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Nilotinib

Pronunciation

(nye LOE ti nib)

Index Terms

  • AMN107
  • Nilotinib Hydrochloride Monohydrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Tasigna: 150 mg, 200 mg

Brand Names: U.S.

  • Tasigna

Pharmacologic Category

  • Antineoplastic Agent, BCR-ABL Tyrosine Kinase Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

Selective tyrosine kinase inhibitor that targets BCR-ABL kinase, c-KIT and platelet derived growth factor receptor (PDGFR); does not have activity against the SRC family. Inhibits BCR-ABL mediated proliferation of leukemic cell lines by binding to the ATP-binding site of BCR-ABL and inhibiting tyrosine kinase activity. Nilotinib has activity in imatinib-resistant BCR-ABL kinase mutations.

Metabolism

Hepatic; oxidation and hydroxylation, via CYP3A4 to primarily inactive metabolites

Excretion

Feces (93%; 69% as parent drug)

Time to Peak

3 hours

Half-Life Elimination

~15 to 17 hours

Protein Binding

~98%

Special Populations: Hepatic Function Impairment

Nilotinib exposure is increased. A lower starting dose is recommended in these patients.

Special Populations Note

Total gastrectomy

Median steady-state trough concentrations are decreased by 53%.

Use: Labeled Indications

Chronic myelogenous leukemia:

Treatment of adults with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in chronic phase.

Treatment of chronic- and accelerated-phase Philadelphia chromosome-positive CML in adults resistant or intolerant to prior therapy that included imatinib.

Use: Unlabeled

Treatment of refractory gastrointestinal stromal tumor (GIST)

Contraindications

Hypokalemia, hypomagnesemia, or long QT syndrome

Canadian labeling: Additional contraindication (not in US labeling): Hypersensitivity to nilotinib or any component of the formulation; persistent QTc >480 msec

Dosing: Adult

Note: If clinically indicated, may be administered in combination with hematopoietic growth factors (eg, erythropoietin, filgrastim) and with hydroxyurea or anagrelide.

Chronic myeloid leukemia (CML), Ph+, newly-diagnosed in chronic phase: Oral: 300 mg twice daily

CML, Ph+, resistant or intolerant in chronic or accelerated phase: Oral: 400 mg twice daily

Gastrointestinal stromal tumor (GIST), refractory (off-label use): Oral: 400 mg twice daily until disease progression or unacceptable toxicity (Reichardt, 2012)

Missed doses: If a dose is missed, do not make up, resume with next scheduled dose.

Dosage adjustment for concomitant CYP3A4 inhibitors/inducers:

CYP3A4 inhibitors: Avoid the concomitant use of a strong CYP3A4 inhibitor with nilotinib. If a strong CYP3A4 inhibitor is required, interruption of nilotinib treatment is recommended.

If therapy cannot be interrupted and concurrent use with a strong CYP3A4 inhibitor cannot be avoided:

US labeling: Consider reducing the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML (chronic or accelerated phase) or to 200 mg once daily in newly-diagnosed chronic phase Ph+ CML, with careful monitoring, especially of the QT interval. When a strong CYP3A4 inhibitor is discontinued, allow a washout period prior to adjusting nilotinib dose upward.

Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling; use caution and monitor QT interval closely

CYP3A4 inducers: Avoid the concomitant use of a strong CYP3A4 inducer with nilotinib (based on pharmacokinetic parameters, an increased nilotinib dose is not likely to compensate for decreased exposure).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied in patients with serum creatinine >1.5 times ULN); however, nilotinib and its metabolites have minimal renal excretion; dosage adjustments for renal dysfunction may not be necessary.

