Ceritinib

Ceritinib is a highly selective and potent oral inhibitor of anaplastic lymphoma kinase (ALK). In some non-small cell lung cancers a chromosomal rearrangement joins ALK to another gene, most often EML4, producing a fusion protein whose kinase is permanently active and drives tumour growth. Ceritinib blocks that kinase.

Mechanism of Action

• ALK inhibition: ceritinib inhibits ALK autophosphorylation, ALK-mediated phosphorylation of downstream signalling proteins (DrugBank names STAT3) and the proliferation of ALK-dependent cancer cells, in vitro and in vivo.
• EML4–ALK activity: in an NSCLC cell line (H2228) ceritinib inhibited EML4–ALK activity and cell proliferation in vitro, and tumours regressed in H2228-derived xenografts in mice and rats.
• Cardiac effect: QTc prolongation has been observed in clinical studies (see Special Instructions).

Pharmacokinetics

• Absorption: peak plasma levels about 4–6 hours after a single oral dose. Oral absorption is estimated at 25% or more; absolute bioavailability has not been determined. Food raises exposure: after a single 500 mg dose in healthy subjects, AUC was about 58% higher with a low-fat meal and 73% higher with a high-fat meal than when fasted (Cmax about 43% and 41% higher). At steady state, 450 mg with food gave exposure comparable to 750 mg fasted (AUC 4% and Cmax 3% higher). After single doses of 50–750 mg fasted, exposure rose in proportion to dose, while trough levels after repeated dosing rose more than in proportion.
• Distribution: about 97% bound to plasma proteins in vitro, independent of concentration, with a slight preference for red blood cells (blood-to-plasma ratio 1.35). Ceritinib is a substrate of P-glycoprotein but not of BCRP or MRP2. DrugBank gives an apparent volume of distribution of about 4,230 L.
• Metabolism: CYP3A is the major enzyme in its metabolic clearance (in vitro). DrugBank reports that unchanged ceritinib is the main circulating component (82% of plasma radioactivity).
• Elimination: mainly faecal. After a radiolabelled 750 mg dose, DrugBank reports 92.3% of the dose in faeces (68% as unchanged ceritinib) and 1.3% in urine, and a terminal half-life of about 41 hours.
• Special populations: kidney elimination is negligible, while the liver is the main route, so severe hepatic impairment needs a dose reduction (see Administration and Dosage). In seven trials, 168 of 925 patients (18.2%) were aged 65 or over, and their safety profile was similar to that of younger patients.

An accurate and validated ALK assay must show ALK-positive status before treatment starts.

• First-line treatment: as monotherapy in adults with ALK-positive advanced non-small cell lung cancer (NSCLC).
• After crizotinib: as monotherapy in adults with ALK-positive advanced NSCLC previously treated with crizotinib.

• Hypersensitivity to ceritinib or to any of the excipients.

The reactions below come from 925 patients with ALK-positive advanced NSCLC who took 750 mg once daily fasted (the dose first authorised) in seven studies, with a median exposure of 44.9 weeks. The frequencies of diarrhoea, nausea and vomiting are based on 108 patients taking the recommended 450 mg with food. In the dose-optimisation study (ASCEND-8) the overall safety profile at 450 mg with food was consistent with 750 mg fasted, apart from fewer gastrointestinal reactions at comparable exposure. Grade 3–4 reactions in at least 5% of patients on 750 mg fasted were abnormal liver laboratory tests, fatigue, vomiting, hyperglycaemia, nausea and diarrhoea.

Very common (≥1/10): anaemia; decreased appetite; diarrhoea, nausea, vomiting, abdominal pain, constipation; oesophageal disorder (dyspepsia, gastro-oesophageal reflux disease, dysphagia); rash; fatigue; abnormal liver laboratory tests (raised ALT, AST, gamma-glutamyltransferase, bilirubin and other liver tests); weight decreased; increased blood creatinine.

Common (≥1/100 to <1/10): hyperglycaemia; hypophosphataemia; visual impairment (including blurred vision, photopsia, vitreous floaters, reduced visual acuity, accommodation disorder, presbyopia); pericarditis (including pericardial effusion); bradycardia; pneumonitis (including interstitial lung disease); abnormal liver function tests; hepatotoxicity; renal failure or impairment; QT prolongation on the electrocardiogram; raised lipase; raised amylase.

Uncommon (≥1/1,000 to <1/100): pancreatitis.

Serious reactions include hepatotoxicity (grade 3 or 4 ALT rises in 25% of patients), severe, life-threatening or fatal interstitial lung disease or pneumonitis, QT prolongation, bradycardia, hyperglycaemia and pancreatitis. With 450 mg with food, 24.1% of patients needed at least one dose reduction and 55.6% at least one dose interruption because of an adverse event.

Ceritinib is a substrate of CYP3A and P-glycoprotein, is classified in vivo as a strong CYP3A4 inhibitor and a weak CYP2C9 inhibitor, and prolongs the QT interval.

