Tasigna 150mg. 200mg Capsule

Treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myelogenous leukaemia (Ph+ CML) in chronic phase. Patients who have been treated with TASIGNA for at least 3 years and have achieved a sustained deep molecular response may be eligible for treatment discontinuation (see sections 4.4 and 5.1).

Treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia (Ph+ CML) in adult 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 TASIGNA for at least 3 years and have achieved a sustained deep molecular response may be eligible for treatment discontinuation (see sections 4.4 and 5.1).

The term u201csustained deep molecular responseu201d, is defined by the following criteria (see section 5.1 Pharmacodynamic properties: Clinical efficacy and safety).

For patients with newly diagnosed Ph+ CML - CP:

• the 4 last quarterly assessments (taken every 12 weeks) were at least MR4 (BCR u2013 ABL / ABL u2264 0.01 % IS), and maintained for one year
• the last assessment being MR4.5 (BCR u2013 ABL / ABL u2264 0.0032 % IS)
• no more than two assessments falling between MR4 and MR4.5 (0.0032 % IS < BCR u2013 ABL / ABL u2264 0.01 % IS).

For Ph+ CML - CP patients with at least one prior therapy including imatinib:

The 4 last quarterly assessments (taken every 12 weeks) showed no confirmed loss of MR4.5 (BCR u2013 ABL / ABL u2264 0.0032 % IS) during 1 year.

Therapy should be initiated by a medical practitioner experienced in the treatment of patients with CML.

Posology

Dosing in patients with newly diagnosed Ph+ CML - chronic phase: The recommended dose of TASIGNA is 300 mg twice daily. Treatment should be continued as long as the patient continues to benefit.

Dosing in patients with Ph+ CML - chronic phase and CML - accelerated phase resistant to or intolerant to at least one prior therapy including imatinib: The recommended dose of TASIGNA is 400 mg twice daily. Treatment should be continued as long as the patient continues to benefit.

Philadelphia chromosome positive CML patients in chronic phase who have been treated with TASIGNA as first-line therapy and who achieved a sustained deep molecular response (MR4.5): Discontinuation of treatment may be considered in eligible Philadelphia chromosome positive (Ph+) CML patients in chronic phase who have been treated with TASIGNA 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. Discontinuation of TASIGNA therapy should be initiated by a medical practitioner experienced in the treatment of patients with CML (see sections 4.4 and 5.1).

Eligible patients who discontinue TASIGNA 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. Monitoring of BCR - ABL transcript levels must be performed with a quantitative diagnostic test validated to measure molecular response levels on the International Scale (IS) with a sensitivity of at least MR4.5 (BCR u2013 ABL / ABL u2264 0.0032 % IS).

For patients who lose MR4 (MR4 = BCR u2013 ABL / ABL u2264 0.01 % IS) but not MMR (MMR = BCR u2013 ABL / ABL u2264 0.1 % IS) during the treatment-free phase, BCR - ABL transcript levels should be monitored every 2 weeks until BCR - ABL levels return to a range between MR4 and MR4.5. 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. TASIGNA 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. Patients who re-initiate TASIGNA therapy should have their BCR - ABL transcript levels monitored monthly until MMR is re-established and every 12 weeks thereafter (see section 4.4).

Monitoring recommendations and dose adjustments or modifications:

Increases in total serum cholesterol levels have been reported with TASIGNA therapy (see section 4.4). Lipid profiles should be determined prior to initiating TASIGNA therapy, 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 TASIGNA therapy (see section 4.4). Blood glucose levels should be assessed prior to initiating TASIGNA therapy and monitored during treatment (see section 4.4).

Due to possible occurrence of Tumor Lysis Syndrome (TLS) correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiating therapy with TASIGNA (see section 4.8), and medical practitioners should consider prescribing concomitant uric acid lowering medicines on an individual patient basis.

TASIGNA may need to be temporarily withheld and/or dose reduced for haematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukaemia (see Table 1)

Known hypersensitivity to nilotinib or to any of the excipients. Safety in pregnancy and lactation has not been established (see section 4.6).

QT prolongation: TASIGNA prolongs the QT interval. Correct hypokalaemia or hypomagnesaemia prior to administration and monitor periodically. Avoid concomitant therapy with medicines known to prolong the QT interval and strong CYP3A4 inhibitors. Use caution in patients with hepatic impairment. Obtain ECGs at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

TASIGNA should be used with caution in patients who have or may develop prolongation of QTc. These include patients with hypokalaemia or hypomagnesaemia, patients with congenital long QT syndrome, patients taking anti-dysrhythmic medicines or other medicines that may lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalaemia or hypomagnesaemia must be corrected prior to TASIGNA administration.

Sudden deaths: There were sudden deaths reported in the safety population and the expanded access program, post-marketing and the expanded access program and post-marketing. Ventricular repolarisation abnormalities may have contributed to their occurrence.

