Ceritinib

Registered South African indications:

• Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Congenital long QT syndrome
• Coadministration with agents prolonging the QT time

Cautions

• Pregnancy
• Women of childbearing potential and for up to 3 months after discontinuing treatment
• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment
• Elderly (>85 years)
• Pre-existing bradycardia (heart rate <60 beats per minute)
• History of or predisposition for QTc prolongation
• Pre-existing cardiac disease and/or electrolyte disturbances
• Pre-existing diabetes mellitus
• Coadministration with steroid 
• Coadministration with agents known to cause bradycardia (e.g. beta blockers, non-dihydropyridine calcium channel blockers, clonidine and digoxin)
• Coadministration with acid-reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) (see additional prescribing points)
• May impair ability to drive and operate machinery  

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

Treatment should be initiated and supervised by a medical practitioner experienced in the use of anti-cancer medicinal agents

Used for the treatment of

Anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC)
- As monotherapy for first-line treatment or as monotherapy patients previously treated with crizotinib

• Oral (cap): 450mg, dly with food at the same time each day; Max: 450mg/24hrs with food

ALK testing: See additional prescribing points

Treatment should continue as long as clinical benefit is observed

If a dose is missed, the patient should make up that dose, unless the next dose is due within 12 hours. If vomiting occurs during the course of treatment, the patient should not take an additional dose, but should continue with the next scheduled dose

Ceritinib should be discontinued in patients unable to tolerate 150mg daily taken with food

Coadministration with strong CYP3A inhibitors: See additional prescribing points

Method of administration: See additional prescribing points

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

Not established for use in children below 18 years

Pregnancy

• Caution; not recommended
• There are no or limited amount of data from the use of ceritinib in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Ceritinib should not be used during pregnancy unless there is no appropriate therapeutic alternative and the potential benefit outweighs the potential risk to the foetus
• Women of childbearing potential should be advised to use a highly effective method of contraception while taking ceritinib and for up to 3 months after discontinuing treatment

Breastfeeding

• Caution; not recommended 
• It is unknown whether ceritinib/metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded. Women on treatment with ceritinib should not breastfeed their babies

Fertility 

• The potential for ceritinib to cause infertility in male and female patients is unknown

Renal Impairment 

• Mild to moderate: No dose adjustment recommended 
  A dedicated pharmacokinetic study in patients with renal impairment has not been conducted. However, based on available data, ceritinib elimination via the kidney is negligible. Therefore, no dose adjustment is necessary
• Severe: Caution; no information available 

Hepatic Impairment

• Mild or moderate: No dose adjustment recommended 
• Severe: Caution; dose adjustment recommended 
  Based on available data, ceritinib is eliminated primarily via the liver. The dose should be reduced by approximately one-third, rounded to the nearest multiple of the 150mg dosage strength 

Elderly 

• ≥65 years: No dose adjustment recommended 
• >85 years: Caution; no information available 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Fatigue

Cardiovascular Disorders 

• Pericarditis
  - Pericardial effusion
• Bradycardia
  - Sinus bradycardia
• Prolonged QT electrocardiogram 

Respiratory Disorders 

• Pneumonitis
  - Interstitial lung disease

Gastrointestinal Disorders 

• Diarrhoea
• Nausea and vomiting
• Abdominal pain
  - Upper abdominal pain
  - Abdominal discomfort
  - Epigastric discomfort
• Constipation
• Oesophageal disorder
  - Dyspepsia
  - Gastro-oesophageal reflux disease
  - Dysphagia
• Pancreatitis

Hepatobiliary Disorders 

• Abnormal hepatic function tests
  - Abnormal hepatic function
  - Hyperbilirubinaemia
• Hepatotoxicity
  - Drug-induced liver injury
  - Cholestatic hepatitis
  - Hepatocellular injury
• Hepatic laboratory test abnormalities
  - Increased alanine aminotransferase 
  - Increased aspartate aminotransferase
  - Increased gamma-glutamyltransferase
  - Increased blood bilirubin
  - Increased transaminases
  - Increased hepatic enzyme
  - Abnormal hepatic function test  
  - Increased hepatic function test 
  - Increased blood alkaline phosphatase 

Genitourinary Disorders

• Renal failure
  - Acute renal injury
• Renal impairment
  - Azotaemia
• Increased blood creatinine

Endocrine and Metabolic Disorders 

• Decreased appetite
• Hyperglycaemia
• Hypophosphatemia
• Decreased weight 
• Increased lipase
• Increased amylase

Skin and Subcutaneous Tissue Disorders 

• Rash
  - Dermatitis acneiform
  - Maculopapular rash 

Immune, Blood and Lymphatic System Disorders 

• Anaemia

Sensory Disorders 

• Vision disorder
  - Vision impairment
  - Blurred vision 
  - Photopsia
  - Vitreous floaters
  - Reduced visual acuity
  - Accommodation disorder
  - Presbyopia

