Nilotinib

FOR MEDICINAL USE OF THE MEDICINAL PRODUCT NILONIB (NILOTINIB)

Composition:

Active substance: nilotinib;

1 capsule contains 150 mg or 200 mg of nilotinib;

Excipients:

lactose monohydrate, crospovidone, SepiTRADE 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;

ink composition (BlackInk): shellac, anhydrous 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;

ink composition (RedInk): shellac, anhydrous 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 the marking "SML" in black ink on the cap and "26" on the body, containing granular powder of white to grey color;

200 mg capsules – light-yellow, opaque capsules with the marking "SML" in red ink on the cap and "27" on the body, containing granular powder of white to grey 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 kinase, acting in cell lines and in primary Philadelphia chromosome–positive leukemic cells. The drug tightly binds to the ATP-binding site, thereby forming a potent inhibitor of wild-type Bcr-Abl, and retains activity against 32 out 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 other tested protein kinases, including serine protein kinase (Src), except for platelet-derived growth factor (PDGF), receptor tyrosine kinase activity (Kit, CSF-1R, DDR), and ephrin receptor kinases, which the drug inhibits 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)

Pharmacokinetics.

Absorption.

Following oral administration, peak concentrations of nilotinib are reached within 3 hours; absorption 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 under fasting conditions. When nilotinib is administered 30 minutes or 2 hours after a meal, bioavailability increases 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 main metabolic pathways are oxidation and hydroxylation. Nilotinib is the predominant circulating component in plasma. None of the metabolites play a significant role in 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 the dose). The parent drug accounted for 69% of the dose.

The apparent elimination half-life calculated from multiple-dose pharmacokinetics with daily administration was 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 a dose of 400 mg twice daily was 35% higher than with 800 mg once daily. Systemic exposure (AUC) of nilotinib at steady state with a dose of 400 mg twice daily was approximately 13.4% higher than with 300 mg twice daily. Mean residual and maximum plasma 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.

It has been demonstrated that a single 400 mg dose of nilotinib (two 200 mg capsules) administered by emptying the contents of each capsule onto one teaspoon of applesauce is 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 the Philadelphia chromosome.

Treatment of chronic and accelerated phase (AP) chronic myeloid leukemia (Ph+ CML) in adult patients with the Philadelphia chromosome in cases of resistance or intolerance to prior therapy, including imatinib therapy.

Contraindications.

Hypersensitivity to nilotinib or to any of the excipients 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 also be used concomitantly with hydroxyurea or anagrelide.

Nilotinib is primarily metabolized in the liver, and CYP3A4 is expected to be the major enzyme responsible for its 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 absorbed nilotinib.

Medicinal products that may increase serum concentrations of nilotinib.

Concomitant administration of nilotinib with imatinib (a substrate and modulator of both Pgp and CYP3A4) resulted in weak inhibitory effects on CYP3A4 and/or Pgp. When both drugs were administered together, the AUC of imatinib increased by 18–39%, and the AUC of nilotinib increased by 18–40%.

The bioavailability of nilotinib in healthy volunteers increased threefold when coadministered with the strong CYP3A4 inhibitor ketoconazole. Therefore, concomitant use of strong CYP3A4 inhibitors (including ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin, but not limited to these) should be avoided. Alternative concomitant medications with minimal or no inhibitory effect on CYP3A4 should be considered.

Medicinal products that may reduce serum concentrations of nilotinib.

Rifampicin, a potent CYP3A4 inducer, increased the C_max of nilotinib by 64% and reduced its AUC by 80%. Rifampicin and nilotinib should not be administered concurrently.

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 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 absorption of nilotinib was only moderately reduced (27% decrease in C_max and 34% decrease in AUC_0–∞). If necessary, nilotinib may be coadministered with esomeprazole or other proton pump inhibitors.

In studies conducted in healthy volunteers, no significant changes in the pharmacokinetics of nilotinib 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 required, 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 the pharmacokinetics of nilotinib. 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 concentrations may be affected by nilotinib.

Nilotinib has been identified in vitro as a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1, 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 the pharmacokinetics or pharmacodynamics of warfarin 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 absence 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 a dose of 400 mg twice daily for 12 days increased the exposure of 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 coadministered with nilotinib. When coadministering 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 that are 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 known to cause QT prolongation (including chloroquine, halofantrine, clarithromycin, haloperidol, methadone, and moxifloxacin), should be avoided (see section "Special warnings and precautions for use").

