Nilotinib

Uses

Treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The study is ongoing and further data will be required to determine long-term outcome.

Treatment of chronic phase (CP) and accelerated phase (AP) Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib. Clinical benefit, such as improvement in disease-related symptoms or increased survival, has not been demonstrated.

Nilotinib is also used to associated treatment for these conditions: Chronic Phase Chronic Myeloid Leukemia, Refractory Gastrointestinal stromal tumor, Refractory, accelerated phase Chronic myeloid leukemia

How Nilotinib works

Chronic myelogenous leukaemia (CML) is caused by the BCR-ABL oncogene. Nilotinib inhibits the tyrosine kinase activity of the BCR-ABL protein. Nilotinib fits into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib, over-riding resistance caused by mutations. The ability of AMN107 to inhibit TEL-platelet-derived growth factor receptor-beta (TEL-PDGFRbeta), which causes chronic myelomonocytic leukaemia, and FIP1-like-1-PDGFRalpha, which causes hypereosinophilic syndrome, suggests potential use of AMN107 for myeloproliferative diseases characterised by these kinase fusions (Stover et al, 2005; Weisberg et al, 2005). AMN107 also inhibits the c-Kit receptor kinase, including the D816V-mutated variant of KIT, at pharmacologically achievable concentrations, supporting potential utility in the treatment of mastocytosis, and gastrointestinal stromal tumours (Weisberg et al, 2005; von Bubnoff et al, 2005; Gleixner et al, 2006).

Dosage

Nilotinib dosage

Adult: 400 mg bid. May continue until patient shows unacceptable toxicity or evidence of progression.

Patient on strong CYP3A4 inhibitor: Reduce dose to 300 mg once daily, or to 200 mg once daily in newly-diagnosed chronic phase Philadelphia chronic myelogenous leukaemia. Dose may be adjusted to usual dose after a washout period.

Patient on drugs that prolong QT interval (e.g. antiarrhythmics): Reduce dose and closely monitor for QT interval prolongation.

Hepatic Impairment: Use a lower starting dose.

Should be taken on an empty stomach. Avoid food at least 2 hr before & at least 1 hr after a dose. Swallow whole, do not chew/crush. Avoid grapefruit products.

Side Effects

Rash, pruritus, hepatotoxicity, headache, fever, fatigue, GI disturbances (nausea, constipation, diarrhoea), alopecia, asthenia, muscle spasms, arthralgia, myalgia, pain (e.g. musculoskeletal or chest pain), oedema, folliculitis, papilloma, insomnia, dizziness, vertigo, anxiety, paraesthesia, hyperhidrosis, dry skin, urticaria, acne, conjunctivitis, dry eye, flushing, dyspnoea, cough, myelosuppression (e.g. thrombocytopenia, neutropenia, and anaemia), thrombotic disorders or haemorrhage, arrhythmias, heart failure, pericarditis, palpitations, HTN, angina, MI; elevated AST/ALT, serum lipase; electrolyte imbalances.

Precaution

Patient with history of pancreatitis, with total gastrectomy. Hepatic impairment. Maintain adequate hydration and correct uric acid levels, hypomagnesaemia, hypokalaemia and other electrolyte imbalances prior to therapy. Pregnancy and lactation.

Interaction

Drugs that inhibit gastric acid secretion (e.g. PPIs) may reduce solubility and bioavailability of nilotinib.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of nilotinib, causing increased serum levels of nilotinib.
• Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of nilotinib.
• Take on an empty stomach. Food increases the AUC of nilotinib. Separate nilotinib administration from meals by at least one hour before and two hours after eating.

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

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

Because nilotinib 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.

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

The mechanism of interaction is unknown.

Compared to the fast state, nilotinib systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high-fat meal.

Because nilotinib 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.

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

In addition, no food should be consumed for at least 2 hours before and 1 hour after a nilotinib dose.

Nilotinib Drug Interaction

Major: escitalopram, hydroxychloroquine, fluoxetineModerate: metoprolol, metoprolol, pantoprazoleUnknown: rosuvastatin, ferrous fumarate, methenamine, furosemide, levothyroxine, pregabalin, acetaminophen, acetaminophen, vitamin a topical, levothyroxine, thiamine, cyanocobalamin, pyridoxine, cholecalciferol

Nilotinib Disease Interaction

Major: pancreatitis, QT prolongationModerate: cardiovascular disease, fluid retention, bone marrow suppression, electrolyte abnormalities, hepatic impairment, lactose intolerance

Elimination Route

Orally available

Half Life

15 hours

Pregnancy & Breastfeeding use

Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Patient with hypokalaemia, hypomagnesaemia or long QT syndrome. Concomitant use with potent CYP3A4 inhibitors or antiarrhythmics and other QT prolonging drugs. Concomitant use with potent CYP3A4 inducers.

Acute Overdose

Symptoms: Neutropenia, vomiting and drowsiness.

Management: Monitor patient and give supportive treatment.

Storage Condition

Store below 30° C.

Innovators Monograph

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