• Strong CYP3A inhibitors (see additional prescribing points)
• Ritonavir
• Saquinavir
• Telithromycin
• Ketoconazole
• Itraconazole
• Voriconazole
• Posaconazole 
• Nefazodone
• P-glycoprotein (p-gp) inhibitors
• Strong CYP3A inducers
• P-glycoprotein (p-gp) inducers
• Rifampicin
• Carbamazepine
• Phenobarbital
• Phenytoin
• Rifabutin
• CYP3A substrates known to have narrow therapeutic indices 
• Astemizole
• Cisapride
• Ciclosporin
• Ergotamine
• Fentanyl
• Pimozide
• Tacrolimus
• Alfentanil
• Sirolimus
• CYP2C9 substrates known to have narrow therapeutic indices
• Phenytoin
• Warfarin
• CYP2A6 substrates
• CYP2E1 substrates
• Oral contraceptives
• Breast cancer resistance protein (BCRP) substrates
• Rosuvastatin
• Topotecan
• Sulfasalazine
• P-glycoprotein (p-gp) substrates
• Digoxin
• Dabigatran
• Colchicine
• Pravastatin
• Anti-dysrhythmic medicinal agents class I
• Quinidine
• Procainamide
• Disopyramide
• Anti-dysrhythmic medicinal agents class III
• Amiodarone
• Sotalol
• Dofetilide
• Ibutilide
• Other medicinal products that may lead to QT prolongation
• Astemizole
• Domperidone
• Droperidol
• Chloroquine
• Halofantrine
• Clarithromycin
• Haloperidol
• Methadone
• Cisapride
• Moxifloxacin

Other interactions

• Grapefruit and grapefruit juice
• St. John’s wort (Hypericum perforatum)

• Anaplastic lymphoma kinase positivity
• Renal function
• Hepatic function (baseline, monthly, and as clinically necessary. Also monitor more frequently in patients who develop transaminase abnormalities)
• Fasting blood glucose (baseline and periodically as clinically necessary)
• Lipase and amylase (baseline and periodically as clinically necessary)
• Electrolytes (baseline and periodically thereafter)
• Blood pressure
• Heart rate
• Hepatitis B virus (HBV) screening (before beginning or at the beginning of systemic anticancer therapy)
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Specific cases may require

• Pregnancy status
• Cardiac function
  - Electrocardiogram
  - Electrolytes

Additional observations

• Signs/symptoms of gastrointestinal or pulmonary toxicity
  -  Interstitial lung disease or pneumonitis
  - Pancreatitis
• Adherence

ALK testing

• An accurate and validated ALK assay is necessary for the selection of ALK-positive NSCLC patients. ALK-positive NSCLC status should be established prior to initiation of ceritinib therapy. Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilised

Method of administration

• Ceritinib is for oral use. The capsules should be administered orally once daily with food at the same time every day. It is important that ceritinib is taken with food to reach the appropriate exposure. Food can range from a light to a full meal
• For patients who develop a concurrent medical condition and are unable to take ceritinib with food, ceritinib can be taken on an empty stomach as the alternate continued treatment regimen, in which no food should be eaten for at least 2 hours before and 1 hour after the dose. Patients should not alternate between fasted and fed dosing. Dose must be adjusted properly, i.e for patients treated with 450mg or 300mg with food, the dose should be increased to 750mg or 450mg taken on an empty stomach, respectively and for patients treated with 150mg with food treatment should be discontinued. For subsequent dose adjustment and management recommendations for adverse drug reactions, please consult a specialist. The maximum allowable dose under fasted condition is 750mg
• The capsules should be swallowed whole with water and should not be chewed or crushed

Coadministration with strong CYP3A inhibitors

• Avoid concomitant use of strong CYP3A inhibitors during treatment with ceritinib. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose by approximately one-third (dose not clinically verified), rounded to the nearest multiple of the 150mg dosage strength. Safety should be monitored. If long-term concomitant treatment with a strong CYP3A inhibitor is necessary and the patient tolerates the reduced dose well, the dose may be increased again with careful monitoring for safety, to avoid potential under-treatment. After discontinuation of a strong CYP3A inhibitor, resume at the dose that was taken prior to initiating the strong CYP3A inhibitor

Coadministration with acid-reducing agents

• Acid reducing agents (e.g., proton pump inhibitors, H₂-receptor antagonists, antacids) can alter the solubility of ceritinib and reduce its bioavailability. Coadministration of a single 750mg fasted ceritinib dose with a proton pump inhibitor (esomeprazole) 40mg daily for 6 days in healthy, fasting subjects decreased ceritinib AUC by 76% and C_max by 79%. The drug-drug interaction study was designed to observe the impact of proton pump inhibitor in the worst scenario, but in clinical use the impact of proton pump inhibitor on ceritinib exposure appears to be less pronounced. A dedicated study to evaluate the effect of gastric acid-reducing medicines on the bioavailability of ceritinib under steady state has not been conducted. Caution is advised when coadministered with proton pump inhibitors, as exposure of ceritinib may be reduced
• There is no data about coadministration with H₂ blockers or antacids. However, the risk for a clinically relevant decrease in bioavailability of ceritinib is possibly lower with coadministration with H₂ blockers if they are administered 10 hours before or 2 hours after the ceritinib dose, and with antacids if they are administered 2 hours before or 2 hours after the ceritinib dose

Ceritinib is a highly selective anaplastic lymphoma kinase (ALK) inhibitor. Ceritinib inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of downstream signalling proteins and proliferation of ALK-dependent cancer cells both in vitro and in vivo. ALK translocation determines expression of the resulting fusion protein and consequent aberrant ALK signalling in non-small cell lung cancer (NSCLC). In the majority of NSCLC cases, EML4 is the translocation partner for ALK. Ceritinib was demonstrated to be effective against EML4-ALK activity.

Capsule 150mg

• Zykadia (Novartis) originator