Nilotinib

Nilotinib is used to treat certain types of chronic myeloid leukemia (CML; a type of cancer of the white blood cells), including treatment in people whose disease could not be treated successfully with imatinib (Gleevec) or people who cannot take imatinib. Nilotinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

• Tasigna^®

>10%

Rash (33%)

Headache (31%)

Nausea (31%)

Pruritus (29%)

Fatigue (28%)

Pyrexia (24%)

Diarrhea (22%)

Constipation (21%)

Vomiting (21%)

Arthralgia (18%)

Cough (17%)

Extremity pain (16%)

Asthenia (14%)

Muscle spasms (14%)

Myalgia (14%)

Abdominal pain (13%)

Bone pain (13%)

Back pain (12%)

Dyspnea (11%)

Nasopharyngitis (11%)

Peripheral edema (11%)

1-10% (selected)

Dizziness

Insomnia

Paresthesia

QT interval prolongation

HTN

Palpitations

QT interval prolongation

Hyperglycemia

Hyperkalemia

Hypomagnesemia

Neutropenia

Pancytopenia

<1%

Peripheral arterial occlusive disease

Tumor lysis syndrome

Aortic valve sclerosis

Abscess

Amnesia

Dehydration

Postmarketing Reports

Infections: Hepatitis B virus reactivation

Sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis

Black Box Warnings

Nilotinib prolongs the QT interval. Sudden deaths reported in patients receiving nilotinib. Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Must correct hypokalemia or hypomagnesemia prior to nilotinib administration.

Monitor potassium and magnesium periodically. Avoid drugs known to prolong the QT interval and strong CYP3A4 inhibitors.

Take on empty stomach; avoid food 2 hours before and 1 hour after taking a nilotinib dose.

Reduced dose recommended in patients with hepatic impairment. Monitor QTc through electrocardiograms (ECGs) at baseline, 7 days after initiation, and periodically thereafter following any dose adjustments.

Contraindications

Pregnancy, planned pregnancy, lactation

Long QT syndrome, hypokalemia, hypomagnesemia

Cautions

Myelosuppression: associated with neutropenia, thrombocytopenia, and anemia; CBC should be done q2wk for first 2 months, then monthly; reversible by withholding dose; dose reduction may be required

Sudden deaths have been reported with resistant or intolerant Ph+ CML; ventricular repolarization abnormalities may have contributed to their occurrence; cardiovascular status should be evaluated and cardiovascular risk factors monitored and managed during nilotinib therapy

Prolongs QT interval; correct hypokalemia or hypomagnesemia before administration

Nilotinib can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia; correct hypokalemia or hypomagnesemia before administration; monitor periodically during therapy

Tumor lysis syndrome; maintain adequate hydration and correct uric acid levels prior to initiating therapy

Use caution in hepatic impairment; monitor hepatic function tests monthly or as clinically indicated

Use caution in history of pancreatitis; monitor serum lipase monthly or as clinically indicated; in case lipase elevations are accompanied by abdominal symptoms, interrupt doses and consider appropriate diagnostics to exclude pancreatitis

Total Gastrectomy: More frequent follow-up of these patients should be considered; if necessary, dose increase may be considered

Avoid concurrency with strong CYP3A4 inhibitors/inducers; if unavoidable, adjust dose

Avoid grapefruit juice

Inhibits P-Glycoprotein (ABCB1)

Women should be advised not to become pregnant while on therapy; may cause fetal harm

Cardiovascular events including ischemic heart disease, peripheral arterial occlusive disease and ischemic cerebrovascular events reported in patients with newly diagnosed Ph+ CML; cardiovascular status should be evaluated and cardiovascular risk factors monitored and managed during therapy

May result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Monitor hepatic function tests monthly or as clinically indicated

Hemorrhage from various sites reported in patients with newly diagnosed CML and observed in postmarketing reports of patients receiving therapy

Food increases blood levels of nilotinib; avoid food 2 hr before and 1 hour after a dose

Monitor lipid profiles and glucose periodically during the first year of therapy and at least yearly during chronic therapy

Should treatment with any HMG-CoA reductase inhibitor (a lipid lowering agent) be needed to treat lipid elevations, evaluate potential for a drug-drug interaction before initiating therapy

Monitor patients for signs of severe fluid retention (e.g., unexpected rapid weight gain or swelling) and for symptoms of respiratory or cardiac compromise (e.g., shortness of breath) during treatment; evaluate etiology and treat patients accordingly

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

Pregnancy 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.

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)

The blood concentration of nilotinib may be increased by several drugs that reduce its break down by the liver. Examples include amiodarone (Cordarone), disopyramide, procainamide, quinidine, and sotalol. Increased blood concentrations of nilotinib may increase the occurrence of adverse effects.

Certain drugs decrease the concentration of nilotinib resulting in decreased blood levels and possibly reduced effect. Examples include dexamethasone, carbamazepine, phenobarbital, rifampin, rifabutin, rifapentin, phenytoin, and St John's Wort.

Food increases the blood concentration of nilotinib. Therefore, nilotinib should be taken on an empty stomach, at least 2 hours after eating any food. Individuals should wait one hour after taking nilotinib before eating any food.

Capsules: 150 and 200 mg

Nilotinib should be stored nilotinib at room temperature between 15 C - 30 C (59 F - 86 F).

Avoid taking a stomach acid reducers (Axid, Pepcid, Tagamet, Zantac, and others) within 10 hours before or 2 hours after you take nilotinib.

Avoid taking an antacid (Di-Gel, Gaviscon, Maalox, Milk of Magnesia, Mylanta, Rolaids, and others) within 2 hours before or 2 hours after you take nilotinib.

Grapefruit and grapefruit juice may interact with nilotinib and lead to unwanted side effects. Avoid the use of grapefruit products while taking nilotinib.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Many drugs can interact with nilotinib, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with nilotinib. Not all possible interactions are listed in this medication guide.

If you take too much nilotinib, call your doctor or poison control center right away. Symptoms may include vomiting and drowsiness.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about nilotinib, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about nilotinib. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using nilotinib.

Review Date: October 4, 2017

• Tasigna

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

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, 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.

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).

Refer to adult dosing.

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).

Data not available