Lotnilib^® (Capsules) Instructions for Use

Marketing Authorization Holder

Izvarino Pharma LLC (Russia)

Manufactured By

Nanopharma Development, LLC (Russia)

ATC Code

L01EA03 (Nilotinib)

Active Substance

Nilotinib (Rec.INN registered by WHO)

Dosage Forms

	Lotnilib®	Capsules 150 mg
		Capsules 200 mg

Dosage Form, Packaging, and Composition

Capsules

8 pcs. – blister packs (15 pcs.) – cardboard packs (120 pcs.) – By prescription
8 pcs. – blister packs (150 pcs.) – cardboard boxes (1200 pcs.) – In-Bulk
8 pcs. – blister packs (200 pcs.) – cardboard boxes (1600 pcs.) – In-Bulk
8 pcs. – blister packs (300 pcs.) – cardboard boxes (2400 pcs.) – In-Bulk
8 pcs. – blister packs (400 pcs.) – cardboard boxes (3200 pcs.) – In-Bulk
8 pcs. – blister packs (5 pcs.) – cardboard packs (40 pcs.) – By prescription
8 pcs. – blister packs (500 pcs.) – cardboard boxes (4000 pcs.) – In-Bulk
8 pcs. – blister packs (600 pcs.) – cardboard boxes (4800 pcs.) – In-Bulk

Capsules

8 pcs. – blister packs (15 pcs.) – cardboard packs (120 pcs.) – By prescription
8 pcs. – blister packs (150 pcs.) – cardboard boxes (1200 pcs.) – In-Bulk
8 pcs. – blister packs (200 pcs.) – cardboard boxes (1600 pcs.) – In-Bulk
8 pcs. – blister packs (300 pcs.) – cardboard boxes (2400 pcs.) – In-Bulk
8 pcs. – blister packs (400 pcs.) – cardboard boxes (3200 pcs.) – In-Bulk
8 pcs. – blister packs (5 pcs.) – cardboard packs (40 pcs.) – By prescription
8 pcs. – blister packs (500 pcs.) – cardboard boxes (4000 pcs.) – In-Bulk
8 pcs. – blister packs (600 pcs.) – cardboard boxes (4800 pcs.) – In-Bulk

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; BCL-ABL tyrosine kinase inhibitors

Pharmacological Action

Antitumor agent, protein tyrosine kinase inhibitor. It effectively inhibits the tyrosine kinase activity of the Bcr-Abl oncoprotein in cell lines and primary Philadelphia chromosome-positive (Ph-positive) leukemic cells.

It has a high affinity for ATP-binding sites and thus exerts a pronounced inhibitory effect on the free form of the Bcr-Abl oncoprotein, and also demonstrates activity against imatinib-resistant 32/33 mutant forms of Bcr-Abl tyrosine kinase, with the exception of the T315I mutation. Nilotinib selectively inhibits proliferation and induces apoptosis of cell lines and Ph-positive leukemic cells in patients with chronic myeloid leukemia (CML).

Nilotinib has no or minimal effect on other known protein kinases (including Src family protein kinases), except for kinases with platelet-derived growth factor receptors, Kit receptors, and ephrin receptors. Inhibition of these types of protein kinases occurs at nilotinib concentrations within the range of therapeutic oral doses recommended for the treatment of CML.

Pharmacokinetics

After oral administration, the absorption of nilotinib is about 30%. The mean T_max in blood plasma is about 3 hours. In healthy volunteers, when taken simultaneously with food, the C_max and AUC of nilotinib increased by 112% and 82%, respectively, compared to taking nilotinib on an empty stomach. When taken 30 minutes or 2 hours after a meal, the bioavailability of nilotinib increases by 29% and 15%, respectively.

The blood-to-plasma ratio for nilotinib is 0.68. In vitro binding to plasma proteins is about 98%.

C_ss of nilotinib was reached by day 8 and was less dose-dependent than the systemic concentration, which increased with doses above 400 mg compared to a single dose. The daily C_ss of nilotinib in plasma was 35% higher when administered at a dose of 400 mg twice daily than when administered at a dose of 800 mg once daily. There was no significant increase in C_ss of nilotinib when the dose was increased from 400 mg twice daily to 600 mg twice daily. The increase in nilotinib plasma concentration between the first dose and reaching C_ss was approximately 2-fold when nilotinib was taken once daily and 3.8-fold when taken twice daily.