• Strong CYP3A inhibitors (for example ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone): ketoconazole raised ceritinib exposure (AUC) 2.9-fold. Avoid the combination; if unavoidable, reduce the ceritinib dose by about one third (see Administration and Dosage).
• P-glycoprotein inhibitors: an increase in ceritinib concentration is likely. Use with caution and monitor for adverse reactions.
• Strong CYP3A and P-gp inducers (carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St John’s wort): rifampicin cut ceritinib AUC by 70% and Cmax by 44%. Avoid strong CYP3A inducers; use caution with P-gp inducers.
• Acid-reducing agents (proton pump inhibitors, H2-receptor antagonists, antacids): ceritinib is less soluble at higher pH. Esomeprazole 40 mg daily lowered ceritinib AUC by 76% and Cmax by 79% in fasting healthy subjects, an effect that appears smaller in clinical use. Use proton pump inhibitors with caution. There are no data for H2 blockers or antacids, but the risk is possibly lower if H2 blockers are taken 10 hours before or 2 hours after ceritinib, and antacids 2 hours before or after.
• CYP3A substrates: midazolam exposure rose 5.4-fold. Avoid substrates mainly cleared by CYP3A, and those with a narrow therapeutic index (for example alfuzosin, amiodarone, cisapride, ciclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quetiapine, quinidine, lovastatin, simvastatin, sildenafil, midazolam, triazolam, tacrolimus, alfentanil, sirolimus); if unavoidable, consider reducing the dose of the co-administered medicine.
• CYP2C9 substrates: S-warfarin exposure rose by 54%. Avoid substrates with a narrow therapeutic index (for example phenytoin, warfarin); if unavoidable, consider dose reduction, and monitor INR more often with warfarin.
• CYP2A6 and CYP2E1 substrates: ceritinib inhibits these enzymes in vitro, so exposure to co-administered medicines may rise. Use caution and monitor.
• Oral contraceptives: induction of other PXR-regulated enzymes cannot be excluded, and the effectiveness of oral contraceptives may be reduced.
• BCRP and P-gp substrates: ceritinib is predicted to inhibit intestinal P-gp and BCRP. Use caution with BCRP substrates (rosuvastatin, topotecan, sulfasalazine) and P-gp substrates (digoxin, dabigatran, colchicine, pravastatin).
• QT-prolonging medicines: class I anti-arrhythmics (quinidine, procainamide, disopyramide), class III anti-arrhythmics (amiodarone, sotalol, dofetilide, ibutilide) and other QT-prolonging medicines such as domperidone, droperidol, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, cisapride and moxifloxacin. Monitor the QT interval if combined.
• Bradycardia-causing medicines (beta blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin): avoid as far as possible.
• Food and drink: ceritinib is taken with food, which raises its bioavailability. Avoid grapefruit and grapefruit juice, which may inhibit CYP3A in the gut wall and raise ceritinib exposure; DrugBank also advises avoiding St John’s wort.

Treatment is started and supervised by a physician experienced in anti-cancer medicinal products. ALK-positive status is established beforehand with a validated assay in a laboratory with proven proficiency in the technology. The capsules or tablets are taken once daily with food at the same time each day and swallowed whole with water; they must not be chewed or crushed. The meal can be light or full.

Recommended Dose

• 450 mg once daily with food, which is also the maximum recommended dose with food.
• Treatment continues as long as clinical benefit is observed.
• Ceritinib is stopped in patients who cannot tolerate 150 mg daily with food.

Dose Adjustments for Side Effects

Doses are reduced in steps of 150 mg daily. Management of selected reactions:

• Severe or intolerable nausea, vomiting or diarrhoea despite optimal supportive treatment: withhold until improved, then restart 150 mg lower.
• ALT or AST above 5 times the upper limit of normal (ULN) with total bilirubin up to 2 times ULN: withhold until recovery to baseline or to 3 times ULN or less, then restart 150 mg lower.
• ALT or AST above 3 times ULN with total bilirubin above 2 times ULN (without cholestasis or haemolysis): stop permanently.
• Any grade of treatment-related interstitial lung disease or pneumonitis: stop permanently.
• QTc above 500 msec on at least two separate ECGs: withhold until recovery to baseline or QTc of 480 msec or less, check and correct electrolytes, then restart 150 mg lower.
• QTc above 500 msec or a change of more than 60 msec from baseline, with torsade de pointes, polymorphic ventricular tachycardia or signs of serious arrhythmia: stop permanently.
• Symptomatic bradycardia that is not life-threatening: withhold until it is asymptomatic (grade 1 or less) or the heart rate is 60 bpm or above. Review medicines that cause bradycardia and antihypertensives; if a contributor is found and stopped or adjusted, restart at the previous dose, otherwise restart 150 mg lower.
• Life-threatening bradycardia: stop permanently if no contributing medicine is found. If one is found and stopped or adjusted, restart 150 mg lower with frequent monitoring; stop permanently if it recurs.
• Persistent hyperglycaemia above 250 mg/dL despite optimal treatment: withhold until controlled, then restart 150 mg lower; stop permanently if control cannot be achieved.
• Lipase or amylase elevation of grade 3 or higher: withhold until grade 1 or less, then restart 150 mg lower.

