CONTRAINDICATIONS

Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.

WARNINGS AND PRECAUTIONS

Myelosuppression

Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Perform complete blood counts every 2 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 dose reduction.

QT Prolongation

TASIGNA prolongs the QT interval. ECGs should be performed at baseline, 7 days after initiation, periodically as clinically indicated, and following dose adjustments. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically.

Significant prolongation of the QT interval may occur when TASIGNA is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further enhance this effect.

Sudden Deaths

Sudden deaths have been reported in patients with CML treated with TASIGNA in clinical studies (n=5661; 0.3%). The relative early occurrence of some of these deaths relative to the initiation of TASIGNA suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.

Elevated Serum Lipase

Caution is recommended in patients with a history of pancreatitis. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated.

Hepatotoxicity

Serum bilirubin and hepatic transaminases

The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated.

Electrolyte Abnormalities

TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating TASIGNA and these electrolytes should be monitored periodically during therapy.

Drug Interactions

The concomitant use of QT-prolonging drugs and strong inhibitors or inducers of CYP3A4 should be avoided as they may affect serum concentration of TASIGNA.

Concomitant strong CYP3A4 inhibitors

The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with TASIGNA be interrupted. If interruption of treatment with TASIGNA is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, consider a dose reduction to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. If the strong inhibitor is discontinued, a washout period should be allowed before TASIGNA is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. Grapefruit products and other foods that are known to inhibit CYP3A4 should also be avoided.

Concomitant strong CYP3A4 inducers

The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital). Patients should also refrain from taking St. John's wort. Based on the nonlinear pharmacokinetic profile of nilotinib, increasing the dose of TASIGNA when co-administered with such agents is unlikely to compensate for the loss of exposure. TASIGNA is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8, and CYP2C9 and decrease the concentrations of drugs that are eliminated by these enzymes. Single-dose administration of TASIGNA to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of TASIGNA to induce metabolism has not been determined in vivo. Caution should be exercised when co-administering TASIGNA with substrates for these enzymes that have a narrow therapeutic index. TASIGNA inhibits human P-glycoprotein. If TASIGNA is administered with drugs that are substrates of Pgp, increased concentrations of the substrate are likely and caution should be exercised.

Proton pump inhibitors

Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with TASIGNA should be used with caution.

Food Effects

Food increases blood levels of TASIGNA. Patients should avoid food 2 hours before and at least 1 hour after the dose is taken.

Hepatic Impairment

Nilotinib exposure is increased in patients with impaired hepatic function.

Tumor Lysis Syndrome

Cases of tumor lysis syndrome have been reported in TASIGNA-treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts, and/or dehydration were present in the majority of these cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA.

Total Gastrectomy

The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered in patients with total gastrectomy.

Lactose

Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption.

Use in Pregnancy

There are no adequate and well-controlled studies of TASIGNA in pregnant women. However, TASIGNA may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do.

ADVERSE REACTIONS

Newly diagnosed Ph+ CML-CP

The most common (>10%) nonhematologic adverse drug reactions (ADRs) were rash, pruritus, headache, nausea, fatigue, and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (≤10% and >5%) and have been mild to moderate in severity, manageable, and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported in 2.5% of patients.
The most common hematologic ADR (all grades) was myelosuppression, including thrombocytopenia (17%), neutropenia (15%), and anemia (7%).

Resistant or intolerant Ph+ CML-CP and CML-AP

In chronic phase patients, the most commonly reported nonhematologic ADRs (≥10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting, and myalgia. The common serious ADRs (≥1% and <10%) were thrombocytopenia, neutropenia, and anemia.

In accelerated phase patients, the most commonly reported nonhematologic ADRs (≥10%) were rash, pruritus, and fatigue. The common serious ADRs (≥1% and <10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia.

DOSE ADJUSTMENTS OR MODIFICATIONS

TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors.

For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. For Grade 3 to 4 bilirubin or hepatic transaminase elevations, dosing should be withheld, and may be resumed at 400 mg once daily.

Hepatic Impairment

If possible, consider alternative therapies. If TASIGNA must be administered to patients with hepatic impairment, a lower starting dose is recommended and QT interval should be monitored. The following dose reductions should be considered:

Newly diagnosed Ph+ CML-CP

For patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), and severe hepatic impairment (Child-Pugh Class C), an initial dosing regimen of 200 mg twice daily followed by dose escalation to 300 mg twice daily based on tolerability should be considered.

Resistant or intolerant Ph+ CML-CP and CML-AP

For patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an initial dosing regimen of 300 mg twice daily followed by dose escalation to 400 mg twice daily based on tolerability should be considered. For patients with severe hepatic impairment (Child-Pugh Class C), a starting dose of 200 mg twice daily followed by a sequential dose escalation to 300 mg twice daily and then to 400 mg twice daily based on tolerability should be considered.

OTHER PATIENTS IN WHOM TASIGNA SHOULD BE USED WITH CAUTION

TASIGNA should not be used during pregnancy. Sexually active female patients should use effective contraception during treatment. Women should not breast-feed while taking TASIGNA. The safety and effectiveness of TASIGNA in pediatric patients have not been established.

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