ni-LO-ti-nib

• Newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in chronic phase.
• Chronic or accelerated phase Ph+ CML in adult patients who are resistant or intolerant to prior treatment, including imatinib.
• Chronic or accelerated phase Ph+ CML in pediatric patients 1 yr who are resistant or intolerant to prior tyrosine-kinase inhibitor treatment.

• Inhibits kinases which may be produced by malignant cell lines.

• Inhibits production of malignant cells lines with decreased proliferation of leukemic cells.

Absorption: Well absorbed following oral administration. Blood levels are significantly ↑ by food.

Distribution: Unknown.

Metabolism/Excretion: Mostly metabolized by the liver; metabolites are not active.

Half-life: 17 hr.

Contraindicated in:

• Hypokalemia or hypomagnesemia
• Long QT syndrome
• Concurrent use of QT interval prolonging medications
• Concurrent use of strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, voriconazole, grapefruit juice)
• Concurrent use of strong CYP3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John's wort)
• Galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption (capsules contain lactose)
• OB: Pregnancy (may cause fetal harm)
• Lactation: Lactation.

Use Cautiously in:

• Concurrent use of proton pump inhibitors (may ↓ bioavailability of nilotinib)
• Electrolyte abnormalities; correct prior to administration to ↓ risk of arrhythmias
• Hepatic impairment (↓ dose required for Grade 3 elevated bilirubin, transaminases or lipase)
• Total gastrectomy (may need to ↑ dose or use alterative therapy)
• History of pancreatitis
• Patients with genetically reduced UGT1A1 activity (presence of UGT1A1*28 allele) (↑ risk of hyperbilirubinemia)
• Rep: Women of reproductive potential
• Pedi: May affect growth and development of children; safety and effectiveness not established in children <1 yr.

CV: MI, STROKE, TORSADES DE POINTES, hypertension, palpitations, pericardial effusion, peripheral arterial disease, QT interval prolongation.

Derm: pruritus, rash, alopecia, flushing.

EENT: vertigo.

F and E: hyperkalemia, hypocalcemia, hypokalemia, hyponatremia, hypophosphatemia.

GI: HEPATOTOXICITY, ↑lipase, constipation, diarrhea, nausea, vomiting, abdominal discomfort, anorexia, ascites, dyspepsia, flatulence, hepatitis B virus reactivation.

Hemat: bleeding, myelosupression.

Metab: hyperglycemia.

MS: ↓growth, musculoskeletal pain.

Neuro: fatigue, headache, dizziness., paresthesia.

Resp: pleural effusion, pulmonary edema.

Misc: fever, night sweats, tumor lysis syndrome.

Drug-Drug:

• Strong CYP3A4 inhibitors including ketoconazole, itraconazole, voriconazole, clarithromycin, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir, and nefazodone may result in ↑ blood levels and toxicity and should be avoided if possible; if concurrent use is necessary, ↓ nilotinib dose.
• Strong CYP3A4 inducers including carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine may ↓ blood levels and effectiveness and should be avoided.
• May ↑ levels of CYP3A4 substrates, including alfentanil, atorvastatin, cyclosporine, dihydroergotamine, ergotamine, fentanyl, lovastatin, midazolam, simvastatin, sirolimus, and tacrolimus.
• Concurrent use of other drugs that prolong QT interval; may ↑ risk of serious arrhythmias; avoid concomitant use.
• Proton pump inhibitors, H₂ receptor antagonists, and antacids may ↓ the bioavailability of nilotinib; avoid concurrent use of proton pump inhibitors; doses of H₂ receptor antagonists may be administered 10 hr before or 2 hr after nilotinib; doses of antacids may be administered 2 hr before or after nilotinib.

Drug-Natural Products:

• St. John's wort may ↓ levels and effectiveness; avoid concurrent use.

Drug-Food:

• Grapefruit juice may ↑ blood levels and toxicity and should be avoided.

