Nilotinib
Nilotinib 150mg/200mg Capsules

What is the most important information I should know about Nilotinib?

Nilotinib can cause a possible life-threatening heart problem called QTc prolongation. QTc prolongation causes an irregular heartbeat, which may lead to sudden death.

Your doctor should check the electrical activity of your heart with a test called an electrocardiogram (ECG):

• before starting Nilotinib
• 7 days after starting Nilotinib
• with any dose changes
• regularly during Nilotinib treatment

You may lower your chances for having QTc prolongation with Nilotinib if you:

• Take Nilotinib on an empty stomach:
  • Avoid eating food for at least 2 hours before the dose is taken, and
  • Avoid eating food for at least 1 hour after the dose is taken.
• Avoid grapefruit, grapefruit juice, and any supplement containing grapefruit extract while taking Nilotinib.  Food and grapefruit products increase the amount of Nilotinib in your body. 
• Avoid taking other medicines or supplements with Nilotinib that can also cause QTc prolongation.
• Nilotinib can interact with many medicines and supplements and increase your chance for serious and life-threatening side effects.
• Do not take any other medicine while taking Nilotinib unless your doctor tells you it is okay to do so.
• If you cannot swallow Nilotinib capsules whole, you may open the Nilotinib capsule and sprinkle the contents of each capsule in 1 teaspoon of applesauce (puréed apple). Swallow the mixture right away (within 15 minutes). For more information, see “How should I take Nilotinib?”

Call your doctor right away if you feel lightheaded, faint, or have an irregular heartbeat while taking Nilotinib. These can be symptoms of QTc prolongation.

What is Nilotinib?

Nilotinib is a prescription medicine used to treat a type of leukemia called Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in adults who:

• are newly diagnosed, or
• are no longer benefiting from previous other treatments, including treatment with imatinib (Gleevec®), or
• have taken other treatments, including imatinib (Gleevec), and cannot tolerate them

It is not known if Nilotinib is safe and effective in children.

Who should not take Nilotinib?

Do not take if you have:

• low levels of potassium or magnesium in your blood
• long QTc syndrome

What should I tell my doctor before starting Nilotinib?

Before taking Nilotinib, tell your doctor about all of your medical conditions, including if you have:

• heart problems
• had a stroke or other problems due to decreased blood flow to the brain
• problems with decreased blood flow to your legs
• irregular heartbeat
• QTc prolongation or a family history of it
• liver problems
• had pancreatitis
• low blood levels of potassium or magnesium in your blood
• a severe problem with lactose (milk sugar) or other sugars. Nilotinib capsules contain lactose. Most patients who have mild or moderate lactose intolerance can take Nilotinib.
• had a surgical procedure involving the removal of the entire stomach (total gastrectomy)
• are pregnant or plan to become pregnant. Nilotinib may harm your unborn baby. If you are able to become pregnant, you should use effective birth control during treatment with Nilotinib. Talk to your doctor about the best birth control methods to prevent pregnancy while you are taking Nilotinib.
• are breastfeeding or plan to breastfeed. It is not known if Nilotinib passes into your breast milk. You and your doctor should decide if you will take Nilotinib or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements.

If you need to take antacids (medicines to treat heartburn) do not take them at the same time that you take Nilotinib. If you take:

• a medicine to block the amount of acid produced in the stomach (H2 blocker): Take these medicines about 10 hours before you take Nilotinib, or about 2 hours after you take Nilotinib.
• >an antacid that contains aluminum hydroxide, magnesium hydroxide, and simethicone to reduce the amount of acid in the stomach: Take these medicines about 2 hours before or about 2 hours after you take Nilotinib.

Nilotinib can interact with many medicines and supplements and increase your chance for serious and life-threatening side effects. See “What is the most important information I should know about Nilotinib?”

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take Nilotinib?

• Take Nilotinib exactly as your doctor tells you to take it. Do not change your dose or stop taking Nilotinib unless your doctor tells you.
• Nilotinib is a long-term treatment.
• Your doctor will tell you how many Nilotinib capsules to take and when to take them.
• Nilotinib must be taken on an empty stomach.
  • Avoid eating food for at least 2 hours before the dose is taken, and
  • Avoid eating food for at least 1 hour after the dose is taken.
• Swallow Nilotinib capsules whole with water. If you cannot swallow Nilotinib capsules whole, tell your doctor.
• If you cannot swallow Nilotinib capsules whole:
  • Open the Nilotinib capsules and sprinkle the contents in 1 teaspoon of applesauce (puréed apple).
    • Do not use more than 1 teaspoon of applesauce.
    • Only use applesauce. Do not sprinkle Nilotinib onto other foods.
  • Swallow the mixture right away (within 15 minutes).
• Do not drink grapefruit juice, eat grapefruit, or take supplements containing grapefruit extract at any time during treatment. See “What is the most important information I should know about Nilotinib?”
• If you miss a dose, just take your next dose at your regular time. Do not take 2 doses at the same time to make up for a missed dose.
• If you take too much Nilotinib, call your doctor or poison control center right away. Symptoms may include vomiting and drowsiness. During treatment with Nilotinib your doctor will do tests to check for side effects and to see how well Nilotinib is working for you. The tests will check your:
  • heart
  • blood cells (white blood cells, red blood cells, and platelets). Your blood cells should be checked every 2 weeks for the first 2 months and then monthly.
  • electrolytes (potassium, magnesium)
  • pancreas and liver function
  • bone marrow samples
• Your doctor may change your dose. Your doctor may have you stop Nilotinib for some time or lower your dose if you have side effects with it.

