Tasigna

Therapy should be initiated by a physician experienced in the diagnosis and the treatment of patients with CML. Posology Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs. If a dose is missed the patient should not take an additional dose, but take the usual prescribed next dose.

Posology for Philadelphia chromosome positive CML adult patients The recommended dose is: - 300 mg twice daily in newly diagnosed patients with CML in the chronic phase, - 400 mg twice daily in patients with chronic or accelerated phase CML with resistance or intolerance to prior therapy.

Posology for Philadelphia chromosome positive CML paediatric patients Dosing in paediatric patients is individualised and is based on body surface area (mg/m2). The recommended dose of nilotinib is 230 mg/m2 twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg) (see Table 1).

Different strengths of Tasigna hard capsules can be combined to attain the desired dose. There is no experience with treatment of paediatric patients below 2 years of age. There are no data in newly diagnosed paediatric patients below 10 years of age and limited data in imatinib-resistant or intolerant paediatric patients below 6 years of age.

5) Discontinuation of treatment may be considered in eligible adult Philadelphia chromosome positive (Ph+) CML patients in chronic phase who have been treated with nilotinib at 300 mg twice daily for a minimum of 3 years if a deep molecular response is sustained for a minimum of one year immediately prior to discontinuation of therapy.

1). Eligible patients who discontinue nilotinib therapy must have their BCR-ABL transcript levels and complete blood count with differential monitored monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter.

0032% IS). 5. Patients who maintain BCR-ABL levels between MMR and MR4 for a minimum of 4 consecutive measurements can return to the original monitoring schedule. Patients who lose MMR must re-initiate treatment within 4 weeks of when loss of remission is known to have occurred.

Nilotinib therapy should be re-initiated at 300 mg twice daily or at a reduced dose level of 400 mg once daily if the patient had a dose reduction prior to discontinuation of therapy. 4). 5) on nilotinib following prior imatinib therapy Discontinuation of treatment may be considered in eligible adult Philadelphia chromosome positive (Ph+) CML patients in chronic phase who have been treated with nilotinib for a minimum of 3 years if a deep molecular response is sustained for a minimum of one year immediately prior to discontinuation of therapy.

Summary of the safety profile The safety profile is based on pooled data from 3,422 patients treated with Tasigna in 13 clinical studies in the approved indications: adults and paediatric patients with newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia (CML) in the chronic phase (5 clinical studies with 2,414 patients), adult patients with chronic phase and accelerated phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib (6 clinical studies with 939 patients) and paediatric patients with chronic phase Philadelphia chromosome positive CML with resistance or intolerance to prior therapy including imatinib (2 clinical studies with 69 patients).

34 patient-years of exposure. The safety profile of nilotinib is consistent across indications. 4%). Tabulated list of adverse reactions Adverse reactions from clinical studies and post-marketing reports (Table 3) are listed by MedDRA system organ class and frequency category.

Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 3 Adverse drug reactions Infections and infestations Very common:

Upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis) Common: Folliculitis, bronchitis, candidiasis (including oral candidiasis), pneumonia, gastroenteritis, urinary tract infection Uncommon: Herpes virus infection, anal abscess, candidiasis (candida infection), furuncle, sepsis, subcutaneous abscess, tinea pedis Rare: Hepatitis B reactivation Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon: Skin papilloma Rare: Oral papilloma, paraproteinaemia Blood and lymphatic system disorders Very common: Anaemia, thrombocytopenia Common: Leukopenia, leukocytosis, neutropenia, thrombocythaemia Uncommon: Eosinophilia, febrile neutropenia, lymphopenia, pancytopenia Immune system disorders Uncommon: Hypersensitivity Endocrine disorders Very common: Growth retardation Common: Hypothyroidism Uncommon: Hyperthyroidism Rare: Hyperparathyroidism secondary, thyroiditis 14 Metabolism and nutrition disorders Common: Electrolyte imbalance (including hypomagnesaemia, hyperkalaemia, hypokalaemia, hyponatraemia, hypocalcaemia, hypercalcaemia, hyperphosphataemia), diabetes mellitus, hyperglycaemia, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia, decreased appetite, gout, hyperuricaemia, hypophosphataemia (including blood phosphorus decreased) Uncommon: Dehydration, increased appetite, dyslipidaemia, hypoglycaemia Rare: Appetite disorder, tumour lysis syndrome Psychiatric disorders Common: Depression, insomnia, anxiety Uncommon: Amnesia, confusional state, disorientation Rare: Dysphoria Nervous system disorders Very common: Headache Common: Dizziness, hypoaesthesia, paraesthesia, migraine Uncommon: Cerebrovascular accident, intracranial/cerebral haemorrhage, ischaemic stroke, transient ischaemic attack, cerebral infarction, loss of consciousness (including syncope), tremor, disturbance in attention, hyperaesthesia, dysaesthesia, lethargy, peripheral neuropathy, restless legs syndrome, facial paralysis Rare: Basilar artery stenosis, brain oedema, optic neuritis Eye disorders Common: Conjunctivitis, dry eye (including xerophthalmia), eye irritation, hyperaemia (scleral, conjunctival, ocular), vision blurred Uncommon: Visual impairment, conjunctival haemorrhage, visual acuity reduced, eyelid oedema, blepharitis, photopsia, conjunctivitis allergic, diplopia, eye haemorrhage, eye pain, eye pruritus, eye swelling, ocular surface disease, periorbital oedema, photophobia Rare: Chorioretinopathy, papilloedema Ear and labyrinth disorders Common: Vertigo, ear pain, tinnitus Uncommon: Hearing impaired (hypoacusis) Cardiac disorders Common: Angina pectoris, arrhythmia (including atroventricular block, cardiac flutter, ventricular extrasystoles, tachycardia, atrial fibrillation, bradycardia), palpitations, electrocardiogram QT prolonged, coronary artery disease Uncommon: Myocardial infarction, cardiac murmur, pericardial effusion, cardiac failure, diastolic dysfunction, left bundle branch block, pericarditis Rare: Cyanosis, ejection fraction decreased Not known: Ventricular dysfunction Vascular disorders Common: Hypertension, flushing, peripheral arterial occlusive disease Uncommon: Hypertensive crisis, intermittent claudication, peripheral artery stenosis, haematoma, arteriosclerosis, hypotension, thrombosis Rare: Shock haemorrhagic Respiratory, thoracic and mediastinal disorders Very common: Cough Common: Dyspnoea, dyspnoea exertional, epistaxis, oropharyngeal pain Uncommon: Pulmonary oedema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, throat irritation, dysphonia, pulmonary hypertension, wheezing Rare: Pharyngolaryngeal pain 15 Gastrointestinal disorders Very common: Nausea, upper abdominal pain, constipation, diarrhoea, vomiting Common: Pancreatitis, abdominal discomfort, abdominal distension, flatulence, abdominal pain, dyspepsia, gastritis, gastroesophageal reflux, haemorrhoids, stomatitis Uncommon: Gastrointestinal haemorrhage, melaena, mouth ulceration, oesophageal pain, dry mouth, sensitivity of teeth (hyperaesthesia teeth), dysgeusia, enterocolitis, gastric ulcer, gingivitis, hiatus hernia, rectal haemorrhage Rare: Gastrointestinal ulcer perforation, haematemesis, oesophageal ulcer, oesophagitis […]

Myelosuppression Treatment with nilotinib is associated with (National Cancer Institute Common Toxicity Criteria grade 3 and 4) thrombocytopenia, neutropenia and anaemia. Occurrence is more frequent in patients with imatinib-resistant or intolerant CML, in particular in patients with accelerated-phase CML.

Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. 2). QT prolongation Nilotinib has been shown to prolong cardiac ventricular repolarisation as measured by the QT interval on the surface ECG in a concentration-dependent manner in adult and paediatric patients.

In the Phase III study in patients with newly diagnosed CML in chronic phase receiving 300 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 6 msec. No patient had a QTcF >480 msec.

No episodes of torsade de pointes were observed. In the Phase II study in imatinib-resistant and intolerant CML patients in chronic and accelerated phase receiving 400 mg nilotinib twice daily, the change from baseline in mean time-averaged QTcF interval at steady state was 5 and 8 msec, respectively.

QTcF of >500 msec was observed in <1% of these patients. No episodes of torsade de pointes were observed in clinical studies. In a healthy volunteer study with exposures that were comparable to the exposures observed in patients, the time-averaged mean placebo-subtracted QTcF change from baseline was 7 msec (CI ± 4 msec).

No subject had a QTcF >450 msec. Additionally, no clinically relevant arrhythmias were observed during the conduct of the trial. In particular, no episodes of torsade de pointes (transient or sustained) were observed. 5). The presence of hypokalaemia and hypomagnesaemia may further enhance this effect.

Prolongation of the QT interval may expose patients to the risk of fatal outcome. Tasigna should be used with caution in patients who have or who are at significant risk of developing prolongation of QTc, such as those: - with congenital long QT prolongation - with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia.

1. 7