nilotinib 150 mg Capsule, 112-count — NDC 13668-710-57 (Billing 13668-0710-57)
This is a package of 112 capsules of nilotinib 150 mg Capsule from Torrent Pharmaceuticals Limited, marketed since Dec 2025 and currently FDA-listed. It is the main listing for this product, which comes in 2 package sizes.
NDC database record
One package, one record: these facts belong to NDC 13668-710-57 alone.
- Record
- FDA NDC Directory package listing · Human prescription drug
- Code segments
- 13668 labeler · 710 product · 57 package
- Package marketed since
- Dec 16, 2025
- Sample package
- No — commercial package
- Listing certified through
- Dec 31, 2027
- Billing quantity
- 112 EA per package
- Barcode (UPC-A, from the NDC)
- 3 1366871057 1
- FDA record last changed
- Oct 1, 2026
Other active recalls for Nilotinib (different manufacturers) — 2 · tap to view
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification
- GSN (GCN sequence number): 066453
- GCN: 28737
- HICL (First Databank): 035149
- AHFS class code: 10:00.00.00
- RxCUI (RxNorm): 746606
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 3, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 1, 2026
RxNorm drug class
This medicine belongs to the Kinase Inhibitor class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
Nilotinib is used to treat certain types of chronic myeloid leukemia (CML; a type of cancer of the white blood cells). Nilotinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein in cancer cells. This helps to stop or slow the spread of cancer cells.
Read the full MedlinePlus article ↗- It treats Ph+ CML, a type of chronic myeloid leukemia. It is used in newly diagnosed patients and in those whose earlier treatment, such as imatinib, stopped working or caused prob...
- Take it by mouth twice a day, about 12 hours apart. Tasigna and nilotinib capsules must be taken with no food 2 hours before and 1 hour after. Danziten and Cavhanza can be taken wi...
- Not on your own. Danziten and Cavhanza do not convert milligram for milligram with other nilotinib products, and a mix-up could mean too much or too little drug. Always check with...
- Rash, itching, headache, nausea, tiredness, and constipation or diarrhea are common. Regular blood tests will track your blood counts and liver and other labs. Call right away for...
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with nilotinib — tap one for details:
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 3, 2026
Ask a licensed pharmacist directly — free, answered by our team.
Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per each | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · Q2 2026 | $116.98 | $13,102.31 / 112 capsules |
Where does this data come from?
- CMS NADAC weekly file
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · refreshed Oct 4, 2026
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Marketing end | Status |
|---|---|---|---|---|
| 13668-0710-57 You're viewing this Main listing | 4 BLISTER PACK in 1 CARTON / 28 CAPSULE in 1 BLISTER PACK | 2025-12-16 | — | Active |
| 13668-0710-91 13668-710-91 | 1 BLISTER PACK in 1 CARTON / 28 CAPSULE in 1 BLISTER PACK | 2025-12-16 | — | Active |
Pack size FAQ
What quantity is in this package?
How does this package differ from NDC 13668-0710-91?
What NDC number is used to bill for this package of nilotinib 150 mg Capsule?
Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Tasigna 150 mg 00078-0592-51 | Novartis | 28 capsules | — | AB | FDA listed | — |
| nilotinib 150 mgthis 13668-0710-57 | Torrent | 112 capsules | — | AB | FDA listed | — |
| Nilotinib 150 mg 31722-0779-33 | Camber | 112 capsules | — | AB | FDA listed | — |
| Nilotinib 150 mg 43598-0455-46 | Dr. | 112 capsules | — | AB | FDA listed | — |
| Nilotinib 150 mg 60505-3801-02 | Apotex | 1792 capsules | — | AB | FDA listed | — |
| nilotinib 150 mg 72205-0238-63 | Novadoz | 28 capsules | — | AB | FDA listed | — |
| nilotinib 150 mg 73190-0033-11 | AvKARE | 28 capsules | — | AB | FDA listed | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA Orange Book · refreshed Oct 3, 2026
- CMS NADAC weekly file
Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
Where does this data come from?
- FDA Orange Book · refreshed Oct 3, 2026
What it looks like
Where does this data come from?
- FDA label on DailyMed · label index refreshed Oct 3, 2026
Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
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UNII 2S7830E561
Crospovidone is a synthetic polymer derived from povidone. It acts as a disintegrant, helping the tablet or capsule break apart quickly in the stomach so the active ingredient can be absorbed.
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UNII 1K09F3G675
Ferric oxide red is an inorganic iron compound used as a colorant in medicines. It gives tablets, capsules, or other dosage forms a red or reddish tint for identification and appearance.
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UNII EX438O2MRT
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UNII XM0M87F357
A dark iron oxide compound that gives medicines their black or dark color. It's used as a colorant in tablets and capsules to help identify the product and make it visually distinctive.
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UNII 2G86QN327L
Gelatin is a protein derived from animal collagen, commonly used in medicines as a gelling agent and capsule material. It helps create soft or hard capsule shells that hold and release medication, and can also thicken liquid formulations.
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UNII EWQ57Q8I5X
Lactose monohydrate is a natural sugar derived from milk. It serves as a filler and binder in tablets and capsules, helping create the proper size, texture, and consistency of the medicine.
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UNII 70097M6I30
Magnesium stearate is a salt made from magnesium and stearic acid, a fatty substance. It's used in tablets and capsules as a lubricant and glidant to help ingredients flow smoothly during manufacturing and prevent sticking.
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UNII WZH3C48M4T
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UNII 6DC9Q167V3
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UNII 46N107B71O
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UNII 15FIX9V2JP
Titanium dioxide is a bright white mineral powder commonly used as a colorant and opacifying agent. It makes pills and tablets white or lighter in color and helps make coatings non-transparent.
