You are using an outdated browser. We suggest you update your browser for a better experience. Click here for update.
Close this notification.
Skip to main content Skip to search
A - Drug Name

alectinib

SYNONYM(S):   ALK inhibitor CH5424802

COMMON TRADE NAME(S):   Alecensaro™ ()

 
B - Mechanism of Action and Pharmacokinetics

Alectinib is a highly selective and potent ALK and RET (Rearranged during Transfection) tyrosine kinase inhibitor.  It inhibits ALK phosphorylation and ALK-mediated downstream signalling pathways (STAT 3 and PI3K/AKT) and induces apoptosis.  Alectinib has shown activity against mutant forms of the ALK enzyme, including mutations responsible for resistance to crizotinib.



Absorption

Rapidly absorbed; Tmax approx. 4 to 6 hours after oral administration

Time to reach steady state

7 days (with continuous 600 mg BID dosing)

Bioavailability

36.9% under fed conditions (healthy subjects)

Effects with food

Exposure increased 3-fold after a high-fat, high-calorie meal vs fasting


Distribution
PPB

Highly bound to human plasma proteins (>99%)

Cross blood brain barrier?

Yes (alectinib).  CNS penetration of M4 metabolite has not been studied.

Metabolism
Main enzymes involved

CYP3A4

Active metabolites

M4 (has shown similar in vitro potency and activity to alectinib)

Elimination
Feces

98% (84% alectinib and 6% M4)

Half-life

32.5 hours (alectinib) and 30.7 hours (M4)

 
C - Indications and Status
Health Canada Approvals:

First-line treatment of patients with anaplastic lymphoma kinase (ALK)-positive, locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC).



Health Canada Conditional Approvals
(pending the result of studies to verify the drug’s clinical benefit. Patients should be advised of the nature of the marketing authorization granted.)

Monotherapy for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, locally advanced (not amenable to curative therapy) or metastatic NSCLC who have progressed on or are intolerant to crizotinib.

Note: Approval is based on tumour objective response rate and duration of response; no overall survival benefit has been demonstrated.



 
D - Adverse Effects

Emetogenic Potential:  

Low

Extravasation Potential:   Not applicable

The following table lists adverse effects that occurred in ≥ 2% of patients treated with alectinib in the Phase III clinical trial in first-line NSCLC.  Severe adverse effects from other studies or post-marketing are also included.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Atrioventricular block (rare) E  D
Bradycardia (11%) E
QT interval prolonged (rare) E  D
Dermatological Dry skin (4%) E
Photosensitivity (5%) E  D
Rash (15%) E
Gastrointestinal Constipation (34%) E
Diarrhea (12%) E
GI perforation (rare) E  D
Mucositis (3%) E
Nausea, vomiting (14%) E
General Edema (22%) E
Fatigue (26%) E  D
Hematological Anemia (62%) (7% severe) E  D
Hepatobiliary ↑ LFTs (53%) (6% severe) E
Musculoskeletal Musculoskeletal pain (23%) E
↑CPK (37%) (3% severe) E
Nervous System Dizziness (8%) E
Dysgeusia (3%) E
Ophthalmic Visual disorders (5%) E
Renal Creatinine increased (38%) (3% severe) E
Respiratory Other Pneumonitis /eosinophilic pneumonia (maybe severe) E  D


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for alectinib include anemia, ↑ LFTs, creatinine increased, ↑CPK, constipation, fatigue, musculoskeletal pain, edema, rash, nausea and vomiting.

Bradycardia correlates with plasma levels and is reversible. Patients should be informed about symptoms of bradycardia and advised to report these to the health care team. Co-administration of medications that lower HR should be avoided, if possible.

Hepatotoxicity usually occurs during the first 3 months of therapy and is usually transient and reversible.

Myalgia and elevations of creatinine phosphokinase (CPK) are common, usually present early and are rarely severe.

Photosensitivity has been reported.  Patients should avoid prolonged sun exposure while taking alectinib and for at least 7 days after discontinuation.

 
E - Dosing

Refer to protocol by which patient is being treated.



Adults:


Patients must have documented ALK-positive status, based on a validated ALK assay, prior to starting treatment with alectinib.

