These highlights do not include all the information needed to use Tasigna safely and effectively . See full prescribing information for Tasigna . Tasigna
Tasigna prolongs the QT interv al (5.2) . Sudden deaths have been reported in patients receiving nilotinib (5.3) . Tasigna should not be used in patients with hypokalemia , hypomagnesemia , or long QT syndrome (4) . Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and sh ould be periodically monitored (5.2) . Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided (5.7) . Patients should avoid food 2 hours befo re and 1 hour after taking dose (5.8) . A dose reduction is recommended in patients with hepatic impairment (5. 9 ) . ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments . (5.2, 5.3, 5.6, 5.12)
Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies (14 .1 )]. The study is ongoing and further data will be required to determine long-term outcome.
Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates [ s ee Clinical Studies (14 .2 )].
Tasigna should be taken twice daily at approximately 12 hour intervals and must not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken [ s ee Box ed Warning, Warnings and Precautions (5. 8 ), Clinical Pharmacology ( 12. 3 ) ].
For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in one teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use [ s ee Clinical Pharmacology (12.3)].
Tasigna may be given in combination with hematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.
Newly Diagnosed Ph+ CML-CP
The recommended dose of Tasigna is 300 mg orally twice daily [see Clinical Pharmacology (12.3)].
Resistant or Intolerant Ph+ CML-CP and CML-AP
The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily [see Clinical Pharmacology (12.3)].
QT interval prolongation:
Myelosuppression
Tasigna may need to be withheld and/or dose reduced for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 2).
*ANC = absolute neutrophil count
See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases [ s ee Adverse R eactions (6.1)] .
Other N on-hematologic T oxicities
If other clinically significant moderate or severe non-hematologic toxicity develops, withhold dosing, and resume at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose back to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CML-AP) twice daily should be considered. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test serum lipase levels monthly or as clinically indicated. For Grade 3 to 4 bilirubin or hepatic transaminase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test bilirubin and hepatic transaminases levels monthly or as clinically indicated [ s ee Warnings and Precautions (5 .4, 5.5 ) , Use in Specific Populations (8 .7 )].
Hepatic Impairment
If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, consider the following dose reduction:
* Mild = mild hepatic impairment (Child-Pugh Class A); Moderate = moderate hepatic impairment (Child-Pugh Class B); Severe = severe hepatic impairment (Child-Pugh Class C) [ s ee Boxed Warning, Warnings and Precautions (5.9) , Use in Specific Populations (8.7)].
Concomitant Strong CYP3A4 Inhibitors
Avoid the concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit products may also increase serum concentrations of nilotinib and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. 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. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period should be allowed before the Tasigna dose 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 [ s ee Boxed Warning, Warnings and Precautions (5. 2 , 5.7 ) , Drug Interactions (7. 2 )].
Concomitant Strong CYP3A4 Inducers
Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, 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 [ s ee Drug Interactions (7. 2 )] .
