Nilotinib-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Nilotinib-Vista (NILOTINIB-VISTA)

Composition:

Active substance: nilotinib;

Each capsule contains 56.85 mg of nilotinib hydrochloride dihydrate equivalent to 50 mg of nilotinib, or 170.54 mg of nilotinib hydrochloride dihydrate equivalent to 150 mg of nilotinib, or 227.38 mg of nilotinib hydrochloride dihydrate equivalent to 200 mg of nilotinib;

Excipients: lactose monohydrate, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate.

Capsule shell:

50 mg and 150 mg dosage: hypromellose (E 464), purified water, carrageenan (E 407), potassium chloride (E 508), erythrosine (E 127), iron oxide yellow (E 172), iron oxide red (E 172), titanium dioxide (E 171);

200 mg dosage: hypromellose (E 464), purified water, carrageenan (E 407), potassium chloride (E 508), iron oxide yellow (E 172), titanium dioxide (E 171).

Black printing ink: shellac (E 904), propylene glycol (E 1520), potassium hydroxide (E 525), iron oxide black (E 172).

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics:

50 mg capsules: hard capsules made of hydroxypropylmethylcellulose (HPMC) with a red opaque cap and a light-yellow opaque body, size 4, with a black horizontal marking "50 mg" on the body, containing a white to yellowish powder;

150 mg capsules: red opaque hard capsules made of hydroxypropylmethylcellulose (HPMC), size 1, with a black horizontal marking "150 mg" on the body, containing a white to yellowish powder;

200 mg capsules: light-yellow opaque hard capsules made of hydroxypropylmethylcellulose (HPMC), size 0, with a black horizontal marking "200 mg" on the body, containing a white to yellowish powder.

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 on cell lines and primary Philadelphia chromosome–positive leukemic cells. Nilotinib binds tightly 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 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 reduced 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), tyrosine kinase receptors (Kit, CSF-1R, DDR), and Eph receptor kinases, which nilotinib 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)

Bcr-Abl	PDGFR	KIT
20	69	210

Pharmacokinetics.

Absorption

Following oral administration, peak concentrations (Cmax) 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) increase by 112% and 82%, respectively, compared to administration under fasting conditions. Administration of nilotinib 30 minutes or 2 hours after a meal increases nilotinib 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 main metabolic pathways are oxidation and hydroxylation. The primary circulating component in plasma is nilotinib. No metabolite contributes 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 the dose). Unchanged nilotinib accounted for 69% of the dose.

The apparent elimination half-life, calculated from multiple-dose pharmacokinetics with daily dosing, is approximately 17 hours. The extent of pharmacokinetic variability of nilotinib across different patients ranges from moderate to high.

Linearity/Non-linearity

At steady state, nilotinib exposure is dose-dependent, with less than dose-proportional increases in systemic exposure at doses exceeding 400 mg once daily. The steady-state plasma exposure of nilotinib at a dose of 400 mg twice daily is 35% higher than with 800 mg once daily. The steady-state AUC of nilotinib at 400 mg twice daily is approximately 13.4% higher than at 300 mg twice daily. Average residual and maximum 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 generally achieved by Day 8. Plasma exposure of nilotinib increased approximately 2-fold between the first dose and steady state with once-daily dosing, and 3.8-fold with twice-daily dosing.

Bioavailability/Bioequivalence Studies

A single 400 mg dose of nilotinib (two 200 mg capsules) with the contents of each capsule sprinkled onto one teaspoon of apple sauce has been shown to be bioequivalent to a single dose of two intact 200 mg capsules.

Pediatric Patients

Following administration of nilotinib to pediatric patients at a dose of 230 mg/m² twice daily, rounded to the nearest 50 mg dose (up to a maximum single dose of 400 mg), steady-state exposure and clearance of nilotinib were similar (within 2-fold) to those in adults receiving 400 mg twice daily. Pharmacokinetic exposure of nilotinib after single or multiple doses was comparable in children aged 2 to <10 years and those aged ≥10 to <18 years.

Clinical characteristics.

Indications.