13 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.- FDA label on DailyMed · label index refreshed Oct 3, 2026
- FDA openFDA NDC Directory · synced Oct 1, 2026
Inactive ingredient FAQ
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Manufacturer & labeler
More NDCs from Torrent Pharmaceuticals Limited labeler code 13668
- Tiopronin 100 mg Tablet, Delayed Release NDC 13668-691-03
- Tiopronin 300 mg Tablet, Delayed Release NDC 13668-692-90
- Lamotrigine 25 mg Tablet, Orally Disintegrating NDC 13668-693-01
- Lamotrigine 50 mg Tablet, Orally Disintegrating NDC 13668-694-01
- Lamotrigine 100 mg Tablet, Orally Disintegrating NDC 13668-695-01
- Lamotrigine 200 mg Tablet, Orally Disintegrating NDC 13668-696-01
- nilotinib 200 mg Capsule NDC 13668-711-57
- Rosuvastatin Calcium 5 mg Tablet NDC 13668-720-05
- Rosuvastatin Calcium 10 mg Tablet NDC 13668-721-05
- Rosuvastatin Calcium 20 mg Tablet NDC 13668-722-05
- Rosuvastatin Calcium 40 mg Tablet NDC 13668-723-05
- Lamotrigine 1 kg/kg Powder NDC 13668-734-15
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: QT PROLONGATION and SUDDEN DEATHS Nilotinib capsules prolongs the QT interval. Prior to nilotinib capsules administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies [see Warnings and Precautions ( 5.2 )]. Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments [see Warnings and Precautions ( 5.2 , 5.3 , 5.7 , 5.12 )] .
Sudden deaths have been reported in patients receiving nilotinib capsules [see Warnings and Precautions ( 5.3 )]. Do not administer nilotinib capsules to patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )]. Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors [see Drug Interactions ( 7.1 , 7.2 )].
Avoid food 2 hours before and 1 hour after taking the dose [see Dosage and Administration ( 2.1 )]. WARNING: QT PROLONGATION and SUDDEN DEATHS See full prescribing information for complete boxed warning. Nilotinib c apsules prolongs the QT interval.
Prior to nilotinib capsules administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. ( 5.2 ) Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments. ( 5.2 , 5.3 , 5.7 , 5.12 ) Sudden deaths have been reported in patients receiving nilotinib c apsules.
(5.3) Do not administer nilotinib capsules to patients with hypokalemia, hypomagnesemia, or long QT syndrome. ( 4 , 5.2 ) Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. ( 7.1 , 7.2 ) Avoid food 2 hours before and 1 hour after taking the dose.
( 2.1 )
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Nilotinib capsules are a kinase inhibitor indicated for the treatment of: Adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. ( 1.1 ) Adult patients with chronic phase (CP) and accelerated phase (AP) Ph+ CML resistant to or intolerant to prior therapy that included imatinib. ( 1.2 ) Pediatric patients greater than or equal to 1 year of age with Ph+ CML-CP resistant or intolerant to prior tyrosine-kinase inhibitor (TKI) therapy.
(1.3)
1.1Adult and Pediatric Patients With Newly Diagnosed Ph+ CML-CP Nilotinib capsules are indicated for the treatment of adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.
1.2Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP Nilotinib capsules are indicated for the treatment of adult patients with chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) resistant or intolerant to prior therapy that included imatinib.
1.3Pediatric Patients With Resistant or Intolerant Ph+ CML-CP Nilotinib capsules are indicated for the treatment of pediatric patients greater than or equal to 1 year of age with chronic phase Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) with resistance or intolerance to prior tyrosine-kinase inhibitor (TKI) therapy. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s TASIGNA (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Recommended Adult Dose: Newly diagnosed Ph+ CML-CP: 300 mg orally twice daily. Resistant or intolerant Ph+ CML-CP and CML-AP: 400 mg orally twice daily. ( 2.1 ) Recommended Pediatric Dose: Newly Diagnosed Ph+ CML-CP or Ph+ CML-CP resistant or intolerant to prior TKI therapy: 230 mg/m 2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg).
(2.1) See Dosage and Administration for full dosing instructions and dose-reduction instructions for toxicity. ( 2.1 ) Reduce starting dose in patients with baseline hepatic impairment. ( 2.7 ) Eligible newly diagnosed adult patients with Ph+ CML-CP who have received nilotinib capsules for a minimum of 3 years and have achieved a sustained molecular response (MR4.5) and patients with Ph+ CML-CP resistant or intolerant to imatinib who have received nilotinib capsules for at least 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation.
( 2.2 , 2.3 , 5.16 )
2.1Recommended Dosage Dose nilotinib capsules twice daily at approximately 12-hour intervals 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 [see Boxed Warning, Clinical Pharmacology ( 12.3 )] .
Nilotinib capsules may be given in combination with hematopoietic growth factors, such as erythropoietin or G-CSF if clinically indicated. Nilotinib capsules may be given with hydroxyurea or anagrelide if clinically indicated. Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP The recommended dosage of nilotinib capsules is 300 mg orally twice daily.
Dosage in Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dosage of nilotinib capsules is 400 mg orally twice daily. Dosage in Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+CML-CP The recommended dosage of nilotinib capsules for pediatric patients is 230 mg/m 2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg) (see Table 1). If needed, attain the desired dose by combining different strengths of nilotinib capsules.
Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs. Table 1: Pediatric Dosing of Nilotinib capsules (230 mg/m 2 Twice Daily, Maximum Single Dose of 400 mg) Body surface area Single dose Total daily dose Up to 0.32 m 2 50 mg 100 mg 0.33 – 0.54 m 2 100 mg 200 mg 0.55 – 0.76 m 2 150 mg 300 mg 0.77 – 0.97 m 2 200 mg 400 mg 0.98 – 1.19 m 2 250 mg 500 mg 1.20 – 1.41 m 2 300 mg 600 mg 1.42 – 1.63 m 2 350 mg 700 mg ≥ 1.64 m 2 400 mg 800 mg Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's TASIGNA (nilotinib) capsules.