Newly Diagnosed Chronic Phase Ph+ Chronic Myelogenous Leukemia

• PO (Adults): 300 mg twice daily; treatment discontinuation may be considered in patients who have received nilotinib for 3 yr and achieved a sustained molecular response; if patients lose molecular response after discontinuing therapy, restart nilotinib within 4 wk at the dose level prior to discontinuation; Concurrent use of strong CYP3A4 inhibitor (ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, voriconazole) — 200 mg once daily.
• PO (Children 1 yr): 230 mg/m² twice daily (max single dose = 400 mg) until disease progression or unacceptable toxicity; treatment discontinuation may be considered in patients who have received nilotinib for 3 yr and achieved a sustained molecular response; if patients lose molecular response after discontinuing therapy, restart nilotinib within 4 wk at the dose level prior to discontinuation; Concurrent use of strong CYP3A4 inhibitor (ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, voriconazole) — 200 mg once daily.

Resistant or Intolerant Chronic or Accelerated Phase Ph+ Chronic Myelogenous Leukemia

• PO (Adults): 400 mg twice daily; treatment discontinuation may be considered in patients who have received nilotinib for 3 yr and achieved a sustained molecular response; if patients lose molecular response after discontinuing therapy, restart nilotinib within 4 wk at the dose level prior to discontinuation; Concurrent use of strong CYP3A4 inhibitor (ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, voriconazole) — 300 mg once daily.
• PO (Children 1 yr): 230 mg/m² twice daily (max single dose = 400 mg) until disease progression or unacceptable toxicity; treatment discontinuation may be considered in patients who have received nilotinib for 3 yr and achieved a sustained molecular response; if patients lose molecular response after discontinuing therapy, restart nilotinib within 4 wk at the dose level prior to discontinuation; Concurrent use of strong CYP3A4 inhibitor (ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, voriconazole) — 200 mg once daily.

• Do not confuse nilotinib with neratinib or niraparib.
• Correct hypokalemia and hypomagnesemia prior to beginning therapy.
• PO: Administer twice daily at 12-hr intervals on an empty stomach, at least 1 hr before and 2 hr after food. DNC: Swallow capsule whole with water; do not open capsule.
  • Patients unable to swallow capsule may open capsule and sprinkle contents of each capsule in 1 teaspoon of applesauce. Swallow mixture within 15 min. Do not use more than 1 teaspoon of applesauce and use only applesauce.
  • Avoid antacids less than 2 hr before or after and H₂ antagonists less than 10 hr before or less than 2 hr after administration

Tasigna

Therapeutic Classification: antineoplastics

Pharmacologic Classification: enzyme inhibitors, kinase inhibitors

• Capsules: 50 mg; 150 mg; 200 mg;

(blood levels)

• Monitor ECG to assess the QTc interval at baseline, 7 days after initiation of therapy, after any dose adjustment, and periodically thereafter. For ECGs with QTc >480 msec, withhold nilotinib and check serum potassium and magnesium. If below lower limit of normal, correct to normal with supplements. Review concomitant medications for effects on electrolytes. If QTc returns to <450 msec and within 20 msec of baseline within 2 wk, return to prior dose. If QTc is <480 msec and >450 msec after 2 wk, reduce nilotinib dose to 400 mg once daily. Following dose reduction to 400 mg once daily, if QTc return to >480 msec, discontinue nilotinib. Repeat ECG approximately 7 days after any dose adjustment.
• Monitor for myelosuppression. Assess for bleeding (bleeding gums, bruising, petechiae, blood in stools, urine, emesis) and avoid IM injections and taking rectal temperatures if platelet count is low. Apply pressure to venipuncture sites for at least 10 min. Assess for signs of infection during neutropenia. Anemia may occur. Monitor for fatigue, dyspnea, and orthostatic hypotension.
• Monitor for tumor lysis syndrome (malignant disease progression, high WBC counts, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and/or dehydration). Prevent by maintain adequate hydration and correcting uric acid levels prior to starting nilotinib.
• Monitor for signs of severe fluid retention (unexpected rapid weight gain or swelling) and for symptoms of respiratory or cardiac compromise (shortness of breath) periodically during therapy; evaluate cause and treat patients as needed.
• Monitor growth and development in pediatric patients receiving nilotinib.

