Spexib

Uses

Spexib is used for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
Pediatric Use: The safety and effectiveness of Spexib in pediatric patients have not been established.

Geriatric Use: Of the 925 patients in clinical studies of Spexib, 18% were 65 years or older, while 5% were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Hepatic Impairment: For patients with severe hepatic impairment (Child-Pugh C), reduce the dose of Spexib. No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

Spexib is also used to associated treatment for these conditions: Refractory, locally advanced Non-small cell lung cancer, Refractory, metastatic Non small cell lung cancer

How Spexib works

Spexib inhibits Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), which is an enzyme that in humans is encoded by the ALK gene. About 4-5% of NSCLCs have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Spexib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Spexib has been shown to inhibit in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats.

Dosage

Spexib dosage

The recommended dosage of Spexib is 450 mg orally once daily with food until disease progression or unacceptable toxicity. If a dose of Spexib is missed, make up that dose unless the next dose is due within 12 hours. If vomiting occurs during the course of treatment, do not administer an additional dose and continue with the next scheduled dose of Spexib.

Side Effects

The most common adverse reactions (incidence of ≥ 25%) in patients treated with Spexib 450 mg with food are diarrhea, nausea, abdominal pain, vomiting, and fatigue and with Spexib 750 mg under fasted conditions are diarrhea, nausea, vomiting, fatigue, abdominal pain, decreased appetite, and weight loss.

Toxicity

There is not currently any data on carcinogenicity, effect on human fertility, or on early embryonic development. However, based on its mechanism of action, ceritinib may cause fetal harm when administered to pregnant women and should therefore be administered with effective contraception during treatment. Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients. Drug-induced hepatotoxicity also occurred in 27% of 255 patients, presenting as alanine aminotransferase (ALT) levels greater than 5 times the upper limit of normal (ULN). Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis, hyperglycaemia, and bradycardia have also been reported.

Precaution

• Gastrointestinal Adverse Reactions: Spexib can cause gastrointestinal adverse reactions. If severe or intolerable, withhold if not responsive to antiemetics or antidiarrheals; upon improvement, resume Spexib at a reduced dose.
• Hepatotoxicity: Spexib can cause hepatotoxicity. Monitor liver laboratory tests at least monthly. Withhold then dose reduce, or permanently discontinue Spexib.
• Interstitial Lung Disease/Pneumonitis: Occurred in 2.4% of patients. Permanently discontinue Spexib in patients diagnosed with treatment-related ILD/pneumonitis.
• QT Interval Prolongation: Spexib can cause QTc interval prolongation. Monitor electrocardiograms and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc interval. Withhold then dose reduce, or permanently discontinue Spexib.
• Hyperglycemia: Spexib can cause hyperglycemia. Monitor fasting glucose prior to treatment and periodically thereafter. Initiate or optimize anti-hyperglycemic medications as indicated. Withhold then dose reduce, or permanently discontinue Spexib.
• Bradycardia: Spexib can cause bradycardia. Monitor heart rate and blood pressure regularly. Withhold then dose reduce, or permanently discontinue Spexib.
• Pancreatitis: Elevations of lipase and/or amylase and pancreatitis can occur. Monitor lipase and amylase prior to treatment and periodically thereafter as clinically indicated. Withhold then dose reduce Spexib.
• Embryo-Fetal Toxicity: Spexib can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

Interaction

• CYP3A Inhibitors and Inducers: Avoid concurrent use of Spexib with strong CYP3A inhibitors or inducers. If concurrent use of a strong CYP3A inhibitor is unavoidable, dose reduce Spexib.
• CYP3A Substrates: Avoid coadministration of Spexib with sensitive CYP3A substrates.
• CYP2C9 Substrates: Avoid coadministration of Spexib with CYP2C9 substrates for which minimal concentration changes may lead to serious toxicities.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits the CYP3A metabolism of ceritinib, which may increase its serum concentration.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of ceritinib and may reduce its serum concentration.
• Take with food. Food increases the bioavailability of ceritinib. Taking ceritinib in a fasted state increases the risk of adverse gastrointestinal effects like nausea, vomiting, and abdominal pain.

[Major] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ceritinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Because ceritinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

Other, more common side effects such as diarrhea, nausea, vomiting, abdominal pain, hyperglycemia, and bradycardia may also increase.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ceritinib.

The mechanism of interaction is unknown.

Compared to the fast state, administration of a single 500 mg dose of ceritinib with a high-fat meal (approximately 1000 calories; 58 grams of fat) increased ceritinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 41% and 73%, respectively, and administration with a low-fat meal (approximately 330 calories; 9 grams of fat) increased ceritinib Cmax and AUC by 43% and 58%, respectively.

A dose of 600 mg or higher taken with a meal is expected to produce systemic exposure exceeding that from a 750 mg dose taken in the fasted state, which may lead to increased adverse effects.

MANAGEMENT: Patients treated with ceritinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract.

Spexib should be administered on an empty stomach (i.e., avoid administration within 2 hours of a meal).

Spexib Drug Interaction

Major: diltiazemModerate: glycerinMinor: sulfamethoxazole / trimethoprimUnknown: charcoal, aspirin, lorazepam, ubiquinone, copper gluconate, glucose, econazole topical, ethanol, heparin, sodium iodide, ferrous sulfate, levetiracetam, arginine, levocarnitine, cysteine, bioflavonoids, cyanocobalamin

Spexib Disease Interaction

Major: QT prolongationModerate: bradycardia, GI complications, hepatic impairment, hyperglycemia, pancreatitis, renal impairment, lung toxicity

Volume of Distribution

The apparent volume of distribution (Vd/F) is 4230 L following a single 750 mg dose.

Elimination Route

After oral administration of ceritinib, peak concentrations were achieved after approximately 4 to 6 hours.

Half Life

The terminal half life is 41 hours.

Clearance

The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h).

Elimination Route

Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine.

Pregnancy & Breastfeeding use

Based on animal studies and its mechanism of action, Spexib can cause fetal harm when administered to a pregnant woman. The limited available data on the use of Spexib in pregnant women are insufficient to inform risk. Administration of ceritinib to rats and rabbits during the period of organogenesis at maternal plasma exposures below the recommended human dose caused increases in skeletal anomalies in rats and rabbits. Advise a pregnant woman of the potential risk to a fetus.

There are no data regarding the presence of ceritinib or its metabolites in human milk, the effects of ceritinib on the breastfed child or its effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Spexib and for 2 weeks following completion of therapy.

Storage Condition

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

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