Dosing: Hepatic Impairment

For hepatic impairment at treatment initiation: Note: Consider alternative therapies first if possible; recommendations vary by indication

US labeling:

Newly-diagnosed Ph+ CML in chronic phase: Mild-to-severe impairment (Child-Pugh class A, B, or C): Initial: 200 mg twice daily; may increase to 300 mg twice daily based on patient tolerability

Resistant or intolerant Ph+ CML in chronic or accelerated phase:

Mild-to-moderate impairment (Child-Pugh class A or B): Initial: 300 mg twice daily; may increase to 400 mg twice daily based on patient tolerability

Severe impairment (Child-Pugh class C): Initial: 200 mg twice daily; may increase to 300 mg twice daily and then further increase to 400 mg twice daily based on patient tolerability

Canadian labeling: No dosage adjustment necessary; use caution and monitor (including QT interval) closely.

For hepatotoxicity during treatment:

If bilirubin >3 times ULN (≥grade 3): Withhold treatment, monitor bilirubin, resume treatment at 400 mg once daily when bilirubin returns to ≤1.5 times ULN (≤grade 1)

If ALT or AST >5 times ULN (≥grade 3): Withhold treatment, monitor transaminases, resume treatment at 400 mg once daily when ALT or AST returns to ≤2.5 times ULN (≤grade 1)

Dosing: Adjustment for Toxicity

Dosage adjustment for hematologic toxicity unrelated to underlying leukemia:

ANC <1000/mm3 and/or platelets <50,000/mm3: Withhold treatment, monitor blood counts

If ANC >1000/mm3 and platelets >50,000/mm3 within 2 weeks: Resume at prior dose

If ANC <1000/mm3 and/or platelets <50,000/mm3 for >2 weeks: Reduce dose to 400 mg once daily

Dosage adjustment for nonhematologic toxicity:

Amylase or lipase >2 times ULN (≥grade 3): Withhold treatment, monitor serum amylase or lipase, resume treatment at 400 mg once daily when lipase or amylase returns to ≤1.5 times ULN (≤grade 1)

Lipase increases in conjunction with abdominal symptoms: Withhold treatment and consider diagnostics to exclude pancreatitis.

Clinically-significant moderate or severe nonhematologic toxicity: Withhold treatment, upon resolution of toxicity, resume at 400 mg once daily; may escalate back to initial dose (300 mg twice daily or 400 mg twice daily depending on indication) if clinically appropriate.

Dosage adjustment for QT prolongation: Note: Repeat ECG ~7 days after any dosage adjustment.

QTc >480 msec: Withhold treatment, monitor and correct potassium and magnesium levels; review concurrent medications.

If QTcF returns to <450 msec and to within 20 msec of baseline within 2 weeks: Resume at prior dose.

If QTcF returns to 450 to 480 msec after 2 weeks: Reduce dose to 400 mg once daily.

If QTcF >480 msec after dosage reduction to 400 mg once daily: Discontinue treatment.

Administration

Administer twice daily with doses ~12 hours apart. Administer on an empty stomach, at least 1 hour before or 2 hours after food. Capsules should be swallowed whole with water. If unable to swallow whole, may empty contents into 5 mL applesauce and administer within 15 minutes (do not save for later use).

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Dietary Considerations

The bioavailability of nilotinib is increased with food. Take on an empty stomach, at least 1 hour before or 2 hours after food. Avoid grapefruit juice.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Antacids: May decrease the serum concentration of Nilotinib. Management: Separate the administration of nilotinib and any antacid by at least 2 hours whenever possible in order to minimize the risk of a significant interaction. Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination

Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Consider therapy modification

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor or temporarily stopping budesonide therapy during CYP3A4 inhibitor use. Monitor patients closely for signs/symptoms of corticosteroid excess. Consider therapy modification

Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Monitor therapy

Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Consider therapy modification

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP2B6 Substrates: Nilotinib may decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Nilotinib. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Nilotinib. Avoid combination

CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Monitor therapy

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg/day when used together with a moderate inhibitor of CYP3A4. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dexamethasone (Systemic): May decrease the serum concentration of Nilotinib. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations may vary depending on international labeling. Consult appropriate labeling for specific recommendations. Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Canadian labeling recommends an initial 50% reduction in guanfacine dose with further dose titration as needed. However, US labeling does not call for any specific guanfacine dose reduction with this combination. Monitor therapy

