Nilotinib
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NILONITIB (NILOTINIB)
Composition:
Active substance: nilotinib;
1 capsule contains 150 mg or 200 mg of nilotinib;
Excipients:
lactose monohydrate, crospovidone, Sepitrap 80, magnesium stearate, colloidal silicon dioxide;
150 mg: composition of hard gelatin capsule (size "1"): gelatin, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), purified water;
composition of ink (BlackInk): shellac, absolute alcohol, isopropyl alcohol, butanol, propylene glycol, concentrated ammonia solution, black iron oxide (E 172), potassium hydroxide, purified water.
200 mg: composition of hard gelatin capsule (size "0"): gelatin, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), purified water;
composition of ink (RedInk): shellac, absolute alcohol, isopropyl alcohol, butanol, propylene glycol, sodium hydroxide, titanium dioxide, povidone, FD&C Red No. 40.
Pharmaceutical form. Hard capsules.
Main physicochemical properties:
150 mg capsules – red opaque capsules with black ink marking "SML" on the cap and "26" on the body, containing granular powder from white to grey in color;
200 mg capsules – light-yellow opaque capsules with red ink marking "SML" on the cap and "27" on the body, containing granular powder from white to grey in color.
Pharmacotherapeutic group. Antineoplastic agents. BCR-ABL tyrosine kinase inhibitors.
ATC code L01E A03.
Pharmacological Properties.
Pharmacodynamics.
Mechanism of Action.
Nilotinib is a potent and selective inhibitor of the tyrosine kinase activity of the Bcr-Abl oncoprotein Abl, acting in cell lines and in primary Philadelphia chromosome–positive leukemic cells. The drug binds tightly to the ATP-binding site, thereby forming a potent inhibitor of wild-type Bcr-Abl, and retains activity against 32 of 33 imatinib-resistant mutant forms of Bcr-Abl. Due to this biochemical activity, nilotinib selectively inhibits proliferation and induces apoptosis in cell lines and in primary Philadelphia chromosome–positive leukemic cells obtained from patients with chronic myeloid leukemia (CML). In a mouse model of CML, oral administration of nilotinib alone resulted in reduction of tumor mass and prolonged survival.
Pharmacodynamic Effects.
Nilotinib has little or no effect on most of the other protein kinases investigated, including serine-protein kinase (Src), except for platelet-derived growth factor (PDGF), receptor tyrosine kinase activity (Kit, CSF-1R, DDR), and Eph receptor kinases, which are inhibited by nilotinib at concentrations achieved after oral administration at therapeutic doses recommended for the treatment of CML (see table below).
Kinase profile of nilotinib (phosphorylation IC50 nM)
| Bcr-Abl |
PDGFR |
KIT |
| 20 |
69 |
210 |
Pharmacokinetics.
Absorption.
Following oral administration, peak concentrations of nilotinib are reached within 3 hours; bioavailability is approximately 30%. When administered with food, Cmax and the area under the plasma concentration-time curve (AUC) of nilotinib increase by 112% and 82%, respectively, compared to administration in the fasted state. Administration of nilotinib 30 minutes or 2 hours after a meal increases bioavailability by 29% and 15%, respectively. Absorption of nilotinib (relative bioavailability) may be reduced by approximately 48% and 22% in patients who have undergone total gastrectomy or partial gastrectomy, respectively.
Distribution.
The blood-to-plasma ratio of nilotinib is 0.71. Plasma protein binding, based on in vitro data, is approximately 98%.
Metabolism.
The primary metabolic pathways are oxidation and hydroxylation. The major circulating component in plasma is nilotinib. None of the metabolites contribute significantly to the pharmacological activity of nilotinib. Nilotinib is primarily metabolized by CYP3A4, and possibly partially by CYP2C8.
Elimination.
After a single dose of radiolabeled nilotinib administered to healthy volunteers, more than 90% of the dose was excreted within 7 days, predominantly in feces (94% of dose). The parent compound accounted for 69% of the dose.
The apparent elimination half-life, calculated from multiple-dose pharmacokinetics during daily administration, is approximately 17 hours. The extent of pharmacokinetic variability of nilotinib across different patients ranges from moderate to high.
Linearity/Non-linearity.
Exposure to nilotinib at steady state is dose-dependent, with less than dose-proportional increases in systemic exposure at doses exceeding 400 mg once daily. Daily plasma exposure to nilotinib at steady state with 400 mg twice daily is 35% higher than with 800 mg once daily. Systemic exposure (AUC) to nilotinib at steady state with 400 mg twice daily is approximately 13.4% higher than with 300 mg twice daily. Mean trough and peak concentrations of nilotinib over 12 months were approximately 15.7% and 14.8% higher, respectively, after administration of 400 mg twice daily compared to 300 mg twice daily. No significant increase in nilotinib exposure was observed when the dose was increased from 400 mg twice daily to 600 mg twice daily.
Steady state was primarily achieved by Day 8. The increase in plasma exposure of nilotinib between the first dose and steady state was approximately 2-fold with once-daily dosing and 3.8-fold with twice-daily dosing.
Bioavailability/Bioequivalence Studies.
A single 400 mg dose of nilotinib, administered as the contents of two 200 mg capsules sprinkled onto one teaspoon of apple sauce, has been shown to be bioequivalent to a single dose of two intact 200 mg capsules.