However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
2.2Discontinuation of Treatment After a Sustained Molecular Response (MR4.5) on Nilotinib Capsules Patient Selection Eligibility for Discontinuation of Treatment Ph+ CML-CP patients with typical BCR-ABL transcripts, who have been taking nilotinib capsules for a minimum of 3 years and have achieved a sustained molecular response (MR4.5, corresponding to = BCR-ABL/ABL ≤ 0.0032% IS), may be eligible for treatment discontinuation [see Clinical Studies ( 14.3 , 14.4 )]. Information on FDA authorized tests for the detection and quantitation of BCR-ABL transcripts to determine eligibility for treatment discontinuation is available at http://www.fda.gov/CompanionDiagnostics.
Patients with typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), who achieve the sustained MR4.5 criteria, are eligible for discontinuation of nilotinib capsules. Patients must continue to be monitored for possible loss of molecular remission after treatment discontinuation. Use the same FDA-authorize… [Excerpted — this section continues on DailyMed.]
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Capsules: 150 mg red opaque hard gelatin capsules imprinted with "N12" on body with black ink. 200 mg light yellow opaque hard gelatin capsules imprinted with "N11" on body with red ink. Capsules: 150 mg, and 200 mg ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Nilotinib capsules are contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning]. Nilotinib capsules are contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome. ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Myelosuppression: Monitor complete blood count (CBC) during therapy and manage by treatment interruption or dose reduction. (5.1 ) Cardiac and Arterial Vascular Occlusive Events: Evaluate cardiovascular status, monitor and manage cardiovascular risk factors during nilotinib capsules therapy. ( 5.4 ) Pancreatitis and Elevated Serum Lipase: Monitor serum lipase; if elevations are accompanied by abdominal symptoms, interrupt doses and consider appropriate diagnostics to exclude pancreatitis.
( 5.5 ) Hepatotoxicity: Monitor hepatic function tests monthly or as clinically indicated. ( 5.6 ) Electrolyte Abnormalities: Nilotinib capsules can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating nilotinib capsules and monitor periodically during therapy.
( 5.7 ) Tumor Lysis Syndrome: Maintain adequate hydration and correct uric acid levels prior to initiating therapy with nilotinib capsules. ( 5.8 ) Hemorrhage: Hemorrhage from any site may occur. Advise patients to report signs and symptoms of bleeding and medically manage as needed.( 5.9) Fluid Retention: Monitor patients for unexpected rapid weight gain, swelling, and shortness of breath.
Manage medically. ( 5.13 ) Effects on Growth and Development in Pediatric Patients: Growth retardation has been reported in pediatric patients treated with nilotinib capsules. Monitor growth and development in pediatric patients.
( 5.14 ) Embryo-Fetal Toxicity: Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.15 , 8.1 , 8.3 ) Treatment Discontinuation: Patients must have typical BCR-ABL transcripts. An FDA-authorized test with a detection limit below MR4.5 must be used to determine eligibility for discontinuation.
Patients must be frequently monitored by the FDA authorized test to detect possible loss of remission. ( 5.16 )
5.1Myelosuppression Treatment with nilotinib capsules can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Perform CBCs 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 nilotinib capsules temporarily or dose reduction [see Dosage and Administration ( 2.5 )].
5.2QT Prolongation Nilotinib capsules has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface electrocardiogram (ECG) in a concentration-dependent manner [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.2 )]. 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. Electrocardiograms should be performed at baseline, 7 days after initiation of nilotinib capsules, and periodically as clinically indicated and following dose adjustments [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.12 )].
Nilotinib capsules should not be used in patients who have hypokalemia, hypomagnesemia, or long QT syndrome. Before initiating nilotinib capsules and periodically, test electrolyte, calcium, and magnesium blood levels. Hypokalemia or hypomagnesemia must be corrected prior to initiating nilotinib capsules and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions ( 5.12 )].
Significant prolongation of the QT interval may occur when nilotinib capsules are 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 [see Dosage and Administration ( 2.1 ), Drug Interactions ( 7.1 , 7.2 )] . The presence of hypokalemia and hypomagnesemia may further prolong the QT interval [see W… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following clinically significant adverse reactions can occur with nilotinib capsules and are discussed in greater detail in other sections of labeling: Myelosuppression [see Warnings and Precautions ( 5.1 )] QT Prolongation [see Boxed Warning, Warnings and Precautions ( 5.2 )] Sudden Deaths [see Boxed Warning, Warnings and Precautions ( 5.3 )] Cardiac and Arterial Vascular Occlusive Events [see Warnings and Precautions ( 5.4 )] Pancreatitis and Elevated Serum Lipase [see Warnings and Precautions ( 5.5 )] Hepatotoxicity [see Warnings and Precautions ( 5.6 )] Electrolyte Abnormalities [see Boxed Warning, Warnings and Precautions ( 5.7 )] Hemorrhage [see Warnings and Precautions ( 5.9 )] Fluid Retention [see Warnings and Precautions ( 5.13 )] The most commonly reported non-hematologic adverse reactions (≥ 20%) in adult and pediatric patients were nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats.
Hematologic adverse drug reactions include myelosuppression: thrombocytopenia, neutropenia, and anemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience 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 Adult Patients With Newly Diagnosed Ph+ CML-CP The data below reflect exposure to nilotinib capsules from 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 capsules 300 mg twice daily group was 61 months (range, 0.1 to 71 months). The median actual dose intensity was 593 mg/day in the nilotinib capsules 300 mg twice daily group. The most common (greater than 10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia, and upper abdominal pain.
Constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (less than or equal to 10% and greater than 5%) and have been of mild-to-moderate severity, manageable and generally did not require dose reduction. Increase in QTcF greater than 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 greater than 500 msec while on study drug.
The most common hematologic adverse drug reactions (all Grades) were myelosuppression, including: thrombocytopenia (18%), neutropenia (15%), and anemia (8%). See Table 9 for Grade 3/4 laboratory abnormalities. Discontinuation due to adverse reactions, regardless of relationship to study drug, was observed in 10% of patients.
In Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP In the single-arm, 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 1,096) and 264 (range, 2 to 1,160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range, 151 to 1,110) and 780 mg/day (range, 150 to 1,149), 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-hemato… [Excerpted — this section continues on DailyMed.]
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid concomitant use with nilotinib capsules, or reduce nilotinib capsules dose if coadministration cannot be avoided. (7.1 ) Strong CYP3A Inducers: Avoid concomitant use with nilotinib capsules. ( 7.1 ) Proton Pump Inhibitors: Use short-acting antacids or H2 blockers as an alternative to proton pump inhibitors. ( 7.1 )
7.1Effect of Other Drugs on Nilotinib Capsules Strong CYP3A Inhibitors Concomitant use with a strong CYP3A inhibitor increased nilotinib concentrations compared to nilotinib capsules alone [see Clinical Pharmacology ( 12.3 ) ], which may increase the risk of nilotinib capsules toxicities. Avoid concomitant use of strong CYP3A inhibitors with nilotinib capsules. If patients must be coadministered a strong CYP3A4 inhibitor, reduce nilotinib capsules dose [see Dosage and Administration ( 2.8 )].
Strong CYP3A Inducers Concomitant use with a strong CYP3A inducer decreased nilotinib concentrations compared to nilotinib capsules alone [see Clinical Pharmacology ( 12.3 )], which may reduce nilotinib capsules efficacy. Avoid concomitant use of strong CYP3A inducers with nilotinib capsules. Proton Pump Inhibitors Concomitant use with a proton pump inhibitor (PPI) decreased nilotinib concentrations compared to nilotinib capsules alone [see Clinical Pharmacology ( 12.3 )], which may reduce nilotinib capsules efficacy.
Avoid concomitant use of PPI with nilotinib capsules. As an alternative to PPIs, use H2 blockers approximately 10 hours before or approximately 2 hours after the dose of nilotinib capsules, or use antacids approximately 2 hours before or approximately 2 hours after the dose of nilotinib capsules.
7.2Drugs That Prolong the QT Interval Avoid coadministration of nilotinib capsules with agents that may prolong the QT interval, such as anti-arrhythmic drugs [see Boxed Warning, Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.2 )].
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed. ( 8.2 ) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's TASIGNA (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
8.1Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, nilotinib capsules can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of nilotinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal lethality, fetal effects, and fetal variations in rats and rabbits at maternal exposures (AUC) approximately 2 and 0.5 times, respectively, the exposures in patients at the recommended dose (see Data) .
Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of nilotinib up to 100 mg/kg/day and 300 mg/kg/day, respectively, during the period of organogenesis. In rats, oral administration of nilotinib produced embryo-lethality/fetal effects at doses ≥ 30 mg/kg/day.
At ≥ 30 mg/kg/day, skeletal variations of incomplete ossification of the frontals and misshapen sternebra were noted, and there was an increased incidence of small renal papilla and fetal edema. At 100 mg/kg/day, nilotinib was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption) and resulted in a single incidence of cleft palate and two incidences of pale skin were noted in the fetuses. A single incidence of dilated ureters was noted in a fetus also displaying small renal papilla at 100 mg/kg/day.
Additional variations of forepaw and hindpaw phalanx unossified, fused sternebra, bipartite sternebra ossification, and incomplete ossification of the cervical vertebra were noted at 100 mg/kg/day. In rabbits, oral administration of nilotinib resulted in the early sacrifice of two females, maternal toxicity and increased resorption of fetuses at 300 mg/kg/day. Fetal skeletal variations (incomplete ossification of the hyoid, bent hyoid, supernumerary short detached ribs and the presence of additional ossification sites near the nasals, frontals and in the sternebral column) were also increased at this dose in the presence of maternal toxicity.
Slight maternal toxicity was evident at 100 mg/kg/day but there were no reproductive or embryo-fetal effects at this dose. At 30 mg/kg/day in rats and 300 mg/kg/day in rabbits, the maternal systemic exposure (AUC) were 72,700 ng*hr/mL and 17,100 ng*hr/mL, respectively, representing approximately 2 and 0.5 times the exposure in humans at the highest recommended dose 400 mg twice daily. 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 60 mg/kg (i.e., 360 mg/m 2 , approximately 0.7 times the clinical dose of 400 mg twice daily based on body surface area).
At doses up to 20 mg/kg (i.e., 120 mg/m 2 , approximately 0.25 times the clinical dose of 400 mg twice daily based on body surface area) no adverse eff… [Excerpted — this section continues on DailyMed.]
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, nilotinib capsules can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of nilotinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal lethality, fetal effects, and fetal variations in rats and rabbits at maternal exposures (AUC) approximately 2 and 0.5 times, respectively, the exposures in patients at the recommended dose (see Data) .
Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of nilotinib up to 100 mg/kg/day and 300 mg/kg/day, respectively, during the period of organogenesis. In rats, oral administration of nilotinib produced embryo-lethality/fetal effects at doses ≥ 30 mg/kg/day.
At ≥ 30 mg/kg/day, skeletal variations of incomplete ossification of the frontals and misshapen sternebra were noted, and there was an increased incidence of small renal papilla and fetal edema. At 100 mg/kg/day, nilotinib was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption) and resulted in a single incidence of cleft palate and two incidences of pale skin were noted in the fetuses. A single incidence of dilated ureters was noted in a fetus also displaying small renal papilla at 100 mg/kg/day.
Additional variations of forepaw and hindpaw phalanx unossified, fused sternebra, bipartite sternebra ossification, and incomplete ossification of the cervical vertebra were noted at 100 mg/kg/day. In rabbits, oral administration of nilotinib resulted in the early sacrifice of two females, maternal toxicity and increased resorption of fetuses at 300 mg/kg/day. Fetal skeletal variations (incomplete ossification of the hyoid, bent hyoid, supernumerary short detached ribs and the presence of additional ossification sites near the nasals, frontals and in the sternebral column) were also increased at this dose in the presence of maternal toxicity.