What are the possible side effects of Nilotinib?

Nilotinib may cause serious side effects including:

• See “What is the most important information I should know about Nilotinib?”
• Decreased blood flow to the leg, heart, or brain. People who have recently been diagnosed with Ph+ CML and take Nilotinib may develop decreased blood flow to the leg, the heart, or brain.
  Get medical help right away if you suddenly develop any of the following symptoms:
  • chest pain or discomfort
  • numbness or weakness
  • problems walking or speaking
  • leg pain
  • your leg feels cold
  • change in the skin color of your leg
• Low blood counts. Low blood counts are common with Nilotinib. Your doctor will check your blood counts regularly during treatment with Nilotinib. Symptoms of low blood counts include:
  • unexplained bleeding or bruising
  • blood in urine or stool
  • unexplained weakness
• Liver problems  Symptoms include yellow skin and eyes.
  
• Pancreas inflammation (pancreatitis).  Symptoms include sudden stomach area pain with nausea and vomiting.
  
• Bleeding in the brain. Symptoms include sudden headache, changes in your eyesight, not being aware of what is going on around you and becoming unconscious.
  
• Tumor Lysis Syndrome (TLS). TLS is caused by a fast breakdown of cancer cells. TLS can cause you to have:
  • kidney failure and the need for dialysis treatment
  • an abnormal heart beat

Your doctor may do blood tests to check you for TLS.

The most common side effects of Nilotinib include:

Tell your doctor if you have any side effect that bothers you or does not go away.

These are not all of the possible side effects of Nilotinib. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA.

How should I store Nilotinib?

• Store Nilotinib at room temperature between 68°F to 77°F (20°C to 25°C).
• Safely throw away medicine that is out of date or no longer needed.

Keep Nilotinib and all medicines out of the reach of children.

General information about Nilotinib

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Nilotinib for a condition for which it was not prescribed. Do not give Nilotinib to other people, even if they have the same problem you have. It may harm them.

This Medication Guide summarizes the most important information about Nilotinib. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Nilotinib that is written for health professionals.

What are the ingredients in Nilotinib?

Active ingredient: Nilotinib
Inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and poloxamer 188.

The capsule shell contains gelatin, iron oxide (red), iron oxide (yellow), iron oxide (black), and titanium dioxide.

Nilotinib
Nilotinib 150mg/200mg Capsules

INDICATIONS AND USAGE

Nilotinib(nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Nilotinibis based on major molecular response and cytogenetic response rates. The study is ongoing and further data will be required to determine long-term outcome.

Nilotinib is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Nilotinibis based on hematologic and cytogenetic response rates. 

DOSAGE AND ADMINISTRATION

Nilotinibshould be taken twice daily at approximately 12-hour intervals and must be taken on an empty stomach. No food should be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is taken. Advise patients to swallow the capsules whole with water.

For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in 1 teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use.

Nilotinib may be given in combination with hematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Nilotinibmay be given with hydroxyurea or anagrelide if clinically indicated.

Newly Diagnosed Ph+ CML-CP
The recommended dose of Nilotinibis 300 mg orally twice daily.

Resistant or Intolerant Ph+ CML-CP and CML-AP
The recommended dose of Nilotinib(nilotinib) is 400 mg orally twice daily.

QT Interval Prolongation:

Myelosuppression

Withhold or dose reduce Nilotinibfor hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 2)

See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases.

Other Non-hematologic Toxicities
If other clinically significant moderate or severe non-hematologic toxicity develops, withhold dosing, and resume at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose back to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CML-AP) twice daily should be considered. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test serum lipase levels monthly or as clinically indicated. For Grade 3 to 4 bilirubin or hepatic transaminase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test bilirubin and hepatic transaminases levels monthly or as clinically indicated.

