Nilotinib

Registered South African indications:

• Newly diagnosed with Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in chronic phase
  - Patients who have been treated with nilotinib for at least 3 years and have achieved a sustained deep molecular response may be eligible for treatment discontinuation
• Chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia (Ph+ CML) in patients resistant to or intolerant to at least one prior therapy including imatinib
  - Ph+ CML patients in chronic phase, who have been previously treated with imatinib and whose treatment has been switched to nilotinib for at least 3 years and have achieved a sustained deep molecular response may be eligible for treatment discontinuation

Registered South African contraindications

• Hypersensitivity to the active ingredient or to its excipients
• Pregnancy
• Lactation

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or to its excipients

• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (Recommendations in other jurisdictions)
• Renal impairment
• Hepatic impairment
• Women of childbearing potential and for an additional 2 weeks after stopping treatment
• Males of reproductive potential and for an additional 2 weeks after stopping treatment (South African recommendations)
• Congenital QT prolongation and risk factors thereof
• Uncontrolled or significant cardiac disease
• Recent myocardial infarction
• Congestive cardiac failure
• Unstable angina
• Significant bradycardia
• Hypokalaemia 
• Hypomagnesaemia
• Chronic Hepatitis B
• History of pancreatitis
• Children 
• Dehydration
• Hyperuricaemia
• Total gastrectomy
• Glucose intolerance and diabetes
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

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

South African registered indications and dosages

Therapy should be initiated by a medical practitioner experienced in the treatment of patients with chronic myelogenous leukaemia

Used for the treatment of

Newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia (Ph+ CML) in chronic phase

• Oral (cap): 300mg, twice daily (approx. 12hrs apart); Treatment duration: Continued as long as beneficial

Chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia (Ph+ CML) in patients resistant to or intolerant to at least one prior therapy including imatinib

• Oral (cap): 400mg, twice daily (approx. 12hrs apart); Treatment duration: Continued as long as beneficial

Philadelphia chromosome positive CML patients in chronic phase who have been treated with nilotinib as first-line therapy and who achieved a sustained deep molecular response (MR4.5)

• Those treated with 300mg, twice daily for a minimum of 3 years can consider stopping if the deep molecular response is maintained for a year before discontinuation; After stopping, patients must have their BCR - ABL transcript levels and complete blood count with differential monitored monthly for a year, every 6 weeks the next year, and every 12 weeks after that, using a validated quantitative diagnostic test to measure molecular response levels on the International Scale (IS) with a sensitivity of at least MR4.5 (BCR–ABL/ ABL ≤0.0032% IS)
• In the treatment-free phase, if MR4 is lost but not MMR, monitor BCR-ABL levels every 2 weeks until they return to the MR4 and MR4.5 range; If patients maintain BCR-ABL between MMR and MR4 for four consistent measurements, revert to the original monitoring schedule. If MMR is lost, restart nilotinib within four weeks: At a dose of 300mg, twice daily OR a reduced 400mg once daily dose if previously reduced; Once restarted, monitor BCR-ABL monthly until MMR is re-established and every 12 weeks after

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Discontinuation of nilotinib therapy should be initiated by a medical practitioner experienced in the treatment of patients with CML

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Sustained deep molecular response is defined as:1
For newly diagnosed Ph+ CML-CP: The 4 last quarterly assessments (taken every 12 weeks) were at least MR4 (BCR – ABL / ABL ≤0.01% IS) and maintained for one year; with the last assessment being MR4.5 (BCR – ABL / ABL ≤0.0032% IS); and no more than two assessments falling between MR4 and MR4.5 (0.0032% IS < BCR – ABL / ABL ≤0.01% IS)1
For Ph+ CML-CP treated with imatinib: The 4 last quarterly assessments (taken every 12 weeks) showed no confirmed loss of MR4.5 (BCR – ABL / ABL ≤ 0.0032 % IS) during 1 year

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The capsules should be swallowed whole with water and should not be taken with food. For patients who are unable to swallow capsules, the content of each capsule may be dispersed in one teaspoon of applesauce (pureed apple) and should be taken immediately. See additional prescribing points for food effects

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For monitoring recommendations and dose adjustments or modifications see additional prescribing points

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Nilotinib should not be used during pregnancy as safety and efficacy in pregnancy has not been established
• Nilotinib can cause foetal harm when administered to a pregnant woman. Reproductive studies in rats and rabbits have demonstrated that nilotinib induced embryotoxicity and/or fetotoxicity (following prenatal exposure to nilotinib) at exposures equal to the one achieved in humans at the maximum recommended human dose of 400mg twice daily
• If a woman who is being treated with nilotinib is considering pregnancy, treatment discontinuation may be considered based on the eligibility criteria for discontinuing treatment
• There is a limited amount of data on pregnancies in patients while attempting treatment-free remission (TFR). If pregnancy is planned during the TFR phase, the patient must be informed of a potential need to re initiate treatment with nilotinib during pregnancy

