NILOTINIB Drug Interactions: What You Need to Know

5.8 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) cases have been reported in nilotinib treated patients with resistant or intolerant CML. Malignant disease progression, high white blood cell (WBC) counts and/or dehydration were present in the majority of these cases. Due to potential for TLS, maintain adequate hydration and correct uric acid levels prior to initiating therapy with nilotinib capsules.

7 DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid concomitant use with nilotinib capsules, or reduce nilotinib capsules dose if coadministration cannot be avoided. ( 7.1 ) Strong CYP3A Inducers: Avoid concomitant use with nilotinib capsules. ( 7.1 )

Proton Pump

Inhibitors: Use short-acting antacids or H2 blockers as an alternative to proton pump inhibitors. ( 7.1 )

7.1 Effect of Other Drugs on Nilotinib Capsules Strong CYP3A Inhibitors Concomitant use with a strong CYP3A inhibitor increased nilotinib concentrations compared to nilotinib alone <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> , which may increase the risk of nilotinib toxicities. Avoid concomitant use of strong CYP3A inhibitors with nilotinib capsules. If patients must be coadministered a strong CYP3A4 inhibitor, reduce nilotinib capsules dose <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.8 )]</span> . Strong CYP3A Inducers Concomitant use with a strong CYP3A inducer decreased nilotinib concentrations compared to nilotinib alone <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , which may reduce nilotinib capsules efficacy. Avoid concomitant use of strong CYP3A inducers with nilotinib capsules.

Proton Pump Inhibitors

Concomitant use with a proton pump inhibitor (PPI) decreased nilotinib concentrations compared to nilotinib alone [see Clinical Pharmacology ( 12.3 )] , which may reduce nilotinib capsules efficacy. Avoid concomitant use of PPI with nilotinib capsules. As an alternative to PPIs, use H2 blockers approximately 10 hours before or approximately 2 hours after the dose of nilotinib capsules, or use antacids approximately 2 hours before or approximately 2 hours after the dose of nilotinib capsules.

7.2 Drugs That Prolong the QT Interval Avoid coadministration of nilotinib capsules with agents that may prolong the QT interval, such as anti-arrhythmic drugs <span class="opacity-50 text-xs">[see Boxed Warning, Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.2 )]</span> .

Nilotinib Capsules is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning and Warnings and Precautions (5.2)].

Nilotinib

Capsules is contraindicated in patients with,

• hypokalemia ( 4 )
• hypomagnesemia ( 4 )
• long QT syndrome ( 4 )

AND PRECAUTIONS

• Substitution with Other Nilotinib Products and Risk of Medication Errors : DANZITEN (nilotinib) tablets may not be substitutable with other nilotinib products, including other nilotinib tablets, on a milligram per milligram basis. Confirm that the intended nilotinib product is being prescribed and dispensed. ( 5.1 )
• Myelosuppression : Monitor complete blood count (CBC) during therapy and manage by treatment interruption or dose reduction. ( 5.2 )
• Cardiac and Arterial Vascular Occlusive Events : Evaluate cardiovascular status, monitor and manage cardiovascular risk factors during DANZITEN therapy. ( 5.5 )
• Pancreatitis and Elevated Serum Lipase : Monitor serum lipase; if elevations are accompanied by abdominal symptoms, interrupt doses and consider appropriate diagnostics to exclude pancreatitis. ( 5.6 )
• Hepatotoxicity : Monitor hepatic function tests monthly or as clinically indicated. ( 5.7 )
• Electrolyte Abnormalities : DANZITEN can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating DANZITEN and monitor periodically during therapy. ( 5.8 )
• Tumor Lysis Syndrome : Maintain adequate hydration and correct uric acid levels prior to initiating therapy with DANZITEN. ( 5.9 )
• Hemorrhage : Hemorrhage from any site may occur. Advise patients to report signs and symptoms of bleeding and medically manage as needed. ( 5.10 )
• Fluid Retention : Monitor patients for unexpected rapid weight gain, swelling, and shortness of breath. Manage medically. ( 5.13 )
• Effects on Growth and Development in Pediatric Patients : Growth retardation has been reported in pediatric patients treated with nilotinib. Monitor growth and development in pediatric patients. ( 5.14 )
• Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.15 , 8.1 , 8.3 )
• Treatment Discontinuation : Patients must have typical BCR-ABL transcripts. An FDA-authorized test with a detection limit below MR4.5 must be used to determine eligibility for discontinuation. Patients must be frequently monitored by the FDA authorized test to detect possible loss of remission. ( 5.16 )

5.1 Substitution with Other Nilotinib Products and Risk of Medication Errors Nilotinib is available in different formulations, recommended dosages, and tablet strengths, and for different indications. DANZITEN (nilotinib) tablets may not be substitutable with other nilotinib products, including other nilotinib tablets, on a milligram per milligram basis. When switching patients between other nilotinib products and DANZITEN (nilotinib) tablets, a dose conversion may be required <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 and 2.2 )]</span> . Substitution of DANZITEN (nilotinib) tablets for another nilotinib product to achieve the same daily nilotinib dosage on a milligram per milligram basis may result in a clinically significant:

• Increase in nilotinib exposure which may increase the risk of nilotinib-associated adverse reactions.
• Decrease in nilotinib exposure which may reduce DANZITEN effectiveness. Confirm that the intended nilotinib product is being prescribed and dispensed.