Clinical characteristics.
Indications.
Treatment of newly diagnosed chronic phase chronic myeloid leukemia (Ph+ CML) in adult patients with Philadelphia chromosome.
Treatment of chronic and accelerated phase (AP) chronic myeloid leukemia (Ph+ CML) in adult patients with Philadelphia chromosome in cases of resistance or intolerance to prior therapy, including imatinib therapy.
Contraindications.
Hypersensitivity to nilotinib and to other components of the medicinal product.
Interaction with other medicinal products and other forms of interaction.
Nilotinib may be used clinically in combination with hematopoietic growth factors such as erythropoietin or granulocyte colony-stimulating factor (G-CSF). When clinically necessary, it may be used concomitantly with hydroxyurea or anagrelide.
Nilotinib is predominantly metabolized in the liver, and CYP3A4 is expected to be the major contributor to oxidative metabolism. Nilotinib is a substrate for the efflux pump P-glycoprotein (Pgp). Therefore, drugs that inhibit CYP3A4 and/or Pgp may affect the absorption and subsequent systemic elimination of systemically absorbed nilotinib.
Medicinal products that may increase serum concentration of nilotinib.
Concomitant administration of nilotinib with imatinib (a substrate and modulator of Pgp and CYP3A4) caused weak inhibitory effects on CYP3A4 and/or Pgp. When both drugs were administered together, imatinib AUC increased by 18–39%, and nilotinib AUC increased by 18–40%.
Nilotinib bioavailability in healthy volunteers increased threefold when co-administered with ketoconazole, a strong CYP3A4 inhibitor. Therefore, concomitant use of strong CYP3A4 inhibitors (including ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin, but not limited to these) should be avoided. Consideration should be given to using alternative concomitant medications with minimal or no CYP3A4 inhibitory activity.
Medicinal products that may reduce serum concentration of nilotinib.
Rifampicin, a potent CYP3A4 inducer, increased nilotinib Cmax by 64% and reduced AUC by 80%. Rifampicin and nilotinib should not be used concomitantly.
Concomitant use of CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John’s wort) may reduce nilotinib exposure. When CYP3A4 inducers are indicated for patients, consideration should be given to using alternative agents with less pronounced enzyme-inducing potential.
Nilotinib exhibits pH-dependent solubility, with lower solubility at higher pH. In healthy volunteers, administration of 40 mg esomeprazole daily for 5 days significantly increased gastric pH, but nilotinib absorption was only moderately reduced (27% decrease in Cmax and 34% decrease in AUC0–∞). If needed, nilotinib may be co-administered with esomeprazole or other proton pump inhibitors.
In studies conducted in healthy volunteers, no significant changes in nilotinib pharmacokinetics were observed when a single 400 mg dose of nilotinib was administered 10 hours after or 2 hours before famotidine. Therefore, when concomitant use of an H2-receptor antagonist is necessary, it may be administered approximately 10 hours before or 2 hours after nilotinib.
In similar studies, administration of antacids (aluminum hydroxide/magnesium hydroxide/simethicone) 2 hours before or after a single 400 mg dose of nilotinib did not result in significant changes in nilotinib pharmacokinetics. Therefore, when concomitant use of antacids is necessary, they may be taken approximately 2 hours before or 2 hours after nilotinib.
Medicinal products whose systemic concentration may be affected by nilotinib.
Nilotinib has been identified as a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1 in vitro, with the lowest Ki value for CYP2C9 (Ki = 0.13 µM).
In a single-dose drug interaction study involving healthy volunteers, administration of 25 mg warfarin, a sensitive CYP2C9 substrate, together with 800 mg nilotinib, did not result in any changes in warfarin pharmacokinetics or pharmacodynamics as measured by prothrombin time (PT) and international normalized ratio (INR). Steady-state data are lacking. These study results suggest that clinically significant drug interaction between nilotinib and warfarin is unlikely at warfarin doses up to 25 mg. However, due to the lack of steady-state data, monitoring of warfarin pharmacodynamic parameters (INR or PT) is recommended after initiation of nilotinib therapy (at least during the first 2 weeks).
In patients with CML, nilotinib administered at 400 mg twice daily for 12 days increased exposure to orally administered midazolam (a CYP3A4 substrate) by 2.6-fold and 2-fold, respectively. Nilotinib is a moderate inhibitor of CYP3A4. As a result, exposure to other drugs metabolized by CYP3A4 (e.g., certain HMG-CoA reductase inhibitors) may be increased when co-administered with nilotinib. When co-administering nilotinib with drugs that are CYP3A4 substrates and have a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, sirolimus, tacrolimus), appropriate monitoring and dose adjustments may be necessary.
Combining nilotinib with statins primarily eliminated via CYP3A4 may increase the potential for statin-induced myopathy, including rhabdomyolysis.
Antiarrhythmic drugs and other medicinal products that may prolong the QT interval
Concomitant use of antiarrhythmic drugs (including amiodarone, disopyramide, procainamide, quinidine, and sotalol), as well as other medicinal products capable of causing QT interval prolongation (including chloroquine, halofantrine, clarithromycin, haloperidol, methadone, and moxifloxacin), should be avoided (see section "Special precautions for use").
