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- Myelosuppression [see WARNINGS AND PRECAUTIONS]
- QT Prolongation [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Sudden Deaths [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Cardiac and Arterial Vascular Occlusive Events [see WARNINGS AND PRECAUTIONS]
- Pancreatitis and Elevated Serum Lipase [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Electrolyte Abnormalities [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Hemorrhage [see WARNINGS AND PRECAUTIONS]
- Fluid Retention [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In Patients with Newly Diagnosed Ph+ CML-CP
The data below reflect exposure to Tasigna from a randomized trial in patients 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 in the nilotinib 300 mg twice-daily group was 61 months (range 0.1 to 71 months). The median actual dose intensity was 593 mg/day in the nilotinib 300 mg twice-daily group.
The most common ( > 10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia, and upper abdominal pain. Constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly ( ≤ 10% and > 5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction.
Increase in QTcF > 60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice-daily treatment group. No patient had an absolute QTcF of > 500 msec while on study drug.
The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (18%), neutropenia (15%) and anemia (8%). See Table 7 for Grade 3/4 laboratory abnormalities.
Discontinuation due to adverse reactions, regardless of relationship to study drug, was observed in 10% of patients.
In Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP
In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice-daily.
The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1 to 1096) and 264 (range 2 to 1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151 to 1110) and 780 mg/day (range 150 to 1149), respectively and corresponded to the planned 400 mg twice-daily dosing.
The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1 to 345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1 to 234).
In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions ( ≥ 10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions ( ≥ 1% and < 10%) were thrombocytopenia, neutropenia and anemia.
In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions ( ≥ 10%) were rash, pruritus and fatigue. The common serious adverse drug reactions ( ≥ 1% and < 10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.
Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF > 60 msec from baseline was observed in 4.1% of the patients and QTcF of > 500 msec was observed in 4 patients ( < 1%) [see BOXED WARNING, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].
Discontinuation due to adverse drug reactions was observed in 16% of CML-CP and 10% of CML-AP patients.
Most Frequently Reported Adverse Reactions
Tables 5 and 6 show the percentage of patients experiencing non-hematologic adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least 1 dose of Tasigna are listed.
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) 60-Month Analysisa
|Patients with Newly Diagnosed Ph+ CML-CP|
|TASIGNA 300 mg twice-daily
|Imatinib 400 mg once-daily
|TASIGNA 300 mg twice-daily
|Imatinib 400 mg once-daily
|Body System and Preferred Term||All Grades (%)||CTC Gradesb 3/4 (%)|
|Skin and subcutaneous tissue disorders||Rash||38||19||< 1||2|
|Vomiting||15||27||< 1||< 1|
|Abdominal pain upper||18||14||1||< 1|
|Nervous system disorders||Headache||32||23||3||< 1|
|Dizziness||12||11||< 1||< 1|
|General disorders and administration site conditions||Fatigue||23||20||1||1|
|Peripheral edema||9||20||< 1||0|
|Face edema||< 1||14||0||< 1|
|Musculoskeletal and connective tissue disorders||Myalgia||19||19||< 1||< 1|
|Arthralgia||22||17||< 1||< 1|
|Pain in extremity||15||16||< 1||< 1|
|Respiratory, thoracic and mediastinal disorders||Cough||17||13||0||0|
|Infections and infestations||Nasopharyngitis||27||21||0||0|
|Upper respiratory tract infection||17||14||< 1||0|
|Eye disorders||Eyelid edema||1||19||0||< 1|
|Periorbital edema||< 1||15||0||0|
|Vascular disorder||Hypertension||10||4||1||< 1|
|aExcluding laboratory abnormalities
bNCI Common Terminology Criteria for Adverse Events, Version 3.0
Table 6: Most Frequently Reported Non-hematologic
Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving
Tasigna 400 mg Twice-Daily (Regardless of Relationship to Study Drug)
( ≥ 10% in any Group) 24-Month Analysisa
|Body System and Preferred Term||CML-CP
|All Grades (%)||CTC Gradesb 3/4 (%)||All Grades (%)||CTC Gradesb 3/4 (%)|
|Skin and subcutaneous tissue disorders||Rash||36||2||29||0|
|Night sweat||12||< 1||27||0|
|Gastrointestinal disorders||Nausea||37||1||22||< 1|
|Abdominal pain upper||14||< 1||12||< 1|
|Nervous system disorders||Headache||35||2||20||1|
|General disorders and administration site conditions||Fatigue||32||3||23||< 1|
|Peripheral edema||15||< 1||12||0|
|Musculoskeletal and connective tissue disorders||Myalgia||19||2||16||< 1|
|Muscle spasms||13||< 1||15||0|
|Bone pain||14||< 1||15||2|
|Pain in extremity||20||2||18||1|
|Back pain||17||2||15||< 1|
|Musculoskeletal pain||11||< 1||12||1|
|Respiratory, thoracic and mediastinal disorders||Cough||27||< 1||18||0|
|Infections and infestations||Nasopharyngitis||24||< 1||15||0|
|Upper respiratory tract infection||12||0||10||0|
|Metabolism and nutrition disorders||Decreased appetite'||15||< 1||17||< 1|
|Vascular disorders||Hypertension||10||2||11||< 1|
|aExcluding laboratory abnormalities
bNCI Common Terminology Criteria for Adverse Events, Version 3.0 cAlso includes preferred term anorexia
Table 7 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.