Treatment of newly diagnosed chronic phase chronic myeloid leukemia (Ph+ CML) in adult and pediatric patients with the Philadelphia chromosome. Treatment of chronic and accelerated phase (AP) chronic myeloid leukemia (Ph+ CML) in adult patients with the Philadelphia chromosome who are resistant to or intolerant of prior therapy, including imatinib therapy. Treatment of pediatric patients with Ph+ CML in chronic phase who are resistant to or intolerant of 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 types of interactions.

The medicinal product 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 primarily metabolized in the liver; CYP3A4 is expected to be the main contributor to oxidative metabolism. Nilotinib is a substrate of the efflux pump P-glycoprotein (Pgp). Therefore, medicinal products that inhibit CYP3A4 and/or Pgp may affect the absorption and subsequent systemic elimination of absorbed nilotinib.

Medicinal products that may increase serum concentration of nilotinib
Concomitant administration of nilotinib with imatinib (a substrate and modulator of both Pgp and CYP3A4) caused weak inhibitory effects on CYP3A4 and/or Pgp. When both medicinal products 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 co-administered with ketoconazole, a strong CYP3A4 inhibitor. Therefore, concomitant use with strong inhibitors of CYP3A4 (including ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, and telithromycin, but not limited to these) should be avoided. Alternative concomitant therapy with minimal or no inhibitory effect on CYP3A4 should be considered.

Medicinal products that may decrease serum concentration of nilotinib
Rifampicin, a potent CYP3A4 inducer, increased the Cmax of nilotinib by 64% and reduced its 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 medicinal products with less pronounced enzyme-inducing potential.

Nilotinib has 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% reduction in Cmax and 34% reduction in AUC0–∞). If needed, the medicinal product may be administered concomitantly with esomeprazole or other proton pump inhibitors.

In clinical studies 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 before or 2 hours after famotidine. Therefore, when concomitant use of an H2-blocker 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 administered approximately 2 hours before or 2 hours after nilotinib.

Medicinal products whose systemic concentration 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 in healthy volunteers, co-administration of 25 mg warfarin, a sensitive CYP2C9 substrate, 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 a 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 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 medicinal products metabolized by CYP3A4 (e.g., certain HMG-CoA reductase inhibitors) may be increased when co-administered with nilotinib. When co-administering nilotinib with medicinal products 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.

Combination of nilotinib with statins primarily eliminated via CYP3A4 may increase the potential for statin-induced myopathy, including rhabdomyolysis.

Antiarrhythmic medicinal products and other medicinal products that may prolong the QT interval
Concomitant use of antiarrhythmic agents (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").

Interaction 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 any time.

Pediatric patients
Drug interaction studies have been conducted only in adults.

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's Common Toxicity Criteria). The incidence of such events is higher in patients with CML who are resistant or intolerant to imatinib, particularly in patients with CML-BCR-ABL. 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

Available data indicate that nilotinib may concentration-dependently prolong ventricular repolarization (QT interval on ECG).

In a phase III study in 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. Episodes of bidirectional ventricular tachycardia were not observed.

In a phase II study in patients with imatinib-resistant or imatinib-intolerant chronic phase and accelerated phase CML receiving nilotinib 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 studies, episodes of torsades de pointes were not observed.

In a study conducted in healthy volunteers, at exposures comparable to those in patients, the mean time-averaged change in QTcF, adjusted for placebo, was 7 msec (90% 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, no episodes of torsades de pointes (transient or sustained) were observed.

Significant QT interval prolongation may occur when nilotinib is administered incorrectly—concomitantly with food and/or strong CYP3A4 inhibitors, and/or with drugs known to prolong the QT interval (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.

The medicinal product 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 the QT interval.

Careful monitoring of the effect on the QTc interval is recommended. A baseline ECG should be performed before initiating treatment and subsequently as clinically indicated. Hypokalemia or hypomagnesemia should be corrected prior to starting nilotinib and monitored periodically during treatment.

Sudden death

In clinical studies, rare cases (0.1–1%) of sudden death were reported in patients with chronic phase or accelerated phase CML who were resistant or intolerant to imatinib and who had a history of cardiac disease or significant risk factors for cardiac disease. Concomitant comorbidities, including malignancies requiring concomitant drug therapy, 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, was infrequently observed (0.1–1%) in the phase III study in patients with newly diagnosed CML. Similar events were reported in the post-marketing period. Unexplained rapid weight gain should be carefully investigated. In the presence of signs of significant fluid retention during nilotinib therapy, the cause should be evaluated and appropriate therapy initiated (see section "Dosage and administration", recommendations for management of non-hematologic toxicity).

