Dosing and uses of Tasigna (nilotinib)
Adult dosage forms and strengths
capsule
- 150mg
- 200mg
Chronic Myeloid Leukemia (CML), Newly Diagnosed
Indicated for initial treatment of newly diagnosed Philadelphia chromosome positive chronic phase chronic myeloid leukemia (Ph+ CP-CML)
300 mg PO q12hr
Chronic Myeloid Leukemia (CML), Resistant/Intolerant
Indicated for treatment of chronic phase and accelerated pase Ph+ CML in patients resistant to or intolerant to prior therapy that included imatiniB
400 mg PO q12hr
Gastrointestinal Stromal Tumors (Orphan)
Orphan indication sponsor
- Novartis Pharmaeuticals Corporation; One Health Plaza; East Hanover, NJ 07936-1080
Dose Modifications
Elevated serum lipase or amylase: Withhold; resume at 400 mg qDay if serum lipase or amylase return to Grade 1 or lower
Elevated bilirubin or hepatic transaminases: Withhold; resume at 400 mg qDay if bilirubin/transaminases return to Grade 1 or lower
Coadministration with strong CYP3A4 inhibitors
- Avoid if possible; for patients who cannot avoid use of strong CYP3A4 inhibitors, monitor closely for prolongation of the QT interval
- If must coadminister consider reducing to 300 mg/day in patients with resistant or intolerant Ph+ CML or to 200 mg/day with newly diagnosed Ph+ CML-CP
- However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors
Coadministration with strong CYP3A4 inducers
- Avoid coadministration
- Based on nonlinear pharmacokinetic profile of nilotinib, increasing the dose is unlikely to compensate for loss of nilotinib systemic exposure
Neutropenia
- ANC <1000/mm³ or Platelet <50 K/mm³: Withhold
- Within 2 weeks of recovery: Resume original dose if ANC >1000/mm³ & Platelet >50 K/mm³
- If levels remain low: Reduce dose to 400 mg qDay
QT Prolongation (QTc >480 msec)
- Withhold drug and analyze serum potassium and magnesium; if below lower limit of normal, correct with supplements to within normal limits
- Review concomitant medications for additive effects or interactions that increase nilotinib systemic exposure
- Resume within 2 weeks at prior dose if QTc returns to <450 msec and to within 20 msec of baseline
- If QTc is between 450 msec and 480 msec after 2 weeks, reduce nilotinib dose to 400 mg qDay
- Discontinue if QTc returns to >480 msec despite reducing the dose to 400 mg/day
- Repeat ECG ~7 days after any dose adjustment
Hepatic Impairment
Newly diagnosed Ph+ CML (chronic phase at 300 mg BID)
- Mild, moderate, or severe hepatic impairment: Start initial dose at 200 mg BID; if tolerated, may increase to 300 mg BID
Resistant or intolerant Ph+ CML (chronic phase or accelerated phase at 400 mg BID)
- Mild or moderate hepatic impairment: Start initial dose at 300 mg BID; if tolerated, may increase to 400 mg BID
- Severe hepatic impairment: Start initial dose at 200 mg BID; if tolerated, may increase to 300 mg BID, and then 400 mg BID
Administration
Take twice daily at ~12-hr intervals
Must be taken on an empty stomach at least 1 hr before or 2 hr after a meaL
Swallow capsule whole with water
If unable to swallow capsules, capsule contents may be dispersed in 1 teaspoon of applesauce; take mixture immediately (within 15 minutes) and do not be stored for future use
Other Information
Monitor: CBC q2Weeks for 2 months, THEN qMonth; LFTs; ECg
Pediatric dosage forms and strengths
<18 years old: Not recommended
Tasigna (nilotinib) adverse (side) effects
>10%
Rash (33%)
Headache (31%)
Nausea (31%)
Pruritus (29%)
Fatigue (28%)
Pyrexia (24%)
Diarrhea (22%)
Constipation (21%)
Vomiting (21%)
Arthralgia (18%)
Cough (17%)
Extremity pain (16%)
Asthenia (14%)
Muscle spasms (14%)
Myalgia (14%)
Abdominal pain (13%)
Bone pain (13%)
Back pain (12%)
Dyspnea (11%)
Nasopharyngitis (11%)
Peripheral edema (11%)
1-10% (selected)
Dizziness
Insomnia
Paresthesia
QT interval prolongation
HTn
Palpitations
QT interval prolongation
Hyperglycemia
Hyperkalemia
Hypomagnesemia
Neutropenia
Pancytopenia
<1%
Peripheral arterial occlusive disease
Tumor lysis syndrome
Aortic valve sclerosis
Abscess
Amnesia
Dehydration
Postmarketing Reports
Infections: Hepatitis B virus reactivation
Warnings
Black box warnings
Nilotinib prolongs the QT interval. Sudden deaths reported in patients receiving nilotinib. Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Must correct hypokalemia or hypomagnesemia prior to nilotinib administration.
