Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
WARNINGS AND PRECAUTIONS
Cardiac and Arterial Vascular Occlusive Events
- With a median time on therapy of 60 months in the clinical trial, cardiovascular events, including arterial vascular occlusive events, occurred in 9.3% and 15.2% of patients in the Tasigna 300 and 400 mg bid arms, respectively, and in 3.2% in the imatinib arm. These included cases of cardiovascular events including ischemic heart disease-related cardiac events (5.0% and 9.4% in the Tasigna 300 mg and 400 mg bid arms respectively, and 2.5% in the imatinib arm), peripheral arterial occlusive disease (3.6% and 2.9% in the Tasigna 300 mg and 400 mg bid arms respectively, and 0% in the imatinib arm), and ischemic cerebrovascular events (1.4% and 3.2% in the Tasigna 300 mg and 400 mg bid arms respectively, and 0.7% in the imatinib arm).
- In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing Tasigna and imatinib, Grade 3 or 4 hemorrhage occurred in 1.1% of patients in the Tasigna 300 mg bid arm, in 1.8% patients in the Tasigna 400 mg bid arm, and 0.4% of patients in the imatinib arm. GI hemorrhage occurred in 2.9% and 5.1% of patients in the Tasigna 300 mg bid and 400 mg bid 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 Tasigna 300 mg bid and 400 mg bid arms, respectively, and in no patients in the imatinib arm.
Monitoring Laboratory Tests
- Monitor lipid profiles and glucose periodically during the first year of Tasigna 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 [see Drug Interactions (7.1)]. Assess glucose levels before initiating treatment with Tasigna and monitor during treatment as clinically indicated. If test results warrant therapy, physician should follow their local standards of practice and treatment guidelines.
- 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 Tasigna 300 mg bid and 400 mg bid, 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 Tasigna 300 mg bid and 400 mg bid, 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 Tasigna 300 mg bid and 400 mg bid, 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 Tasigna treatment; evaluate etiology and treat patients accordingly.
7 DRUG INTERACTIONS
7.1 new section added: results of Study CAMN107A2128 entitled “An open-label, two-period, fixed-sequence study to evaluate the effects of multiple doses of nilotinib on the pharmacokinetics of midazolam in CML patients who are resistant and/or intolerant against at least one prior therapy with a BCR-ABL tyrosine kinase inhibitor.”
7.1 Effects of Nilotinib on Drug Metabolizing Enzymes and Drug Transport Systems.
- Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 in vitro, potentially increasing the concentrations of drugs eliminated by these enzymes. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8 and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes. In patients with CML, multiple doses of Tasigna increased .....
Clinical Trials Experience
- Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Imatinib 400 mg once daily groups) 36-Month Analysisa…
- peripheral arterial occlusive disease
WARNINGS AND PRECAUTIONS
Tumor Lysis Sydrome
- added ... new section; moved from Adverse Reactions, Postmarketing experience
"What are the possible side effects...?"
- updated to include tumor lysis syndrome
5 WARNINGS AND PRECAUTIONS
5.3 Sudden Deaths
- Sudden deaths have been reported in patients with CML treated with nilotinib in clinical studies (n=5,661; 0.3%). 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.
5.8 Food Effects
- Patients should avoid food…..
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Additional Data from Clinical Trials
- Changes to Infections and Infestations, Endocrine Disorders, General Disorders and Administration Site Conditions, and Investigations sections
- Reflects new, updated dosing information concerning mixing the contents of the capsules with applesauce (see Medication Guide for specifics)
Also see changes to Dosage and administration: Recommended Dosing (2.1)
Effects of Nilotinib on Drug Metabolizing Enzymes and Drug Transport Systems
- Single-dose administration of Tasigna with midazolam (a CYP3A4 substrate) to healthy subjects increased midazolam exposure by 30%.
Drugs that Affect Gastric pH
- Nilotinib has pH-dependent solubility, with decreased solubility at higher pH. Drugs such as proton pump inhibitors that inhibit gastric acid secretion to elevate the gastric pH may decrease the solubility of nilotinib and reduce its bioavailability. In healthy subjects, coadministration of a single 400 mg dose of Tasigna with multiple doses of esomeprazole (a proton pump inhibitor) at 40 mg daily decreased the nilotinib AUC by 34%. Increasing the dose of Tasigna when co-administered with such agents is not likely to compensate for the loss of exposure. 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.