Cardiovascular events

Cardiovascular events were recorded in a randomized phase III trial of nilotinib in patients with newly diagnosed CML and have been reported in post-marketing experience. With a median treatment duration of 60.5 months in clinical studies, grade 3/4 cardiovascular events 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 disease 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 has occurred in patients who are chronic carriers of the virus following treatment with BCR-ABL tyrosine kinase inhibitors. In some cases, this has led to acute liver failure or fulminant hepatitis requiring liver transplantation or resulting in death. Before initiating nilotinib therapy, patients should be tested for HBV infection. Patients with a positive serological test 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. Patients who are hepatitis B virus carriers and require treatment with nilotinib should be closely monitored for signs of active hepatitis B infection during treatment and for several months after discontinuation of therapy (see section "Undesirable effects").

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

Criteria for treatment discontinuation

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

Monitoring of patients who discontinue treatment

Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation should be performed using a quantitative diagnostic test validated for measuring molecular response levels, with a 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 "Pharmacodynamics" and "Dosage and administration").

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, warrants resumption of treatment within 4 weeks of loss of remission. 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 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, testing for BCR-ABL kinase domain mutations should be performed.

Laboratory tests and monitoring

Blood 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, but not in patients receiving 300 mg nilotinib twice daily. Lipid profile should be assessed before initiating nilotinib therapy and monitored at 3 and 6 months after initiation 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 pathway as CYP3A4.

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. If treatment is required, standard management approaches should be used.

Interaction with medicinal products

Concomitant use of nilotinib with strong CYP3A4 inhibitors and drugs that may 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 drugs is necessary, 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, careful monitoring for QT interval prolongation is indicated (see sections "Pharmacokinetics", "Interaction with other medicinal products and other forms of interaction", "Dosage and administration").

Concomitant use of nilotinib with potent CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine, phenobarbital, and St. John’s wort) is likely to result in clinically significant reduction in nilotinib exposure. Therefore, alternative therapeutic agents with less potential to induce CYP3A4 should be selected for concomitant use (see section "Interaction with other medicinal products and other forms of interaction").

Effect of food

Food increases the bioavailability of nilotinib. The medicinal product should not be taken with food. It 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. Do not use more than one teaspoon of applesauce or any other food.

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of nilotinib is modest. A single 200 mg dose of nilotinib resulted in increases in AUC of 35%, 35%, and 19% in patients with mild, moderate, and severe hepatic impairment, respectively, compared to control patients with normal hepatic 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 studies. Since nilotinib is primarily metabolized in the liver, patients with hepatic impairment may have increased nilotinib exposure. Therefore, caution is recommended when administering the medicinal product to patients with hepatic impairment (see section "Dosage and administration").

Serum lipase

Elevated serum lipase levels have been observed. The medicinal product should be used with caution in patients with a history of pancreatitis. If elevated lipase levels are accompanied by abdominal symptoms, the medicinal product should be discontinued and appropriate diagnostic measures initiated 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 initiating nilotinib therapy (see section "Undesirable effects").

Pediatric patients

Laboratory abnormalities, including mild to moderate transient elevations in aminotransferases and total bilirubin, were observed more frequently in children than in adults, indicating a higher risk of hepatotoxicity in the pediatric population (see section "Special precautions for use"). Liver function (bilirubin and liver transaminases) should be monitored monthly or as clinically indicated. Elevations in bilirubin and liver transaminases should be managed by temporary interruption, dose reduction, and/or discontinuation of nilotinib (see section "Dosage and administration"). Growth retardation has been documented in pediatric CML patients receiving nilotinib in a pediatric study (see section "Undesirable effects"). Careful monitoring of growth in pediatric patients during nilotinib therapy is recommended.

Lactose

Since the capsules contain lactose, the medicinal product 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 the medicinal product in pregnant women. Animal studies have shown reproductive toxicity. The medicinal product should not be used during pregnancy except in cases of urgent medical need. If the medicinal product is used during pregnancy, the patient should be informed of the potential risk to the fetus.