Table 1: Dose Adjustments for QT Prolongation
|
|
|
ECGs with a QTc
>480 msec
|
1. Withhold Tasigna, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed.
2. Resume within 2 weeks at prior dose if QTcF returns to <450 msec and to within 20 msec of baseline.
3. If QTcF is between 450 msec and 480 msec after 2 weeks, reduce the dose to 400 mg once daily.
4. If, following dose-reduction to 400 mg once daily, QTcF returns to >480 msec, Tasigna should be discontinued.
5. An ECG should be repeated approximately 7 days after any dose adjustment. |
Table 2: Dose Adjustments for Neutropenia and Thrombocytopenia
|
|
|
|
Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily
Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily |
ANC* <1.0 x 109/L and/or platelet counts <50 x 109/L
|
1. Stop Tasigna, and monitor blood counts
2. Resume within 2 weeks at prior dose if ANC >1.0 x 109/L and platelets >50 x 109/L
3. If blood counts remain low for >2 weeks, reduce the dose to 400 mg once daily
|
Table 3: Dose Adjustments for Selected Non-hematologic Laboratory Abnormalities
|
|
|
|
Elevated serum lipase or amylase ≥Grade 3 |
1. Withhold Tasigna, and monitor serum lipase or amylase
2. Resume treatment at 400 mg once daily if serum lipase or amylase return to ≤Grade 1 |
|
Elevated bilirubin ≥Grade 3 |
1. Withhold Tasigna, and monitor bilirubin
2. Resume treatment at 400 mg once daily if bilirubin return to ≤Grade 1 |
Elevated hepatic transaminases
≥Grade 3 |
1. Withhold Tasigna, and monitor hepatic transaminases
2. Resume treatment at 400 mg once daily if hepatic transaminases return to ≤Grade 1 |
Table 4: Dose Adjustments for Hepatic Impairment (At Baseline)
|
Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily |
Mild, Moderate or Severe* |
An initial dosing regimen of 200 mg twice daily followed by dose escalation to 300 mg twice daily based on tolerability |
|
Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily |
Mild or Moderate* |
An initial dosing regimen of 300 mg twice daily followed by dose escalation to 400 mg twice daily based on tolerability |
|
|
Severe* |
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 |
150 mg red opaque hard gelatin capsules with black axial imprint “NVR/BCR”.
200 mg light yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI”.
Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome [ s ee Boxed Warning] .
Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every two 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 [ s ee Dosage and Administration ( 2 .2 )] .
Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner [ s ee Adverse Reactions (6.1), Clinical Pharmacology (12.4)]. 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. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments [see Warnings and Precautions (5.12)].
Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)].
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 [ s ee Warnings and Precautions (5.7 , 5.8 )]. The presence of hypokalemia and hypomagnesemia may further enhance this effect [ s ee Warnings and Precautions ( 5.6 , 5.1 2 )].
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.
The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous 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.
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 [see Warnings and Precautions (5.12)].
The use of 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 [see Warnings and Precautions (5.12 ) ].
The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong 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 [ s ee Boxed Warning, Dos age and Administration (2 .2 ), Drug Interactions (7. 2 )] .
The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided [ s ee Boxed Warning, Drug Interactions (7. 2 ) and Clinical Pharmacology (12.3)].
Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment (at baseline) and QT interval should be monitored closely [ s ee Boxed Warnin g , Dosage and Administration (2 .2 ) and Use in Specific Populations (8.7)].
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 [ see Clinical Pharmacology 12.3)].
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.
Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels, including the lipid profile, should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments [ s ee Warnings and Precautions (5.2)] . Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion.
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. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna [see Use in Specific Populations (8.1)].
The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert [ s ee Boxed Warning , Warnings and Precautions (5) ] .
Myelosuppression [see Warnings and Precautions (5.1)]
QT prolongation [ s ee Boxed Warning, Warnings and Precautions (5.2)]
Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3 ) ]
Elevated serum lipase [ s ee Warnings and Precautions (5. 4 ) ]
Hepatotoxicity [ s ee Warnings and Precautions (5. 5 ) ]
Electrolyte abnormalities [ s ee Boxed Warning , Warnings and Precautions (5.6) ]
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.
Newly diagnosed Ph+ CML-CP
The data below reflect exposure to Tasigna from a randomized trial in newly diagnosed patients with 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 18.6 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 and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema 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. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported in 0.4% of patients.
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.
The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (17%), neutropenia (15%) and anemia (7%). See Table 7 for Grade 3/4 laboratory abnormalities.
Discontinuation due to adverse events regardless of causality was observed in 7% of patients.
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 1-1096) and 264 (range 2-1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151–1110) and 780 mg/day (range 150-1149), 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 1-345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1–234).
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%) 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%) 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%) [ s ee Boxed Warning , Warnings and Precautions (5.2 , 5.3 ), Clinical Pharmacology (12.4) ].
Discontinuation due to drug-related adverse 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 treatment-emergent adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least one dose of Tasigna are listed.
Excluding laboratory abnormalities NCI Common Terminology Criteria for Adverse Events, Version 3.0
Excluding laboratory abnormalities NCI Common Terminology Criteria for Adverse Events, Version 3.0
Laboratory Abnormalities
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.