Table 7: Percent Incidence of Clinically Relevant
Grade 3/4* Laboratory Abnormalities
|Newly Diagnosed Ph+ CML-CP||Resistant or Intolerant Ph+|
|TASIGNA 300 mg twice-daily
|Imatinib 400 mg once-daily
|TASIGNA 400 mg twice-daily
|TASIGNA 400 mg twice-daily
|Elevated bilirubin (total)||4||< 1||7||9|
|Elevated SGPT (ALT)||4||3||4||4|
|Elevated SGOT (AST)||1||1||3||2|
|Decreased albumin||0||< 1||4||3|
|Hypocalcemia||< 1||< 1||2||5|
|Elevated alkaline phosphatase||0||< 1||< 1||1|
|Elevated creatinine||0||< 1||< 1||< 1|
|*NCI Common Terminology Criteria for Adverse Events,
1CML-CP: Thrombocytopenia: 12% were Grade 3, 18% were Grade 4
2CML-CP: Neutropenia: 16% were Grade 3, 15% were Grade 4
3CML-AP: Thrombocytopenia: 11% were Grade 3, 32% were Grade 4
4CML-AP: Neutropenia: 16% were Grade 3, 26% were Grade 4
Elevated total cholesterol (all grades) occurred in 28% (Tasigna 300 mg bid) and 4% (imatinib). Elevated triglycerides (all grades) occurred in12% and 8% of patients in the Tasigna and imatinib arms, respectively. Hyperglycemia (all grades) occurred in 50% and 31% of patients in the Tasigna and imatinib arms, respectively.
Most common biochemistry laboratory abnormalities (all grades) were alanine aminotransferase increased (72%), blood bilirubin increased (59%), aspartate aminotransferase increased (47%), lipase increased (28%), blood glucose increased (50%), blood cholesterol increased (28%), and blood triglyceride increased (12%).
Additional Data From Clinical Trials
The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common ( ≥ 1% and < 10%), uncommon ( ≥ 0.1% and < 1%), and unknown frequency (single events). For laboratory abnormalities, very common events ( ≥ 10%), which were not included in Tables 5 and 6, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category, obtained from 2 clinical studies:
- Newly diagnosed Ph+ CML-CP 60 month analysis and,
- Resistant or intolerant Ph+ CML-CP and CMP-AP 24 months' analysis.
Infections and Infestations: Common: folliculitis. Uncommon: pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis). Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis.
Neoplasms Benign, Malignant, and Unspecified: Common: skin papilloma. Unknown frequency: oral papilloma, paraproteinemia.
Immune System Disorders: Unknown frequency: hypersensitivity.
Metabolism and Nutrition Disorders: Very Common: hypophosphatemia. Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia. Uncommon: gout, dehydration, increased appetite. Unknown frequency: hyperuricemia, hypoglycemia.
Nervous System Disorders: Common: peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, ischemic stroke, transient ischemic attack, cerebral infarction, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: basilar artery stenosis, brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome.