H2-Antagonists: May decrease the serum concentration of Nilotinib. Management: The nilotinib dose should be given 10 hours after or 2 hours before the H2 receptor antagonist in order to minimize the risk of a significant interaction. Consider therapy modification

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Hydrocodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Hydrocodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: If a moderate CYP3A inhibitor must be used, consider reducing the dose of ibrutinib to 140mg daily and monitor closely for signs of toxicity. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy

Irinotecan Products: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination

Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult prescribing information for specific age- and weight-based recommendations. Consider therapy modification

Ledipasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ledipasvir. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: U.S. labeling: start at 20 mg/day and limit to max of 80 mg/day with moderate CYP3A4 inhibitor. Canadian labeling: limit to max of 40 mg/day with moderate CYP3A4 inhibitor; avoid concomitant use of grapefruit products. Consider therapy modification

Metoprolol: CYP2D6 Inhibitors may increase the serum concentration of Metoprolol. Management: Consider an alternative for one of the interacting drugs in order to avoid metoprolol toxicity. If the combination must be used, monitor response to metoprolol closely. Metoprolol dose reductions may be necessary. Consider therapy modification

Mifepristone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine. Monitor therapy

Nintedanib: Combined Inhibitors of CYP3A4 and P-glycoprotein may increase the serum concentration of Nintedanib. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily. Avoid combination

OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Avoid combination

Proton Pump Inhibitors: May decrease the serum concentration of Nilotinib. Management: Avoid this combination when possible since separation of doses is not likely to be an adequate method of minimizing the interaction. Consider therapy modification

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Consider therapy modification

Rifaximin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rifaximin. Monitor therapy

Rivaroxaban: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Rivaroxaban. Management: No action is needed in patients with normal renal function. US labeling recommends avoidance in patients with estimated creatinine clearance 15 to 80 mL/min unless prospective benefits outweigh the risks. See monograph for details of Canadian labeling. Consider therapy modification

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Saxagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Saxagliptin. Monitor therapy

Sildenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Sonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Consider therapy modification

St John's Wort: May decrease the serum concentration of Nilotinib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tamoxifen: CYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Consider alternatives with less of an inhibitory effect on CYP2D6 activity when possible. Consider therapy modification

Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Thioridazine: CYP2D6 Inhibitors may increase the serum concentration of Thioridazine. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Avoid combination

TraMADol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Monitor therapy

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (≤15%; grade 3/4: <1%), hypertension (10% to 11%)

Central nervous system: Headache (20% to 35%), fatigue (21% to 32%), insomnia (7% to 12%), dizziness (≤12%)

Dermatologic: Skin rash (≤38%; grades 3/4: ≤2%), pruritus (20% to 32%), night sweats (12% to 27%), alopecia (11% to 13%), xeroderma (>5% to 12%)

Endocrine & metabolic: Increased serum glucose (50%), hyperglycemia (≤50%; grades 3/4: 7% to 12%), increased serum cholesterol (28%), hypophosphatemia (≥10%; grades 3/4: 5% to 17%)

Gastrointestinal: Nausea (20% to 37%), vomiting (11% to 29%), diarrhea (14% to 28%), increased serum lipase (28%; grades 3/4: 9% to 18%), constipation (17% to 26%), upper abdominal pain (12% to 18%; grade 3/4: <1%), abdominal pain (15% to 16%), decreased appetite (including anorexia 15%)

Hematologic & oncologic: Neutropenia (grades 3/4: 12% to 42%; median duration: 15 days), thrombocytopenia (grades 3/4: 10% to 42%; median duration: 22 days), anemia (grades 3/4: 4% to 27%)