Food interactions

When administered with food, absorption and bioavailability of nilotinib increase, resulting in 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 incidence of these 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 for 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 in patients with newly diagnosed chronic phase CML, the change in mean time-corrected QTcF interval 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. Episodes of bidirectional ventricular tachycardia were 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-corrected QTcF interval at steady state was 5 msec and 8 msec, respectively. QTcF values exceeding 500 msec were recorded in 4 patients (<1% of patients). In clinical studies, episodes of torsades de pointes ventricular tachycardia were not observed.

In a study conducted in healthy volunteers at exposures comparable to those in patients, the mean time-corrected change in QTcF, adjusted for placebo, was 7 msec (90% CI: ±4 msec). No participant had a QTcF interval exceeding 450 msec. Furthermore, no cases of clinically significant arrhythmias were recorded during the study. Specifically, no episodes of bidirectional ventricular tachycardia (transient or sustained) were observed.

Significant QT interval prolongation may occur when nilotinib is used incorrectly—taken 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, including:

• 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 the QT interval.

Careful monitoring of the effect on QTc interval is recommended. A baseline ECG should be performed before starting nilotinib treatment and periodically thereafter 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, including malignancies requiring concomitant medication, were often present. Ventricular repolarization abnormalities may also have been contributing factors. No cases of sudden death were reported in the phase III study in patients with newly diagnosed chronic phase CML.

Fluid retention and edema.

Severe fluid retention, such as pleural effusion, pulmonary edema, and pericardial effusion, occurred rarely (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 studies 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 cerebrovascular 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 in patients who are chronic carriers of the virus has occurred after these patients 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 starting nilotinib treatment, patients should be tested for HBV infection.

Patients with positive serological tests for hepatitis B (including those with active disease) and patients with confirmed HBV infection should be referred for consultation with infectious disease specialists and hepatologists experienced in managing hepatitis B before initiating treatment. Carriers of hepatitis B virus who require treatment with nilotinib should be closely monitored for signs of active hepatitis B infection during treatment and for several months after treatment discontinuation (see section "Adverse reactions").

Special monitoring of patients with chronic Ph+ CML who achieve sustained deep molecular response.

Criteria for treatment discontinuation.

Treatment discontinuation may be considered in patients who express typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2. Patients should have typical BCR-ABL transcripts that allow quantitative BCR-ABL measurement, assessment of depth of molecular response, and monitoring for possible loss of molecular remission after discontinuation of nilotinib.

Monitoring of patients who discontinue 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, should prompt resumption of treatment within 4 weeks of loss of remission being detected. Molecular relapse may occur during the treatment-free phase; therefore, long-term outcomes are not yet available. Frequent monitoring of BCR-ABL transcript levels and complete blood counts with differential is 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, mutation testing of the BCR-ABL kinase domain 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 levels were observed in 1.1% of patients receiving 400 mg of nilotinib twice daily; however, no grade 3–4 increases in cholesterol were observed in the group receiving 300 mg of nilotinib twice daily. Lipid profiling is recommended before starting nilotinib therapy, and monitoring should be performed at 3 and 6 months after initiation of treatment and at least annually during long-term therapy. If treatment with HMG-CoA reductase inhibitors (lipid-lowering agents) becomes necessary, 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 levels were observed in 6.9% of patients receiving 400 mg of nilotinib twice daily and in 7.2% of patients receiving 300 mg of 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 treatment 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 required, temporary interruption of nilotinib therapy is recommended, if possible (see section "Interaction with other medicinal products and other forms of interaction"). If temporary interruption of nilotinib is not feasible, close monitoring for QT interval prolongation is indicated (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 administered 2 hours after a meal. Food should not be consumed for at least 1 hour after dosing. Grapefruit juice and other food products known to inhibit CYP3A4 should be avoided at all times.

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 should be used.

Hepatic impairment.

The effect of hepatic impairment on the pharmacokinetics of nilotinib is modest. 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 control patients 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 nilotinib 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 "Adverse reactions").

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 syndrome.

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 urgent medical need. 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 reproductive potential. Women of reproductive potential must use effective contraception during treatment with nilotinib and for two weeks after the end of therapy.