• Verify negative pregnancy test before starting therapy.
  • Monitor serum electrolytes prior to and periodically during therapy. May cause hypokalemia, hypomagnesemia, hypophosphatemia, hyperkalemia, hypocalcemia, hyperglycemia, and hyponatremia.
  • Monitor CBC every 2 wk for first 2 mo and monthly thereafter or as indicated. May cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. If ANC is <1.0 × 10⁹/L and/or platelet counts <50 × 10⁹/L, stop nilotinib and monitor blood counts. Resume within 2 wk at prior dose if ANC >1.0 × 10⁹/L and platelets >50 × 10⁹/L. If blood counts remain low for >2 wk, reduce dose to 400 mg once daily. Myelosuppression is generally reversible.
  • May cause ↑ serum lipase or amylase. If ↑ to Grade 3, withhold nilotinib and monitor serum levels. Resume treatment at 400 mg once daily (230 mg/m² once daily if prior dose was 230 mg/m² twice daily; if serum lipase or amylase return to Grade 1. For pediatric patients, hold nilotinib until serum lipase or amylase return to Grade 1. Resume therapy at 230 mg/m² once daily if prior dose was 230 mg/m² twice daily; discontinue therapy if prior dose was 230 mg/m² once daily.
  • Monitor liver function tests monthly. May cause ↑ serum ALT, AST, alkaline phosphatase and serum bilirubin. If ↑ to Grade 3, withhold nilotinib and monitor bilirubin. Resume treatment at 400 mg once daily if serum lipase or amylase return to Grade 1. For pediatric patients, hold nilotinib until serum bilirubin returns to Grade 1. Resume therapy at 230 mg/m² once daily if prior dose was 230 mg/m² twice daily; discontinue therapy if prior dose was 230 mg/m² once daily, and recovery to Grade 1 takes >28 days.
  • Monitor lipid panel and glucose prior to and periodically during first yr of therapy, and then yearly during chronic therapy.
  • Upon discontinuation, monitor BCR-ABL transcript levels and CBC with differential monthly for 1 yr, then every 6 wk for 2nd yr, and every 12 wk thereafter.

• Instruct patient to take nilotinib as directed, approximately 12 hr apart. If a dose is missed, skip dose and resume taking next prescribed dose. Nilotinib is a long-term treatment; do not stop medication or change dose without consulting health care professional. Advise patient to read the Medication Guide before starting and with each Rx refill, in case of changes.
• Advise patient to avoid grapefruit, grapefruit juice or products with grapefruit extract during therapy; may cause toxicity.
• May cause dizziness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort, during therapy.
• Instruct patient to notify health care professional promptly if fever; chills; cough; hoarseness; sore throat; signs of infection; lower back or side pain; painful or difficulty urination; bleeding gums; bruising; petechiae; blood in stools, urine, or emesis; increased fatigue; dyspnea; signs of fluid retention, or orthostatic hypotension occurs. Caution patient to avoid crowds and persons with known infections. Instruct patients to use a soft toothbrush and electric razor and to avoid falls. Caution patient not to drink alcoholic beverages or take medication containing aspirin or NSAIDs; may precipitate bleeding.
• Instruct patient not to receive any vaccinations without advice of health care professional.
• Discuss the possibility of hair loss with patient. Explore methods of coping. Regrowth usually occurs 2–3 mo after discontinuation of therapy.
• Rep: May cause fetal harm. Advise women of reproductive potential to use highly effective contraception during therapy and for at least 14 days following last dose and to avoid breast feeding for at least 14 days following last dose. Advise patient to notify health care professional immediately if pregnancy is suspected.

• Decrease in production of leukemic cells.

NDC Code^*

• 0078- Novartis Pharmaceuticals Corporation
  • 0078-0526- Tasigna
    • 0078-0526-51- 28 CAPSULE in 1 BLISTER PACK (0078-0526-51)

• 0078- Novartis Pharmaceuticals Corporation
  • 0078-0526- Tasigna
    • 0078-0526-87- 4 BLISTER PACK in 1 CARTON (0078-0526-87) > 28 CAPSULE in 1 BLISTER PACK

• 0078- Novartis Pharmaceuticals Corporation
  • 0078-0592- Tasigna
    • 0078-0592-51- 28 CAPSULE in 1 BLISTER PACK (0078-0592-51)

• 0078- Novartis Pharmaceuticals Corporation
  • 0078-0592- Tasigna
    • 0078-0592-87- 4 BLISTER PACK in 1 CARTON (0078-0592-87) > 28 CAPSULE in 1 BLISTER PACK

• 0078- Novartis Pharmaceuticals Corporation
  • 0078-0951- Tasigna
    • 0078-0951-66- 120 CAPSULE in 1 BOTTLE, PLASTIC (0078-0951-66)