Hepatic Impairment
If possible, consider alternative therapies. If Nilotinibmust be administered to patients with hepatic impairment, consider the following dose reduction:

Concomitant Strong CYP3A4 Inhibitors
Avoid the concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Avoid grapefruit products since they may also increase serum concentrations of nilotinib. Should treatment with any of these agents be required, therapy with Nilotinibshould be interrupted. If patients must be coadministered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, consider a dose reduction to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period should be allowed before the Nilotinibdose is adjusted upward to the indicated dose. For patients who cannot avoid use of strong CYP3A4 inhibitors, monitor closely for prolongation of the QT interval.

Concomitant Strong CYP3A4 Inducers
Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). Also inform patients not to take St. John’s Wort since these agents may reduce the concentration of Nilotinib. Based on the nonlinear pharmacokinetic profile of nilotinib, increasing the dose of Nilotinibwhen coadministered with such agents is unlikely to compensate for the loss of exposure

DOSAGE FORMS AND STRENGTHS

150 mg red opaque hard gelatin capsules with black axial imprint “NVR/BCR”.
200 mg light yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI”.

CONTRAINDICATIONS

Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.

WARNINGS AND PRECAUTIONS

Treatment with Nilotinib can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every 2 weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Nilotinibtemporarily or dose reduction.

Nilotinibhas been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner [see Adverse Reactions, Clinical Pharmacology]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, 7 days after initiation of Nilotinib, and periodically as clinically indicated and following dose adjustments [see Warnings and Precautions].

Nilotinibshould not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Before initiating Nilotiniband periodically, test electrolyte, calcium and magnesium blood levels. Hypokalemia or hypomagnesemia must be corrected prior to initiating Nilotiniband these electrolytes should be monitored periodically during therapy [see Warnings and Precautions].

Significant prolongation of the QT interval may occur when Nilotinibis inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, coadministration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further prolong the QT interval.

Sudden deaths have been reported in 0.3% of patients with CML treated with nilotinib in clinical studies of 5,661 patients. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.

Cardiovascular events, including arterial vascular occlusive events, were reported in a randomized, clinical trial in newly diagnosed CML patients and observed in the post-marketing reports of patients receiving nilotinib therapy. With a median time on therapy of 48 months in the clinical trial, cases of cardiovascular events included ischemic heart disease-related events (5.0% and 5.8% in the nilotinib 300 mg and 400 mg bid arms respectively, and 1.8% in the imatinib arm), peripheral arterial occlusive disease (1.8% and 2.2% in the nilotinib 300 mg and 400 mg bid arms respectively, and 0% in the imatinib arm), and ischemic cerebrovascular events (1.1% and 1.8% in the nilotinib 300 mg and 400 mg bid arms respectively, and 0.7% in the imatinib arm). If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and actively managed during Nilotinibtherapy according to standard guidelines.

Nilotinibcan cause increases in serum lipase. Patients with a previous history of pancreatitis may be at greater risk of elevated serum lipase. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated.

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

The use of Nilotinibcan cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Nilotiniband these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.14)].

Avoid administration of Nilotinibwith agents that may increase nilotinib exposure (e.g., strong CYP3A4 inhibitors) or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide). Should treatment with any of these agents be required, interrupt therapy with Nilotinib. If interruption of treatment with Nilotinibis not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval.

The bioavailability of nilotinib is increased with food, thus Nilotinibmust not be taken with food. No food should be consumed for at least 2 hours before and for at least 1 hour after the dose is taken. Also avoid grapefruit products and other foods that are known to inhibit CYP3A4

Nilotinib exposure is increased in patients with impaired hepatic function. Use a lower starting dose for patients with mild to severe hepatic impairment (at baseline) and monitor the QT interval frequently.

Tumor lysis syndrome cases have been reported in Nilotinibtreated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with Nilotinib.

Since the exposure of nilotinib is reduced in patients with total gastrectomy, perform more frequent monitoring of these patients. Consider dose increase or alternative therapy in patients with total gastrectomy.

Since the capsules contain lactose, Nilotinibis not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption.

Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. Chemistry panels, including electrolytes, calcium, magnesium, lipid profile, and glucose should be checked prior to therapy and periodically. ECGs should be obtained at baseline, 7 days after initiation and periodically thereafter, as well as following dose adjustments [see Warnings and Precautions]. Laboratory monitoring for patients receiving Nilotinibmay need to be performed more or less frequently at the physician’s discretion.

There are no adequate and well controlled studies of Nilotinibin pregnant women. However, Nilotinibmay cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should avoid becoming pregnant while taking Nilotinib[see Use in Specific Populations (8.1)].

ADVERSE REACTIONS

The following serious adverse reactions can occur with Nilotiniband are discussed in greater detail in other sections of the package insert [see Boxed Warning, Warnings and Precautions].