In healthy volunteers, the main pathways of nilotinib metabolism are oxidation and hydroxylation. In blood plasma, Nilotinib circulates mainly unchanged. All metabolites of nilotinib have minimal pharmacological activity.

After a single dose of nilotinib in healthy volunteers, more than 90% of the dose was excreted within 7 days, mainly in the feces. 69% is excreted unchanged. T_1/2 with multiple administrations of the daily dose was approximately 17 hours.

Individual differences in pharmacokinetics among patients ranged from moderate to pronounced.

Indications

Treatment of Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase and accelerated phase in adult patients with intolerance or resistance to prior therapy, including imatinib.

ICD codes

Dosage Regimen

Take orally. The recommended dose is 400 mg twice daily. Treatment is continued as long as the clinical effect persists.

If neutropenia and thrombocytopenia occur that are not related to leukemia, temporary discontinuation of the drug or a reduction in its dose is required, depending on the severity of these side effects.

If moderate or severe non-hematological side effects associated with taking nilotinib develop, therapy should be interrupted. After the side effects disappear, treatment can be resumed at a dose of 400 mg once daily. If necessary, the dose can be increased to 400 mg twice daily.

If the lipase level increases to 5 times the upper limit of normal (ULN) or bilirubin increases to more than 3 times the ULN, it is recommended to reduce the dose of nilotinib to 400 mg/day.

Adverse Reactions

From the hematopoietic system: very often – thrombocytopenia (27%), neutropenia (15%), anemia (13%); often – febrile neutropenia, pancytopenia; frequency unknown – thrombocythemia, leukocytosis.

From the central and peripheral nervous system: very often – headache (15%); often – dizziness, paresthesia, insomnia; sometimes – intracranial hemorrhage, migraine, tremor, hypesthesia, hyperesthesia, depression, anxiety; frequency unknown – cerebral edema, loss of consciousness, optic neuritis and peripheral neuropathy, confusion, disorientation.

From the digestive system: very often – nausea (19%), constipation (11%), diarrhea (11%); often – vomiting (9%), abdominal pain (5%), anorexia (5%), abdominal discomfort, dyspepsia, flatulence; sometimes – pancreatitis, gastrointestinal bleeding, melena, gastroesophageal reflux, stomatitis, dry mouth, increased or decreased appetite, hepatitis; frequency unknown – perforation of gastrointestinal ulcers, retroperitoneal hemorrhage, bloody vomiting, gastric ulcer, ulcerative esophagitis, partial intestinal obstruction, hepatomegaly, jaundice.

Dermatological reactions: very often – rash (26%), itching (22%); often – alopecia (7%), eczema, urticaria, hyperhidrosis, dry skin; sometimes – exfoliative rash, ecchymosis; frequency unknown – erythema nodosum, skin ulcers, petechiae, increased photosensitivity.

From metabolism: often – hypomagnesemia, hyperkalemia, hyperglycemia; sometimes – hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, dehydration; frequency unknown – hypercalcemia, hyperphosphatemia.

From the endocrine system: sometimes – hyperthyroidism; frequency unknown – hypothyroidism, thyroiditis, diabetes mellitus.

From the senses: often – vertigo; sometimes – intraocular hemorrhage, decreased visual acuity, periorbital edema, conjunctivitis, eye irritation, dry eye syndrome; frequency unknown – optic disc edema, diplopia, blurred vision, photophobia, eyelid swelling, blepharitis, eye pain, hearing loss, ear pain.

From the cardiovascular system: often – palpitations, increased QT interval on ECG, flushing, increased blood pressure; sometimes – heart failure, angina pectoris, atrial fibrillation, pericardial effusion, coronary artery disease, cardiomegaly, heart murmurs, bradycardia, hypertensive crisis, hematomas; frequency unknown – myocardial infarction, pericarditis, atrial flutter, extrasystole, hemorrhagic shock, decreased blood pressure, thrombosis.

From the respiratory system: often – dyspnea at rest and on exertion, cough, dysphonia; sometimes – pulmonary edema, pleural effusion, interstitial lung disease, chest pain, pleurisy, nosebleed, pain in the pharynx and/or larynx, irritation of the pharyngeal mucosa; frequency unknown – pulmonary hypertension.

From the musculoskeletal system: often – myalgia (8%), arthralgia (6%), bone pain (6%), muscle spasm (6%); sometimes – muscle weakness; frequency unknown – arthritis, joint swelling.

From the urinary system: sometimes – dysuria, painful urination, nocturia, pollakiuria; frequency unknown – renal failure, hematuria, urinary incontinence.