If a woman receiving nilotinib plans 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 the TFR phase, 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 last dose.

Breastfeeding. It is unknown whether nilotinib is excreted in human breast milk. Animal studies show that nilotinib is excreted in milk. Since risk to the newborn/infant cannot be excluded, women should not breastfeed during nilotinib therapy and for two weeks after the last dose.

Fertility. Animal studies did not reveal any effect on fertility in male or female rats.

Ability to influence the speed of reactions when driving or operating machinery.

The medicinal product has no effect or a negligible effect on the ability to drive or operate machinery. However, patients experiencing dizziness, fatigue, visual disturbances, or other adverse reactions that may potentially affect the ability to safely drive or operate machinery should refrain from such activities while these symptoms persist (see section "Undesirable effects").

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 prescribed dose should be taken at the usual time.

Recommended dosage for adult patients with Philadelphia chromosome-positive CML

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

Dosage for pediatric patients with Philadelphia chromosome-positive CML

Dosing for children is individualized and based on body surface area (mg/m²). The recommended dose of nilotinib is 230 mg/m² twice daily, rounded to the nearest 50 mg dose strength (up to a maximum single dose of 400 mg) (see table below). Nilotinib hard capsules of different strengths may be combined to achieve the desired dose. There is no experience in treating children under 2 years of age. There are no data available for newly diagnosed children under 10 years of age, and limited data for children under 6 years of age with resistance to or intolerance of imatinib.

Pediatric dosing regimen for nilotinib: 230 mg/m² twice daily

Body surface area (BSA)	Dose in mg (twice daily)
up to 0.32 m2	50 mg
0.33–0.54 m2	100 mg
0.55–0.76 m2	150 mg
0.77–0.97 m2	200 mg
0.98–1.19 m2	250 mg
1.20–1.41 m2	300 mg
1.42–1.63 m2	350 mg
≥ 1.64 m2	400 mg

Patients with chronic phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) treated with nilotinib as first-line therapy and who have achieved sustained deep molecular response (MR 4.5)

Discontinuation of treatment should be considered in patients with chronic phase Ph+ CML who have received nilotinib at a dose of 300 mg twice daily for at least 3 years and who 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 patients with CML (see sections "Pharmacological properties" and "Special instructions"). Patients who discontinue nilotinib must 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 on the international scale (IS) with a sensitivity of at least MR 4.5 (BCR-ABL/ABL ≤ 0.0032% IS).

Patients who lose MR 4 (MR 4 = 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 MR 4 and MR 4.5. Patients whose BCR-ABL levels fluctuate between MMR and MR 4 for at least 4 consecutive monitoring assessments may return to the initial monitoring schedule.

Patients who lose MMR must reinitiate treatment within 4 weeks of confirmed loss of remission. Nilotinib therapy 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 previously receiving a reduced dose prior to treatment discontinuation. Patients who restart nilotinib should be monitored monthly for BCR-ABL transcript levels until MMR is re-established, thereafter every 12 weeks (see section "Special instructions").

Patients with chronic phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) who achieved sustained deep molecular response (MR 4.5) on nilotinib therapy following prior imatinib treatment

Discontinuation of treatment should be considered in patients with chronic phase Ph+ CML who have received nilotinib at a dose of 300 mg twice daily for at least 3 years and who 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 patients with CML (see sections "Pharmacological properties" and "Special instructions"). Patients who discontinue nilotinib must 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 on the international scale (IS) with a sensitivity of at least MR 4.5 (BCR-ABL/ABL ≤ 0.0032% IS).

Patients with confirmed loss of MR 4 (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) must resume treatment within 4 weeks of confirmed loss of remission. Nilotinib therapy should be restarted 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, thereafter every 12 weeks (see section "Special instructions").