• Myelosuppression [see Warnings and Precautions]
• QT Prolongation [see Boxed Warning, Warnings and Precautions]
• Sudden Deaths [see Boxed Warning, Warnings and Precautions]
• Pancreatitis and Elevated Serum Lipase [see Warnings and Precautions]
• Hepatotoxicity [see Warnings and Precautions]
• Electrolyte Abnormalities [see Boxed Warning, Warnings and Precautions]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In Patients with Newly Diagnosed Ph+ CML-CP
The data below reflect exposure to Nilotinibfrom a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 48 months (range 0.1 to 59 months). The median actual dose intensity was 594 mg/day in the nilotinib 300 mg twice daily group.

The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue, alopecia and myalgia. Upper abdominal pain, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (=10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions, occurred in 1% and <1% of patients, respectively. Gastrointestinal hemorrhage was reported in 3% of patients.

Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec while on study drug.

The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (18%), neutropenia (15%) and anemia (7%). See Table 7 for Grade 3/4 laboratory abnormalities.

Discontinuation due to adverse reactions, regardless of relationship to study drug, was observed in 10% of patients.

In Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP
In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily.

The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1 to 1096) and 264 (range 2 to 1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151 to 1110) and 780 mg/day (range 150 to 1149), respectively and corresponded to the planned 400 mg twice daily dosing.

The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1 to 345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1 to 234).

In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (=10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (=1% and <10%) were thrombocytopenia, neutropenia and anemia.

In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (=10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (=1% and <10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.

Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF >60 msec from baseline was observed in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.6)].

Discontinuation due to adverse drug reactions was observed in 16% of CML-CP and 10% of CML-AP patients.

Most Frequently Reported Adverse Reactions
Tables 5 and 6 show the percentage of patients experiencing non-hematologic adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least 1 dose of Nilotinibare listed.

Laboratory Abnormalities
Table 7 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Nilotinib.

The following adverse drug reactions were reported in patients in the Nilotinibclinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (=1% and <10%), uncommon (=0.1% and <1%), and unknown frequency (single events). For laboratory abnormalities, very common events (=10%), which were not included in Tables 5 and 6, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category, obtained from 2 clinical studies:

• Newly diagnosed Ph+CML-CP 48 month analysis and,
• Resistant or intolerant Ph+CML-CP and CMP-AP 24 months’ analysis.

Infections and Infestations:
 Common: folliculitis, upper respiratory tract infection (including pharyngitis, nasopharyngitis, rhinitis). Uncommon: pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis), gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis.

Neoplasms Benign, Malignant, and Unspecified:
Common: skin papilloma. Unknown frequency: oral papilloma, paraproteinemia.

Blood and Lymphatic System Disorders:
Common: eosinophilia, febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythemia, leukocytosis.

Immune System Disorders:
Unknown frequency: hypersensitivity.

Endocrine Disorders:
Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis.

Metabolism and Nutrition Disorders:
Very Common: hypophosphatemia. Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia. Uncommon: gout, dehydration, increased appetite. Unknown frequency: hyperuricemia, hypoglycemia.

Psychiatric Disorders:
Common: depression, insomnia, anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria.

Nervous System Disorders:
Common: dizziness, peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: transient ischemic attack, brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome.

Eye Disorders:
Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye (including xerophthalmia). Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation, conjunctival hemorrhage. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctivitis allergic, ocular surface disease.

Ear and Labyrinth Disorders:
Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus.

Cardiac Disorders:
Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease. 

Vascular Disorders:
Common: hypertension, flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, intermittent claudication, arterial stenosis limb, hematoma, arteriosclerosis. Unknown frequency: shock hemorrhagic, hypotension, thrombosis.

Respiratory, Thoracic and Mediastinal Disorders:
Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing, oropharyngeal pain.

Gastrointestinal Disorders:
Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth, gastritis, sensitivity of teeth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis.

Hepatobiliary Disorders:
Very Common: hyperbilirubinemia. Common: hepatic function abnormal. Uncommon: hepatotoxicity, toxic hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly.

Skin and Subcutaneous Tissue Disorders:
Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform), dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: psoriasis, erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis.

Musculoskeletal and Connective Tissue Disorders:
Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis.

Renal and Urinary Disorders:
 Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia.

Reproductive System and Breast Disorders:
Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling.

General Disorders and Administration Site Conditions:
Common: pyrexia, chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise. Uncommon: face edema, gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema.

Investigations:
Very Common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased. Common: hemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased, lipoprotein increased (including very low density and high density). Uncommon: blood lactate dehydrogenase increased, blood urea increased, globulins decreased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, insulin C-peptide decreased, blood parathyroid hormone increased.

7 DRUG INTERACTIONS

Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6 and UGT1A1 In vitro, potentially increasing the concentrations of drugs eliminated by these enzymes. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8 and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes.

Single-dose administration of Nilotinibwith midazolam (a CYP3A4 substrate) to healthy subjects increased midazolam exposure by 30%. Single-dose administration of Nilotinibto healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of Nilotinibto induce metabolism has not been determined in vivo. Exercise caution when coadministering Nilotinibwith substrates for these enzymes that have a narrow therapeutic index.