Hepatic: Hepatic: Increased serum ALT (10% to 72%; grades 3/4: 4%), increased serum AST (10% to 47%; grades 3/4: 1% to 3%), hyperbilirubinemia (≥10%; grades 3/4: 4% to 9%), increased serum ALT (≥10%; grades 3/4: 4%), increased serum AST (≥10%; grades 3/4: 1% to 3%)

Infection: Influenza (≤13%)

Neuromuscular & skeletal: Arthralgia (16% to 26%), limb pain (11% to 20%), myalgia (14% to 19%), back pain (15% to 19%), weakness (11% to 16%), ostealgia (14% to 15%), muscle spasm (11% to 15%), musculoskeletal pain (11% to 12%)

Respiratory: Cough (14% to 27%), nasopharyngitis (≤27%), upper respiratory tract infection (≤17%), dyspnea (9% to 15%), oropharyngeal pain (≤12%), flu-like symptoms (11%)

Miscellaneous: Fever (11% to 28%)

1% to 10%:

Cardiovascular: Peripheral arterial disease (3% to 4%), cerebral ischemia (1% to 3%), ischemic heart disease (5% to 9%), pericardial effusion (≤2%; grades 3/4: ≤1%), angina pectoris, cardiac arrhythmia (including AV block, atrial fibrillation, bradycardia, cardiac flutter, extrasystoles, and tachycardia), chest discomfort, chest pain (including noncardiac), flushing, palpitations, prolonged Q-T interval on ECG

Central nervous system: Anxiety, depression, flank pain, hypoesthesia, malaise, myasthenia, pain, paresthesia, peripheral neuropathy, vertigo, voice disorder

Dermatologic: Acne vulgaris, dermatitis (including allergic and acneiform), eczema, erythema, folliculitis, hyperhidrosis, urticaria

Endocrine & metabolic: Hypokalemia (grades 3/4: ≤9%), hyponatremia (grades 3/4: ≤7%), hyperkalemia (grades 3/4: 2% to 6%), hypocalcemia (grades 3/4: ≤5%), decreased serum albumin (grades 3/4: ≤4%), fluid retention (grades 3/4: 3% to 4%), diabetes mellitus, hypercalcemia, hypercholesterolemia, hyperlipidemia, hyperphosphatemia, hypertriglyceridemia, hypomagnesemia, increased gamma-glutamyl transferase, increased HDL cholesterol, increased VLDL, weight gain, weight loss

Gastrointestinal: Dyspepsia (4% to 10%), gastrointestinal hemorrhage (≤5%), abdominal distension, abdominal distress, dysgeusia, flatulence, increased serum amylase, pancreatitis

Genitourinary: Pollakiuria

Hematologic & oncologic: Hemorrhage (grades 3/4: 1% to 2%), bruise, cutaneous papilloma, decreased hemoglobin, eosinophilia, febrile neutropenia, hemophthalmos, leukopenia, lymphocytopenia, pancytopenia

Hepatic: Ascites (≤2%; grades 3/4: ≤1%), increased serum alkaline phosphatase (grades 3/4: ≤1%), hepatic insufficiency

Immunologic: Decreased serum globulins

Neuromuscular & skeletal: Increased creatine phosphokinase, neck pain

Ophthalmic: Eyelid edema (1%), conjunctivitis, eye pruritus, periorbital edema, xerophthalmia

Respiratory: Pleural effusion (≤2%; grades 3/4: ≤1%), pulmonary edema (≤2%; grades 3/4: ≤1%), dyspnea (exertional), epistaxis

