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nilotinib (Rx)Brand and Other Names:Tasigna

 
 
 

Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 150mg
  • 200mg
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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

<18 years old: Not recommended

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Interactions

Interaction Checker

nilotinib and

No Results

     
     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse 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

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            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

            Contains lactose; avoid in galactose intolerance, lactase deficiency or glucose-galactose malabsorption

            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

            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

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            Pregnancy & 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.

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            Pharmacology

            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 (http://www.asuragen.com/)
            • Dako (http://www.dakousa.com/)
            • Invitrogen (http://www.invitrogen.com/)
            • Ipsogen (http://www.ipsogen.com)
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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
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            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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