Nilotinib inhibits human P-glycoprotein (P-gp). If Nilotinibis administered with drugs that are substrates of P-gp, increased concentrations of the substrate drug are likely, and caution should be exercised.

Nilotinib undergoes metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 can increase or decrease nilotinib concentrations significantly. The administration of Nilotinibwith agents that are strong CYP3A4 inhibitors should be avoided [see Boxed Warning, Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.8)]. Concomitant use of Nilotinibwith medicinal products and herbal preparations that are potent inducers of CYP3A4 is likely to reduce exposure to nilotinib to a clinically relevant extent. Therefore, in patients receiving Nilotinib, concomitant use of alternative therapeutic agents with less potential for CYP3A4 induction should be selected.

Ketoconazole:
In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 400 mg once daily for 6 days, systemic exposure (AUC) to nilotinib was increased approximately 3-fold.

Rifampicin:
In healthy subjects receiving the CYP3A4 inducer, rifampicin, at 600 mg daily for 12 days, systemic exposure (AUC) to nilotinib was decreased approximately 80%.

Nilotinib has pH-dependent solubility, with decreased solubility at higher pH. Drugs such as proton pump inhibitors that inhibit gastric acid secretion to elevate the gastric pH may decrease the solubility of nilotinib and reduce its bioavailability. In healthy subjects, coadministration of a single 400 mg dose of Nilotinibwith multiple doses of esomeprazole (a proton pump inhibitor) at 40 mg daily decreased the nilotinib AUC by 34%. Increasing the dose of Nilotinibwhen coadministered with such agents is not likely to compensate for the loss of exposure. Since proton pump inhibitors affect pH of the upper GI tract for an extended period, separation of doses may not eliminate the interaction. The concomitant use of proton pump inhibitors with Nilotinibis not recommended.

In healthy subjects, no significant change in nilotinib pharmacokinetics was observed when a single 400 mg dose of Nilotinibwas administered 10 hours after and 2 hours before famotidine (an H2 blocker). Therefore, when the concurrent use of a H2 blocker is necessary, it may be administered approximately 10 hours before and approximately 2 hours after the dose of Nilotinib.

Administration of an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) to healthy subjects, 2 hours before or 2 hours after a single 400 mg dose of Nilotinibdid not alter nilotinib pharmacokinetics. Therefore, if necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the dose of Nilotinib.

Nilotinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Nilotinibis administered with drugs that inhibit P-gp, increased concentrations of nilotinib are likely, and caution should be exercised.

The administration of Nilotinibwith agents that may prolong the QT interval such as anti-arrhythmic medicines should be avoided [see Boxed Warning, Dosage and Administration, Warnings and Precautions.

USE IN SPECIFIC POPULATIONS

Pregnancy Category D [see Warnings and Precautions].

Risk Summary
Based on its mechanism of action and findings in animals, Nilotinibmay cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while on Nilotinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Animal Data
Nilotinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 10, 30, 100 mg/kg/day, and 30, 100, 300 mg/kg/day, respectively, during organogenesis. In rats, nilotinib at doses of 100 mg/kg/day (approximately 5.7 times the AUC in patients at the dose of 400 mg twice daily) was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption). Nilotinib at doses =30 mg/kg/day (approximately 2 times the AUC in patients at the dose of 400 mg twice daily) resulted in embryo-fetal toxicity as shown by increased resorption and post-implantation loss, and at 100 mg/kg/day, a decrease in viable fetuses. In rabbits, maternal toxicity at 300 mg/kg/day (approximately one-half the human exposure based on AUC) was associated with mortality, abortion, decreased gestation weights and decreased food consumption. Embryonic toxicity (increased resorption) and minor skeletal anomalies were observed at a dose of 300 mg/kg/day. Nilotinib is not considered teratogenic.

When pregnant rats were dosed with nilotinib during organogenesis and through lactation, the adverse effects included a longer gestational period, lower pup body weights until weaning and decreased fertility indices in the pups when they reached maturity, all at a maternal dose of 360 mg/m2 (approximately 0.7 times the clinical dose of 400 mg twice daily based on body surface area). At doses up to 120 mg/m2 (approximately 0.25 times the clinical dose of 400 mg twice daily based on body surface area) no adverse effects were seen in the maternal animals or the pups.

It is not known whether nilotinib is excreted in human milk. One study in lactating rats demonstrates that nilotinib is excreted into milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nilotinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of Nilotinibin pediatric patients have not been established.

In the clinical trials of Nilotinib(patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP), approximately 12% and 30% of patients were 65 years or over respectively.

