Tasigna® [Nilotinib]

Brand Novartis

In stock 1742 Items

Available since: 2019-09-19

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Clinical Pharmacology

Antitumor agent, protein tyrosine kinase inhibitor. Effectively inhibits the tyrosine kinase activity of Bcr-Abl oncoprotein cell lines and primary positive for Philadelphia chromosome (Ph-positive) leukemia cells.

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

Nilotinib does not or has little effect on other known protein kinases (including the protein kinase of the Src family), except for kinases that have platelet growth factor receptors, Kit receptors and efrin receptors. Inhibition of this type of protein kinase occurs at nilotinib concentrations within the range of therapeutic doses for oral administration recommended for the treatment of CML.

Pharmacokinetics

After oral administration, the absorption of nilotinib is about 30%. Average t_max blood plasma is about 3 hours. In healthy volunteers while taking with food C_max and nilotinib AUC increased by 112% and 82%, respectively, compared with fasting nilotinib. When taken 30 minutes or 2 hours after a meal, the bioavailability of nilotinib increases by 29% and 15%, respectively.

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

C_ss nilotinib was achieved by day 8 and was less dose-dependent than the systemic concentration, increasing with an increase in dose of more than 400 mg, compared with a single dose. Daily C_ss Plasma nilotinib was 35% higher when used at a dose of 400 mg 2 times / day than when applied at a dose of 800 mg 1 time / day. There was no significant increase in C_ss nilotinib with an increase in dose from 400 mg 2 times / day to 600 mg 2 times / day. Increasing the plasma concentration of nilotinib between the first dose and reaching C_ss It was noted about 2 times when taking nilotinib 1 time / day and 3.8 times when used twice.

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

After a single dose of nilotinib in healthy volunteers, more than 90% of the dose is eliminated within 7 days, mostly with feces. 69% is displayed unchanged. T_1/2 with repeated use of the daily dose was approximately 17 hours

Individual differences in pharmacokinetics among patients were moderate to severe.

Indications

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

Composition

1 capsule contains:

Active substances: Nilotinib hydrochloride monohydrate is 165.45 mg, which corresponds to the nilotinib content of 150 mg.

Excipients: lactose monohydrate - 117.08 mg, crospovidone - 11.93 mg, poloxamer 188 - 2.39 mg, colloidal silicon dioxide - 1.58 mg, magnesium stearate - 1.58 mg.

The composition of the capsule shell: gelatin - 74.54 mg, titanium dioxide (E171) - 0.76 mg, iron dye yellow oxide (E172) - 0.34 mg, iron dye red oxide (E172) - 0.36 mg.

Ink composition: shellac (E904), iron dye black oxide (E172), water, propylene glycol.

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Dosage and Administration

For oral use. The recommended dose is 400 mg 2 times / day. The treatment is carried out until the clinical effect is maintained.

In the event of neutropenia and thrombocytopenia not associated with leukemia, a temporary withdrawal of the drug or a reduction in its dose is required, depending on the severity of these side effects.

With the development of moderate or severe non-hematological side effects associated with taking nilotinib, therapy should be interrupted. After the disappearance of side effects, treatment can be resumed at a dose of 400 mg 1 time / day. If necessary, you can increase the dose to 400 mg 2 times / day.

With an increase in the level of lipase 5 times higher than VGN or bilirubin more than 3 times higher than VGN, it is recommended to reduce the dose of nilotinib to 400 mg / day.

Adverse reactions

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

From the side of the central nervous system and peripheral nervous system: very often - headache (15%); often - dizziness, paresthesia, insomnia; sometimes - intracranial hemorrhage, migraine, tremor, hypoesthesia, hyperesthesia, depression, anxiety; frequency is 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 is unknown - perforation of gastrointestinal ulcers, retroperitoneal hemorrhage, vomiting with blood, 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 is unknown - erythema nodosum, skin ulcers, petechiae, increased photosensitivity.

Metabolism: often - hypomagnesemia, hyperkalemia, hyperglycemia; sometimes - hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, dehydration; frequency is unknown - hypercalcemia, hyperphosphatemia.

On the part of the endocrine system: sometimes hyperthyroidism; frequency is unknown - hypothyroidism, thyroiditis, diabetes.

From the senses: often vertigo; sometimes intraocular hemorrhage, reduced visual acuity, periorbital edema, conjunctivitis, eye irritation, dry eye syndrome; frequency is unknown - edema of the optic nerve, diplopia, blurring of vision, photophobia, eyelid swelling, blepharitis, eye pain, hearing loss, ear pain.