<1% (Limited to important or life-threatening): Abscess, amnesia, arthritis, auditory impairment, blurred vision, cardiac failure, cardiomegaly, cerebral infarction, cholestasis, chorioretinopathy, confusion, conjunctival hemorrhage, cyanosis, dehydration, dermal ulcer, diplopia, ecchymoses, enterocolitis, erectile dysfunction, erythema nodosum, exfoliative dermatitis, gastroenteritis, gout, gynecomastia, heart murmur, hemorrhagic shock, hepatitis, hepatomegaly, hepatotoxicity, herpes simplex infection, hiatal hernia, hyperemia (scleral, conjunctival, ocular), hyperparathyroidism (secondary), hypersensitivity, hypertensive crisis, hyperthyroidism, hypoglycemia, hypothyroidism, interstitial pulmonary disease, intracranial hemorrhage, increased lactate dehydrogenase, increased parathyroid hormone, leukocytosis, localized edema, loss of consciousness, mesenteric artery occlusion, migraine, myocardial infarction, nonhemorrhagic stroke, optic neuritis, oral papilloma, palmar-plantar erythrodysesthesia, pericarditis, pneumonia, psoriasis, pulmonary hypertension, rectal hemorrhage, renal failure, restless leg syndrome, retroperitoneal hemorrhage, sepsis, sinusitis, skin atrophy, skin hyperpigmentation, skin hypertrophy, stomatitis, stricture of artery (basilar, coronary, peripheral), subileus, thrombocythemia, thrombosis, thyroiditis, tinea pedis, transient ischemic attacks, tumor lysis syndrome, ulcerative esophagitis, urinary tract infection, vasculitis

ALERT: U.S. Boxed Warning

QT Prolongation and Sudden Deaths:

Nilotinib prolongs the QT interval. Prior to nilotinib administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain electrocardiograms (ECGs) to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, and following any dose adjustments. Sudden deaths have been reported in patients receiving nilotinib. Do not use nilotinib in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Patient should avoid food 2 hours before and 1 hour after taking a nilotinib dose.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Reversible myelosuppression, including grades 3 and 4 thrombocytopenia, neutropenia and anemia may occur; may require dose reductions and/or treatment delay. Monitor blood counts.

• Cardiovascular: Cardiovascular events such as ischemic heart disease-related events, arterial vascular occlusive events, peripheral arterial occlusive disease, and ischemic cerebrovascular accident have been reported. Use caution in patients with preexisting risk factors, and monitor for new or worsening symptoms suggestive of cardiovascular events.

• Electrolyte imbalance: Electrolyte abnormalities may occur during treatment, including hypophosphatemia, hyper-/hypokalemia, hypocalcemia and hyponatremia. Correct electrolyte abnormalities prior to treatment initiation; monitor periodically.

• Fluid retention: Fluid retention, including pleural and pericardial effusions, ascites, and pulmonary edema were reported; may be severe. Monitor closely for signs/symptoms of fluid retention (eg, rapid weight gain or swelling) and for symptoms of respiratory or cardiac distress (eg, shortness of breath). Evaluate promptly and manage as appropriate.

• Hemorrhage: In a clinical study comparing nilotinib and imatinib in the treatment of newly diagnosed Ph+ chronic phase CML, hemorrhagic events (eg, gastrointestinal hemorrhage, including grade 3 or 4 events) occurred more frequently in the nilotinib arm.

• Hepatotoxicity: May cause hepatotoxicity, including dose-limiting elevations in bilirubin, transaminases, and alkaline phosphatase; monitor liver function.

• QT prolongation/sudden death: [US Boxed Warning]: May prolong the QT interval; sudden deaths have been reported. Use in patients with hypokalemia, hypomagnesemia, or long QT syndrome is contraindicated. Correct hypomagnesemia and hypokalemia prior to initiating therapy; monitor electrolytes periodically. Monitor ECG and QTc (baseline, at 7 days, with dose change, and periodically). Avoid the use of QT-prolonging agents and strong CYP3A4 inhibitors; also avoid concurrent use with antiarrhythmics; may increase the risk of potentially-fatal arrhythmias. The sudden deaths reported appear to be related to dose-dependent ventricular repolarization abnormalities. Prolonged QT interval may result in torsade de pointes, which may cause syncope, seizure, and/or death. Patients with uncontrolled or significant cardiovascular disease were excluded from studies.