Interactions with food
When administered with food, absorption and bioavailability of nilotinib are increased, leading to higher serum concentrations.
Grapefruit juice and other products known to inhibit CYP3A4 should be avoided at all times.
Special precautions for use.
Myelosuppression.
Treatment with nilotinib is frequently associated with thrombocytopenia, neutropenia, and anemia (grade 3 and 4 according to the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTC]). The frequency of such events is higher in patients with CML who have resistance or intolerance to imatinib, particularly in patients with CML-BCR. Complete blood counts should be performed every two weeks during the first two months and then monthly or as clinically indicated. In most cases, myelosuppression is reversible and managed by temporary interruption of nilotinib or dose reduction (see section "Dosage and administration").
QT interval prolongation.
Data indicate that nilotinib may prolong ventricular repolarization (QT interval on ECG) in a concentration-dependent manner.
In a phase III study involving patients with newly diagnosed chronic phase CML, the change in mean time-averaged QTcF at steady state observed in the nilotinib group (300 mg twice daily) was 6 msec. No patient had an absolute QTcF value exceeding 480 msec. Torsades de pointes was not observed.
In a phase II study in patients with chronic phase and accelerated phase CML with resistance or intolerance to imatinib, when nilotinib was administered at a dose of 400 mg twice daily, the change in mean time-averaged QTcF at steady state was 5 and 8 msec, respectively. QTcF values exceeding 500 msec were recorded in 4 patients (<1% of patients). In clinical trials, episodes of torsades de pointes were not observed.
In a study involving healthy volunteers, at exposures comparable to those in patients, the mean time-averaged change in QTcF, adjusted for placebo, was 7 msec (CI ± 4 msec). No participant had a QTcF duration exceeding 450 msec. Furthermore, no cases of clinically significant arrhythmias were recorded during the study. In particular, episodes of torsades de pointes (transient or sustained) were not observed.
Significant QT interval prolongation may occur when nilotinib is taken incorrectly—concomitantly with food and/or strong CYP3A4 inhibitors and/or drugs known to prolong QT (see section "Interaction with other medicinal products and other forms of interaction"). Hypokalemia and hypomagnesemia may further enhance this effect. QT interval prolongation may lead to fatal outcomes.
Nilotinib should be used with caution in patients with prolonged QT or at high risk of QT prolongation, namely:
- Patients with congenital long QT syndrome;
- Patients with uncontrolled or severe cardiac diseases, including recent myocardial infarction, congestive heart failure, unstable angina, or clinically significant bradycardia;
- Patients taking antiarrhythmic drugs or other substances known to prolong QT.
Careful monitoring of the effect on QTc interval is recommended. A baseline ECG should be performed before starting nilotinib treatment and subsequently as clinically indicated. Hypokalemia or hypomagnesemia should be corrected before initiating nilotinib and monitored periodically during treatment.
Sudden death.
In clinical trials, rare cases (0.1% to 1%) of sudden death were reported in patients with chronic phase or accelerated phase CML with resistance or intolerance to imatinib who were treated with nilotinib and had a history of cardiac disease or significant risk factors for cardiac disease. Concomitant comorbidities were often present, including malignancies requiring concomitant pharmacological treatment. Ventricular repolarization abnormalities may also have been contributing factors. No cases of sudden death were reported in the phase III study of newly diagnosed chronic phase CML.
Fluid retention and edema.
Severe fluid retention, such as pleural effusion, pulmonary edema, and pericardial effusion, was observed infrequently (0.1% to 1%) in the phase III study of patients with newly diagnosed CML. Similar events were reported in the post-marketing period. Unexplained rapid weight gain should be carefully evaluated. If signs of significant fluid retention occur during nilotinib treatment, the cause should be assessed and appropriate therapy initiated (see section "Dosage and administration", recommendations for management of non-hematologic toxicity).
Cardiovascular events.
Cardiovascular events were reported in a randomized phase III trial of nilotinib in patients with newly diagnosed CML and observed in post-marketing reports. With a median treatment duration of 60.5 months, grade 3/4 cardiovascular events in clinical trials included peripheral arterial occlusive disease (1.4% and 1.1% with 300 mg and 400 mg twice daily, respectively), ischemic heart disease (2.2% and 6.1% with 300 mg and 400 mg twice daily, respectively), and ischemic vascular events (1.1% and 2.2% with 300 mg and 400 mg twice daily, respectively). If acute signs or symptoms of cardiovascular events occur, patients should seek immediate medical attention. The cardiovascular status of patients should be evaluated, and cardiovascular risk factors should be monitored and managed during nilotinib therapy according to standard treatment guidelines. Appropriate therapy should be initiated to manage cardiovascular risk factors (see section "Dosage and administration", recommendations for management of non-hematologic toxicity).
Hepatitis B reactivation.
Hepatitis B reactivation occurred in patients who were chronic carriers of the virus after they received BCR-ABL tyrosine kinase inhibitors. In some cases, this led to acute liver failure or fulminant hepatitis, resulting in liver transplantation or death. Before initiating nilotinib treatment, patients should be screened for HBV infection.
Patients with positive serology for hepatitis B (including those with active disease) and those with confirmed HBV infection should be referred for consultation with infectious disease specialists and hepatologists experienced in managing hepatitis B before starting treatment. Carriers of hepatitis B virus who require treatment with nilotinib should be closely monitored for symptoms of active hepatitis B infection during treatment and for several months after treatment completion (see section "Undesirable effects").
