Alectinib

Registered South African indications:

• Anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic adenocarcinoma of the lung
• ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC)

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

South African manufacturer recommendations

• Women of childbearing potential and for at least 3 months following the last dose of alectinib
• Women of childbearing potential who are partners of male patients receiving alectinib
• Severe hepatic impairment (Child-Pugh C)
• Prolonged sun exposure and for at least 7 days after discontinuation
• Galactose intolerance e.g. galactosaemia
• Glucose-galactose malabsorption
• Lapp lactase deficiency 
• Fructose intolerance
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Women of childbearing potential and for at least 3 months following the last dose of alectinib
• Women of childbearing potential who are partners of male patients receiving alectinib
• Breastfeeding
• Severe hepatic impairment (Child-Pugh C) 
• Elderly (>80 years of age) 
• Increased risk of gastrointestinal perforation
  - History of diverticulitis
  - Metastases to the gastrointestinal tract
  - Coadministration with agents with a recognized risk of gastrointestinal perforation
• Prolonged sun exposure and for at least 7 days after discontinuation
• Galactose intolerance
• Glucose-galactose malabsorption
• Congenital lactase deficiency
• Sodium-controlled diet 
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Used for the treatment of

Anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic adenocarcinoma of the lung
- As first line monotherapy
ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) 
- As monotherapy in those who have progressed on or are intolerant to crizotinib

• Oral (cap): 600mg, 12hrly; Max: 1200mg/24hrs 

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Treatment should be continued until disease progression or unmanageable toxicity

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Capsules should be taken with food, swallowed whole, and must not be opened or dissolved

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A validated ALK assay is required for the selection of ALK-positive NSCLC patients. ALK-positive NSCLC status should be established prior to initiation of therapy

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Consult specialist for dosages and regimens (including dose modifications during the management of adverse reactions)

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Indications and dosages registered in other jurisdictions

Treatment should be initiated and supervised by a physician experienced in the use of anticancer medicinal products

Used for the treatment of

Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)
- As first line monotherapy
- As monotherapy in those previously treated with crizotinib

• Oral (cap): 600mg, 12hrly; Max: 1200mg/24hrs 

---

Capsules should be taken with food, swallowed whole, and must not be opened or dissolved

---

A validated ALK assay is necessary for the selection of ALK-positive NSCLC patients. ALK-positive NSCLC status should be established prior to initiation of therapy

---

Treatment should be continued until disease progression or unacceptable toxicity

---

Consult specialist for dosages and regimens (including dose modifications during the management of adverse reactions)

Not established for use in children below 18 year

Pregnancy 

South African manufacturer recommendations

• Contraindicated 
• Based on its mechanism of action, alectinib may cause foetal harm when administered to a pregnant woman. In animal studies, alectinib caused embryo-foetal toxicity
• Female patients or women who are partners of male patients receiving alectinib, 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
• Female patients of childbearing potential, or women of childbearing potential who are partners of male patients receiving alectinib, must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of alectinib

Recommendations in other jurisdictions

• Caution; positive evidence of risk in animal studies
• 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. When administrated to pregnant rats and rabbits, alectinib caused embryo-foetal toxicity
• Women of childbearing potential must be advised to avoid pregnancy while on alectinib. Female patients of childbearing potential, or women of childbearing potential who are partners of male patients receiving alectinib, must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of alectinib
• 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

Breastfeeding

South African manufacturer recommendations

• Contraindicated 
• Alectinib is contraindicated in mothers who are breastfeeding their infants

Recommendations in other jurisdictions

• Caution; not recommended 
• 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 breastfeeding while receiving alectinib

Fertility

South African manufacturer recommendations

• No information available 

Recommendations in other jurisdictions

• 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 

Renal Impairment

• No dose adjustment recommended 

Hepatic Impairment 

• Mild (Child-Pugh A) to moderate (Child-Pugh B): No dose adjustment recommended 
• Severe (Child-Pugh C): Caution; dose adjustment recommended 
  Oral (cap): 450mg, 12hrly; Max: 900mg/24hrs 

Elderly

South African manufacturer recommendations

• No dose adjustment recommended  

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended 
  There are no available data on patients over 80 years of age