Dose adjustment or modification

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

Dose adjustment for neutropenia and thrombocytopenia

Chronic phase newly diagnosed CML at a dose of 300 mg twice daily. Chronic phase CML with resistance or intolerance at a dose of 400 mg twice daily.	ANC1 < 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.
Accelerated phase CML with resistance or intolerance to imatinib at a dose of 400 mg twice daily.	ANC1 < 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.
Pediatric patients with newly diagnosed chronic phase CML at a dose of 230 mg/m2 twice daily and imatinib-resistant or intolerant chronic phase CML at a dose of 230 mg/m2 twice daily	ANC* < 1.0 x 109/L and/or platelet count < 50 x 109/L	Nilotinib treatment should be interrupted and blood counts monitored.

1ANC – absolute neutrophil count.

If clinically significant moderate or severe non-hematologic toxicity develops, the drug should be discontinued and patients should be monitored. If the previous dose was 300 mg twice daily in adult patients with newly diagnosed CML in chronic phase or 400 mg twice daily in adult patients with imatinib-resistant or intolerant CML in chronic or accelerated phase, or 230 mg/m² twice daily in pediatric patients, dosing may be resumed at 400 mg once daily for adult patients and 230 mg/m² once daily for pediatric patients after resolution of toxicity. If the previous dose was 400 mg once daily for adult patients or 230 mg/m² once daily for pediatric patients, treatment should be discontinued. If clinically appropriate, dose escalation may be repeated to the initial dose of 300 mg twice daily in adult patients with newly diagnosed CML in chronic phase or to 400 mg twice daily in adult patients with imatinib-resistant or intolerant CML in chronic or accelerated phase, or to 230 mg/m² twice daily in pediatric patients.

Elevated serum lipase levels

In case of grade 3–4 elevation of serum lipase levels, the dose in adult patients should be reduced to 400 mg once daily or discontinued. In pediatric patients, treatment should be discontinued until the event resolves to grade ≤1. After that, if the previous dose was 230 mg/m² twice daily, treatment may be resumed at 230 mg/m² once daily. If the previous dose was 230 mg/m² once daily, treatment 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 grade 3–4 elevation of bilirubin and liver transaminases in adult patients, the dose should be reduced to 400 mg once daily or discontinued. In pediatric patients, if bilirubin increases to ≥grade 2 or liver transaminases to ≥grade 3, treatment should be interrupted until levels return to ≤grade 1. After that, if the previous dose was 230 mg/m² twice daily, treatment may be resumed at 230 mg/m² once daily. If the previous dose was 230 mg/m² once daily and recovery to ≤grade 1 takes longer than 28 days, treatment 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 imatinib-resistant or intolerant CML in chronic or accelerated phase 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 concentrations more than 1.5 times the upper limit of normal were excluded from clinical trials.

Since nilotinib and its metabolites are not excreted by 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 therapy (see section "Special instructions"). Lipid profile should be assessed prior to initiating nilotinib therapy, and 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 evaluated prior to starting nilotinib therapy and monitored throughout the course of treatment.

Administration

The drug 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 dispersed in one teaspoon of apple sauce and taken immediately. No more than one teaspoon of apple sauce or any other food should be used (see sections "Pharmacological properties" and "Special instructions").

Children

The safety and efficacy of nilotinib have been established in children aged 2 to 18 years with Philadelphia chromosome-positive CML in chronic phase. There is no experience with use in pediatric patients under 2 years of age or in pediatric patients with Philadelphia chromosome-positive CML in accelerated phase or blast crisis.

There are no data on newly diagnosed (acute phase) cases in children under 10 years of age and limited data in children under 6 years of age with imatinib-resistant or imatinib-intolerant disease.

The drug should be administered to children according to the section "Dosage and administration".

Overdose.

Symptoms. Isolated reports of intentional nilotinib overdose have been received, in which an unspecified number of nilotinib capsules were taken in combination with alcohol and other drugs. Adverse reactions observed in these cases included neutropenia, vomiting, and somnolence. No ECG changes or signs of hepatotoxicity were reported. Outcomes in these cases were reported as recovery.