Special monitoring of patients with chronic Ph+ CML who achieve sustained deep molecular response.
Criteria for treatment discontinuation.
Consideration may be given to treatment discontinuation in patients who demonstrate expression of typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2. Patients should have typical BCR-ABL transcripts allowing quantitative assessment of BCR-ABL, evaluation of depth of molecular response, and analysis of possible loss of molecular remission after discontinuation of nilotinib.
Monitoring of patients who discontinued treatment.
Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation should be performed using a validated quantitative diagnostic test with sensitivity of at least MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS). BCR-ABL transcript levels should be assessed before and after treatment discontinuation (see sections "Dosage and administration" and "Pharmacodynamics").
Loss of major molecular response (MMR = BCR-ABL/ABL ≤ 0.1% IS) in CML patients treated with nilotinib as first- or second-line therapy, or confirmed loss of MR4 (based on two consecutive measurements at least 4 weeks apart indicating loss of MR4 (MR4 = BCR-ABL/ABL ≤ 0.01% IS) in CML patients treated with nilotinib as second-line therapy, is an indication to resume treatment within 4 weeks of loss of remission being detected. Molecular relapse may occur during the treatment-free phase; therefore, long-term outcomes are currently unknown. Thus, frequent monitoring of BCR-ABL transcript levels and regular complete blood counts with differential counts are essential to detect possible loss of remission (see section "Dosage and administration"). For patients who fail to achieve MMR after three months of re-treatment, testing for BCR-ABL kinase domain mutations should be performed.
Laboratory tests and monitoring.
Lipid profile.
In a phase III study in patients with newly diagnosed CML, grade 3–4 increases in cholesterol were observed in 1.1% of patients receiving 400 mg nilotinib twice daily; however, no grade 3–4 increases in cholesterol were observed in the group receiving 300 mg nilotinib twice daily. Lipid profile should be assessed before starting nilotinib therapy and monitored at 3 and 6 months after initiation of treatment and at least annually during long-term therapy. If lipid-lowering therapy with HMG-CoA reductase inhibitors (statins) is required, the potential for drug interactions should be considered, as certain HMG-CoA reductase inhibitors are metabolized via the same CYP3A4 pathway.
Blood glucose.
In a phase III study in patients with newly diagnosed CML, grade 3–4 increases in glucose were observed in 6.9% of patients receiving 400 mg nilotinib twice daily and in 7.2% of patients receiving 300 mg nilotinib twice daily. Blood glucose levels should be assessed before starting nilotinib therapy, during treatment, and as clinically indicated. Standard treatment regimens should be used if therapy is required.
Drug interactions.
Concomitant use of nilotinib with strong CYP3A4 inhibitors and drugs known to prolong the QT interval, such as antiarrhythmics (including ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, but not limited to these), should be avoided. If treatment with one of these agents is necessary, temporary interruption of nilotinib therapy is recommended (see section "Interaction with other medicinal products and other forms of interaction"). If temporary interruption of nilotinib is not possible, close monitoring for QT interval prolongation is required (see sections "Interaction with other medicinal products and other forms of interaction", "Dosage and administration", "Pharmacokinetics").
Concomitant use of nilotinib with potent CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, phenobarbital, St. John's wort) is likely to result in clinically significant reduction in nilotinib exposure. Therefore, alternative therapeutic agents with less pronounced CYP3A4 induction potential should be selected for concomitant use in patients receiving nilotinib (see section "Interaction with other medicinal products and other forms of interaction").
Effect of food.
Food increases the bioavailability of nilotinib. Nilotinib must not be taken with food.
The drug should be taken 2 hours after a meal. Food should not be consumed for at least 1 hour after taking the dose. Grapefruit juice and other food products known to inhibit CYP3A4 should be avoided at any time.
Patients unable to swallow the capsule may empty the capsule contents onto one teaspoon of applesauce and consume immediately. No more than one teaspoon of applesauce or any other food product should be used.
Hepatic impairment.
The effect of hepatic impairment on the pharmacokinetics of nilotinib is minimal. A single 200 mg dose of nilotinib resulted in AUC increases of 35%, 35%, and 19% in patients with mild, moderate, and severe hepatic impairment, respectively, compared to the control group with normal liver function. The predicted steady-state Cmax of nilotinib showed increases of 29%, 18%, and 22%, respectively. Patients with alanine aminotransferase and/or aspartate aminotransferase levels more than 2.5 times (or more than 5 times if liver disease is present) the upper limit of normal and/or total bilirubin levels more than 1.5 times the upper limit of normal were excluded from clinical trials. Since nilotinib is primarily metabolized in the liver, patients with hepatic impairment may have increased nilotinib exposure. Therefore, caution is recommended when administering nilotinib to patients with hepatic impairment (see section "Dosage and administration").
Serum lipase.
Elevated serum lipase levels have been observed. Caution is recommended when administering the drug to patients with a history of pancreatitis. If elevated lipase levels are accompanied by abdominal symptoms, the drug should be discontinued and appropriate diagnostic measures undertaken to rule out pancreatitis.
Total gastrectomy.