Recommendations in other jurisdictions

• Caution; not recommended
• There are no or limited amount of data from the use of nilotinib in pregnant women
• Studies in animals have shown reproductive toxicity
• Nilotinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with nilotinib. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus
• If a woman who is being treated with nilotinib is considering pregnancy, treatment discontinuation may be considered based on the eligibility criteria for discontinuing treatment
• There is a limited amount of data on pregnancies in patients while attempting treatment-free remission (TFR). If pregnancy is planned during the TFR phase, the patient must be informed of a potential need to re-initiate nilotinib treatment during pregnancy
• Women of childbearing potential have to use highly effective contraception during treatment with nilotinib and for up to two weeks after ending treatment

Breastfeeding

South African recommendations

• Contraindicated
• Safety and efficacy in lactation has not been established
• Studies in animals demonstrate that nilotinib is excreted into breast milk
• The effects of low-dose exposure of the infant to nilotinib are unknown
• Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is contraindicated during treatment and for at least 15 days after stopping treatment with nilotinib

Recommendations in other jurisdictions

• Caution; not recommended
• It is unknown whether nilotinib is excreted in human milk
• Available toxicological data in animals have shown excretion of nilotinib in milk
• Since a risk to the newborns/infants cannot be excluded, women should not breastfeed during nilotinib treatment and for 2 weeks after the last dose

Fertility

South African recommendations

• Women of childbearing potential must be advised to use highly effective contraception (methods that result in less than 1% pregnancy rates) while receiving nilotinib and up to 2 weeks after ending treatment
• Sexually active males taking nilotinib should also use highly effective contraception nilotinib remains in semen for up to 2 weeks after ending treatment

Recommendations in other jurisdictions

• Animal studies did not show an effect on fertility in male and female rats

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available
  Clinical studies have not been conducted in patients with impaired renal function
  Patients with serum creatinine concentration >1.5 times the upper limit of the normal range were excluded from clinical studies (South African recommendations)
  Nilotinib and its metabolites are not excreted through the kidneys
  A decrease in total body clearance is not expected in patients with renal impairment

South African recommendations

• Caution; no information available
  Nilotinib has not been investigated in patients with hepatic impairment
  Clinical studies have excluded patients with ALT and/or AST > 2.5 (or >5, if related to disease) times the upper limit of the normal range and/or total bilirubin >1.5 times the upper limit of the normal range
  Metabolism of nilotinib is mainly hepatic. Cases of hepatic failure including fatal outcome have occurred in patients treated with nilotinib

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
  Hepatic impairment has a modest effect on the pharmacokinetics of nilotinib
  Dose adjustment is not considered necessary in patients with hepatic impairment. However, patients with hepatic impairment should be treated with caution

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended

Central Nervous System Disorders

• Headache
• Depression
• Insomnia
• Anxiety
• Dizziness
• Peripheral neuropathy
• Parasthesia
• Hypoaesthesia
• Hyperaesthesia
• Intracranial haemorrhage
• Ischaemic stroke
• Transient ischaemic attacks
• Cerebral infarction
• Cerebrovascular accident
• Migraine
• Syncope
• Tremor
• Disorientation
• Confusional state
• Amnesia
• Dysphoria
• Brain oedema
• Optic neuritis
• Malaise
• Dysaesthesia
• Restless legs syndrome

Cardiovascular Disorders

• QT prolongation
• Angina pectoris
• Arrhythmia 
• Palpitations
• Hypertension
• Flushing
• Peripheral artery stenosis
• Intermittent claudication
• Haematoma

Respiratory Disorders

• Pharyngitis
• Nasopharyngitis 
• Rhinitis
• Dyspnoea
• Epistaxis
• Cough
• Dysphonia
• Pulmonary oedema
• Pleural effusion
• Interstitial lung disease

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Diarrhoea
• Abdominal pain
• Dyspepsia

Hepatobiliary Disorders

• Pancreatitis

Genitourinary Disorders

• Urinary tract infection

Endocrine and Metabolic Disorders

• Decreased apetite
• Elevated creatinine
• Elevated lipase
• Elevated aspartate transaminase
• Elevated alanine transaminase
• Hypophosphataemia 
• Elevated bilirubin
• Elevated glucose
• Elevated cholesterol
• Elevated triglycerides

Musculoskeletal Disorders

• Myalgia
• Muscle spasms
• Arthralgia
• Bone pain
• Pain in extremity

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Alopecia
• Dry skin
• Erythema

Immune, Blood and Lymphatic System Disorders

• Herpes virus infection 
• Candidiasis
• Neutropaenia
• Thrombocytopaenia
• Anaemia
• Hypersensitivity 

Sensory Disorders

• Eye haemorrhage
• Periorbital oedema
• Eye pruritus
• Conjunctivitis
• Dry eye
• Visual impairment
• Blurred vision
• Vertigo

• CYP3A4 inhibitors
• CYP3A4 inducers
• Coadministration with food
• Amiodarone
• Disopyramide
• Procainamide
• Quinidine
• Sotalol
• Chloroquine
• Halofantrine
• Clarithromycin
• Haloperidol
• Methadone
• Moxifloxacin
• Grapefruit juice