Slight maternal toxicity was evident at 100 mg/kg/day but there were no reproductive or embryo-fetal effects at this dose. At 30 mg/kg/day in rats and 300 mg/kg/day in rabbits, the maternal systemic exposure (AUC) were 72,700 ng*hr/mL and 17,100 ng*hr/mL, respectively, representing approximately 2 and 0.5 times the exposure in humans at the highest recommended dose 400 mg twice daily. 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 60 mg/kg (i.e., 360 mg/m 2 , approximately 0.7 times the clinical dose of 400 mg twice daily based on body surface area).
At doses up to 20 mg/kg (i.e., 120 mg/m 2 , 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.
🧒 Pediatric Use ▾
8.4Pediatric Use The safety and effectiveness of nilotinib capsules have been established in pediatric patients greater than or equal to 1 year of age with newly diagnosed and resistant or intolerant Ph+ CML in chronic phase [see Clinical Studies (14.5)] . There are no data for pediatric patients under 2 years of age. Use of nilotinib capsules in pediatric patients 1 year to less than 2 years of age with newly diagnosed or resistant or intolerant Ph+ CML in chronic phase is supported by efficacy in pediatric patients 2 to 6 years of age for these indications.
Use of nilotinib capsules in pediatric patients 1 to less than 18 years of age is supported by evidence from two clinical trials [see Clinical Studies (14.5)] . The 25 patients with newly diagnosed Ph+ CML-CP were in the following age groups: 6 children (age 2 to less than 12 years) and 19 adolescents (age 12 to less than 18 years). The 44 patients with resistant or intolerant Ph+ CML-CP included 18 children (age 2 to less than 12 years) and 26 adolescents (age 12 to less than 18 years).
All pediatric patients received nilotinib capsules treatment at a dose of 230 mg/m 2 twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg). No differences in efficacy or safety were observed between the different age subgroups in the two trials. The frequency, type, and severity of adverse reactions observed were generally consistent with those observed in adults, with the exception of the laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 16%) and transaminase elevation (AST Grade 3/4: 2.9%, ALT Grade 3/4: 10%), which were reported at a higher frequency in pediatric patients than in adults [see Adverse Reactions (6.1)] .
For pediatric growth and development, growth retardation has been reported in pediatric patients with Ph+ CML-CP treated with nilotinib capsules [see Warnings and Precautions (5.14 ), Adverse Reactions (6.1)] . The safety and effectiveness of nilotinib capsules in pediatric patients below the age of 1 year with newly diagnosed, or resistant or intolerant Ph+ CML in chronic phase and accelerated phase, have not been established. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's TASIGNA (nilotinib) capsules.
However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
🧓 Geriatric Use ▾
8.5Geriatric Use In the clinical trials of nilotinib capsules (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 less than 65 years and those greater than or equal to 65 years. • Patients with resistant or intolerant CML-CP: There was no difference in major cytogenetic response rate between patients aged less than 65 years and those greater than or equal to 65 years. • Patients with resistant or intolerant CML-AP: The hematologic response rate was 44% in patients less than 65 years of age and 29% in patients greater than or equal to 65 years.
No major differences for safety were observed in patients greater than or equal to 65 years of age as compared to patients less than 65 years.
🆘 Overdosage ▾
10 OVERDOSAGE Overdose with nilotinib has been reported, where an unspecified number of nilotinib capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, observe the patient and provide appropriate supportive treatment.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action 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. 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).
12.2Pharmacodynamics Based on exposure-response analyses for efficacy, a relationship between drug exposure and a greater likelihood of response was observed in clinical studies. Based on exposure-response analyses for safety, a relationship between exposure and a greater likelihood of safety events, including a higher occurrence of total bilirubin elevations, was observed in clinical studies. Cardiac Electrophysiology Nilotinib capsules are associated with concentration-dependent QT prolongation.
At a dose of nilotinib capsules 400 mg twice daily given without food in healthy subjects, the maximum mean placebo-adjusted QTcF changes were 10.4 msec (90% CI: 2.85, 18.0). After a single dose of nilotinib capsules 800 mg (two times the maximum approved recommended dosage) given with a high fat meal to healthy subjects, the maximum mean placebo-adjusted QTcF changes were) 18.0 msec (90% CI: 9.65, 25.8). Peak plasma concentrations in the QT study were 26% lower than or comparable with those observed in patients enrolled in the single-arm study [see Boxed Warning, Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6.1 )] .
12.3Pharmacokinetics 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 or twice daily dosing. In adult patients with resistant or intolerant Ph+ CML given nilotinib capsules 400 mg twice daily, the steady-state mean (% CV) C max and AUC 0-12h were 2,260 ng/mL (35%) and 18,000 ng∙h/mL (33%), respectively. In adult patients with newly diagnosed Ph+ CML given nilotinib capsules 300 mg twice daily, the steady-state mean (% CV) C max and AUC 0-12h were 1,540 ng/mL (48%) and 13,337 ng∙h/mL (46%), respectively.
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. The average steady state nilotinib trough and peak concentrations did not change over 12 months.
Absorption Relative bioavailability of nilotinib capsule is approximately 50%, as compared to an oral drink solution (pH of 1.2 to 1.3). Peak concentrations of nilotinib are reached 3 hours after oral administration. Nilotinib is a substrate of P-gp in vitro .
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 (5.10)]. Effect of Food Compared to the fasted state, the systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high fat meal (meal of 800 to 1000 calories with fat being 50% of total caloric content; approximately: 150 calories from protein, 250 calories from carbohydrates, and 500 to 600 calories from fat).
Distribution The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98%. Elimination The mean (CV%) apparent elimination half-life is estimated to be approximately 17 hours (69%) and the mean (CV%) apparent clearance approximates 29 L/h (61%).