The bioavailability of nilotinib may be reduced in patients who have undergone total gastrectomy. More frequent monitoring of such patients should be considered.
Tumor lysis syndrome.
Due to the potential for tumor lysis syndrome (TLS), correction of clinically significant dehydration and treatment of elevated uric acid levels are recommended before starting nilotinib therapy (see section "Undesirable effects").
Lactose.
Since the capsules contain lactose, nilotinib is not recommended for patients with rare hereditary conditions such as galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding.
Pregnancy. There are no adequate data on the use of nilotinib in pregnant women. Animal studies have shown reproductive toxicity. Nilotinib should not be used during pregnancy except in cases of medical necessity. If the drug is used during pregnancy, the patient should be informed of the potential risk to the fetus.
If a woman receiving nilotinib is planning pregnancy, the possibility of discontinuing treatment may be considered based on the criteria for treatment discontinuation described in sections "Dosage and administration" and "Special precautions for use". Data on pregnancy in patients attempting treatment-free remission (TFR) are limited. If pregnancy is planned during TFR, the patient should be informed of the potential need to resume nilotinib therapy during pregnancy.
Women of childbearing potential. Women of childbearing potential must use effective contraception during nilotinib therapy and for two weeks after the end of treatment.
Breastfeeding. It is unknown whether nilotinib passes into human breast milk. Animal studies show that the drug is excreted in milk. Since risk to newborns/infants cannot be excluded, women should not breastfeed during nilotinib therapy and for 2 weeks after the last dose.
Fertility. Animal studies showed no effect on fertility in male and female rats.
Ability to drive and use machines.
Nilotinib has no or negligible influence on the ability to drive or operate machinery. However, patients experiencing dizziness, fatigue, visual disturbances, or other adverse reactions that may potentially affect their ability to safely drive or operate machinery are advised to refrain from such activities while these effects persist (see section "Undesirable effects").
Administration and Dosage
Treatment must be prescribed by a physician experienced in the diagnosis and treatment of patients with CML.
Dosage
Treatment should be continued as long as the patient continues to benefit or until unacceptable toxicity develops.
If a patient misses a dose, an additional dose should not be taken; the next dose should be taken according to the prescribed schedule.
Dosage for adult patients with Philadelphia chromosome-positive CML
Recommended dosage:
- 300 mg twice daily for patients with newly diagnosed chronic phase CML.
- 400 mg twice daily for patients with chronic phase or accelerated phase CML who are resistant to or intolerant of prior therapies.
Patients with chronic phase Philadelphia chromosome-positive (Ph+) CML who have received nilotinib as first-line therapy and achieved sustained deep molecular response (MR4.5)
Consideration should be given to treatment discontinuation in patients with chronic phase Ph+ CML who have been treated with nilotinib at a dose of 300 mg twice daily for at least 3 years and have maintained a deep molecular response for at least one year immediately prior to stopping treatment. Discontinuation of nilotinib should be initiated by a physician experienced in the management of CML (see sections "Special Warnings and Precautions" and "Pharmacological Properties").
Patients who discontinue nilotinib therapy should undergo differential monitoring of BCR-ABL transcript levels and complete blood counts monthly during the first year, every 6 weeks during the second year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels should be performed using a validated quantitative diagnostic test capable of measuring molecular response levels on the International Scale (IS) with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS).
Patients who during the treatment-free phase lose MR4 (MR4 = BCR-ABL/ABL ≤ 0.01% IS), but do not lose MMR (MMR = BCR-ABL/ABL ≤ 0.1% IS), should undergo BCR-ABL transcript level monitoring every 2 weeks until BCR-ABL levels return to the range between MR4 and MR4.5. Patients whose BCR-ABL levels fluctuate between MMR and MR4 over at least 4 consecutive monitoring assessments may return to the initial monitoring schedule.
Patients who lose MMR must restart treatment within 4 weeks of loss of remission being confirmed. Nilotinib should be restarted at a dose of 300 mg twice daily or at a reduced dose of 400 mg once daily if the patient was receiving a reduced dose prior to treatment discontinuation. Patients who restart nilotinib should undergo monthly monitoring of BCR-ABL transcript levels until MMR is regained, followed by monitoring every 12 weeks (see section "Special Warnings and Precautions").
Patients with chronic phase Philadelphia chromosome-positive (Ph+) CML who achieved sustained deep molecular response (MR4.5) on nilotinib after prior imatinib therapy
Consideration should be given to treatment discontinuation in patients with chronic phase Ph+ CML who have been treated with nilotinib at a dose of 300 mg twice daily for at least 3 years and have maintained a deep molecular response for at least one year immediately prior to stopping treatment. Discontinuation of nilotinib should be initiated by a physician experienced in the management of CML (see sections "Special Warnings and Precautions" and "Pharmacological Properties").
Patients who discontinue nilotinib therapy should undergo differential monitoring of BCR-ABL transcript levels and complete blood counts monthly during the first year, every 6 weeks during the second year, and every 12 weeks thereafter. Monitoring of BCR-ABL transcript levels should be performed using a validated quantitative diagnostic test capable of measuring molecular response levels on the International Scale (IS) with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS).