5.2 Myelosuppression Treatment with DANZITEN can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Perform CBCs 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 DANZITEN temporarily or dose reduction [ see Dosage and Administration ( 2.6 ) ].

5.3 QT Prolongation Nilotinib has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface electrocardiogram (ECG) in a concentration-dependent manner <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.2 )]</span> . Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. Electrocardiograms should be performed at baseline, 7 days after initiation of DANZITEN, and periodically as clinically indicated and following dose adjustments <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ) and Warnings and Precautions ( 5.12 )]</span> . DANZITEN should not be used in patients who have hypokalemia, hypomagnesemia, or long QT syndrome. Before initiating DANZITEN and periodically, test electrolyte, calcium, and magnesium blood levels. Hypokalemia or hypomagnesemia must be corrected prior to initiating DANZITEN and these electrolytes should be monitored periodically during therapy <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.12 )]</span> . Significant prolongation of the QT interval may occur when DANZITEN is inappropriately taken with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, avoid concomitant DANZITEN use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.9 ), Drug Interactions ( 7.1 , 7.2 )]</span> . The presence of hypokalemia and hypomagnesemia may further prolong the QT interval <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.8 , 5.12 )]</span> .

5.4 Sudden Deaths Sudden deaths have been reported in 0.3% of patients with CML treated with nilotinib in clinical studies of 5661 patients. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.

5.5 Cardiac and Arterial Vascular Occlusive Events Cardiovascular events, including arterial vascular occlusive events, were reported in a randomized, clinical trial in newly diagnosed CML patients and observed in the postmarketing reports of patients receiving nilotinib therapy <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . With a median time on therapy of 60 months in the clinical trial, cardiovascular events, including arterial vascular occlusive events, occurred in 9% and 15% of patients receiving nilotinib dosages equivalent to DANZITEN 142 mg and 190 mg twice daily, respectively, and in 3.2% in the imatinib arm. These included cases of cardiovascular events, including ischemic heart disease-related cardiac events (5% and 9% in the nilotinib dosages equivalent to DANZITEN 142 mg and 190 mg twice daily, respectively and 2.5% in the imatinib arm), peripheral arterial occlusive disease (3.6% and 2.9% in the nilotinib dosages equivalent to DANZITEN 142 mg and 190 mg twice daily, respectively and 0% in the imatinib arm), and ischemic cerebrovascular events (1.4% and 3.2% in the nilotinib dosages equivalent to DANZITEN 142 mg and 190 mg twice daily, respectively and 0.7% in the imatinib arm). 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 during DANZITEN therapy according to standard guidelines <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

5.6 Pancreatitis and Elevated Serum Lipase Nilotinib can cause increases in serum lipase [ see Adverse Reactions ( 6.1 ) ]. Patients with a previous history of pancreatitis may be at greater risk of elevated serum lipase. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis [ see Dosage and Administration ( 2.7 ) ]. Test serum lipase levels monthly or as clinically indicated.

5.7 Hepatotoxicity Nilotinib may result in hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase.

Grade

3-4 elevations of bilirubin, AST, and ALT were reported in adult patients.

Grade

3-4 elevations of bilirubin, AST, and ALT were reported at a higher frequency in pediatric than in adult patients. Monitor hepatic function tests monthly or as clinically indicated [see Warnings and Precautions ( 5.12 )] and following dose adjustments. [see Dosage and Administration ( 2.8 )] .

5.8 Electrolyte Abnormalities The use of nilotinib can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating DANZITEN and during therapy. Monitor these electrolytes periodically during therapy <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.12 )]</span>.

5.9 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) cases have been reported in nilotinib treated patients with resistant or intolerant CML. Malignant disease progression, high white blood cell (WBC) counts and/or dehydration were present in the majority of these cases. Due to potential for TLS, maintain adequate hydration and correct uric acid levels prior to initiating therapy with DANZITEN.

5.10 Hemorrhage Serious hemorrhagic events, including fatal events, have occurred in patients with CML treated with nilotinib. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing nilotinib and imatinib, Grade 3 or 4 hemorrhage occurred in 1.1% of patients in the nilotinib dosage equivalent to DANZITEN 142 mg twice daily arm, in 1.8% of patients in the nilotinib dosage equivalent to DANZITEN 190 mg twice daily arm, and 0.4% of patients in the imatinib arm. GI hemorrhage occurred in 2.9% and 5% of patients in the nilotinib dosage equivalent DANZITEN 142 mg and 190 mg twice daily arms and in 1.4% of patients in the imatinib arm, respectively.