• Full blood count
• ECG
• Serum lipase
• Hepatic function
• Electrolytes

Tyrosine kinase inhibitors (TKI) and cerebrovascular adverse events safety concern

• TKI containing medicines may have different kinase inhibition profiles and/or off target binding profiles, with some TKIs approved for very similar indications and others approved for different indications
• Although many adverse events/side effects/toxicities could not be explained by a class related adverse event or a related off-target kinase inhibition effect, there is some evidence that the TKIs share to a variable degree, class related cerebrovascular adverse events
• The abovementioned cerebrovascular adverse events may occur in patients on treatment with TKI containing medicines with or without risk factors for these events and may occur at any time during treatment with TKIs
• Patients on treatment with TKI containing medicine should be carefully monitored, and relevant risk factors managed to reduce the risk for these class related cerebrovascular adverse events
• Treatment with TKI containing medicines should be discontinued, and alternative treatment options be considered in patients who develop these class related cerebrovascular adverse events

Food effect

• The bioavailability of nilotinib is increased by food
• Nilotinib must not be taken in conjunction with food and should be taken 2 hours after a meal
• No food should be consumed for at least one hour after the dose is taken
• For patients who are unable to swallow capsules, the content of each capsule may be dispersed in one teaspoon of applesauce (pureed apple) and should be taken immediately
• Not more than one teaspoon of applesauce and no food other than applesauce must be used
• Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided

Monitoring recommendations and dose adjustments or modifications

• Increases in total serum cholesterol levels have been reported with nilotinib therapy
• Lipid profiles should be determined prior to initiating nilotinib therapy, and assessed at month 3 and 6 after initiating therapy, and at least yearly during chronic therapy. Increases in blood glucose levels have been reported commonly with nilotinib therapy
• Blood glucose levels should be assessed prior to initiating  nilotinib therapy and monitored during treatment
• Due to possible occurrence of Tumour Lysis Syndrome (TLS) correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiating therapy with nilotinib, and medical practitioners should consider prescribing concomitant uric acid lowering medicines on an individual patient basis
• Nilotinib may need to be temporarily withheld and/or dose reduced for haematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukaemia

Dose adjustments for neutropenia and thrombocytopenia

Newly diagnosed CML in chronic phase at 300mg twice daily Resistant or intolerant CML chronic phase at 400mg twice daily	ANC* <1x109/L and/or platelet counts <50x109/L	1. Stop nilotinib, and monitor blood counts 2. Resume within 2 weeks at prior dose if ANC 1x109/L and/or platelet counts <50x109/ L 3. If blood counts remain low a dose reduction to 400mg once daily may be required
Resistant or intolerant CML in accelerated phase at 400mg twice daily	(ANC) <0.5x109/L or platelet counts <10x109/L	1. Stop nilotinib and monitor blood counts 2. Resume within 2 weeks at prior dose if ANC >1.0x109/L and/or platelets >20x109/L 3. If blood counts remain low, a dose reduction to 400mg once daily may be required

*ANC absolute neutrophil count

• If clinically significant moderate or severe non-haematologic toxicity develops, dosing should be interrupted, and may be resumed at 400mg once daily once the toxicity has resolved
• If clinically appropriate, re-escalation of the dose to 300mg (newly diagnosed Ph+ CML - CP) or 400mg (resistant or intolerant Ph+ CML - chronic phase and CML - accelerated phase) twice daily should be attempted
• Asymptomatic serum lipase elevations were observed and also elevations associated with clinical symptoms such as abdominal pain or a diagnosis of pancreatitis
• Elevations in serum lipase did not lead to treatment discontinuation in any patient in clinical studies
• Overall, this finding was clinically manageable in the majority of patients without requirement for dose reduction or interruption. For Grade 3 to 4 lipase elevations, doses were reduced to 400mg once daily
• In clinical studies, the majority of bilirubin and hepatic transaminase laboratory abnormalities in patients were of low-grade toxicity which did not require dose interruption or reduction
• Treatment discontinuation due to elevated serum bilirubin occurred in only 1 patient (0.3%). For Grade 3 to 4 bilirubin or hepatic transaminase elevations, doses were reduced to 400mg once daily
• If a dose is missed the patient should not take an additional dose but take the usual prescribed next dose

Nilotinib is a potent inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein both in cell lines and in primary Philadelphia-chromosome positive leukaemia cells. The substance binds with high affinity to the ATP-binding site in such a manner that it is a potent inhibitor of wild-type BCR-ABL and maintains activity against 32/33 imatinib-resistant mutant forms of BCR-ABL. As a consequence of this biochemical activity, nilotinib selectively inhibits the proliferation and induces apoptosis in cell lines and in primary Philadelphia-chromosome positive leukaemia cells from CML patients. In murine models of CML, as a single agent nilotinib reduces tumour burden and prolongs survival following oral administration.

Capsule 150mg

• Tasigna (Novartis) originator

Capsule 200mg

• Tasigna (Novartis) originator