Patients with confirmed loss of MR4 (MR4 = BCR-ABL/ABL ≤ 0.01% IS) during the treatment-free phase (two consecutive measurements at least 4 weeks apart showing loss of MR4) or loss of major molecular response (MMR = BCR-ABL/ABL ≤ 0.1% IS) must restart treatment within 4 weeks of the loss of remission being confirmed. Nilotinib treatment should be resumed at a dose of 300 mg or 400 mg twice daily. Patients who restart nilotinib should undergo monthly monitoring of BCR-ABL transcript levels until MMR or MR4 level is regained, followed by monitoring every 12 weeks (see section "Special Warnings and Precautions").
Dose adjustment or modification
Temporary interruption and/or dose reduction of nilotinib may be required in the event of hematologic toxicity (neutropenia and thrombocytopenia) not related to the underlying leukemia.
Dose adjustment for neutropenia and thrombocytopenia.
| Newly diagnosed CP-CML at a dose of 300 mg twice daily. CP-CML with resistance or intolerance at a dose of 400 mg twice daily. |
ANC <1*109/L and/or platelet count <50*109/L |
Discontinue nilotinib and monitor blood counts. Resume treatment within 2 weeks at the previous dose if ANC >1*109/L and/or platelets >50*109/L. If blood cell counts remain low, dose reduction to 400 mg once daily may be required. |
| AP-CML with resistance or intolerance to imatinib at a dose of 400 mg twice daily. |
ANC <0.5*109/L and/or platelet count <10*109/L |
Discontinue nilotinib and monitor blood counts. Resume treatment within 2 weeks at the previous dose if ANC >1*109/L and/or platelet count >20*109/L. If blood cell counts remain low, dose reduction to 400 mg once daily may be required. |
1ANC – absolute neutrophil count.
If clinically significant moderate or severe non-hematologic toxicity occurs, treatment with the drug should be discontinued. The patient should be examined and appropriate treatment prescribed. If the previous dose was 300 mg twice daily in patients with newly diagnosed CML in chronic phase or 400 mg twice daily in patients with CML in chronic phase or accelerated phase with resistance or intolerance to imatinib, after normalization of condition, treatment may be resumed at a dose of 400 mg once daily. If the previous dose was 400 mg once daily, treatment should be discontinued. If clinically indicated, re-escalation of the dose to 300 mg (newly diagnosed Ph+ CML-CP) or to 400 mg (Ph+ CML-CP or CML-AP with resistance to imatinib or intolerance to treatment) twice daily may be considered.
Elevated serum lipase level. In case of increase in lipase level to grade 3–4, the dose should be reduced to 400 mg once daily or the drug should be discontinued. Serum lipase levels should be monitored monthly or as clinically indicated (see section "Special instructions").
Elevated bilirubin and liver transaminase levels. In case of increase in bilirubin or liver transaminase levels to grade 3–4, the dose should be reduced to 400 mg once daily or the drug should be discontinued. Bilirubin and liver transaminase levels should be monitored monthly or as clinically indicated.
Special patient groups.
Elderly patients.
Approximately 12% of participants in phase III clinical trials involving patients with newly diagnosed CML in chronic phase and approximately 30% of participants in phase II clinical trials involving patients with CML in chronic phase and accelerated phase with resistance to or intolerance of imatinib were aged 65 years or older. No significant differences in efficacy and safety of the drug in patients aged ≥65 years compared to adult patients aged 18 to 65 years were observed.
Patients with renal impairment.
Clinical studies in patients with renal impairment have not been conducted. Patients with serum creatinine concentration more than 1.5 times the upper limit of normal were excluded from clinical trials.
Since nilotinib and its metabolites are not excreted via kidneys, there is no reason to expect reduced total clearance in patients with renal impairment.
Patients with hepatic impairment.
The effect of hepatic impairment on the pharmacokinetics of nilotinib is minimal. Dose adjustment in patients with hepatic impairment is considered unnecessary; however, treatment of such patients should be performed with caution.
Cardiac disease.
Patients with uncontrolled or severe cardiac diseases, including recent myocardial infarction, congestive heart failure, unstable angina, or clinically significant bradycardia, were excluded from clinical trials. The drug should be used with caution in patients with serious cardiac diseases (see section "Special instructions").
Elevated serum cholesterol levels have been reported during nilotinib treatment (see section "Special instructions"). Lipid profiles should be assessed prior to starting nilotinib therapy, evaluated at 3 and 6 months after initiation of therapy, and at least once yearly during long-term therapy.
Hyperglycemia has been observed during nilotinib therapy (see section "Special instructions"). Blood glucose levels should be assessed prior to starting nilotinib therapy and monitored throughout the course of treatment.
Administration method
Nilotinib should be administered twice daily approximately 12 hours apart; the drug should not be taken with food. Capsules should be swallowed whole with water. Food should be avoided for at least 2 hours before and for at least 1 hour after administration of the drug.
For patients unable to swallow capsules, the contents of one capsule may be mixed with one teaspoon of applesauce and taken immediately. No more than one teaspoon of applesauce or any other food should be used (see section "Special instructions" and "Pharmacological properties").
Children.
Safety and efficacy of the drug in children under 18 years of age have not been established.
Overdose.
Isolated reports of intentional overdosage with nilotinib have been received, in which an unspecified number of nilotinib capsules were taken in combination with alcohol and other medicinal products. Adverse reactions observed in these cases included neutropenia, vomiting, and somnolence. No ECG changes or signs of hepatotoxicity were reported. The reactions observed following overdosage were reversible.
