identified. |
| ALT or AST elevation of Grade ≥3 (>5 times ULN) with total bilirubin ≤2 times ULN | Temporarily withhold until recovery to baseline or ≤ Grade 1 (≤3 times ULN), then resume at reduced dose. |
| ALT or AST elevation of Grade ≥2 (>3 times ULN) with total bilirubin elevation >2 times ULN in the absence of cholestasis or haemolysis | Permanently discontinue alectinib. |
| 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 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 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. |
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).
Myalgia or musculoskeletal pain was reported in patients in pivotal trials with alectinib, including Grade 3 events.
Elevations of CPK occurred in pivotal trials with alectinib, including Grade 3 events. 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, alectinib should be withheld, then resumed or dose reduced.
Photosensitivity to sunlight has been reported with alectinib administration. Patients should be advised to avoid prolonged sun exposure while taking alectinib, 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.
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 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 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.
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.
The data described below reflect exposure to alectinib 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 alectinib was 11 months. In BO28984 (ALEX; N=152) the median duration of exposure to alectinib 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).
The following list presents the ADRs occurring in patients who received alectinib across two phase II clinical trials (NP28761, NP28673) and one phase III clinical trial (BO28984; ALEX), and during post-marketing.
The ADRs in the list 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.
ADRs reported in alectinib clinical trials (NP28761, NP28673. BO28984; N=405) and during post-marketing:
| System organ class (ADRs) (MedDRA) | Alectinib N=405 | ||
|---|---|---|---|
| All grades (%) | Frequency category (all grades) | Grades 3-4 (%) | |
| Blood and lymphatic system disorders | |||
| Anaemia1 | 17 | Very common | 3.0 |
| Nervous system disorders | |||
| Dysgeusia2 | 5.2 | Common | 0.2 |
| Eye disorders | |||
| Vision disorders3 | 8.6 | Common | 0 |
| Cardiac disorders | |||
| Bradycardia4 | 8.9 | Common | 0 |
| Respiratory, thoracic and mediastinal disorders | |||
| Interstitial lung disease/pneumonitis | 0.7 | Uncommon | 0.2 |
| Gastrointestinal disorders | |||
| Constipation | 35 | Very common | 0 |
| Nausea | 19 | Very common | 0.5 |
| Diarrhoea | 16 | Very common | 0.7 |
| Vomiting | 11 | Very common | 0.2 |
| Stomatitis5 | 3.0 | Common | 0 |
| Hepatobiliary disorders | |||
| Increased bilirubin6 | 18 | Very common | 3.2 |
| Increased AST | 15 | Very common | 3.7 |
| Increased ALT | 14 | Very common | 3.7 |
| Increased alkaline phosphatase** | 6.2 | Common | 0.2 |
| Drug-induced liver injury7 | 0.7 | Uncommon | 0.7 |
| Skin and subcutaneous tissue disorders | |||
| Rash8 | 18 | Very common | 0.5 |
| Photosensitivity | 9.1 | Common | 0.2 |
| Musculoskeletal and connective tissues disorders | |||
| Myalgia9 | 28 | Very common | 0.7 |
| Increased blood creatine phosphokinase | 10 | Very common | 3.2 |
| Renal and urinary disorders | |||
| Blood creatinine increased | 7.2 | Common | 0.7* |
| Acute kidney injury | 1.0 | Common | 1.0* |
| General disorders and administration site conditions | |||
| Oedema10 | 30 | Very common | 0.7 |
| Investigations | |||
| Weight increased | 12 | Very common | 0.7 |
* 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
The safety profile of alectinib was generally consistent across the pivotal phase III clinical trial BO28984 (ALEX) and phase II trials (NP28761, NP28673).
Severe ILD/pneumonitis occurred in patients treated with alectinib. Across clinical trials (NP28761, NP28673. BO28984), 1 out of 405 patients treated with alectinib (0.2%) had a Grade 3 ILD. This event led to withdrawal from alectinib treatment. 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.
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 alectinib treatment. Adverse reactions of increased AST and ALT levels (15% and 14% respectively) were reported in patients treated with alectinib 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 alectinib 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 alectinib treatment. Grade 3 or 4 ALT or AST elevations were each observed in 5% of patients receiving alectinib 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 alectinib 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 alectinib treatment. In the phase III clinical trial BO28984, Grade 3 or 4 bilirubin elevations occurred in 3.3% 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 as outlined in section 4.4 and managed as recommended in section 4.2.
Cases of bradycardia (8.9%) of Grade 1 or 2 have been reported in patients treated with alectinib across clinical trials (NP28761, NP28673. BO28984). No patients had events of Grade ≥3 severity. There were 66 of 365 patients (18%) treated with alectinib 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 alectinib 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 alectinib treatment.
Cases of myalgia (28%) including myalgia events (22%) and musculoskeletal pain (7.4%) have been reported in patients treated with alectinib 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 alectinib treatment due to these adverse events were only required for two patients (0.5%); alectinib 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 alectinib. 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 alectinib 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 alectinib 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).
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 alectinib 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 alectinib 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.
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