Metabolism Nilotinib is primarily metabolized via CYP3A4-mediated oxidation and to a minor extent by CYP2C8. Nilotinib is the main circulating component in the… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
12.1Mechanism of Action 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. 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).
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Nilotinib 150 mg capsules are red opaque hard gelatin capsules, size 1 imprinted with "N12" on body with black ink. Nilotinib 200 mg capsules are light yellow opaque hard gelatin capsules, size 0 imprinted with "N11" on body with red ink. Nilotinib 150 mg and 200 mg capsules are supplied in blister packs.
150 mg Carton of 4 blister packs of (4 x 28) .................NDC 13668-710-57 Blisters of 28 capsules ......................................NDC 13668-710-91 200 mg Carton of 4 blister packs of (4 x 28) .................NDC 13668-711-57 Blisters of 28 capsules ......................................NDC 13668-711-91 Nilotinib capsules should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].
📋 Description ▾
11 DESCRIPTION Nilotinib capsule contains nilotinib, which belongs to a pharmacologic class of drugs known as kinase inhibitors. Nilotinib drug substance, in the form of monohydrochloride monohydrate, is a white to slightly yellowish to slightly greenish yellow powder with the molecular formula and weight, respectively, of C 28 H 22 F 3 N 7 O•HCl • H 2 O and 584 g/mol (corresponding molecular formula and weight of nilotinib base, anhydrous are C 28 H 22 F 3 N 7 O and 529 g/mol, respectively). The solubility of nilotinib in aqueous solutions decreases with increasing pH.
Nilotinib is not optically active. The pK a 1 was determined to be 2.1; pK a 2 was estimated to be 5.4. The chemical name of nilotinib monohydrochloride monohydrate 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 capsules, for oral use, contain 150 mg, or 200 mg nilotinib base, anhydrous (equivalent to 166 mg and 221 mg nilotinib monohydrochloride monohydrate respectively) with the following inactive ingredients: colloidal silicone dioxide, crospovidone, lactose monohydrate, magnesium stearate and poloxamer 188. The capsule shell for 150 mg and 200 mg contains gelatin, iron oxide (yellow) and titanium dioxide. Additionally, the capsule shell for 150 mg contains iron oxide red.
The black imprinting ink for 150 mg contains iron oxide (black), potassium hydroxide, propylene glycol and shellac. The red imprinting ink for 200 mg contains FD&C Red No. 40 aluminum lake, povidone, propylene glycol, shellac, sodium hydroxide and titanium dioxide.
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💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). A Medication Guide is required for distribution with nilotinib capsules. The complete text of the Medication Guide is reprinted at the end of this document.
Myelosuppression Advise patients that treatment with nilotinib capsules can cause serious thrombocytopenia, neutropenia, and anemia. Advise patients to seek immediate medical attention if symptoms suggestive of low blood counts occur, such as fever, chills or other signs of infection, unexplained bleeding or bruising, or unexplained weakness or shortness of breath [see Warnings and Precautions ( 5.1 )]. QT Prolongation Advise patients that nilotinib capsules can cause possibly life-threatening, abnormal heart beat.
Advise patients to seek immediate medical attention if symptoms of abnormal heart beat occur, such as feeling light-headed, faint or experiencing an irregular heartbeat [see Warnings and Precautions ( 5.2 )] . Cardiac and Arterial Vascular Occlusive 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 if any symptoms suggestive of a cardiovascular event occur, such as chest or leg pain, numbness or weakness, or problems walking or speaking occur suddenly [see Warnings and Precautions ( 5.4 )] .
Pancreatitis and Elevated Serum Lipase Advise patients that nilotinib capsules can increase the risk of pancreatitis and that patients with a previous history of pancreatitis may be at greater risk. Advise patients to seek immediate medical attention if symptoms suggestive of pancreatitis occur, such as sudden stomach area pain with accompanying nausea and vomiting [see Warnings and Precautions ( 5.5 )] . Hepatotoxicity Advise patients that nilotinib capsules can increase the risk of hepatotoxicity and that patients with previous history of liver diseases may be at risk.
Advise patients to seek immediate medical attention if any symptoms suggestive of hepatotoxicity occur, such as stomach pain, yellow skin and eyes, and dark-colored urine [see Warnings and Precautions ( 5.6 )]. Tumor Lysis Syndrome Advise patients that nilotinib capsules can cause TLS and to seek immediate medical attention if any symptoms suggestive of TLS occur, such as an abnormal heartbeat or less urine production [see Warnings and Precautions ( 5.8 )] . Hemorrhage Advise patients that serious hemorrhagic events, including fatal events, have occurred in patients with CML treated with nilotinib capsules.
Advise patients to seek immediate medical attention if symptoms suggestive of hemorrhage occur, such as uncontrolled bleeding, changes in eyesight, unconsciousness, or sudden headache or sudden confusion in surroundings [see Warnings and Precautions ( 5.9 )] . Fluid Retention Advise patients that nilotinib capsules can cause fluid retention and to seek immediate medical attention if any symptoms suggestive of fluid retention, such as shortness of breath, rapid weight gain, or swelling occur [see Warnings and Precautions ( 5.13 )] .
Effects on Growth and Development in Pediatric Patients Inform pediatric patients and their caregivers of the possibility of developing growth abnormalities. Growth retardation has been reported in pediatric patients treated with nilotinib capsules. Therefore, monitor growth and development in pediatric patients [see Warnings and Precautions ( 5.14 )] .
Treatment-Free Remission (TFR) Advise patients that frequent monitoring is required to detect possible loss of remission if TFR is attempted. Advise patients that musculoskeletal symptoms, such as muscle pain, pain in extremity, joint pain, bone pain, or spinal pain, may occur more frequently than before treatment discontinuation [see Warnings and Precautions (5.16 )]. Embryo-Fetal Toxicity Advise pregnant women of the potential risk to… [Excerpted — this section continues on DailyMed.]