Eye Disorders: Common: eye hemorrhage, eye pruritus, conjunctivitis, dry eye (including xerophthalmia). Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation, conjunctival hemorrhage. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctivitis allergic, ocular surface disease.
Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, myocardial infarction, coronary artery disease, cardiac murmur, coronary artery stenosis, myocardial ischemia, pericardial effusion, cyanosis. Unknown frequency: ventricular dysfunction, pericarditis, ejection fraction decrease.
Vascular Disorders: Common: flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, intermittent claudication, arterial stenosis limb, hematoma, arteriosclerosis. Unknown frequency: shock hemorrhagic, hypotension, thrombosis, peripheral artery stenosis.
Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea exertional, epistaxis, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing.
Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth, gastritis, sensitivity of teeth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis.
Skin and Subcutaneous Tissue Disorders: Common: eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform). Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis. Unknown frequency: psoriasis, erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis.
Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, flank pain, muscular weakness. Uncommon: musculoskeletal stiffness, joint swelling. Unknown frequency: arthritis.
General Disorders and Administration Site Conditions: Common: pyrexia, chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise. Uncommon: gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema.
Investigations: Very Common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, lipoprotein cholesterol (including very low density and high density) increased, total cholesterol increased, blood triglycerides increased. Common: hemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased, globulins decreased. Uncommon: blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, insulin C-peptide decreased, blood parathyroid hormone increased.
Read the Tasigna Capsules (nilotinib capsules) Side Effects Center for a complete guide to possible side effects
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 the systemic exposure of oral midazolam (a substrate of CYP3A4) 2.6-fold. Tasigna is a moderate CYP3A4 inhibitor. As a result, the systemic exposure of drugs metabolized by CYP3A4 (e.g., certain HMG-CoA reductase inhibitors) may be increased when coadministered with Tasigna. Dose adjustment may be necessary for drugs that are CYP3A4 substrates, especially those that have narrow therapeutic indices (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus and tacrolimus) when coadministered with Tasigna.
Single-dose administration of Tasigna to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of multiple doses of Tasigna to induce metabolism of drugs other than midazolam has not been determined in vivo. Monitor patients closely when coadministering Tasigna with drugs that have a narrow therapeutic index and are substrates for CYP2B6, CYP2C8, or CYP2C9 enzymes.
Nilotinib inhibits human P-glycoprotein (P-gp). If Tasigna is administered with drugs that are substrates of P-gp, increased concentrations of the substrate drug are likely, and caution should be exercised.
Drugs That Inhibit Or Induce Cytochrome P450 3A4 Enzymes
Nilotinib undergoes metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease nilotinib concentrations significantly. The administration of Tasigna with agents that are strong CYP3A4 inhibitors should be avoided [see BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]. Concomitant use of Tasigna with medicinal products and herbal preparations that are potent inducers of CYP3A4 is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving Tasigna, concomitant use of alternative therapeutic agents with less potential for CYP3A4 induction should be selected.
In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 400 mg once-daily for 6 days, systemic exposure (AUC) to nilotinib was increased approximately 3-fold.
In healthy subjects receiving the CYP3A4 inducer, rifampicin, at 600 mg daily for 12 days, systemic exposure (AUC) to nilotinib was decreased approximately 80%.
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 coadministered 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 is not recommended.
In healthy subjects, no significant change in nilotinib pharmacokinetics was observed when a single 400 mg dose of Tasigna was administered 10 hours after and 2 hours before famotidine (an H2 blocker). Therefore, when the concurrent use of a H2 blocker is necessary, it may be administered approximately 10 hours before and approximately 2 hours after the dose of Tasigna.
Administration of an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) to healthy subjects, 2 hours before or 2 hours after a single 400 mg dose of Tasigna did not alter nilotinib pharmacokinetics. Therefore, if necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the dose of Tasigna.
Drugs That Inhibit Drug Transport Systems
Nilotinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Tasigna is administered with drugs that inhibit P-gp, increased concentrations of nilotinib are likely, and caution should be exercised.
Drugs That May Prolong The QT Interval
The administration of Tasigna with agents that may prolong the QT interval such as anti-arrhythmic medicines should be avoided [see BOXED WARNING, DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Read the Tasigna Capsules Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/30/2015
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