Cardiovascular events: Cardiovascular events were reported in a randomized, Phase III nilotinib trial in newly diagnosed CML patients and observed in the post-marketing reports. With a median time on therapy of 60.5 months in the clinical trial, cardiovascular events included occurred in 7.5 % of patients at 300 mg and 13.4 % at 400 mg twice a day in particular ischaemic heart disease events occurred in 3.9 % and 8.7 % respectively; peripheral arterial occlusive disease resulted occurred in 2.5 % of patients at both 300 mg and 400 mg twice a day and resulted in withdrawal in 0.4 % and 1.1 % of patients at 300 mg and 400 mg twice a day, respectively. TASIGNA should not be used as first line therapy in patients with prior severe peripheral arterial occlusive disease (PAOD), including angina pectoris. In patients with mild to moderate pre-existing PAOD, nilotinib may be prescribed with caution. If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and actively managed prior to initiating and during TASIGNA therapy according to standard guidelines (please refer to section 4.2).

Fluid retention: Severe fluid retention manifestations occurred in 8 % of patients treated with TASIGNA. These cases included patients developing pleural effusion, pericardial effusion, including cardiac tamponade (0.1 u2013 1 %). Unexpected, rapid weight gain should be carefully investigated. If signs of severe fluid retention appear during treatment with TASIGNA, the aetiology should be evaluated and patients treated accordingly (please refer to dosage and directions for use and side effects).

Hepatitis B reactivation: Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving a BCR - ABL tyrosine kinase inhibitor (TKI), such as TASIGNA. Some cases involving medicines of the BCR - ABL TKI class resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or death. Patients should be tested for hepatitis B infection before initiating treatment with TASIGNA. Patients currently on TASIGNA should have baseline testing for hepatitis B infection in order to identify chronic carriers of the virus. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for hepatitis B infection during treatment. Carriers of hepatitis B virus who require treatment with TASIGNA should be frequently monitored for signs and symptoms of active hepatitis B infection throughout therapy and for several months following termination of therapy.

Special monitoring of Ph+ CML patients in chronic phase who have achieved a sustained deep molecular response. Eligibility for discontinuation of treatment: Eligible patients who are confirmed to express the typical BCR - ABL transcripts, e13a2 / b2a2 or e14a2 / b3a2, can be considered for treatment discontinuation. Patients must have typical BCR - ABL transcripts to allow quantitation of BCR - ABL, evaluation of the depth of molecular response, and determination of a possible loss of molecular remission after discontinuation of treatment with TASIGNA.

Monitoring of patients who have discontinued therapy: Frequent monitoring of BCR - ABL transcript levels in patients eligible for treatment discontinuation must be performed with a quantitative diagnostic test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR u2013 ABL / ABL u2264 0.0032 % IS). BCR - ABL transcript levels must be assessed prior to and during treatment discontinuation (see sections 4.2 and 5.1).

Loss of major molecular response (MMR = BCR u2013 ABL / ABL u2264 0.1 % IS) or confirmed loss of MR4 (two consecutive measures separated by at least 4 weeks showing loss of MR4 (MR4 = BCR u2013 ABL / ABL u2264 0.01 % IS)) will trigger treatment re-initiation within 4 weeks of when loss of remission is known to have occurred. Molecular relapse can occur during the treatment-free phase, and long-term outcome data are not yet available. It is therefore crucial to perform frequent monitoring of BCR - ABL transcript levels and complete blood count with differential in order to detect possible loss of remission (see section 4.2). For patients who fail to achieve MMR after three months of treatment re-initiation, BCR - ABL kinase domain mutation testing should be performed.

Myelosuppression: Treatment with TASIGNA is associated with thrombocytopenia, neutropenia and anaemia (NCI CTC Grade 3 / 4). The occurrence is more frequent in patients with imatinib-resistant or intolerant CML and, in particular in patients with Chronic Myelogenous Leukaemia - Accelerated Phase (CML - AP). Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding TASIGNA temporarily or reducing the dose (see section 4.2).

Serum lipase: Elevation in serum lipase has been observed. Caution is recommended in patients with previous history of pancreatitis. In case lipase elevations are accompanied by abdominal symptoms, doses should be interrupted and appropriate diagnostics should be considered in order to exclude pancreatitis.

Liver function abnormality: TASIGNA may result in elevations in bilirubin, AST / ALT, and alkaline phosphatase. Check hepatic function tests periodically.

Electrolyte abnormalities: TASIGNA can cause hypophosphataemia, hypokalaemia, hyperkalaemia, hypocalcaemia, and hyponatraemia. Correct electrolyte abnormalities prior to initiating TASIGNA and monitor periodically during therapy.

Hepatic impairment: TASIGNA 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 normal range and/or total bilirubin > 1.5 times the upper limit of the normal range. Metabolism of nilotinib is mainly hepatic. Caution is recommended in patients with hepatic impairment (see section 4.2). Caution is recommended in these patients and QT interval should be monitored closely.

Avoid concomitant use of strong inhibitors or inducers of CYP3A4. If patients must be co-administered a strong CYP3A4 inhibitor, dose reduction should be considered and the QT interval should be monitored closely.

Total gastrectomy: The bioavailability of nilotinib may be reduced in patients with total gastrectomy. More frequent follow up of these patients should be considered.