*NCI Common Terminology Criteria for Adverse Events, version 3.0
CML-CP: Thrombocytopenia: 12% were grade 3, 18% were grade 4
CML-CP: Neutropenia: 16% were grade 3, 15% were grade 4
CML-AP: Thrombocytopenia: 11% were grade 3, 32% were grade 4
CML-AP: Neutropenia: 16% were grade 3, 26% were grade 4
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 Gleevec 400 mg once daily groups)a
|
|
Patients with Newly Diagnosed Ph+ CML-CP |
|
|
|
|
|
TASIGNA
300 mg
twice
daily |
GLEEVEC
400 mg
once
daily |
TASIGNA
300 mg
twice
daily |
GLEEVEC
400 mg
once
daily |
|
|
N=279 |
N=280 |
N=279 |
N=280 |
|
Body System and Preferred Term |
All Grades |
CTC Grades b 3 / 4 (%) |
|
Skin and subcutaneous tissue disorders |
Rash |
36 |
16 |
<1 |
1 |
|
|
Pruritus |
19 |
7 |
<1 |
0 |
|
|
Alopecia |
10 |
5 |
0 |
0 |
|
Gastrointestinal disorders |
Nausea |
19 |
38 |
1 |
1 |
|
|
Constipation |
15 |
4 |
0 |
0 |
|
|
Diarrhea |
14 |
37 |
<1 |
2 |
|
|
Vomiting |
9 |
22 |
0 |
<1 |
|
|
Abdominal pain upper |
15 |
10 |
<1 |
<1 |
|
|
Abdominal pain |
12 |
9 |
1 |
<1 |
|
Nervous system disorders |
Headache |
28 |
16 |
3 |
<1 |
|
General disorders and administration site conditions |
Fatigue |
19 |
14 |
<1 |
1 |
|
|
Pyrexia |
10 |
12 |
0 |
0 |
|
|
Asthenia |
11 |
9 |
<1 |
0 |
|
|
Edema, peripheral |
8 |
17 |
0 |
0 |
|
Musculoskeletal and connective tissue disorders |
Myalgia |
14 |
16 |
<1 |
0 |
|
|
Arthralgia |
15 |
13 |
<1 |
0 |
|
|
Muscle spasms |
10 |
29 |
0 |
<1 |
|
|
Pain in extremity |
9 |
13 |
0 |
<1 |
|
|
Back pain |
12 |
10 |
<1 |
1 |
|
Respiratory, thoracic and mediastinal disorders |
Cough |
12 |
9 |
0 |
0 |
|
Infections and infestations |
Nasopharyngitis |
19 |
15 |
0 |
0 |
|
|
Upper respiratory tract infection |
13 |
9 |
0 |
0 |
|
Eye disorders |
Eyelid edema |
1 |
14 |
0 |
<1 |
Manufacturer
Novartis Pharmaceuticals Corporation (NPC), a US subsidiary of Novartis AG
Active Ingredients
Source
-
U.S. National Library of Medicine
-
DailyMed
-
Last Updated: 2nd of March 2011
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)a
|
Body System and Preferred Term |
CML-CP |
CML-AP |
|
|
N=321 |
N= 137 |
|
|
All Grades (%) |
CTC Grades b 3 / 4 (%) |
All Grades (%) |
CTC Grades b 3 / 4 (%) |
|
Skin and subcutaneous tissue disorders |
Rash |
36 |
2 |
29 |
0 |
|
|
Pruritus |
32 |
<1 |
20 |
0 |
|
|
Night sweat |
12 |
<1 |
27 |
0 |
|
|
Alopecia |
11 |
0 |
12 |
0 |
|
Gastrointestinal disorders |
Nausea |
37 |
1 |
22 |
<1 |
|
|
Constipation |
26 |
<1 |
19 |
0 |
|
|
Diarrhea |
28 |
3 |
24 |
2 |
|
|
Vomiting |
29 |
<1 |
13 |
0 |
|
|
Abdominal pain |
15 |
2 |
16 |
3 |
|
|
Abdominal pain upper |
14 |
<1 |
12 |
<1 |
|
|
Dyspepsia |
10 |
<1 |
4 |
0 |
|
Nervous system disorders |
Headache |
35 |
2 |
20 |
1 |
|
General disorders and administration site conditions |
Fatigue |
32 |
3 |
23 |
<1 |
|
|
Pyrexia |
22 |
<1 |
28 |
2 |
|
|
Asthenia |
16 |
0 |
14 |
1 |
|
|
Edema, peripheral |
15 |
<1 |
12 |
0 |
|
|
Myaglia |
19 |
2 |
16 |
<1 |
<