• Patients with newly diagnosed Ph+ CML-CP: There was no difference in major molecular response between patients aged <65 years and those =65 years.
• Patients with resistant or intolerant CML-CP: There was no difference in major cytogenetic response rate between patients aged <65 years and those =65 years.
• Patients with resistant or intolerant CML-AP: The hematologic response rate was 44% in patients <65 years of age and 29% in patients =65 years.

No major differences for safety were observed in patients =65 years of age as compared to patients <65 years.

In the clinical trials, patients with a history of uncontrolled or significant cardiovascular disease, including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia, were excluded. Caution should be exercised in patients with relevant cardiac disorders [see Boxed Warning, Warnings and Precautions].

Nilotinib exposure is increased in patients with impaired hepatic function. In a study of subjects with mild to severe hepatic impairment following a single dose administration of 200 mg of Nilotinib, the mean AUC values were increased on average of 35%, 35%, and 56% in subjects with mild (Child-Pugh class A, score 5 to 6), moderate (Child-Pugh class B, score 7 to 9) and severe hepatic impairment (Child-Pugh class C, score 10 to 15), respectively, compared to a control group of subjects with normal hepatic function. Table 8 summarizes the Child-Pugh Liver Function Classification applied in this study. A lower starting dose is recommended in patients with hepatic impairment and the QT interval should be monitored closely in these patients [see Dosage and Administration, Warnings and Precautions].

Clinical studies have not been performed in patients with impaired renal function. Clinical studies have excluded patients with serum creatinine concentration >1.5 times the upper limit of the normal range.

Since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not anticipated in patients with renal impairment.

OVERDOSAGE

Overdose with nilotinib has been reported, where an unspecified number of Nilotinibcapsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

DESCRIPTION

Nilotinib belongs to a pharmacologic class of drugs known as kinase inhibitors.

Nilotinib drug substance, a monohydrate monohydrochloride, is a white to slightly yellowish to slightly greenish yellow powder with the anhydrous molecular formula and weight, respectively, of C28H22F3N7O•HCl • H2O and 584. The solubility of nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is not optically active. The pKa1 was determined to be 2.1; pKa2 was estimated to be 5.4.

The chemical name of nilotinib is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrate. Its structure is shown below:

Nilotinib(nilotinib) capsules, for oral use, contain 150 mg or 200 mg nilotinib base, anhydrous (as hydrochloride, monohydrate) with the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and poloxamer 188. The capsules contain gelatin, iron oxide (red), iron oxide (yellow), iron oxide (black), and titanium dioxide.

CLINICAL PHARMACOLOGY

Nilotinib is an inhibitor of the BCR-ABL kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of ABL protein. In vitro, nilotinib inhibited BCR-ABL mediated proliferation of murine leukemic cell lines and human cell lines derived from patients with Ph+ CML. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from BCR-ABL kinase mutations, in 32 out of 33 mutations tested. in vivo, nilotinib reduced the tumor size in a murine BCR-ABL xenograft model. Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: BCR-ABL (20 to 60 nM), PDGFR (69 nM), c-KIT (210 nM), CSF-1R (125 to 250 nM), and DDR1 (3.7 nM).

Absorption and Distribution
The absolute bioavailability of nilotinib has not been determined. As compared to an oral drink solution (pH of 1.2 to 1.3), relative bioavailability of nilotinib capsule is approximately 50%. Peak concentrations of nilotinib are reached 3 hours after oral administration.

Steady-state nilotinib exposure was dose-dependent with less than dose-proportional increases in systemic exposure at dose levels higher than 400 mg given as once daily dosing. Daily serum exposure to nilotinib following 400 mg twice daily dosing at steady state was 35% higher than with 800 mg once daily dosing. Steady state exposure (AUC) of nilotinib with 400 mg twice daily dosing was 13% higher than with 300 mg twice daily dosing. The average steady state nilotinib trough and peak concentrations did not change over 12 months. There was no relevant increase in exposure to nilotinib when the dose was increased from 400 mg twice daily to 600 mg twice daily.

The bioavailability of nilotinib was increased when given with a meal. Compared to the fasted state, the systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high fat meal.

Single dose administration of two 200 mg nilotinib capsules each dispersed in 1 teaspoon of applesauce and administered within 15 minutes was shown to be bioequivalent to a single dose administration of two 200 mg intact capsules. The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98% on the basis of In vitro experiments.

Median steady-state trough concentration of nilotinib was decreased by 53% in patients with total gastrectomy compared to patients who had not undergone surgeries [see Warnings and Precautions].

Pharmacokinetics, Metabolism and Excretion
The apparent elimination half-life estimated from the multiple dose pharmacokinetic studies with daily dosing was approximately 17 hours. Inter-patient variability in nilotinib AUC was 32% to 64%. Steady state conditions were achieved by Day 8. An increase in serum exposure to nilotinib between the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold for twice-daily dosing.

Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is the main circulating component in the serum. None of the metabolites contribute significantly to the pharmacological activity of nilotinib.

