About Tasigna®

Tasigna Safety and Tolerability

Hypersensitivity

• Tasigna is contraindicated in patients who are hypersensitive to the active substance (nilotinib) or to any of the excipients.

Myelosuppression

• Treatment with Tasigna is associated with Grade 3/4 thrombocytopenia (27%), neutropenia (15%), and anemia (13%). Occurrence is more frequent in patients with accelerated phase CML.
• Complete blood counts should be performed every 2 weeks for the first 2 months of treatment with Tasigna and then monthly thereafter, or as clinically indicated.
• Myelosuppression is generally reversible and usually can be managed by temporarily withholding or reducing the dose of Tasigna.

QT prolongation

• Tasigna has been shown to prolong cardiac ventricular repolarisation as measured by the QT interval on the surface ECG in a concentration dependent manner. In the Phase II study in imatinib-resistant and intolerant CML patients in chronic and accelerated phase, the change from baseline in mean time-averaged QTcF interval at steady state was 6 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 Ph+ CML 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 trial. In particular, no episodes of torsades de pointes (transient or sustained) were observed.
• Tasigna should be used with caution in Ph+ CML patients who have or may develop QTc prolongation. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia, patients taking antiarrhythmic medicines such as amiodarone, disopyramide, procainamide, quinidine and sotalol or other drugs that may lead to QT prolongation such as chloroquine, halofantrine, clarithromycin, haloperidol and methadone, and cumulative high-dose anthracycline therapy. Prolongation of the QT interval may expose patients to the risk of fatal outcome.
• Close monitoring for an effect on the QTc interval is advisable and a baseline ECG is recommended prior to initiating therapy with Tasigna as clinically indicated. Hypokalemia or hypomagnesemia must be corrected prior to administration of Tasigna and monitored periodically during therapy.

Sudden Death

• Uncommon cases (0.1% to 1%) of sudden deaths have been reported in patients receiving Tasigna with a past history of cardiac disease or significant cardiac risk factors. Co-morbidities in addition to the underlying malignancy were also frequently present as were concomitant medications. Ventricular repolarisation abnormalities may have been contributory factors.

Drug interactions

• Drugs that may increase serum concentrations:
• The administration of Tasigna with agents that are strong CYP3A4-inhibitors (including, but not limited to, ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin) should be avoided if at all possible. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted if possible. If transient interruption of treatment with Tasigna is not possible, close monitoring of the individual for prolongation of the QT interval is indicated.
• The absorption of Tasigna is increased if it is taken with food, resulting in higher serum concentration.
• Drugs that may decrease serum concentrations:
• Inducers of CYP3A4 activity could increase the metabolism of nilotinib and thereby decrease serum concentrations of nilotinib.
• The concomitant administration of medications that induce CYP3A4 (including phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John's Wort) may reduce exposure to nilotinib. In Ph+ CML patients for whom CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be considered.
• Drugs that may have their concentration altered:
• Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, potentially increasing the concentrations of drug eliminated by these enzymes.
• Single-dose administration of Tasigna with midazolam (a CYP3A4 substrate) to healthy subjects increased midazolam exposure by 30 percent.
• Caution should be exercised when coadministering Tasigna with substrates of these enzymes having a narrow therapeutic index e.g. astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, ergotamine or dihydroergotamine.
• Since warfarin is metabolized by CYP2C9 and CYP3A4 it should be given with caution to patients taking Tasigna. Other medications for anticoagulation should be considered or if warfarin is used then control of warfarin pharmacodynamic markers (INR or PT) is recommended following initiation of Tasigna therapy.
• Anti-arrhythmic medicines and other drugs that may prolong QT:
• Nilotinib should be used with caution in patients who have or may develop prolongation of QT including those patients taking anti-arrhythmic medicines or other drugs that lead to QT prolongation such as amiodarone, disopyramide, procainamide, quinidine, sotalol, chloroquine, halofantrine, clarithromycin, haloperidol, methadone and moxifloxacin.

Food effects

• The bioavailability of nilotinib is increased by food. Tasigna should not be taken in conjunction with food and should be taken at least 2 hours after a meal. No food should be consumed for at least 1 hour after the dose is taken.
• Grapefruit juice and other foods that are known to inhibit CYP3A4 should be avoided with Tasigna.

Hepatic Impairment

• Hepatic impairment has a modest effect (18% to 35%) on the pharmacokinetics of nilotinib (AUC and Cmax). However, metabolism of nilotinib is mainly hepatic and therefore patients with hepatic impairment might have increased exposure to nilotinib and should be treated with caution.

Serum lipase

• Elevation in serum lipase has been observed. Caution is recommended in patients with previous history of pancreatitis.

Total gastrectomy

• The bioavailability of nilotinib might be reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered.

Lactose

• Tasigna capsules contain lactose, and should not be taken by patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

Pregnancy and Lactation

• Patients should be advised that the use of Tasigna during pregnancy may cause harm to the fetus. Tasigna should not be taken during pregnancy unless necessary.
• Male patients, and female patients of childbearing potential, must use effective contraception during treatment with Tasigna.
• Women taking Tasigna should not breastfeed.

Effects on ability to drive and use machines

• Patients experiencing dizziness, fatigue, visual impairment or other effects with a potential to impact their ability to drive or use machine safely should refrain from these activities as long as the effects persist.

SIDE EFFECTS of TASIGNA

Tasigna is generally well tolerated and has demonstrated a low incidence of cross-intolerance with Glivec® (imatinib mesylate). Tasigna also was associated with a low rate of Grade 3/4 nonhematologic AEs, including those related to fluid retention.

Most nonhematologic AEs were mild to moderate in severity.

• The most common AEs in the chronic phase were rash, pruritus, nausea, headache, and fatigue.

Tasigna was associated with a low incidence of AEs related to fluid retention

• Low incidence (<1%) of Grade 3/4 pleural or pericardial effusions

Tasigna has a negligible incidence of cross-intolerance with Glivec

The most common hematologic AEs (Grade 3/4) were neutropenia and thrombocytopenia.

AEs are measured regardless of relation to Tasigna

COMMON SIDE EFFECTS OF Tasigna

• The majority of adult patients who received Tasigna in clinical studies experienced adverse events at some time. Most adverse events were mild to moderate in severity.
• The most frequent nonhematologic drug-related adverse events (all grades) were rash (26%), pruritus (22%), nausea (19%), fatigue (16%), headache (15%), constipation (11%), and diarrhea (10%). Constipation, diarrhoea, bone pain, arthralgia, muscle spasms and peripheral oedema were observed less commonly and were mild to moderate severity.
• Discontinuation for adverse events regardless of causality was observed in 16% of chronic phase and 14% of accelerated phase patients.
• The most frequent hematologic toxicities (all grades) included thrombocytopenia (27%), neutropenia (15%), and anemia (13%).
• Congestive heart failure (1%), gastrointestinal hemorrhage (3%) and CNS hemorrhage (1%) were observed in patients.
• Supportive care may help management of some mild-to-moderate adverse events so that the prescribed dose can be maintained whenever possible.

Overdose

• Isolated reports of intentional overdose with Tasigna have been reported in combination with alcohol and other medicinal products. 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.

Prescribing Tasigna
Tasigna Efficacy
Tasigna Safety and Tolerability
European Summary of Product Characteristics
Tasigna Mechanism of Action
How to Dose
Prescribing Tasigna
Tasigna Efficacy
Tasigna Safety and Tolerability
European Summary of Product Characteristics
Tasigna Mechanism of Action
How to Dose