💬 Medication Guide ▾
This Medication Guide has been approved by the U.S. Food and Drug Administration. Medication Guide Nilotinib (nye loe' ti nib) Capsules What is the most important information I should know about nilotinib capsules?
Nilotinib capsules can cause a possible life-threatening heart problem called QTc prolongation. QTc prolongation causes an irregular heartbeat, which may lead to sudden death. Your healthcare provider should check the electrical activity of your heart with a test called an electrocardiogram (ECG): ● before starting nilotinib capsules ● with any dose changes ● 7 days after starting nilotinib capsules ● regularly during nilotinib capsules treatment You may lower your chances for having QTc prolongation with nilotinib capsules if you: ● Take nilotinib capsules 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 during treatment with nilotinib capsules.
Food and grapefruit products increase the amount of nilotinib capsules in your body. ● Avoid taking other medicines or supplements with nilotinib capsules that can also cause QTc prolongation. ● Nilotinib capsules can interact with many medicines and supplements and increase your chance for serious and life-threatening side effects. ● Do not take any other medicine during treatment with nilotinib capsules unless your healthcare provider tells you it is okay to do so. Call your healthcare provider right away if you feel lightheaded, faint, or have an irregular heartbeat during treatment with nilotinib capsules.
These can be symptoms of QTc prolongation. What is nilotinib capsules? Nilotinib capsules are a prescription medicine used to treat: ● adults and children who have been newly diagnosed with a certain type of leukemia called Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. ● adults with chronic phase Ph+ CML or accelerated phase Ph+ CML who: ○ are no longer benefiting from other treatments, including imatinib (Gleevec), or ○ have taken other treatments, including imatinib (Gleevec), and cannot tolerate them. ● children with chronic phase Ph+ CML who: ○ are no longer benefiting from treatment with a tyrosine-kinase inhibitor medicine, or ○ have taken a tyrosine-kinase inhibitor medicine and cannot tolerate it.
It is not known if nilotinib capsules are safe and effective in children younger than 1 year of age with newly diagnosed, resistant, or intolerant Ph+ CML in chronic phase. The long-term effects of treating children with nilotinib capsules for a long period of time are not known. Who should not take nilotinib capsules?
Do not take if you have: ● low levels of potassium or magnesium in your blood ● long QTc syndrome Before taking nilotinib capsules, tell your healthcare provider about all of your medical conditions, including if you: ● have heart problems ● have had a stroke or other problems due to decreased blood flow to the brain ● have problems with decreased blood flow to your legs ● have irregular heartbeat ● have QTc prolongation or a family history of it ● have liver problems ● have had pancreatitis ● have low blood levels of potassium or magnesium in your blood ● have a severe problem with lactose (milk sugar) or other sugars.
Nilotinib capsules contain lactose. Most people who have mild or moderate lactose intolerance can take nilotinib capsules. ● have bleeding problems ● had a surgical procedure involving the removal of the entire stomach (total gastrectomy) ● are pregnant or plan to become pregnant. Nilotinib capsules can harm your unborn baby.
Tell your healthcare provider right away if you are pregnant, or if you become pregnant during treatment with nilotinib capsules. In females who are able to become pregnant: ● Your healthcare provider should do a pregnancy test before you start treatment with nilotinib capsules. ● Use… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics 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 or twice daily dosing. In adult patients with resistant or intolerant Ph+ CML given nilotinib capsules 400 mg twice daily, the steady-state mean (% CV) C max and AUC 0-12h were 2,260 ng/mL (35%) and 18,000 ng∙h/mL (33%), respectively. In adult patients with newly diagnosed Ph+ CML given nilotinib capsules 300 mg twice daily, the steady-state mean (% CV) C max and AUC 0-12h were 1,540 ng/mL (48%) and 13,337 ng∙h/mL (46%), respectively.
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. The average steady state nilotinib trough and peak concentrations did not change over 12 months.
Absorption Relative bioavailability of nilotinib capsule is approximately 50%, as compared to an oral drink solution (pH of 1.2 to 1.3). Peak concentrations of nilotinib are reached 3 hours after oral administration. Nilotinib is a substrate of P-gp in vitro .
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 (5.10)]. Effect of Food Compared to the fasted state, the systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high fat meal (meal of 800 to 1000 calories with fat being 50% of total caloric content; approximately: 150 calories from protein, 250 calories from carbohydrates, and 500 to 600 calories from fat).
Distribution The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98%. Elimination The mean (CV%) apparent elimination half-life is estimated to be approximately 17 hours (69%) and the mean (CV%) apparent clearance approximates 29 L/h (61%).
Metabolism Nilotinib is primarily metabolized via CYP3A4-mediated oxidation and to a minor extent by CYP2C8. Nilotinib is the main circulating component in the serum. None of the metabolites contribute significantly to the pharmacological activity of nilotinib.
Excretion After a single dose of radiolabeled nilotinib, more than 90% of the administered dose was eliminated within 7 days: 93% of the dose in feces. Parent drug accounted for 69% of the dose. Specific Populations Age, sex, race/ethnicity, or body weight did not significantly affect the pharmacokinetics of nilotinib.
The effect of renal impairment on nilotinib pharmacokinetics is unknown. Pediatric Patients Following administration of the approved recommend pediatric dosage of nilotinib, steady-state exposure of nilotinib were within 2-fold to adult patients treated with 400 mg twice daily. Steady-state C min was comparable across all age groups (pediatric patients from ages 2 to less than 18 years), diseases (patients with newly diagnosed and resistant or intolerant Ph+ CML) and studies.
Body surface area correlated with nilotinib clearance and was the primary factor responsible for the PK differences between pediatrics and adults. Patients with Hepatic Impairment Following a single dose of nilotinib capsules 200 mg (0.5 times the maximum approved recommended dosage), the mean AUC of nilotinib increased 1.4-fold, 1.4-fold, and 1.6-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, respectively, compared to subjects with normal hepatic function.