After a single dose of radiolabeled nilotinib in healthy subjects, more than 90% of the administered dose was eliminated within 7 days: mainly in feces (93% of the dose). Parent drug accounted for 69% of the dose.

Age, body weight, gender, or ethnic origin did not significantly affect the pharmacokinetics of nilotinib.

Drug-Drug Interactions
In a Phase 1 trial of nilotinib 400 mg twice daily in combination with imatinib 400 mg daily or 400 mg twice daily, the AUC increased 30% to 50% for nilotinib and approximately 20% for imatinib.

Nilotinibcan increase bilirubin levels. A pharmacogenetic analysis of 97 patients evaluated the polymorphisms of UGT1A1 and its potential association with hyperbilirubinemia during Nilotinibtreatment. In this study, 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 [see Warnings and Precautions (5.6)].

In a placebo-controlled study in healthy volunteers designed to assess the effects of Nilotinibon the QT interval, administration of Nilotinibwas associated with concentration-dependent QT prolongation; the maximum mean placebo-adjusted QTcF change from baseline was 18 msec (1-sided 95% Upper CI: 26 msec). A positive control was not included in the QT study of healthy volunteers. Peak plasma concentrations in the QT study were 26% lower than those observed in patients enrolled in the single-arm study [see Boxed Warning, Warnings and Precautions (5.2), and Adverse Reactions].

NONCLINICAL TOXICOLOGY

A 2-year carcinogenicity study was conducted orally in rats at nilotinib doses of 5, 15, and 40 mg/kg/day.  Exposures in animals at the highest dose tested were approximately 2 to 3 fold the human exposure (based on AUC) at the nilotinib dose of 400 mg twice daily. The study was negative for carcinogenic findings.  

Nilotinib was not mutagenic in a bacterial mutagenesis (Ames) assay, was not clastogenic in a chromosome aberration assay in human lymphocytes, did not induce DNA damage (comet assay) in L5178Y mouse lymphoma cells, nor was it clastogenic in an in vivo rat bone marrow micronucleus assay with two oral treatments at doses up to 2000 mg/kg/dose.

There were no effects on male or female rat and female rabbit mating or fertility at doses up to 180 mg/kg in rats (approximately 4 to 7 fold for males and females, respectively, the AUC in patients at the dose of 400 mg twice daily) or 300 mg/kg in rabbits (approximately one-half the AUC in patients at the dose of 400 mg twice daily). The effect of Nilotinibon human fertility is unknown. In a study where male and female rats were treated with nilotinib at oral doses of 20 to 180 mg/kg/day (approximately 1 to 6.6 fold the AUC in patients at the dose of 400 mg twice daily) during the pre-mating and mating periods and then mated, and dosing of pregnant rats continued through gestation Day 6, nilotinib increased post-implantation loss and early resorption, and decreased the number of viable fetuses and litter size at all doses tested.

CLINICAL STUDIES

An open-label, multicenter, randomized trial was conducted to determine the efficacy of Nilotinibversus imatinib tablets in adult patients with cytogenetically confirmed newly diagnosed Ph+ CML-CP. Patients were within 6 months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide. Efficacy was based on a total of 846 patients: 283 patients in the imatinib 400 mg once daily group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice daily group.

Median age was 46 years in the imatinib group and 47 years in both nilotinib groups, with 12%, 13%, and 10% of patients =65 years of age in imatinib 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively. There were slightly more male than female patients in all groups (56%, 56%, and 62% in imatinib 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively). More than 60% of all patients were Caucasian, and 25% were Asian.

The primary data analysis was performed when all 846 patients completed 12 months of treatment (or discontinued earlier). Subsequent analyses were done when patients completed 24, 36, and 48 months of treatment (or discontinued earlier). The median time on treatment was approximately 48 months in all three treatment groups. This study is on-going and further data will be required to determine long-term outcome.

The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication. MMR was defined as =0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a =3 log reduction of BCR-ABL transcript from standardized baseline. Efficacy endpoints are summarized in Table 9 below.

Three patients in the nilotinib arm progressed to either accelerated phase (including clonal evolution) or blast crisis (2 within the first 6 months of treatment and 1 within 36 to 48 months while 17 patients on the imatinib arm progressed to either accelerated phase (including clonal evolution) or blast crisis (8 patients within first 6 months, 4 within 6 to 12 months, 4 within 12 to 18 months and 1 within 18 to 24 months).

A single-arm, open-label, multicenter study was conducted to evaluate the efficacy and safety of Nilotinib(400 mg twice daily) in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic and accelerated phase disease. The definition of imatinib resistance included failure to achieve a complete hematologic response (by 3 months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of disease after a previous cytogenetic or hematologic response. Imatinib intolerance was defined as discontinuation of treatment due to toxicity and lack of a major cytogenetic response at time of study entry. At the time of data cut-off, 321 patients with CML-CP and 137 patients with CML-AP with a minimum follow-up of 24 months were enrolled. In this study, about 50% of CML-CP and CML-AP patients were males, over 90% (CML-CP) and 80% (CML-AP) were Caucasian, and approximately 30% were age 65 years or older.