Patients must avoid sun exposure while on treatment and for 7 days after the last dose, and must use UVA/B sunscreen and lip balm (at least SPF 50).


Oral: 600 mg BID with food until disease progression or unacceptable toxicity

Dosage with Toxicity:

Dose reduction levels:

Dose level Dose (mg) BID
Starting Dose 600
-1 450
-2 300*

* if unable to tolerate 300 mg bid, permanently discontinue

 

Dose Modification for Toxicity:

Toxicity

Action

GI perforation

Discontinue.

ILD/pneumonitis of any Grade

Hold; if confirmed, discontinue.

Grade 3 Renal Impairment

Hold until serum creatinine recovers to baseline or ≤ Grade 1, then resume at 1 dose level ↓.

Grade 4 Renal Impairment

Discontinue.

≥ Grade 3 ALT or AST elevation (> 5 x ULN)

and

Total bilirubin ≤ 2 x ULN

Hold until recovery to baseline or ≤ Grade 1;

Resume at 1 dose level ↓.

≥ Grade 2 ALT or AST elevation (> 3 x ULN)

and

Total bilirubin ≥ 2 x ULN

(in absence of cholestasis or hemolysis)

 

Discontinue.

Grade 2 to 3 Bradycardia (HR < 60 bpm) (symptomatic)

Hold until recovery to ≤ Grade 1 (asymptomatic) bradycardia or HR of ≥ 60 bpm.

Evaluate concomitant medications; if contributing, discontinue or reduce dose of concomitant drug. Resume at previous dose.

If no concomitant medication contributing, or contributing medication not stopped/reduced: resume at 1 dose level ↓

Grade 4 Bradycardia (HR < 60 bpm)

(life-threatening consequences, urgent intervention required)

Discontinue if no contributing concomitant medication.

If contributing concomitant medication is discontinued or reduced: Hold until recovery to ≤ Grade 1 (asymptomatic) bradycardia or HR of ≥ 60 bpm, with frequent monitoring. Resume at 1 dose level ↓.

If recurs: discontinue.

CPK elevation > 5 x ULN

Hold until recovery to baseline or ≤ 2.5 x ULN; resume at same dose.

CPK elevation > 10 x ULN

Or

2nd Occurrence of CPK elevation > 5 x ULN

 

Hold until recovery to baseline or ≤ 2.5 x ULN; resume at 1 dose level ↓.



Dosage with Hepatic Impairment:

Pre-existing Hepatic impairment Alectinib Dose

Mild or Moderate

No dose adjustment required.

Severe

450 mg twice daily.


Dosage with Renal Impairment:

Renal impairment Alectinib dose

Mild or Moderate
(CrCl ≥ 30 mL/min)

No dose adjustment required
Severe
(CrCl < 30 mL/min)
Has not been studied


Dosage in the elderly:

No dose adjustment required.  Fatal adverse events were more common in patients 65 years or older compared to younger patients.



Children:

Safety and efficacy has not been established. Non-clinical studies showed effects on bone and dentition.



 
F - Administration Guidelines
  • Oral self-administration; drug available by outpatient prescription.

  • Alectinib should be taken twice daily with food (fasted state decreases exposure three fold).

  • If a dose is missed the next dose should be taken at the next scheduled time.

  • If vomiting occurs, a repeat dose should not be taken; the next dose should be taken at the next scheduled time.

  • Caution with grapefruit, grapefruit juice, products with grapefruit extract, star fruit, Seville oranges, pomegranate, and other similar fruits that inhibit CYP3A4 during alectinib treatment due to risk for increased toxicity.

 

  • Store between 15-30ºC in the original package.
 
G - Special Precautions
Contraindications:

  • Patients with known hypersensitivity to alectinib or excipients. 

Other Warnings/Precautions:

  • Use with caution in patients who are at risk for gastrointestinal perforation (eg. concomitant use of medications with GI perforation risk, history of diverticulitis, metastases to the GI tract).

  • Use with caution in patients with hepatic impairment or renal impairment.

  • Use with caution in patients who have bradycardia at baseline (< 60 bpm), a history of syncope or arrhythmia, sick sinus syndrome, sinoatrial block, AV block, ischemic heart disease, CHF or who are on medications that lower HR.