In case of overdose, the patient should be examined and appropriate supportive treatment should be administered.
Adverse reactions
The safety profile is based on pooled data from 3422 patients who received nilotinib in 13 clinical trials for approved indications: adult patients with Philadelphia chromosome-positive newly diagnosed chronic phase chronic myeloid leukemia (Ph+ CML) (5 clinical trials involving 2414 patients), and adult patients with Philadelphia chromosome-positive CML in chronic or accelerated phase who were resistant to or intolerant of prior therapy, including imatinib (6 clinical trials involving 939 patients).
The most common adverse reactions (incidence ≥ 15%) according to pooled safety data were: rash (26.4%), upper respiratory tract infections (including pharyngitis, nasopharyngitis, rhinitis) (24.8%), headache (21.9%), hyperbilirubinemia (including increased blood bilirubin levels) (18.6%), arthralgia (15.8%), fatigue (15.4%), nausea (16.8%), pruritus (16.7%), and thrombocytopenia (16.4%).
List of adverse reactions in table form
Adverse reactions identified in clinical trials and during the post-marketing period (see the table below "Adverse drug reactions") are listed by system organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA) and by frequency. The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).
Adverse drug reactions
| Infections and infestations |
|
| Very common: |
upper respiratory tract infections (including pharyngitis, nasopharyngitis, rhinitis) |
| Common: |
folliculitis, bronchitis, candidiasis (including oral candidiasis), pneumonia, gastroenteritis, urinary tract infections |
| Uncommon: |
herpes virus infection, anal abscess, candidiasis (candidal infection), furunculosis, sepsis, subcutaneous abscesses, fungal infection of the foot skin |
| Rare: |
reactivation of hepatitis B |
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
|
| Uncommon: |
skin papillomas |
| Rare: |
oral cavity papillomas, paraproteinemia |
| Blood and lymphatic system disorders |
|
| Very common: |
anemia, thrombocytopenia |
| Common: |
leukopenia, leukocytosis, neutropenia, thrombocytosis |
| Uncommon: |
eosinophilia, febrile neutropenia, lymphopenia, pancytopenia |
| Immune system disorders |
|
| Uncommon: |
hypersensitivity |
| Endocrine disorders |
|
| Very common: |
growth retardation |
| Common: |
hypothyroidism |
| Uncommon: |
hyperthyroidism |
| Rare: |
secondary hyperparathyroidism, thyroiditis |
| Metabolism and nutrition disorders |
|
| Common: |
electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, decreased appetite, gout, hyperuricemia, hypophosphatemia (including decreased blood phosphorus levels) |
| Uncommon: |
dehydration, increased appetite, dyslipidemia, hypoglycemia |
| Rare: |
appetite disorder, tumor lysis syndrome |
| Psychiatric disorders |
|
| Common: |
depression, insomnia, anxiety |
| Uncommon: |
amnesia, confusion, disorientation |
| Rare: |
dysphoria |
| Nervous system disorders |
|
| Very common: |
headache |
| Common: |
dizziness, hypoesthesia, paresthesia, migraine |
| Uncommon: |
cerebrovascular disorder, intracranial hemorrhage, ischemic stroke, transient ischemic attack, cerebral infarction, loss of consciousness (including syncope), tremor, attention impairment, hyperesthesia, dysesthesia, lethargy, peripheral neuropathy, restless legs syndrome, facial paralysis |
| Rare: |
basilar artery stenosis, brain edema, optic neuritis |
| Eye disorders |
|
| Common: |
conjunctivitis, dry eyes (including xerophthalmia), eye irritation, hyperemia (of sclera, conjunctiva, eye), blurred vision |
| Uncommon: |
visual disturbance, conjunctival hemorrhage, decreased visual acuity, eyelid edema, blepharitis, photopsia, allergic conjunctivitis, diplopia, eye hemorrhage, eye pain, eye pruritus, eye swelling, superficial eye tissue disorders, periorbital edema, photophobia |
| Rare: |
chorioretinopathy, optic disc edema |
| Ear and labyrinth disorders |
|
| Common: |
vertigo, ear pain, tinnitus |
| Uncommon: |
hearing impairment (hypoacusis) |
| Cardiac disorders |
|
| Common: |
angina pectoris, arrhythmia (including atrioventricular block, palpitations, ventricular extrasystoles, tachycardia, atrial fibrillation, bradycardia), palpitations, prolonged QT interval on ECG, ischemic heart disease |
| Uncommon: |
myocardial infarction, cardiac murmur, pericardial effusion, heart failure, diastolic dysfunction, left bundle branch block, pericarditis |
| Rare: |
cyanosis, reduced ejection fraction |
| Frequency not known: |
ventricular dysfunction |
| Vascular disorders |
|
| Common: |
arterial hypertension, hyperemia, peripheral arterial occlusive disease |
| Uncommon: |
hypertensive crisis, intermittent claudication, peripheral arterial stenosis, hematoma, arteriosclerosis, arterial hypotension, thrombosis |
| Rare: |
hemorrhagic shock |
| Respiratory, thoracic and mediastinal disorders |
|
| Very common: |
cough |
| Common: |
dyspnea, exertional dyspnea, epistaxis, oropharyngeal pain |
| Uncommon: |