Drug Interaction Studies Clinical Studies Strong CYP3A Inhibitors: Coadministration of ketoconazole (a strong CYP3A inhibitor) 400 mg once daily for 6 days increased nilotinib AUC by approximately 3-fold. A single concurrent intake of double-strength grapefruit juice increased the nilotinib AUC by 1.3-fold. Strong CYP3A Inducers: Coadministration of rifampicin (a strong CYP3A inducer) 6… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics Based on exposure-response analyses for efficacy, a relationship between drug exposure and a greater likelihood of response was observed in clinical studies. Based on exposure-response analyses for safety, a relationship between exposure and a greater likelihood of safety events, including a higher occurrence of total bilirubin elevations, was observed in clinical studies. Cardiac Electrophysiology Nilotinib capsules are associated with concentration-dependent QT prolongation.
At a dose of nilotinib capsules 400 mg twice daily given without food in healthy subjects, the maximum mean placebo-adjusted QTcF changes were 10.4 msec (90% CI: 2.85, 18.0). After a single dose of nilotinib capsules 800 mg (two times the maximum approved recommended dosage) given with a high fat meal to healthy subjects, the maximum mean placebo-adjusted QTcF changes were) 18.0 msec (90% CI: 9.65, 25.8). Peak plasma concentrations in the QT study were 26% lower than or comparable with those observed in patients enrolled in the single-arm study [see Boxed Warning, Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6.1 )] .
🔬 Clinical Studies ▾
14 CLINICAL STUDIES
14.1Adult Newly Diagnosed Ph+ CML-CP The ENESTnd (Evaluating Nilotinib Efficacy and Safety in clinical Trials-Newly Diagnosed patients) study ( NCT00471497 ) was an open-label, multicenter, randomized trial conducted to determine the efficacy of nilotinib capsules versus 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 capsules 300 mg twice daily group, 281 patients in the nilotinib capsules 400 mg twice daily group.
Median age was 46 years in the imatinib group and 47 years in both nilotinib capsules groups, with 12%, 13%, and 10% of patients greater than or equal to 65 years of age in imatinib 400 mg once daily, nilotinib capsules 300 mg twice daily and nilotinib capsules 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 capsules 300 mg twice daily and nilotinib capsules 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, 48, and 60 months of treatment (or discontinued earlier).
The median time on treatment was approximately 61 months in all three treatment groups. The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication. MMR was defined as less than or equal to 0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a greater than or equal to 3 log reduction of BCR-ABL transcript from standardized baseline.
Efficacy endpoints are summarized in Table 11. Two patients in the nilotinib capsules arm progressed to either accelerated phase or blast crisis (both within the first 6 months of treatment) while 12 patients on the imatinib arm progressed to either accelerated phase or blast crisis (7 patients within first 6 months, 2 patients within 6 to 12 months, 2 patients within 12 to 18 months and 1 patient within 18 to 24 months). Table 11: Efficacy (MMR and CCyR) of Nilotinib Capsules Compared to imatinib in Adult Newly Diagnosed Ph+ CML-CP (ENESTnd) Abbreviation: CI, confidence interval. a CMH test stratified by Sokal risk group. b CCyR: 0% Ph+ metaphases.
Cytogenetic responses were based on the percentage of Ph+ metaphases among greater than or equal to 20 metaphase cells in each bone marrow sample. Nilotinib Capsules 300 mg twice daily imatinib 400 mg once daily N = 282 N = 283 MMR at 12 months (95% CI) 44% (38.4, 50.3) 22% (17.6, 27.6) P-Value a < 0.0001 CCyR b by 12 months (95% CI) 80% (75.0, 84.6) 65% (59.2, 70.6) MMR at 24 months (95% CI) 62% (55.8, 67.4) 38% (31.8, 43.4) CCyR b by 24 months (95% CI) 87% (82.4, 90.6) 77% (71.7, 81.8) By the 60 months, MMR was achieved by 77% of patients on nilotinib capsules and 60% of patients on imatinib; MR4.5 was achieved by 53.5% of patients on nilotinib capsules and 31.4% on imatinib.
Median overall survival was not reached in either arm. At the time of the 60-month final analysis, the estimated survival rate was 93.7% for patients on nilotinib capsules and 91.7% for patients on imatinib.
14.2Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP Study CAMN107A2101 (referred to as Study A2101) ( NCT00109707 ) was a single-arm, open-label, multicenter study conducted to evaluate the efficacy and safety of nilotinib capsules (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 inc… [Excerpted — this section continues on DailyMed.]
🧪 Nonclinical Toxicology ▾
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility 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.
A 26-week carcinogenicity study was conducted orally in Tg.rasH2 mice, a model genetically modified to enhance susceptibility to neoplastic transformation, at nilotinib doses of 30, 100, and 300 mg/kg/day. Nilotinib induced in the skin and subcutis statistically significant increases in the incidence of papillomas in females and of papillomas and combined papillomas and carcinomas in males at 300 mg/kg/day. The no-observed-adverse-effect-level (NOAEL) for skin neoplastic lesions was 100 mg/kg/day.
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 2,000 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 nilotinib capsules on 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.
📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ▾
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility 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.
A 26-week carcinogenicity study was conducted orally in Tg.rasH2 mice, a model genetically modified to enhance susceptibility to neoplastic transformation, at nilotinib doses of 30, 100, and 300 mg/kg/day. Nilotinib induced in the skin and subcutis statistically significant increases in the incidence of papillomas in females and of papillomas and combined papillomas and carcinomas in males at 300 mg/kg/day. The no-observed-adverse-effect-level (NOAEL) for skin neoplastic lesions was 100 mg/kg/day.
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 2,000 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 nilotinib capsules on 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.
📄 Package Label / Principal Display Panel ▾
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 150 mg – Carton of 28 Capsules 150 mg- Carton of 4 individual blister packs 200 mg – Carton of 28 Capsules 200 mg- Carton of 4 individual blister packs 150mg-carton 150mg-carton-outer 200mg-carton 200mg-carton-outer
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