From the reproductive system: sometimes – breast pain, erectile dysfunction, gynecomastia.

Infectious diseases: sometimes – pneumonia, urinary tract infections, pharyngitis, gastroenteritis; frequency unknown – sepsis, bronchitis, herpes infection (herpes simplex), candidiasis.

Other: very often – increased fatigue (16%); often – asthenia (6%), fluid retention and edema (5%), increased body temperature, night sweats; sometimes – chest pain, facial edema, leg edema, flu-like syndrome, chills, general malaise.

From laboratory parameters: very often – increased lipase activity; often – increased plasma activity of amylase, CPK, ALP, ALT, AST, GGT, bilirubin level, glucose level, decrease or increase in body weight; sometimes – increased plasma activity of LDH, creatinine level, urea, hypoglycemia; frequency unknown – increased troponin level, increased plasma level of conjugated bilirubin. Asymptomatic increase in serum lipase levels is possible; in some cases, this increase was accompanied by clinical symptoms, such as abdominal pain, or developed against the background of pancreatitis.

Pleural and pericardial effusion, as well as other complications resulting from fluid retention, congestive heart failure, prolongation of the QT_cF interval over 500 msec were observed in less than 1% of cases. Gastrointestinal bleeding and central nervous system hemorrhage were reported in 3% and 1% of cases, respectively.

Contraindications

Pregnancy; lactation period (breastfeeding); children and adolescents under 18 years of age; hypersensitivity to nilotinib.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during the lactation period (breastfeeding).

Use in Hepatic Impairment

Use with caution in hepatic insufficiency.

Use in Renal Impairment

Since the kidneys do not play a significant role in the excretion of nilotinib and its metabolites, no reduction in total clearance is expected when using nilotinib in patients with renal insufficiency.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

Use with caution in patients with a prolonged QT_cF interval (QT interval corrected by Fridericia) on ECG (including patients with hypokalemia or hypomagnesemia, with congenital long QT_cF syndrome, receiving treatment with antiarrhythmic drugs or other drugs that prolong the QT_cF interval, when using anthracyclines in a high cumulative dose), in hepatic insufficiency.

No dose adjustment is required in elderly patients.

Since the kidneys do not play a significant role in the excretion of nilotinib and its metabolites, no reduction in total clearance is expected when using nilotinib in patients with renal insufficiency.

There are no data on the use of nilotinib in patients with serum creatinine levels 1.5 times the ULN, with ALT and/or AST activity exceeding 2.5 times (or more than 5 times if associated with the disease) the ULN and/or with a total bilirubin level more than 1.5 times the ULN, severe heart disease (including complete left bundle branch block, unstable angina, uncontrolled chronic heart failure, or recent myocardial infarction).

Drug Interactions

Nilotinib is metabolized mainly in the liver and is also a substrate for the efflux system of many drugs – P-glycoprotein. The absorption and subsequent elimination of nilotinib can be affected by drugs acting on the CYP3A4 isoenzyme and/or P-glycoprotein.

The bioavailability of nilotinib in healthy volunteers increased 3-fold when co-administered with the strong CYP3A4 isoenzyme inhibitor ketoconazole (concomitant use of nilotinib with such drugs, including ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and telithromycin, as well as with grapefruit juice and other products that are known inhibitors of the CYP3A4 isoenzyme, should be avoided).

Inducers of the CYP3A4 isoenzyme may enhance the metabolism of nilotinib and reduce its plasma concentration. When taken concomitantly with drugs that are inducers of the CYP3A4 isoenzyme (including phenytoin, rifampicin, carbamazepine, phenobarbital and St. John’s wort), a decrease in the concentration of nilotinib is possible.

Nilotinib, being a competitive inhibitor of the CYP3A4, CYP2C8, CYP2C9 and CYP2D6 isoenzymes in vitro, may potentially increase the concentration of drugs eliminated by these enzymes. In addition, when a single dose of nilotinib was co-administered with midazolam in healthy volunteers, an increase in midazolam concentration of 30% was noted.

Caution should be exercised when using nilotinib together with drugs that cause QT interval prolongation (for example, with amiodarone, disopyramide, halofantrine, clarithromycin, haloperidol or methadone).

When taken concomitantly with food, an increase in the absorption of nilotinib is noted, leading to an increase in its plasma concentration.

If necessary, nilotinib can be used concomitantly with hematopoietic stimulants, such as erythropoietins, G-CSF, as well as with hydroxycarbamide and anagrelide.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.