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 treatment with nilotinib 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 use machines. However, patients experiencing dizziness, fatigue, visual disturbances, or other adverse reactions that may affect their ability to safely drive or operate machinery should refrain from such activities while these symptoms persist (see section "Adverse reactions").

Method of 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 is:

• 300 mg twice daily for patients with newly diagnosed CML in the chronic phase.
• 400 mg twice daily for patients with CML in the chronic phase and accelerated phase who are resistant to or intolerant of prior therapies.

Patients with Philadelphia chromosome-positive chronic-phase 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 Philadelphia chromosome-positive (Ph+) chronic-phase 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 Instructions" and "Pharmacological Properties").

Patients who discontinue nilotinib 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 quantitative diagnostic test validated for 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 lose MR4 (MR4 = BCR-ABL/ABL ≤ 0.01% IS) but do not lose MMR (MMR = BCR-ABL/ABL ≤ 0.1% IS) during the treatment-free phase should be monitored for BCR-ABL transcript levels 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 had previously been receiving a reduced dose before discontinuation. Patients who restart nilotinib should be monitored monthly for BCR-ABL transcript levels until MMR is re-established, and then every 12 weeks (see section "Special Instructions").

Patients with Philadelphia chromosome-positive chronic-phase 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 Philadelphia chromosome-positive (Ph+) chronic-phase 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 Instructions" and "Pharmacological Properties").

Patients who discontinue nilotinib 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 quantitative diagnostic test validated for 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 taken at least 4 weeks apart showing loss of MR4) or loss of major molecular response (MMR = BCR-ABL/ABL ≤ 0.1% IS) should 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 be monitored monthly for BCR-ABL transcript levels until re-achievement of MMR or MR4 level, and then every 12 weeks (see section "Special Instructions").

Dose Adjustment or Modification

Temporary interruption and/or dose reduction of nilotinib may be required due to hematologic toxicity (neutropenia and thrombocytopenia) not related to the leukemia itself.

Dose adjustment for neutropenia and thrombocytopenia.

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 therapy initiated. If the previous dose was 300 mg twice daily in patients with newly diagnosed CML in the chronic phase or 400 mg twice daily in patients with CML in the chronic phase or accelerated phase with resistance or intolerance to imatinib, after normalization of the 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 appropriate, 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 or intolerance of imatinib) twice daily should be considered.

Elevated serum lipase levels. In case of increased lipase levels 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 increased 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 the chronic phase, and approximately 30% of participants in phase II clinical trials involving patients with CML in the 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 the 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 disease, 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 disease (see section "Special instructions").

Elevated serum cholesterol levels have been reported during nilotinib treatment (see section "Special instructions"). Lipid profiles should be assessed before initiating nilotinib therapy, evaluated at 3 and 6 months after starting therapy, and at least once yearly during long-term treatment.

During nilotinib therapy, increased blood glucose levels have been observed (see section "Special instructions"). Blood glucose levels should be assessed before starting nilotinib therapy and monitored throughout the treatment course.

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 not be consumed at least 2 hours before and at least 1 hour after taking the drug.

For patients unable to swallow the capsule, the contents of one capsule may be mixed with one teaspoon of apple puree and taken immediately. Do not use more than one teaspoon of apple puree or any other food (see section "Special instructions" and "Pharmacological properties").

Children.

The safety and efficacy of the drug in children under 18 years of age have not been established.

Overdose.

There have been isolated reports of intentional nilotinib overdose, where an unspecified number of nilotinib capsules were taken in combination with alcohol and other medications. Adverse reactions observed in these cases included neutropenia, vomiting, and somnolence. No changes on ECG or signs of hepatotoxicity were reported. The reactions observed in cases of overdose were reversible.

In case of overdose, the patient should be examined and appropriate supportive treatment initiated.

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 chronic-phase chronic myeloid leukemia (Ph+ CML) at diagnosis (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%) based on 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 "Adverse Drug Reactions" below) are listed by organ system classes according to the Medical Dictionary for Regulatory Activities (MedDRA) classification 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 available data).

Adverse Drug Reactions

Description of individual adverse reactions.

Sudden death.

During clinical trials with nilotinib, rare cases (0.1% to 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 following administration of 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 is important. It allows continued monitoring of the benefit-risk balance of this medicinal product. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System 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 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.