pulmonary edema, pleural effusion, interstitial lung disease, pleural pain, pleuritis, throat irritation, dysphonia, pulmonary hypertension, wheezing |
| Rare: |
pharyngolaryngeal pain |
| Gastrointestinal disorders |
|
| Very common: |
nausea, upper abdominal pain, constipation, diarrhea, vomiting |
| Common: |
pancreatitis, abdominal discomfort, abdominal distension, flatulence, abdominal pain, dyspepsia, gastritis, gastroesophageal reflux, hemorrhoids, stomatitis |
| Uncommon: |
gastrointestinal hemorrhage, melena, oral mucosal ulcer, esophageal pain, dry mouth, dental sensitivity (dental hyperesthesia), dysgeusia, enterocolitis, gastric ulcer, gingivitis, hiatal hernia, rectal bleeding |
| Rare: |
GIT ulcers with perforation, hematemesis, esophageal ulcer, ulcerative esophagitis, retroperitoneal hemorrhage, partial intestinal obstruction |
| Hepatobiliary disorders |
|
| Very common: |
hyperbilirubinemia (including increased bilirubin levels in blood) |
| Common: |
liver function disorder |
| Uncommon: |
hepatotoxicity, toxic hepatitis, jaundice, cholestasis, hepatomegaly |
| Skin and subcutaneous tissue disorders |
|
| Very common: |
rash, pruritus, alopecia |
| Common: |
night sweats, eczema, urticaria, hyperhidrosis, bruising, acne, dermatitis (including allergic, exfoliative and acneiform), dry skin, erythema |
| Uncommon: |
exfoliative rash, drug-induced dermatitis, skin pain, ecchymosis, facial edema, blisters, skin cysts, nodular erythema, hyperkeratosis, petechiae, photosensitivity, psoriasis, skin color changes, skin exfoliation, hyperpigmentation of the skin, skin hypertrophy, skin ulcers |
| Rare: |
multiform erythema, palmar-plantar erythrodysesthesia, sebaceous gland hyperplasia, skin atrophy |
| Musculoskeletal and connective tissue disorders |
|
| Very common |
myalgia, arthralgia, back pain, limb pain |
| Common: |
musculoskeletal chest pain, musculoskeletal pain, neck pain, muscle weakness, muscle spasms, bone pain |
| Uncommon: |
musculoskeletal stiffness, joint swelling, arthritis, flank pain |
| Renal and urinary disorders |
|
| Common: |
polyuria, dysuria |
| Uncommon: |
urge incontinence, nocturia, chromaturia, hematuria, renal failure, urinary incontinence |
| Reproductive system and breast disorders |
|
| Common: |
erectile dysfunction, menorrhagia |
| Uncommon: |
breast pain, gynecomastia, nipple swelling |
| Rare: |
hardness in the breast |
| General disorders and administration site conditions |
|
| Very common |
fatigue, pyrexia |
| Common: |
chest pain (including non-cardiac chest pain), pain, discomfort in chest, malaise, asthenia and peripheral edema, chills, influenza-like illness |
| Uncommon: |
facial edema, gravitational edema, sensation of body temperature change (including feeling of heat, chills), localized edema |
| Rare: |
sudden death |
| Investigations |
|
| Very common: |
elevated alanine aminotransferase levels, elevated lipase levels |
| Common: |
decreased hemoglobin levels, elevated blood amylase levels, elevated aspartate aminotransferase levels, elevated alkaline phosphatase activity in blood, elevated gamma-glutamyltransferase activity, elevated creatine phosphokinase levels in blood, decreased body weight, increased body weight, elevated creatinine levels, elevated total cholesterol levels |
| Uncommon: |
elevated lactate dehydrogenase levels in blood, elevated blood urea levels, elevated unconjugated bilirubin levels in blood, elevated parathyroid hormone levels in blood, elevated triglyceride levels in blood, decreased globulin levels, elevated lipoprotein cholesterol levels (including low-density and high-density), elevated troponin levels |
| Rare: |
decreased blood glucose levels, decreased blood insulin levels, elevated blood insulin levels, decreased C-peptide insulin levels |
Description of individual adverse reactions.
Sudden fatal outcome.
During clinical studies with nilotinib, rare cases (0.1–1%) of sudden death were reported in patients with chronic phase CML or accelerated phase CML who were resistant to or intolerant of imatinib and who had a history of cardiac disease or significant risk factors for cardiac disease.
Hepatitis B reactivation.
Hepatitis B reactivation has been reported in patients receiving a BCR-ABL tyrosine kinase inhibitor (TKI). In some cases, this led to acute liver failure or fulminant hepatitis, requiring liver transplantation or resulting in fatal outcomes.
Reporting suspected adverse reactions
Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System of Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C, in a place inaccessible to children.
Packaging. №56 (7х8): 7 capsules in a blister, 8 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer. Shilpa Medikea Limited / Shilpa Medicare Limited.
Manufacturer's address and location of its business operations.
Unit 4, Pharmaceutical Formulations SEZ, Plot No's S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahbubnagar, Telangana, 509301, India /
Unit-4, Pharmaceutical Formulations SEZ, Plot No's S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahabооbnagar, Telangana, 509301, India.