Drugs in Sport

• Permitted - No warnings

Cardiovascular Disorders

• Bradycardia
  - Sinus bradycardia

Respiratory Disorders

• Interstitial lung disease
• Pneumonitis

Gastrointestinal Disorders

• Constipation
• Nausea and vomiting
• Diarrhoea
• Stomatitis
• Mouth ulceration

Hepatobiliary Disorders

• Increased bilirubin
  - Hyperbilirubinaemia
  - Increased conjugated bilirubin
• Increased aspartate aminotransferase (AST)
• Increased  alanine aminotransferase (ALT)
• Increased alkaline phosphatase
• Drug-induced liver injury

Genitourinary Disorders

• Increased blood creatinine
• Acute kidney injury

Endocrine and Metabolic Disorders

• Increased weight

Musculoskeletal Disorders

• Myalgia
  - Musculoskeletal pain
• Increased blood creatine phosphokinase (CPK)

Skin and Subcutaneous Tissue Disorders

• Rash
  - Maculopapular rash
  - Dermatitis acneiform
  - Erythema
  - Generalised rash
  - Papular rash
  - Pruritic rash
  - Macular rash
  - Exfoliative rash
• Photosensitivity

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Decreased haemoglobin
• Oedema
  - Peripheral oedema
  - Generalised oedema
  - Eyelid oedema
  - Periorbital oedema
  - Face oedema
  - Localised oedema

Sensory Disorders

• Dysgeusia
• Hypogeusia

Others

• Vision disorders
  - Blurred vision
  - Visual impairment
  - Vitreous floaters
  - Reduced visual acuity
  - Asthenopia
  - Diplopia

• Strong CYP3A inducers
• Carbamazepine
• Phenobarbital
• Phenytoin
• Rifabutin
• Rifampicin 
• CYP3A inhibitors
• Ritonavir
• Saquinavir
• Telithromycin
• Ketoconazole
• Itraconazole
• Voriconazole
• Posaconazole
• Nefazodone
• P-gp substrates
• Digoxin
• Dabigatran etexilate
• Topotecan
• Sirolimus
• Everolimus
• Nilotinib
• Lapatinib
• Breast cancer resistance protein (BCRP) substrates
• Methotrexate
• Mitoxantrone
• Oral contraceptives

Other interactions

• St John’s wort
• Grapefruit
• Seville oranges

• Anaplastic lymphoma kinase (ALK) positivity
• Hepatic function
  - Alanine aminotransferase (ALT)
  - Aspartate aminotransferase (AST)
  - Total bilirubin
• Creatine phosphokinase (CPK)
• Heart rate
• Blood pressure
• Hepatitis B virus screening 
  - Hepatitis B surface antigen 
  - Hepatitis B core antibody 
  - Total Ig or IgG 
  - Antibody to hepatitis B surface antigen

Additional observations

• Signs and symptoms of
  - Hemolytic anaemia
  - Interstitial lung disease or pneumonitis
  - Myalgia
• Adherence

Delayed or missed doses

• If a planned dose is missed, patients can make up that dose unless the next dose is due within 6 hours
• Patients should not take two doses at the same time to make up for a missed dose
• If vomiting occurs after taking a dose, patients should take the next dose at the scheduled time

Dose adjustments

• Management of adverse events may require dose reduction, temporary interruption, or discontinuation of treatment. The dose should be reduced in steps of 150mg twice daily based on tolerability. Treatment should be permanently discontinued if patients are unable to tolerate the 300mg twice daily dose

Alectinib is a highly selective and potent anaplastic lymphoma kinase (ALK) and RET tyrosine kinase inhibitor. In preclinical studies, inhibition of ALK tyrosine kinase activity led to blockage of downstream signalling pathways including STAT 3 and PI3K/AKT and induction of tumour cell death (apoptosis). Alectinib demonstrated in vitro and in vivo activity against mutant forms of the ALK enzyme, including mutations responsible for resistance to crizotinib. The major metabolite of alectinib (M4) has shown similar in vitro potency and activity. Based on preclinical data, alectinib is not a substrate of p-glycoprotein or BCRP, which are both efflux transporters in the blood brain barrier, and is therefore able to distribute into and be retained within the central nervous system. 

Capsule 150mg

• Alecensa (Roche) originator