Nilotinib

Nilotinib is a potent inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein, the abnormal protein produced by the Philadelphia chromosome that drives chronic myeloid leukaemia (CML). It also keeps its activity against most imatinib-resistant mutant forms of BCR-ABL.

Mechanism of Action

• Target: nilotinib inhibits the ABL kinase activity of BCR-ABL, in cell lines and in primary Philadelphia chromosome positive leukaemia cells.
• Binding: it binds with high affinity to the ATP-binding site of the kinase. It is a potent inhibitor of wild-type BCR-ABL and remains active against 32 of 33 imatinib-resistant mutant forms.
• Cellular effect: it selectively blocks proliferation and induces apoptosis in Philadelphia chromosome positive leukaemia cells from CML patients. In mouse models of CML, oral nilotinib reduced tumour burden and prolonged survival.
• Other kinases: it has little or no effect on most other protein kinases tested, including Src. It does inhibit the PDGF, KIT and Ephrin receptor kinases at concentrations reached at the recommended doses (phosphorylation IC50: BCR-ABL 20 nM, PDGFR 69 nM, KIT 210 nM).
• Metabolites: none of the metabolites contributes significantly to the pharmacological activity.
• Cardiac electrophysiology: nilotinib prolongs ventricular repolarisation (the QT interval) in a concentration-dependent way; see Special Instructions.

Pharmacokinetics

• Absorption: peak concentrations are reached about 3 hours after an oral dose. Absorption is about 30%; absolute bioavailability has not been determined. The relative bioavailability of the capsule is about 50% of an acidic oral drink solution (pH 1.2–1.3). With food, Cmax rises by 112% and AUC by 82% compared with fasting; given 30 minutes or 2 hours after food, bioavailability rises by 29% or 15%. After total or partial gastrectomy, relative bioavailability may fall by about 48% or 22%.
• Distribution: blood-to-plasma ratio 0.71; about 98% bound to plasma proteins (in vitro).
• Metabolism: mainly oxidation and hydroxylation, chiefly by CYP3A4, with a possible minor part for CYP2C8. Unchanged nilotinib is the main circulating component. It is also a substrate of the efflux pump P-glycoprotein.
• Elimination: after a radiolabelled dose in healthy subjects, more than 90% was eliminated within 7 days, mainly in faeces (94% of the dose, 69% as unchanged nilotinib). The apparent elimination half-life with daily dosing is about 17 hours. Variability between patients is moderate to high.
• Dose dependence: at steady state, exposure rises less than in proportion to dose above 400 mg once daily. Daily exposure with 400 mg twice daily was 35% higher than with 800 mg once daily, and the AUC at 400 mg twice daily was about 13.4% higher than at 300 mg twice daily.
• Special populations: mild, moderate and severe hepatic impairment raise exposure modestly (see Special Instructions). Nilotinib and its metabolites are not renally excreted, so reduced clearance is not expected in renal impairment.

• Newly diagnosed CML: adults and children with newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia (CML) in the chronic phase.
• Resistant or intolerant CML in adults: adults with chronic-phase or accelerated-phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib. Efficacy data in CML in blast crisis are not available.
• Resistant or intolerant CML in children: children with chronic-phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib.

• Hypersensitivity to nilotinib or to any of the excipients (including lactose).

The safety profile rests on pooled data from 3,422 patients in 13 clinical studies (newly diagnosed adults and children, and adults and children with resistance or intolerance to imatinib), representing 9,039 patient-years, plus post-marketing reports. It is consistent across indications. The most common reactions (incidence of 15% or more) are rash (26.4%), upper respiratory tract infection including pharyngitis, nasopharyngitis and rhinitis (24.8%), headache (21.9%), hyperbilirubinaemia (18.6%), nausea (16.8%), pruritus (16.7%), thrombocytopenia (16.4%), arthralgia (15.8%) and fatigue (15.4%).

Very common (≥1/10): upper respiratory tract infection, anaemia, thrombocytopenia, growth retardation (in children), headache, cough, nausea, upper abdominal pain, constipation, diarrhoea, vomiting, hyperbilirubinaemia, rash, pruritus, alopecia, myalgia, arthralgia, back pain, pain in extremity, fatigue, pyrexia, increased alanine aminotransferase, increased lipase.