  • Vision disorders, asthenia, fatigue and dizziness have been reported.  Patients with these symptoms should use caution when driving or operating machines.

  • Contains lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption


Other Drug Properties:

  • Carcinogenicity: Unknown

     

     

  • Phototoxicity: Likely

     

     

Pregnancy and Lactation:
  • Abortifacient effects: Documented in animals

     

     

  • Breastfeeding: Not recommended

     

     

  • Embryotoxicity: Documented in animals

     

     

  • Fertility effects: Unknown

     

     

  • Fetotoxicity: Documented in animals

    Alectinib is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 3 months after the last dose if there is any potential for pregnancy.  Female patients who become pregnant while taking alectinib or during the 3 months following the last dose must contact their doctor and be advised of the potential harm to the fetus.

     

  • Mutagenicity: Probable

     

     

 
H - Interactions

  • CYP3A4 is the primary enzyme responsible for metabolism of alectinib and M4 (active metabolite).  M4 has shown similar in vitro potency and activity to alectinib against ALK. 

  • Alectinib is not a substrate of P-gp while M4 is a substrate of P-gp

  • Alectinib and M4 are not substrates of BCRP or OATP 1B1/B3

  • Medications that increase gastric pH do not appear to have an effect on alectinib or M4 exposure.

  • Neither alectinib nor M4 are inhibitors of CYP1A2, 2B6, 2C9, 2C19, or 2D6.  Alectinib is a weak inhibitor of 3A4 and 2B6.

  • No dose adjustment is necessary with CYP3A4 substrates.

AGENT EFFECT MECHANISM MANAGEMENT
Strong CYP3A4 inducers (i.e. phenytoin, rifampin, carbamazepine, phenobarbital, St. John’s Wort, etc.) ↓ alectinib exposure and ↑ M4 exposure ↑ metabolism of alectinib Caution; monitor closely
Strong CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) ↑ alectinib exposure and ↓ M4 exposure ↓ metabolism of alectinib Caution; monitor closely
CYP 2C8 substrates (i.e. paclitaxel, sorafenib, amiodarone) ↑ substrate concentration and/or toxicity (in vitro) ↓ metabolism of substrate Caution; monitor closely
BCRP substrates (i.e. topotecan) ↑ substrate concentration and/or toxicity (in vitro) ↓ metabolism of substrate Caution with drugs with narrow therapeutic index
P-glycoprotein substrates (i.e. verapamil, digoxin, morphine, ondansetron) ↑ substrate concentration and/or toxicity (in vitro) ↓ metabolism of substrate Caution with drugs with narrow therapeutic index
Drugs that lower heart rate (e.g. alpha2-adrenoceptor agonists, beta blockers, non-dihydropyridine Ca channel blockers, digoxin, cholinesterase inhibitors, sphingosine-1 phosphate receptor modulators) ↑ risk of bradycardia Additive Avoid if possible; if not possible, monitor closely
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

Blood pressure and heart rate

Baseline, at each visit, and as clinically indicated.

ECG

Baseline and as required to evaluate QTc, AV block.

Electrolytes, including serum calcium and potassium

Baseline and at each visit.

Liver function tests

Baseline, every 2 weeks during the first 3 months of treatment, then at each visit or as clinically indicated; more frequent with abnormal LFTs.

Blood CPK levels

Every 2 weeks for the first month, and as clinically indicated in patients reporting symptoms.

Renal function tests

Baseline and at each visit.

Clinical toxicity assessment for bradycardia, photosensitivity, rash, GI effects, edema, fatigue, anemia, myalgia, dizziness, headache, visual disorders, and respiratory problems

Baseline and at each visit.

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
K - References

Alectinib (Alecensaro) product monograph.  Hoffmann-La Roche Limited.  June 2018.

Ou SI, Ahn JS, De Petris L, et al: Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. J Clin Oncol, 2015.

Shaw AT, Gandhi L, Gadgeel S, et al: Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol 17:234-42, 2016


August 2018 Updated new indication for first line treatment, dose modifications for renal toxicity during treatment and adverse drug reactions to reflect Phase III trial data.

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.