• Tumor lysis syndrome: Tumor lysis syndrome (TLS) has been reported in patients with resistant or intolerant CML; the majority of cases had malignant disease progression, high WBC counts, and/or dehydration. Maintain adequate hydration and treat high uric acid levels prior to nilotinib.

Disease-related concerns:

• Gastrectomy: Consider alternative therapy or a dosage increase (with more frequent monitoring) in patients with total gastrectomy (nilotinib exposure is reduced).

• Hepatic impairment: Dosage reduction is recommended in patients with hepatic impairment, along with close monitoring of QT interval. Nilotinib metabolism is primarily hepatic; exposure is increased in patients with hepatic impairment.

• Pancreatitis: Use with caution in patients with a history of pancreatitis, may cause dose-limiting elevations of serum lipase and amylase; monitor. In patients with abdominal symptoms in conjunction with lipase increases, withhold treatment and consider diagnostics to exclude pancreatitis. Monitor serum lipase levels monthly or as clinically necessary.

Concurrent drug therapy issues:

• Drug-drug/drug-food interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. [US Boxed Warning]: Avoid concurrent use with medications known to prolong the QT interval and with strong CYP3A4 inhibitors.

Special populations:

• Polymorphisms: UGT1A1 polymorphisms may be a risk factor for increased toxicity (eg, hyperbilirubinemia) (Shibata, 2013).

Dosage form specific issues:

• Lactose: Capsules contain lactose; do not use with galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption syndromes.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Appropriate administration: [US Boxed Warning]: Administer on an empty stomach, at least 1 hour before and 2 hours after food. Food increased the bioavailability/serum levels which may then prolong QTc. Nilotinib solubility is decreased at higher pH; concurrent use with proton pump inhibitors is not recommended. If necessary, H2-receptor blockers may be administered ~10 hours before and 2 hours after a nilotinib dose. Antacids (eg, aluminum hydroxide, magnesium hydroxide, simethicone) may be administered ~2 hours before or 2 hours after nilotinib.

Monitoring Parameters

CBC with differential (every 2 weeks for first 2 months, then monthly); electrolytes (including potassium, calcium, and magnesium; baseline and periodic); lipid profile and glucose (baseline and periodically during the first year, then at least yearly), hepatic function (ALT/AST, bilirubin, alkaline phosphatase; baseline and monthly or as clinically indicated); serum lipase/amylase (baseline and monthly or as clinically indicated), uric acid (baseline); bone marrow assessments; ECG and QTc (baseline, 7 days after treatment initiation or dosage adjustments, and periodically thereafter); signs/symptoms of cardiovascular events, hemorrhage, or fluid retention; additional baseline and/or periodic monitoring recommended by Canadian labeling include CPK, creatinine, lactate dehydrogenase, and weight.

Thyroid function testing (Hamnvik, 2011):

Preexisting levothyroxine therapy: Obtain baseline TSH levels, then monitor every 4 weeks until levels and levothyroxine dose are stable, then monitor every 2 months

Without preexisting thyroid hormone replacement: TSH at baseline, then monthly for 4 months, then every 2 to 3 months

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies. May cause fetal harm if administered during pregnancy. Women of childbearing potential should be advised to use effective contraception during treatment. The Canadian labeling recommends that women of childbearing potential and/or male patients receiving nilotinib use highly effective contraception during treatment and for at least 4 weeks after completion of therapy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, dyspepsia, lack of appetite, constipation, diarrhea, arthralgia, myalgia, back pain, alopecia, insomnia, rhinitis, rhinorrhea, sternutation, pharyngitis, night sweats, xeroderma, or muscle spasms. Have patient report immediately to prescriber signs of infection, signs of hepatic impairment, signs of pancreatitis, signs of hyperglycemia, strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision, angina, tachycardia, syncope, arrhythmia, dyspnea, excessive weight gain, edema of extremities, vision changes, considerable headache, signs of hemorrhaging, significant asthenia, or signs of tumor lysis syndrome (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.

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