Common (≥1/100 to <1/10): folliculitis, bronchitis, candidiasis, pneumonia, gastroenteritis, urinary tract infection; leukopenia, leukocytosis, neutropenia, thrombocythaemia; hypothyroidism; electrolyte imbalance (including low or high potassium, low magnesium, sodium or calcium, high phosphate), diabetes mellitus, hyperglycaemia, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia, decreased appetite, gout, hyperuricaemia, hypophosphataemia; depression, insomnia, anxiety; dizziness, hypoaesthesia, paraesthesia, migraine; conjunctivitis, dry eye, eye irritation, hyperaemia, blurred vision; vertigo, ear pain, tinnitus; angina pectoris, arrhythmia (including atrioventricular block, flutter, ventricular extrasystoles, tachycardia, atrial fibrillation, bradycardia), palpitations, QT prolongation on the ECG, coronary artery disease; hypertension, flushing, peripheral arterial occlusive disease; dyspnoea, exertional dyspnoea, epistaxis, oropharyngeal pain; pancreatitis, abdominal discomfort and distension, flatulence, abdominal pain, dyspepsia, gastritis, gastro-oesophageal reflux, haemorrhoids, stomatitis; abnormal hepatic function; night sweats, eczema, urticaria, hyperhidrosis, contusion, acne, dermatitis, dry skin, erythema; musculoskeletal chest pain and other musculoskeletal pain, neck pain, muscular weakness, muscle spasms, bone pain; pollakiuria, dysuria; erectile dysfunction, menorrhagia; chest pain, pain, chest discomfort, malaise, asthenia, peripheral oedema, chills, influenza-like illness; decreased haemoglobin, increased amylase, AST, alkaline phosphatase, gamma-glutamyltransferase, blood creatine phosphokinase, creatinine and total cholesterol, weight decreased, weight increased.

Uncommon (≥1/1,000 to <1/100), selected: sepsis, herpes virus infection, abscess, skin papilloma; febrile neutropenia, pancytopenia, lymphopenia, eosinophilia; hypersensitivity; hyperthyroidism; dehydration, dyslipidaemia, hypoglycaemia; amnesia, confusional state, disorientation; cerebrovascular accident, intracranial or cerebral haemorrhage, ischaemic stroke, transient ischaemic attack, cerebral infarction, loss of consciousness (including syncope), tremor, peripheral neuropathy, restless legs syndrome, facial paralysis; visual impairment, reduced visual acuity, eye haemorrhage, diplopia, photophobia, photopsia; hearing impairment; myocardial infarction, cardiac failure, pericardial effusion, pericarditis, left bundle branch block; hypertensive crisis, intermittent claudication, peripheral artery stenosis, hypotension, thrombosis; pulmonary oedema, pleural effusion, interstitial lung disease, pulmonary hypertension; gastrointestinal, gastric ulcer and rectal haemorrhage, enterocolitis; hepatotoxicity, toxic hepatitis, jaundice, cholestasis, hepatomegaly; photosensitivity, exfoliative rash, skin ulcer; arthritis; renal failure, haematuria; gynaecomastia; face oedema, localised oedema; increased troponin, blood lactate dehydrogenase, blood urea and parathyroid hormone.

Rare (≥1/10,000 to <1/1,000): hepatitis B reactivation, oral papilloma, paraproteinaemia, secondary hyperparathyroidism, thyroiditis, tumour lysis syndrome, appetite disorder, dysphoria, basilar artery stenosis, cerebral oedema, optic neuritis, chorioretinopathy, papilloedema, cyanosis, decreased ejection fraction, haemorrhagic shock, gastrointestinal ulcer perforation, haematemesis, oesophageal ulcer, retroperitoneal haemorrhage, subileus, erythema multiforme, palmar-plantar erythrodysaesthesia syndrome, breast induration, sudden death, decreased blood glucose and changes in blood insulin.

Not known: ventricular dysfunction.

Important and serious reactions: QT prolongation, sudden death (uncommon, 0.1–1%, in patients with imatinib-resistant or intolerant CML who had cardiac disease or significant cardiac risk factors; none in the phase III study of newly diagnosed patients), cardiovascular events, myelosuppression, pancreatitis, hepatotoxicity, hepatitis B reactivation (sometimes with acute liver failure) and tumour lysis syndrome. In children, raised bilirubin (grade 3 or 4 in 10.3%) and raised ALT (grade 3 or 4 in 12.1%) were more frequent than in adults. Growth deceleration was seen in 8 of 58 children after a median of about 52–60 months of treatment, so growth is monitored closely.