Grade

3 or 4 events occurred in 0.7% and 1.4% of patients in the nilotinib dosage equivalent to DANZITEN 142 mg and 190 mg twice daily arms, respectively, and in no patients in the imatinib arm. Monitor for signs and symptoms of bleeding and medically manage as needed.

5.11 Total Gastrectomy Since the exposure of nilotinib is reduced in patients with total gastrectomy, perform more frequent monitoring of these patients. Consider dose increase or alternative therapy in patients with total gastrectomy <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

5.12 Monitoring Laboratory Tests Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. Perform chemistry panels, including electrolytes, calcium, magnesium, liver enzymes, lipid profile, and glucose prior to therapy and periodically. Electrocardiograms should be obtained at baseline, 7 days after initiation and periodically thereafter, as well as following dose adjustments <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> . Monitor lipid profiles and glucose periodically during the first year of DANZITEN therapy and at least yearly during chronic therapy. Should treatment with any HMG-CoA reductase inhibitor (a lipid lowering agent) be needed to treat lipid elevations, evaluate the potential for a drug-drug interaction before initiating therapy as certain HMG-CoA reductase inhibitors are metabolized by the CYP3A4 pathway <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> . Assess glucose levels before initiating treatment with DANZITEN and monitor during treatment as clinically indicated. If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines.

5.13 Fluid Retention In the randomized trial in patients with newly diagnosed Ph+ CML in chronic phase, severe (Grade 3 or 4) fluid retention occurred in 3.9% and 2.9% of patients receiving the nilotinib dosage equivalent to DANZITEN 142 mg and 190 mg twice daily, respectively, and in 2.5% of patients receiving imatinib. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema, were observed in 2.2% and 1.1% of patients receiving the nilotinib dosage equivalent to the recommended dosage of DANZITEN 142 mg twice daily and 190 mg twice daily, respectively, and in 2.1% of patients receiving imatinib. Effusions were severe (Grade 3 or 4) in 0.7% and 0.4% of patients receiving the nilotinib dosage equivalent to the recommended dosage of DANZITEN 142 mg and 190 mg twice daily, respectively, and in no patients receiving imatinib. Similar events were also observed in postmarketing reports. Monitor patients for signs of severe fluid retention (e.g., unexpected rapid weight gain or swelling) and for symptoms of respiratory or cardiac compromise (e.g., shortness of breath) during DANZITEN treatment; evaluate etiology and treat patients accordingly.

5.14 Effects on Growth and Development Growth retardation has been reported in pediatric patients with Ph+ CML in chronic phase treated with nilotinib. Growth deceleration was more pronounced in children who were less than age 12 at baseline. Monitor growth and development in pediatric patients receiving nilotinib treatment. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s Tasigna ® (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

5.15 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, DANZITEN can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nilotinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal lethality/fetal effects (small renal papilla, fetal edema, and skeletal variations) in rats and increased resorptions of fetuses and fetal skeletal variations in rabbits at maternal area under the curve (AUCs) approximately 2 and 0.5 times, respectively, the AUC in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 14 days after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 ), Clinical Pharmacology ( 12.1 )]</span> .

5.16 Monitoring of BCR-ABL Transcript Levels Monitoring of BCR-ABL Transcript Levels in Patients Who Discontinued Nilotinib Monitor BCR-ABL transcript levels in patients eligible for treatment discontinuation using an FDA authorized test validated to measure molecular response levels with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS). In patients who discontinue DANZITEN therapy, assess BCR-ABL transcript levels monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter during treatment discontinuation <span class="opacity-50 text-xs">[see Clinical Studies ( 14.3 , 14.4 ), Dosage and Administration ( 2.3 )]</span> . Newly diagnosed patients must reinitiate DANZITEN therapy within 4 weeks of a loss of major molecular response [(MMR), corresponding to MR3.0 or = BCR-ABL/ABL ≤ 0.1% IS]. Patients resistant or intolerant to prior treatment which included imatinib must reinitiate DANZITEN therapy within 4 weeks of a loss of MMR or confirmed loss of MR4.0 (two consecutive measures separated by at least 4 weeks showing loss of MR4.0, corresponding to = BCR-ABL/ABL ≤ 0.01% IS). For patients who fail to achieve MMR after three months of treatment reinitiation, BCR-ABL kinase domain mutation testing should be performed. Monitoring of BCR-ABL Transcript Levels in Patients Who Have Reinitiated Therapy After Loss of Molecular Response Monitor CBC and BCR-ABL transcripts in patients who reinitiate treatment with DANZITEN due to loss of molecular response quantitation every 4 weeks until a major molecular response is re-established, then every 12 weeks <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> .