With Strong CYP3A Inhibitors

If a strong CYP3A inhibitor cannot be avoided, reduce the dose by about one third (a reduction that has not been clinically verified), rounded to the nearest multiple of 150 mg, and monitor safety closely. If long-term inhibitor treatment is needed and the reduced dose is well tolerated, the dose may be raised again with careful monitoring. After the inhibitor is stopped, resume the earlier dose.

If Food Cannot Be Taken

A patient with a concurrent condition that prevents eating may take ceritinib on an empty stomach (no food for at least 2 hours before and 1 hour after) as an alternative regimen, and must not alternate between fasted and fed dosing. The dose is adjusted: 450 mg or 300 mg with food becomes 750 mg or 450 mg fasted, and treatment at 150 mg with food is discontinued. The maximum fasted dose is 750 mg.

Special Populations

• Renal impairment: no adjustment in mild to moderate impairment; caution in severe impairment, where there is no experience.
• Hepatic impairment: no adjustment in mild or moderate impairment. In severe impairment use particular caution and reduce the dose by about one third, rounded to the nearest multiple of 150 mg.
• Elderly (65 and over): limited data do not suggest a dose adjustment; there are no data over 85 years.
• Children and adolescents: safety and efficacy up to 18 years have not been established.

Missed or Vomited Dose

A missed dose is made up unless the next dose is due within 12 hours. After vomiting, no extra dose is taken; the next scheduled dose is taken as usual.

Hepatotoxicity

Hepatotoxicity occurred in 1.1% of patients in clinical studies, and grade 3 or 4 ALT elevations in 25%. Most cases were managed with interruption or dose reduction, and few needed discontinuation. ALT, AST and total bilirubin are measured before starting, every 2 weeks for the first three months and monthly after that, and more often if transaminases rise. In severe hepatic impairment hepatic encephalopathy worsened in 2 of 10 patients given single 750 mg fasted doses; a link with the drug cannot be fully ruled out.

Interstitial Lung Disease and Pneumonitis

Severe, life-threatening or fatal cases have occurred, and most improved or resolved after interruption. Patients are monitored for pulmonary symptoms, other causes are excluded, and ceritinib is stopped permanently for any grade of treatment-related interstitial lung disease or pneumonitis.

QT Interval Prolongation

QTc prolongation may raise the risk of ventricular tachyarrhythmias such as torsade de pointes, or of sudden death. Ceritinib is avoided in congenital long QT syndrome. Benefit and risk are weighed before starting in patients with a heart rate below 60 bpm, a history of or predisposition to QTc prolongation, anti-arrhythmic or other QT-prolonging medicines, relevant heart disease or electrolyte disturbances, and ECGs and electrolytes (for example potassium) are checked periodically in them. Electrolytes are corrected in vomiting, diarrhoea, dehydration or impaired renal function.

Bradycardia

Asymptomatic bradycardia was seen in 21 of 925 patients (2.3%). Combining ceritinib with other bradycardia-causing agents is avoided as far as possible, and heart rate and blood pressure are monitored regularly.

Gastrointestinal Reactions

At 450 mg with food, diarrhoea, nausea or vomiting occurred in 76.9% of 108 patients, mostly grade 1 (52.8%) or grade 2 (22.2%). Two patients (1.9%) had one grade 3 event each and nine (8.3%) needed an interruption. At 750 mg fasted the reactions were more frequent and severe (diarrhoea 80.0%, nausea 60.0%, vomiting 65.5%; 17.3% had a grade 3 event). They are managed with standard care such as anti-diarrhoeals, anti-emetics and fluid replacement, with interruption or dose reduction when needed.

Hyperglycaemia

Hyperglycaemia of any grade occurred in fewer than 10% of patients, and grade 3–4 in 5.4%; the risk is higher with diabetes mellitus or concurrent steroid use. Fasting plasma glucose is checked before treatment and periodically afterwards, and antihyperglycaemic medicines are started or optimised as needed.

Lipase and Amylase Elevations

Raised lipase and/or amylase has occurred and pancreatitis has been reported. Both are checked before treatment and periodically afterwards.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use a highly effective method of contraception during treatment and for up to 3 months after stopping. Ceritinib may reduce the effectiveness of oral contraceptives.
• Pregnancy: data are limited or absent and animal studies are insufficient. Ceritinib is not used in pregnancy unless the woman’s clinical condition requires it.
• Breastfeeding: it is unknown whether ceritinib or its metabolites pass into human milk. A decision is made whether to stop breastfeeding or to abstain from treatment.
• Fertility: the potential to cause infertility in men and women is unknown.

Sodium

The capsules contain less than 1 mmol sodium (23 mg) per capsule, that is, they are essentially ‘sodium-free’.

Effect on Driving

Zykadia has a minor influence on the ability to drive or use machines. Patients may experience fatigue or vision disorders and should take care.

Zykadia capsules and tablets need no special storage conditions. The capsules come in aluminium blisters of 10, in packs of 40, 90 or 150; not all pack sizes may be marketed.

3 years for both the hard capsules and the film-coated tablets. Do not use after the expiry date on the pack.

Prescription only (Rx), on the prescription of a physician experienced in the use of anti-cancer medicinal products. Ceritinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.