Overall, 73% of patients were imatinib resistant while 27% were imatinib intolerant. The median time of prior imatinib treatment was approximately 32 (CML-CP) and 28 (CML-AP) months. Prior therapy included hydroxyurea in 85% of patients, interferon in 56% and stem cell or bone marrow transplant in 8%. The median highest prior imatinib dose was 600 mg/day for patients with CML-CP and CML-AP, and the highest prior imatinib dose was =600 mg/day in 74% of all patients with 40% of patients receiving imatinib doses =800 mg/day.

Median duration of nilotinib treatment was 18.4 months in patients with CML-CP and 8.7 months in patients with CML-AP.

The efficacy endpoint in CML-CP was unconfirmed major cytogenetic response (MCyR) which included complete and partial cytogenetic responses.

The efficacy endpoint in CML-AP was confirmed hematologic response (HR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL). The rates of response for CML-CP and CML-AP patients are reported in Table 10. 

Median durations of response had not been reached at the time of data analysis.

Patients with Chronic Phase
The MCyR rate in 321 CML-CP patients was 51%. The median time to MCyR among responders was 2.8 months (range 1 to 28 months). The median duration of MCyR cannot be estimated. The median duration of exposure on this single arm-trial was 18.4 months. Among the CML-CP patients who achieved MCyR, 62% of them had MCyR lasting more than 18 months. The CCyR rate was 37%. 

Patients with Accelerated Phase
The overall confirmed hematologic response rate in 137 patients with CML-AP was 39%. The median time to first hematologic response among responders was 1 month (range 1 to 14 months). Among the CML-AP patients who achieved HR, 44% of them had a response lasting for more than 18 months.

After imatinib failure, 24 different BCR-ABL mutations were noted in 42% of chronic phase and 54% of accelerated phase CML patients who were evaluated for mutations.

HOW SUPPLIED/STORAGE AND HANDLING

Nilotinib 150 mg capsules are red opaque hard gelatin capsules, size 1 with black axial imprint “TAJ”. Nilotinib(nilotinib) 200 mg capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint “TAJ” Nilotinibcapsules are supplied in blister packs.

150 mg
Carton of 4 blister packs of (4x28)
Blisters of 28 capsules

200 mg
Carton of 4 blister packs of (4x28)
Blisters of 28 capsules

Nilotinib(nilotinib) capsules should be stored at 25°C (77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Medication Guide).

A Medication Guide is required for distribution with Nilotinib. Encourage patients to read the NilotinibMedication Guide. The complete text of the Medication Guide is reprinted at the end of this document.

Cardiac and Vascular Events
Advise patients that cardiovascular events (including ischemic heart disease, peripheral arterial occlusive disease, and ischemic cerebrovascular events) have been reported. Advise patients to seek immediate medical attention with any symptoms suggestive of a cardiovascular event. Cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and managed during Nilotinibtherapy according to standard guidelines [see Warnings and Precautions].

Taking Nilotinib
Advise patients to take Nilotinibdoses twice daily approximately 12 hours apart. The capsules should be swallowed whole with water.

Advise patients to take Nilotinibon an empty stomach. No food should be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is taken. Patients should not consume grapefruit products and other foods that are known to inhibit CYP3A4 at any time during Nilotinibtreatment [see Dosage and Administration, Warnings and Precautions].

If the patient missed a dose of Nilotinib, the patient should take the next scheduled dose at its regular time. The patient should not take two doses at the same time.

Should patients be unable to swallow capsules, the contents of each capsule may be dispersed in one teaspoon of applesauce and the mixture swallowed immediately (within 15 minutes).

Drug Interactions
Nilotiniband certain other medicines, including over the counter medications or herbal supplements (such as St. John’s Wort), can interact with each other [see Warnings and Precautions and Drug Interactions]. 

Pregnancy
Advise patients that the use of Nilotinibduring pregnancy may cause harm to the fetus and that Nilotinibshould not be taken during pregnancy unless necessary. Women of childbearing potential should use highly effective contraceptives while taking Nilotinib. Sexually active female patients taking Nilotinibshould use adequate contraception [see Warnings and Precautions and Use in Specific Populations].

Compliance
Advise patients of the following:

• Continue taking Nilotinibevery day for as long as their doctor tells them.
• This is a long-term treatment.
• Do not change dose or stop taking Nilotinibwithout first consulting their doctor.
• If a dose is missed, take the next dose as scheduled. Do not take a double dose to make up for the missed capsules.