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Alectinib

Interactions

Active ingredient Alectinib interacts in the following cases:

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

CYP3A4 substrates, CYP2B6 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.

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

Strong CYP3A4 inhibitors

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).

Strong CYP3A4 inducers

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)).

Moderate (Child-Pugh B) to severe (Child-Pugh C) 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). For all patients with hepatic impairment, appropriate monitoring (e.g. markers of liver function) is advised.

Effects on ability to drive and use machines

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.

Lactation

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.

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.

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.

Interstitial lung disease (ILD), pneumonitis

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.

Bradycardia

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 ULNTemporarily 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).

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 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 ULNTemporarily 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).

Severe myalgia, creatine phosphokinase (CPK) elevation

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

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.

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.

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.

Nursing mothers

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.

Carcinogenesis, mutagenesis and fertility

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.

Effects on ability to drive and use machines

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.