Tasigna

nilotinib

Tasigna

Pharmacologic class: Protein-tyrosine kinase inhibitor

Therapeutic class: Antineoplastic

Pregnancy risk category D

FDA Box Warning

Drug prolongs QT interval and may lead to sudden death. Don't give to patients with hypokalemia, hypomagnesemia, or long-QT syndrome. Correct hypokalemia or hypomagnesemia before starting drug and monitor for these imbalances periodically. Avoid concomitant drugs known to prolong QT interval; also avoid strong CYP3A4 inhibitors. Instruct patient not to eat 2 hours before or 1 hour after taking dose. Obtain ECG to monitor QTc at baseline, 7 days after drug initiation, periodically thereafter, and after dosage adjustments.

Reduce dosage in patients with hepatic impairment.

Action

Inhibits proliferation of murine leukemic cell lines mediated by BCR-ABL kinase and human cell lines derived from patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML)

Availability

Capsules: 200 mg

Indications and dosages

➣ Chronic-phase or accelerated-phase Ph+ CML in patients resistant or intolerant to previous imatinib therapy

Adults: 400 mg P.O. q 12 hours

➣ Newly diagnosed Philadelphia chromosome positive CML Adults: 300 mg P.O. q 12 hours

Dosage adjustment

• QTc longer than 480 msec

• Hematologic toxicity

• Moderate or severe non-hematologic toxicity

• Concomitant use of CYP3A4 inducers

• Hepatic impairment

Off-label uses

• Ph+ acute lymphoblastic leukemia (ALL)

• Systemic mastocytosis with c-kit receptor activation

• Hypereosinophilic syndrome

Contraindications

• Hypokalemia

• Hypomagnesemia

• Long-QT syndrome

Precautions

Use cautiously in:

• hepatic impairment

• rare hereditary problems of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption (use not recommended)

• myelosuppression

• electrolyte abnormalities

• history of pancreatitis

• pregnant or breastfeeding patients

• children (safety and efficacy not established).

Administration

Correct hypophosphatemia and hypokalemia before starting drug.

• Don't give with food. Know that patient shouldn't consume food for at least 2 hours before or 1 hour after dose.

• Administer capsule whole with water.

• Be aware that drug may be given in combination with hematopoietic growth factors, if indicated.

Adverse reactions

CNS: headache, fatigue, asthenia, insomnia, dizziness, paresthesia, vertigo, intracranial hemorrhage

CV: palpitations, hypertension, flushing, QT interval prolongation and sudden death

EENT: dysphonia, nasopharyngitis

GI: nausea, vomiting, diarrhea, constipation, abdominal pain, abdominal discomfort, dyspepsia, flatulence, anorexia

Hematologic: anemia, neutropenia, thrombocytopenia, leukopenia, pan-cytopenia, febrile neutropenia

Hepatic: hepatotoxicity

Metabolic: electrolyte abnormalities

Musculoskeletal: arthralgia, myalgia, extremity pain, bone pain, muscle spasms, back pain, chest pain

Respiratory: cough, dyspnea, exertional dyspnea, pneumonia

Skin: rash, pruritus, eczema, urticaria, alopecia, erythema, hyperhidrosis, dry skin

Other: fever, peripheral edema, night sweats, weight changes

Interactions

Drug-drug. Drugs eliminated by CYP2B6, CYP2C8, or CYP2C9: decreased blood levels of these drugs

Drugs eliminated by CYP3A4 (such as warfarin), CYP2C8, CYP2C9, CYP2D6, or UGT1A1: increased blood levels of these drugs

Drugs that inhibit P-glycoprotein

ABCB1: increased nilotinib blood level

Midazolam: increased midazolam exposure

P-glycoprotein substrates: increased blood levels of these drugs

Strong CYP3A4 inducers (such as carba-mazepine, dexamethasone, phenytoin, rifabutin, rifampin, rifapentin, phenobarbital): decreased nilotinib blood level

Strong CYP3A4 inhibitors (such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole): increased nilotinib blood level

Drug-diagnostic tests. Albumin, calcium, magnesium, neutrophils, phosphorus, platelets, sodium, white blood cells: decreased levels

ALP, ALT, AST, bilirubin, blood glucose, creatinine, serum amylase, serum lipase: increased levels

Potassium: increased or decreased level

Drug-food. Grapefruit products: increased nilotinib blood level

High-fat meal: increased nilotinib onset

Drug-herbs. St. John's wort: decreased nilotinib blood level

Patient monitoring

Closely monitor for prolonged QT interval if patient has hepatic impairment or is receiving strong CYP3A4 inhibitors.

• Obtain complete blood count every 2 weeks for first 2 months of therapy and monthly thereafter, or as indicated.

• Periodically monitor electrolyte and lipase levels and liver function tests.

Patient teaching

• Tell patient not to take drug with food and not to consume food for at least 2 hours before or 1 hour after dose.

• Advise patient to take capsules whole with water.

Instruct patient to avoid grapefruit products and St. John's wort.

• Tell lactose-intolerant patient that drug contains lactose.

Instruct patient to immediately notify prescriber if symptoms of QTc prolongation (faintness or irregular heartbeat) occur.

Urge patient to immediately report signs or symptoms of liver damage, such as nausea, fatigue, anorexia, yellowing of skin or eyes, dark urine, light-colored stools, itching, or abdominal tenderness.

• Advise female patient that drug may harm fetus. Caution her to avoid pregnancy.