Since the cardiovascular system: often - palpitations, an increase in the QT interval on the ECG, flushing of the face, increased blood pressure; sometimes - heart failure, stenocardia, atrial fibrillation, pericardial effusion, ischemic heart disease, cardiomegaly, heart murmur, bradycardia, hypertensive crisis, hematomas; frequency is unknown - myocardial infarction, pericarditis, atrial flutter, extrasystole, hemorrhagic shock, decrease in blood pressure, thrombosis.

On the part of the respiratory system: often - shortness of breath at rest and during physical exertion, cough, dysphonia; sometimes - pulmonary edema, pleural effusion, interstitial lung disease, chest pain, pleurisy, nosebleeds, pain in the pharynx and / or larynx, irritation of the pharyngeal mucosa; frequency is unknown - pulmonary hypertension.

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

From the urinary system: sometimes - dysuria, painful urge to urinate, nocturia, pollakiuria; frequency is unknown - renal failure, hematuria, urinary incontinence.

From the reproductive system: sometimes - pain in the mammary gland, erectile dysfunction, gynecomastia.

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

Other: very often - increased fatigue (16%); often - asthenia (6%), fluid retention and edema (5%), fever, night sweats; sometimes - chest pain, swelling of the face, swelling of the legs, flu-like syndrome, chills, general malaise.

From the laboratory indicators: very often - increased lipase activity; often - an increase in the blood plasma activity of amylase, CPK, alkaline phosphatase, ALT, AST, GGT, bilirubin level, glucose level, weight loss or increase in body weight; sometimes - an increase in blood plasma LDH activity, creatinine, urea levels, hypoglycemia; unknown frequency - increased troponin level, increased level of conjugated bilirubin in the blood plasma. An asymptomatic increase in serum lipase level 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 effusions, as well as other complications resulting from fluid retention, congestive heart failure, prolongation of the QTcF interval over 500 msec were observed in less than 1% of cases. The development of gastrointestinal bleeding and hemorrhage in the central nervous system was reported in 3% and 1% of cases, respectively.

Contraindications

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

Drug interactions

Nilotinib is metabolized mainly in the liver, and is also a substrate for the system of excretion of many drugs - P-glycoprotein. Preparations acting on the CYP3A4 isoenzyme and / or P-glycoprotein can affect the absorption and subsequent elimination of nilotinib.

Nilotinib bioavailability in healthy volunteers increased 3 times while applying a strong CYP3A4 isoenzyme inhibitor ketoconazole (avoid the simultaneous application of nilotinib with such drugs, including ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin and telithromycin and grapefruit juice and other products that are known inhibitors of the isoenzyme CYP3A4).

Inductors of CYP3A4 isoenzyme can enhance the metabolism of nilotinib and reduce its concentration in the blood plasma. When taken simultaneously 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, as a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9 and CYP2D6 isoenzymes in vitro, can potentially increase the concentration of drugs that are eliminated with the participation of these enzymes. In addition, with a single application of nilotinib with midazolam in healthy volunteers, an increase in the concentration of midazolam was noted by 30%.

Care should be taken when nilotinib is used with drugs that prolong the QT interval (for example, with amiodarone, disopyramide, halofantrin, clarithromycin, haloperidol or methadone).

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

If necessary, it is possible to use nilotinib together with hematopoietic stimulants, such as erythropoietins, G-CSF, as well as with hydroxycarbamide and anagrelide.

Pregnancy and Lactation

Contraindicated use during pregnancy and lactation (breastfeeding).

Special instructions

Use with caution in patients with an extended QTcF interval (QT interval adjusted by Fridericia) on an ECG (including in patients with hypokalemia or hypomagnesiemia, with congenital prolongation of the QTcF interval, receiving treatment with antiarrhythmic drugs or other drugs that extend the QTcF interval, with the use of anthracyclines in a high total dose), with liver failure.

Elderly patients do not require correction dosing regimen.

Since the kidneys do not play a significant role in the elimination of nilotinib and its metabolites, a decrease in the total clearance is not expected when nilotinib is used in patients with renal insufficiency.

There is no data on the use of nilotinib in patients with serum creatinine 1.5 times as high as VGN, with ALT and / or ACT activities exceeding more than 2.5 times (or more than 5 times if this was due to disease) VGN and / or with a total bilirubin index more than 1.5 times higher than VGN, severe heart disease (including complete blockade of the left bundle of His bundle, unstable angina, uncontrolled chronic heart failure or a recent myocardial infarction).