Nilotinib is metabolised mainly in the liver by CYP3A4 and is a P-glycoprotein substrate, so substances that affect these can change its absorption and elimination.

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, telithromycin): ketoconazole raised nilotinib exposure about 3-fold in healthy subjects. Avoid them. If one is required, interrupt nilotinib if possible; if interruption is not possible, monitor the QT interval closely. Moderate CYP3A4 inhibitors may also raise exposure, and alternatives with no or minimal CYP3A4 inhibition should be considered.
• Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s wort): rifampicin cut nilotinib Cmax by 64% and AUC by 80%, and must not be combined with nilotinib. The other inducers are likely to lower exposure to a clinically relevant degree, so alternatives with less induction potential should be chosen.
• QT-prolonging medicines, including antiarrhythmics: these should be avoided, because they add to the QT effect of nilotinib (see Special Instructions).
• Imatinib: given together, imatinib AUC rose by 18–39% and nilotinib AUC by 18–40%, which is unlikely to be clinically important.
• Haematopoietic growth factors, hydroxycarbamide and anagrelide: nilotinib may be given with erythropoietin or G-CSF, and with hydroxycarbamide or anagrelide, if clinically indicated.
• Statins: some HMG-CoA reductase inhibitors are also metabolised by CYP3A4, so section 4.5 of the SmPC should be checked before one is started.
• Acid-reducing medicines (proton pump inhibitors, H2 blockers, antacids): nilotinib dissolves better in acid, so these can change absorption; the prescriber should follow the timing advice in section 4.5 of the SmPC.
• Food and drink: food raises nilotinib exposure, so the capsules are never taken with food (see Administration and Dosage). Grapefruit juice and other foods known to inhibit CYP3A4 should be avoided, and St John’s wort should not be used.

Treatment should be started by a physician experienced in the diagnosis and treatment of CML, and continued for as long as clinical benefit is seen or until unacceptable toxicity occurs. The capsules are taken twice daily, about 12 hours apart, and must not be taken with food. They are swallowed whole with water. No food is eaten for 2 hours before the dose and for at least 1 hour after it. Patients who cannot swallow the capsules may disperse the contents of each capsule in one teaspoon of apple sauce (puréed apple) and take it immediately; no more than one teaspoon and no food other than apple sauce may be used.

Recommended Dose in Adults

• 300 mg twice daily in newly diagnosed patients with CML in the chronic phase.
• 400 mg twice daily in patients with chronic-phase or accelerated-phase CML with resistance or intolerance to prior therapy.

Recommended Dose in Children and Adolescents

Dosing is individual and based on body surface area (BSA): 230 mg/m² twice daily, rounded to the nearest 50 mg, up to a maximum single dose of 400 mg. Different capsule strengths can be combined to reach the dose.

• BSA up to 0.32 m²: 50 mg twice daily.
• BSA 0.33–0.54 m²: 100 mg twice daily.
• BSA 0.55–0.76 m²: 150 mg twice daily.
• BSA 0.77–0.97 m²: 200 mg twice daily.
• BSA 0.98–1.19 m²: 250 mg twice daily.
• BSA 1.20–1.41 m²: 300 mg twice daily.
• BSA 1.42–1.63 m²: 350 mg twice daily.
• BSA 1.64 m² or more: 400 mg twice daily.

There is no experience in children below 2 years of age, no data in newly diagnosed children below 10 years, and limited data in imatinib-resistant or intolerant children below 6 years.

Stopping Treatment After a Sustained Deep Molecular Response (Adults)

Stopping may be considered in eligible adults with chronic-phase Philadelphia chromosome positive CML who have taken nilotinib 300 mg twice daily as first-line therapy for at least 3 years and whose deep molecular response (MR4.5) has been sustained for at least one year just before stopping. The decision to stop is made by a physician experienced in treating CML.