Monitor potassium and magnesium periodically. Avoid drugs known to prolong the QT interval and strong CYP3A4 inhibitors.
Take on empty stomach; avoid food 2 hours before and 1 hour after taking a nilotinib dose.
Reduced dose recommended in patients with hepatic impairment. Monitor QTc through electrocardiograms (ECGs) at baseline, 7 days after initiation, and periodically thereafter following any dose adjustments.
Contraindications
Pregnancy, planned pregnancy, lactation
Long QT syndrome, hypokalemia, hypomagnesemia
Cautions
Myelosuppression: associated with neutropenia, thrombocytopenia, and anemia; CBC should be done q2wk for first 2 months, then monthly; reversible by withholding dose; dose reduction may be required
Sudden deaths have been reported with resistant or intolerant Ph+ CML; ventricular repolarization abnormalities may have contributed to their occurrence; cardiovascular status should be evaluated and cardiovascular risk factors monitored and managed during nilotinib therapy
Prolongs QT interval; correct hypokalemia or hypomagnesemia before administration
Nilotinib can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia; correct hypokalemia or hypomagnesemia before administration; monitor periodically during therapy
Tumor lysis syndrome; maintain adequate hydration and correct uric acid levels prior to initiating therapy
Use caution in hepatic impairment; monitor hepatic function tests monthly or as clinically indicated
Use caution in history of pancreatitis; monitor serum lipase monthly or as clinically indicated; in case lipase elevations are accompanied by abdominal symptoms, interrupt doses and consider appropriate diagnostics to exclude pancreatitis
Total Gastrectomy: More frequent follow-up of these patients should be considered; if necessary, dose increase may be considered
Avoid concurrency with strong CYP3A4 inhibitors/inducers; if unavoidable, adjust dose
Avoid grapefruit juice
Inhibits P-Glycoprotein (ABCB1)
Women should be advised not to become pregnant while on therapy; may cause fetal harm
Cardiovascular events including ischemic heart disease, peripheral arterial occlusive disease and ischemic cerebrovascular events reported in patients with newly diagnosed Ph+ CML; cardiovascular status should be evaluated and cardiovascular risk factors monitored and managed during therapy
May result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Monitor hepatic function tests monthly or as clinically indicated
Hemorrhage from various sites reported in patients with newly diagnosed CML and observed in postmarketing reports of patients receiving therapy
Food increases blood levels of nilotinib; avoid food 2 hr before and 1 hour after a dose
Monitor lipid profiles and glucose periodically during the first year of 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 potential for a drug-drug interaction before initiating therapy
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 treatment; evaluate etiology and treat patients accordingly
Contains lactose; avoid in galactose intolerance, lactase deficiency or glucose-galactose malabsorption
Pregnancy and lactation
Pregnancy category: d
Lactation: not known if excreted in breast milk; do not nurse
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Tasigna (nilotinib)
Mechanism of action
Selectively binds with high affinity to ATP-binding site of BCR-ABL kinase inhibiting cell proliferation in cell lines and in primary Ph+ CML leukemia cells
Active against imatinib-resistant mutant forms of Bcr-AbL
Inhibits PDGFR and c-Kit kinase
Absorption
Peak Plasma Time: 3 hr
Distribution
Protein Bound: 98%
Metabolism
Oxidation and hydroxylation by liver CYP3A4
Enzymes Inhibited: CYP3A4, CYP2C8, CYP2C9, CYP2D6, UGT1A1
Enzymes Induced CYP2B6, CYP2C8, CYP2C9
Elimination
Half-Life: 15-17 hr
Excretion: Feces 93%
Pharmacogenomics
Confirmed BCR-ABL transcripts
- Tyrosine kinase inhibitors (TKIs) inhibit activity of BCR-ABL fusion protein, resulting in both hematologic response (ie, normal cell counts in the peripheral blood and normal bone marrow morphology), as well as cytogenetic response (ie, disappearance or reduction of the Philadelphia [Ph] chromosome)
- NCCN clinical practice guidelines recommends TKIs in CML with confirmed BCR-ABL transcripts in bone marrow or evidence of translocation on cytogenetics
UGT1A1 and increased bilirubin
- Polymorphisms of UGT1A1 and its potential association with hyperbilirubinemia during nilotinib treatment have been studied
- The (TA)7/(TA)7 genotype was associated with a statistically significant increase in the risk of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes
- However, the largest increases in bilirubin were observed in the (TA)7/(TA)7 genotype (UGT1A1*28) patients during nilotinib treatment
Genetic testing laboratories
- The following companies currently offer FISH and/or transcript quantification testing for BCR-ABL
- Asuragen (https://www.asuragen.com/)
- Dako (https://www.dakousa.com/)
- Invitrogen (https://www.invitrogen.com/)
- Ipsogen (https://www.ipsogen.com)