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

Adverse reactions

The safety profile is based on pooled data from 3422 patients who received nilotinib in 13 clinical trials for the approved indications: adult and pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase at the time of initial diagnosis (5 clinical trials involving 2414 patients), and adult and pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia 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 the 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 (see table below)

Adverse reactions identified in clinical trials and during post-marketing use (see the table below, "Adverse Drug Reactions") are listed by system organ class according to the Medical Dictionary for Regulatory Activities (MedDRA) classification and by frequency. Frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from 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 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 disturbance, hyperesthesia, dysesthesia, lethargy, peripheral neuropathy, restless legs syndrome, facial paralysis
Rare	basilar artery stenosis, brain edema, optic neuritis
Eye disorders
Common	conjunctivitis, dry eye (including xerophthalmia), eye irritation, hyperemia (of sclera, conjunctiva, eye), blurred vision
Uncommon	vision disorders, 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 unknown	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	gastrointestinal ulcer 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 abnormalities
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 swelling, blisters, skin cysts, nodular erythema, hyperkeratosis, petechiae, photosensitivity, psoriasis, skin discoloration, skin exfoliation, skin hyperpigmentation, 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	chest musculoskeletal 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	hardening in the breast
General disorders and administration site conditions
Very common	fatigue, pyrexia
Common	chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise, asthenia and peripheral edema, chills, influenza-like illness
Uncommon	facial swelling, gravitational edema, sensation of body temperature change (including feeling of warmth, chills), localized edema
Rare	sudden death
Investigations
Very common	increased alanine aminotransferase levels, increased lipase levels
Common	decreased hemoglobin levels, increased blood amylase levels, increased aspartate aminotransferase levels, increased alkaline phosphatase activity in blood, increased gamma-glutamyl transferase activity, increased creatine phosphokinase levels in blood, decreased body weight, increased body weight, increased creatinine levels, increased total cholesterol levels
Uncommon	increased blood lactate dehydrogenase levels, increased blood urea levels, increased unconjugated bilirubin levels in blood, increased parathyroid hormone levels in blood, increased blood triglyceride levels, decreased globulin levels, increased lipoprotein cholesterol levels (including low-density and high-density lipoproteins), increased troponin levels
Rare	decreased blood glucose levels, decreased blood insulin levels, increased blood insulin levels, decreased C-peptide insulin levels

Note. Not all adverse reactions to nilotinib have been observed in pediatric studies.

Description of selected adverse reactions

Sudden death

During clinical trials with nilotinib, there have been reports of rare cases (0.1 to 1%) of sudden death in patients with chronic-phase or accelerated-phase chronic myeloid leukemia (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 BCR-ABL tyrosine kinase inhibitors (TKIs). In some cases, this has led to acute liver failure or fulminant hepatitis, resulting in the need for liver transplantation or fatal outcomes.

Pediatric patients

The safety of nilotinib in pediatric patients (aged 2 to <18 years) with Philadelphia chromosome-positive chronic-phase CML (n = 58) was evaluated in one main study over 60 months. The frequency, type, and severity of adverse reactions observed in pediatric patients were generally consistent with those observed in adults, except for hyperbilirubinemia/elevated bilirubin levels (Grade 3/4: 10.3%) and increased transaminases (AST Grade 3/4: 1.7%, ALT Grade 3/4: 12.1%), which were reported more frequently than in adult patients. Bilirubin and liver transaminase levels should be monitored during treatment. Growth retardation in the pediatric population

In a study conducted in the pediatric CML population, with median exposure of 51.9 months in newly diagnosed patients and 59.9 months in patients with imatinib/dasatinib-resistant or imatinib-intolerant Ph+ CML, growth deceleration (crossing at least two major percentile lines from baseline) was observed in 8 patients: 5 (8.6%) crossed two major percentile lines from baseline, and 3 (5.2%) crossed three major percentile lines from baseline. Growth-related events were recorded in 3 patients (5.2%). Careful monitoring of growth in pediatric patients receiving nilotinib is recommended (see section "Special warnings and precautions for use").

Reporting suspected adverse reactions

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

No special storage conditions required. Keep out of reach and sight of children.

Packaging. 7 capsules in a blister, 4 blisters in a cardboard pack.

Prescription category. Prescription only.

Manufacturer.

Pharos MT Limited.

Pharos Pharmaceutical Oriented Services Ltd.

Manufacturer's address and location of manufacturing site.

Hf62x, Hal Far Industrial Estate, Hal Far, Birzebbuga, BBG 3000, Malta.

Lesvi Street End, Chesie Loggos Industrial Estate, Metamorfossi, 144 52, Greece.