Tumour lysis syndrome: Cases of tumour lysis syndrome have been reported in patients treated with TASIGNA. For monitoring recommendations please refer to section 4.2.

Food effect: The bioavailability of TASIGNA is increased by food. TASIGNA should not be taken in conjunction with food (see section 4.2 and 4.6) 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.

TASIGNA should not be used during pregnancy as safety and efficacy in pregnancy and lactation has not been established.

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

Pregnancy: TASIGNA can cause fetal harm when administered to a pregnant woman. Reproductive studies in rats and rabbits have demonstrated that nilotinib induced embryo-toxicity and/or feto-toxicity (following prenatal exposure to nilotinib) at exposures equal to the one achieved in humans at the maximum recommended human dose of 400 mg 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 as described in sections 4.2 and 4.4. 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 TASIGNA during pregnancy (see sections 4.2 and 4.4).

Breastfeeding: 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 TASIGNA.

Patients experiencing dizziness, visual impairment or other undesirable effects with a potential impact on the ability to safely drive or use machines should refrain from these activities as long as these undesirable effects persist. (See section 4.8).

In patients with newly diagnosed Ph+ CML - chronic phase: The data reported below reflect exposure to TASIGNA from a randomised phase III study in patient with newly diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n = 279). The median time on treatment was 60.5 months (range 0.1 u2013 70.8 months).

Non-haematologic adverse drug reactions (ADRu2019s) reported with very common frequency (u2265 10 %) were rash, pruritus, headache, nausea, fatigue, alopecia and myalgia, and upper abdominal pain. Most of these ADRs were mild to moderate in severity (Grade 1 or 2). Constipation, diarrhoea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral oedema, vomiting and asthenia were observed commonly (in 5 u2013 10 %) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions, regardless of causality occurred in 2 % and 500 msec while on study medicine in any of the treatment groups and no events of Torsade de Pointes were observed. QTcF increases from baseline that exceed 60 msec were observed in 4 patients while on study medicine (one in the 300 mg twice daily treatment group and four in the 400 mg twice daily treatment group). No patients in any treatment groups had a LVEF < 45 % during treatment. Also, there were no patients with 15 % or greater decrease from baseline in LVEF. No sudden deaths have been reported.

In the nilotinib 300 mg twice daily group, haematologic ADRu2019s include myelosuppression: thrombocytopenia (18 %), neutropenia (15 %), and anaemia (8 %). Biochemistry ADRs include alanine aminotransferase increased (24 %), hyperbilirubinaemia (16 %), aspartate aminotransferase increased (12 %), lipase increased (11 %), blood bilirubin increased (10 %), hyperglycaemia (4 %), hypercholesterolaemia (3 %), and hypertriglyceridaemia (< 1 %). See Table 3 for grade 3 / 4 laboratory abnormalities. Discontinuation due to adverse events drug reactions was observed in 10 % of patients.

ADRs in patients with resistant or intolerant Ph+ CML - chronic phase (CP) and CML - Accelerated phase (AP): The data reported below reflect exposure to TASIGNA in 458 patients with Ph+ Chronic myelogenous Leukaemia - chronic phase (CML - CP) (n = 321) and chronic myelogenous leukaemia - accelerated phase (CML - AP) resistant to or intolerant to at least one prior therapy including imatinib in an open-label multicentre study treated at the recommended dose of 400 mg twice daily. Non-haematologic adverse drug reactions (ADRu2019s) reported with very common frequency (u2265 10 % in the combined chronic myelogenous leukaemia chronic phase (CML - CP) and chronic myelogenous leukaemia u2013 accelerated phase (CML - AP) patient populations) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhoea vomiting and myalgia. Most of these ADRu2019s were mild to moderate in severity. Vomiting, myalgia, alopecia, muscle spasms, decreased appetite, arthralgia, bone pain, abdominal pain, peripheral oedema and asthenia were observed in 5 % to 10 % and have been of mild to moderate severity (Grade 1 or 2). Discontinuation for adverse events regardless of causality was observed in 16 % of CP and 10 % of AP patients. Pleural and pericardial effusions as well as complications of fluid retention occurred in 1 % of patients receiving TASIGNA. Congestive heart failure was observed in 1 % of patients. Gastrointestinal and CNS haemorrhage were reported in 3 % and 1 % of patients, respectively. Sudden deaths and QT prolongation were reported. QTcF exceeding 500 msec respectively. Sudden deaths and QT prolongation were reported. QTcF exceeding 500 msec was observed in < 1 % of patients. Haematologic ADRu2019s include myelosuppression: thrombocytopenia (31 %), neutropenia (17 %), and anaemia (14 %). See Table 3 for grade 3 / 4 laboratory abnormalities. Discontinuation due to adverse drug reactions was observed in 16 % of CP and 10 % of AP patients.

Isolated reports on intentional overdose with nilotinib were reported, where unspecified number of TASIGNA capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting and drowsiness. No ECG changes or hepatotoxicity were reported. Outcomes were reported as recovered. In the event of overdose, the patient should be observed and appropriate supportive treatment given.