• Patients must have typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), measured with a validated quantitative test sensitive to at least MR4.5.
• After stopping, BCR-ABL transcript levels and the complete blood count with differential are checked monthly for one year, every 6 weeks in the second year, and every 12 weeks after that.
• Loss of major molecular response (MMR, BCR-ABL/ABL of 0.1% IS or below) triggers restart of treatment within 4 weeks of the loss becoming known. The SmPC sets the same trigger for confirmed loss of MR4 in patients who received nilotinib as second-line therapy.
• Patients who do not regain MMR after three months of renewed treatment should be tested for BCR-ABL kinase domain mutations.

Dose Modifications

Myelosuppression is usually managed by withholding nilotinib temporarily or reducing the dose. Raised bilirubin and liver transaminases in children are managed by withholding, dose reduction or discontinuation. Severe fluid retention and cardiovascular events are managed as non-haematological toxicities. Section 4.2 of the SmPC gives the specific thresholds and dose steps for blood-count changes, QT prolongation and other toxicities; they are not reproduced here.

Special Populations

• Elderly: about 12% of patients in the phase III study of newly diagnosed CML and about 30% in the study of imatinib-resistant or intolerant CML were aged 65 or over. Safety and efficacy did not differ markedly from adults aged 18 to 65.
• Renal impairment: no clinical studies were done. Because nilotinib and its metabolites are not renally excreted, reduced clearance is not expected.
• Hepatic impairment: no dose adjustment is considered necessary, but patients should be treated with caution.
• Cardiac disorders: patients with uncontrolled or significant cardiac disease (recent myocardial infarction, congestive heart failure, unstable angina, clinically significant bradycardia) were excluded from the studies. Use caution.
• Laboratory monitoring: blood lipids are measured before starting, at months 3 and 6, and at least yearly during long-term treatment. Blood glucose is checked before starting and monitored during treatment.

Missed Dose

Do not take an extra dose. Take the next dose at the usual time.

QT Prolongation

Nilotinib prolongs ventricular repolarisation, seen as a longer QT interval on the ECG, in a concentration-dependent way in adults and children. At 300 mg twice daily in newly diagnosed patients, the mean time-averaged QTcF change from baseline at steady state was 6 ms, and no patient had a QTcF above 480 ms. At 400 mg twice daily in resistant or intolerant patients it was 5 ms (chronic phase) and 8 ms (accelerated phase), with QTcF above 500 ms in fewer than 1%. No torsade de pointes was seen in the clinical studies. Significant prolongation can occur when nilotinib is taken inappropriately with strong CYP3A4 inhibitors, with medicines known to prolong the QT interval, or with food, and low potassium or magnesium makes it worse. QT prolongation can be fatal. The SmPC therefore requires the following:

• A baseline ECG before treatment starts and further ECGs as clinically indicated; close monitoring of the QTc interval is advisable.
• Low potassium (hypokalaemia) or low magnesium (hypomagnesaemia) must be corrected before the first dose and monitored periodically during treatment.
• Caution in patients with congenital long QT syndrome, uncontrolled or significant cardiac disease (recent myocardial infarction, congestive heart failure, unstable angina, clinically significant bradycardia), or those taking antiarrhythmic medicines or other substances that prolong the QT interval.
• Avoid strong CYP3A4 inhibitors; if one cannot be avoided, interrupt nilotinib if possible, and otherwise monitor the QT interval closely.
• Never take nilotinib with food (see Food Effect).

Food Effect

Food increases the bioavailability of nilotinib, which can add to QT prolongation. The capsules must not be taken with food. They are taken at least 2 hours after a meal, and no food is eaten for at least 1 hour after the dose. Grapefruit juice and other foods known to inhibit CYP3A4 should be avoided. If a patient cannot swallow capsules, the contents may be dispersed in one teaspoon of apple sauce and taken at once.

Myelosuppression

Grade 3 and 4 thrombocytopenia, neutropenia and anaemia occur, more often in imatinib-resistant or intolerant CML and especially in accelerated-phase disease. Complete blood counts are done every two weeks for the first 2 months and then monthly, or as clinically indicated. Myelosuppression is generally reversible.