• Advise breastfeeding patient to seek guidance to help her decide whether to discontinue breastfeeding or discontinue drug.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, food, and herbs mentioned above.

nilotinib

(ni-lo-ti-nib) nilotinib,

Tasigna

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: enzyme inhibitors
Pregnancy Category: D

Indications

genetic implication Newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in chronic phase.genetic implication Chronic or accelerated phase Ph+ CML that has not responded to other treatment, including imatinib.

Action

Inhibits kinases which may be produced by malignant cell lines.

Therapeutic effects

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

Pharmacokinetics

Absorption: Well absorbed following oral administration. Blood levels are significantly ↑ by food.Distribution: Unknown.Metabolism and Excretion: Mostly metabolized by the liver; metabolites are not active.Half-life: 17 hr.

Time/action profile (blood levels)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	3 hr	12 hr

Contraindications/Precautions

Contraindicated in: Hypokalemia or hypomagnesemia;Long QT syndrome;Concurrent use of medications known to prolong QT interval;Concurrent use of strong inhibitors of the CYP3A4 enzyme system (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice);Concurrent use of strong inducers of the CYP3A4 enzyme system (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); Obstetric / Lactation: Pregnancy or lactation.Use Cautiously in: Concurrent use of other drugs that prolong QT interval;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; Obstetric: Women with child-bearing potential (effective contraception required); Pediatric: Safety not established.

Adverse Reactions/Side Effects

Central nervous system

fatigue (most frequent)
headache (most frequent)
dizziness

Ear, Eye, Nose, Throat

vertigo

Cardiovascular

torsades de pointes (life-threatening)
hypertension
palpitations
QT interval prolongation

Gastrointestinal

hepatotoxicity (life-threatening)
↑ lipase (most frequent)
constipation (most frequent)
diarrhea (most frequent)
nausea (most frequent)
vomiting (most frequent)
abdominal discomfort
anorexia
dyspepsia
flatulence

Dermatologic

pruritus (most frequent)
rash (most frequent)
alopecia
flushing

Fluid and Electrolyte

hyperkalemia
hypocalcemia
hypokalemia
hyponatremia
hypophosphatemia

Hematologic

myelosupression

Metabolic

hyperglycemia

Musculoskeletal

musculoskeletal pain

Neurologic

paresthesia

Miscellaneous

fever (most frequent)
night sweats
tumor lysis syndrome

Interactions

Drug-Drug interaction

Strong CYP3A4 inhibitors including ketoconazole, itraconaole, voriconazole, clarithromycin, telithromycin, 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 rifapentin may ↓ blood levels and effectiveness and should be avoided.Nilotinib inhibits the following enzyme systems: CYP3A4, CYP2C8, CYP2C9, and CYP2D6 ; concurrent use of drugs metabolized by these systems may result in toxicity of these agents.Nilotinib induces the following enzyme systems: CYP2D6, CYP2C8, CYP2C9 ; concurrent use of drugs metabolized by these systems may result ↓ therapeutic effectiveness of these agents.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.May ↑ midazolam levels.St. John's wort may ↓ levels and effectiveness; avoid concurrent use.Grapefruit juice may ↑ blood levels and toxicity and should be avoided.

Route/Dosage

Newly Diagnosed Ph+ CML Chronic Phase

Oral (Adults) 300 mg twice daily; adjustment may be required for toxicity; Concurrent use of strong CYP3A4 inhibitor (ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)—200 mg once daily.

Hepatic Impairment

Oral (Adults) Mild, moderate or severe hepatic impairment—200 mg twice daily; may ↑ to 300 mg twice daily if tolerates

Resistant or Intolerant Ph+ CML Chronic or Accelerated Phase

Oral (Adults) 400 mg twice daily; adjustment may be required for toxicity; Concurrent use of strong CYP3A4 inhibitor (ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)—300 mg once daily.

Hepatic Impairment

Oral (Adults) Mild or moderate hepatic impairment—300 mg twice daily; may ↑ to 400 mg twice daily if tolerates; Severe hepatic impairment—200 mg twice daily; may ↑ to 300 mg twice daily, and eventually to 400 mg twice daily if tolerates

Availability

Capsules: 150 mg, 200 mg

Nursing implications

Nursing assessment

Monitor ECG to assess the QTc interval at baseline, 7 days after initiation of therapy, 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 ot 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 othrostatic hypotension.
Monitor for tumor lysis syndrome (malignant disease progression, high WBC counts, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcamia, and/or dehydration). Prevent by maintain adequate hydration and correcting uric acid levels prior to starting nilotinib.
Lab Test Considerations: 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 if serum lipase or amylase return to ≤Grade 1.
- May cause ↑ 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.
- May cause ↑ serum hepatic tranaminases. If ↑ to ≥Grade 3, withhold nilotinib and monitor serum ALT, AST, and alkaline phosphatase. Resume treatment at 400 mg once daily if serum lipase or amylase return to ≤Grade 1.

Potential Nursing Diagnoses

Deficient knowledge, related to medication regimen (Patient/Family Teaching)

Implementation

Correct hypokalemia and hypomagnesemia prior to beginning therapy.
Oral: Administer twice daily at 12-hr intervals on an empty stomach, at least 1 hr before and 2 hr after food. Capsule should be swallowed 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 minutes. 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

Patient/Family Teaching

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; 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.
Advise women of childbearing potential to use highly effective contraception during therapy and to avoid breast feeding.

Evaluation/Desired Outcomes

Decrease in production of leukemic cells.