Sudden Death and Cardiovascular Events

Sudden death was reported uncommonly (0.1–1%) in patients with imatinib-resistant or intolerant CML who had a history of cardiac disease or significant cardiac risk factors; most also had other illnesses or took other medicines, and abnormal repolarisation may have contributed. In the phase III study of newly diagnosed patients (median treatment 60.5 months), grade 3–4 cardiovascular events were peripheral arterial occlusive disease (1.4% at 300 mg and 1.1% at 400 mg twice daily), ischaemic heart disease (2.2% and 6.1%) and ischaemic cerebrovascular events (1.1% and 2.2%). Patients should seek immediate medical attention for acute signs of a cardiovascular event. Cardiovascular status should be evaluated, and cardiovascular risk factors monitored and actively managed, during treatment.

Fluid Retention and Oedema

Severe fluid retention (pleural effusion, pulmonary oedema, pericardial effusion) was seen uncommonly (0.1–1%) in newly diagnosed patients. Unexpected, rapid weight gain should be investigated, and if severe fluid retention appears the cause is evaluated and the patient treated accordingly.

Hepatitis B Reactivation

Hepatitis B can reactivate in chronic carriers after BCR-ABL tyrosine kinase inhibitors, sometimes with acute liver failure, fulminant hepatitis leading to liver transplantation, or death. Patients are tested for HBV infection before treatment. Experts in liver disease and hepatitis B treatment should be consulted for patients with positive serology, including active disease, or who test positive during treatment. Carriers who need nilotinib are monitored closely for signs of active HBV infection throughout treatment and for several months after it ends.

Pancreatitis and Serum Lipase

Serum lipase can rise. Use caution in patients with a history of pancreatitis. If a rise in lipase comes with abdominal symptoms, nilotinib is interrupted and pancreatitis is excluded.

Blood Lipids and Blood Glucose

In the phase III study, grade 3–4 rises in total cholesterol occurred in 1.1% of patients on 400 mg twice daily and in none on 300 mg twice daily; grade 3–4 rises in blood glucose occurred in 6.9% (400 mg) and 7.2% (300 mg). Lipids and glucose are assessed before treatment and monitored as described under Administration and Dosage. If a lipid-lowering medicine is needed, check the interaction advice first, because some statins are also metabolised by CYP3A4.

Tumour Lysis Syndrome

Because tumour lysis syndrome can occur, clinically significant dehydration is corrected and high uric acid levels are treated before nilotinib is started.

Hepatic Impairment

A single 200 mg dose gave AUC increases of 35%, 35% and 19% in mild, moderate and severe hepatic impairment, and predicted steady-state Cmax rose by 29%, 18% and 22%. Studies excluded patients with ALT or AST above 2.5 times the upper limit of normal (5 times if related to the disease) or total bilirubin above 1.5 times the upper limit. Because metabolism is mainly hepatic, patients with hepatic impairment may have higher exposure and should be treated with caution.

Total Gastrectomy

Bioavailability may be lower after total gastrectomy, so more frequent follow-up should be considered.

Children and Adolescents

Mild to moderate transient rises in aminotransferases and total bilirubin were seen more often in children than in adults, indicating a higher risk of liver toxicity. Liver function (bilirubin and transaminases) is monitored monthly or as clinically indicated, and raised values are managed by withholding nilotinib, reducing the dose or stopping. Growth retardation has been documented, so growth is monitored closely.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use highly effective contraception during treatment and for up to two weeks after it ends.
• Pregnancy: data are absent or limited, and animal studies showed reproductive toxicity. Nilotinib should not be used in pregnancy unless the woman’s condition requires it, and she must be told of the risk to the foetus. A woman considering pregnancy may be able to stop treatment if she meets the criteria for stopping described above; if pregnancy is planned during a treatment-free phase, she must be told that nilotinib may need to be restarted during pregnancy.
• Breastfeeding: it is not known whether nilotinib passes into human milk; animal data show that it does. Women should not breastfeed during treatment and for 2 weeks after the last dose.
• Fertility: animal studies showed no effect on fertility in male or female rats.

Lactose

The capsules contain lactose (39.03 mg, 117.08 mg and 156.11 mg per 50 mg, 150 mg and 200 mg capsule). Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effect on Driving

Nilotinib has no or negligible influence on the ability to drive and use machines. Patients with dizziness, fatigue, visual impairment or other effects that could affect driving should refrain from driving and using machines while the effects last.

Do not store above 30 °C. Keep the capsules in the original blister package to protect them from moisture, out of the sight and reach of children.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), as a medicinal product subject to restricted medical prescription, on the prescription of a physician experienced in the diagnosis and treatment of CML. Nilotinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.