Tasigna

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Tasigna: instructions for use and reviews

1. Release form and composition
2. Pharmacological properties
3. Indications for use
4. Contraindications
5. Method of application and dosage
6. Side effects
7. Overdose
8. Special instructions
9. Application during pregnancy and lactation
10. Use in childhood
11. In case of impaired renal function
12. For violations of liver function
13. Use in the elderly
14. Drug interactions
15. Analogs
16. Terms and conditions of storage
17. Terms of dispensing from pharmacies
18. Reviews
19. Price in pharmacies

Latin name: Tasigna

ATX code: L01XE08

Active ingredient: nilotinib (Nilotinib)

Producer: Novartis Pharma, AG (Novartis Pharma, AG) (Switzerland)

Description and photo update: 2019-09-07

Tasigna is an antineoplastic agent.

Release form and composition

Dosage form Tasigna - hard gelatin capsules (contain almost white or white powder):

dosage 150 mg: size # 1, reddish brown, opaque, axially marked "NVR" and "BCR" in black ink;
dosage 200 mg: size # 0, light yellow, opaque, axially marked "NVR" and "TKI" in red ink.

Packing: 4 pcs. in a blister, 7 blisters in a carton box (4 carton packs can be packed in a cardboard box); 8 pcs. in a blister, 5 blisters in a cardboard box (it is possible to pack 3 cardboard boxes in a cardboard box). Each pack also contains instructions for using Tasigna.

Composition of 1 capsule:

active substance: nilotinib (in the form of monohydrate hydrochloride) - 150 or 200 mg;
auxiliary components: colloidal silicon dioxide, crospovidone, magnesium stearate, poloxamer 188, lactose monohydrate;
capsule shell: 150 mg capsules - gelatin, titanium dioxide (E171), iron dye red oxide (E172), iron dye yellow oxide (E172); capsules 200 mg - gelatin, titanium dioxide (E171), iron dye yellow oxide (E172);
ink composition: capsules 150 mg - shellac (E904), water, butanol, isopropanol, denatured ethanol (methylated alcohol), macrogol, iron dye black oxide (E172); capsules 200 mg - shellac (E904), water, propylene glycol, potassium hydroxide, iron dye red oxide (E172).

Pharmacological properties

Pharmacodynamics

Nilotinib is a protein tyrosine kinase inhibitor, anticancer drug. The mechanism of its action is due to the ability to suppress the tyrosine kinase activity of the Bcr-Abl oncoprotein of cell lines and leukemia cells primarily positive on the Philadelphia chromosome (Ph +).

The pronounced inhibitory effect on the Bcr-Abl wild-type oncoprotein is explained by the high affinity for the binding sites with adenosine triphosphate (ATP). The drug is also active against imatinib-resistant 32 and 33 mutant forms of Bcr-Abl tyrosine kinase, except for the T315I mutation.

In patients with chronic myeloid leukemia (CML), nilotinib induces apoptosis in cell lines and Ph-positive leukemia cells, and selectively inhibits proliferation.

Tasigna has little or no effect on other known protein kinases (including kinase of proteins of the Src family), with the exception of kinases possessing receptors for platelet growth factors (PDGRF), DDR receptors, as well as Kit and ephrin receptors - they are inhibited at concentrations of nilotinib within the therapeutic doses (for oral administration) recommended for the treatment of CML.

In the chronic phase of Ph + CML, therapy with the drug at a dose of 400 mg 2 times a day with ineffectiveness or intolerance to previous therapy (including imatinib) allows a greater cytogenetic response to be achieved (52% of cases). At the same time, the response is achieved quickly (on average, within 2.8 months) and with continued therapy (for 2 years) persists in 77% of patients. The overall survival rate of patients after 24 months of treatment with nilotinib is 87%.

In the phase of acceleration of Ph + CML, therapy with the drug at a dose of 400 mg 2 times a day with the ineffectiveness of previous therapy (including imatinib) or the development of resistance to it, the hematological response is achieved in 55% of cases. In this case, the response is achieved quickly (within 1 month) and with continued therapy (for 2 years) persists in 49% of patients. A greater cytogenetic response is achieved in 32% of patients and, with continued treatment, persists in 66% of cases.

Pharmacokinetics

After oral administration of Tasigna, about 30% of the drug is absorbed. The maximum concentration (C _max) is reached within about 3 hours. In healthy volunteers who took the drug with food, there was an increase in C _max and AUC (area under the concentration-time curve) by 112 and 82%, respectively, compared with individuals who received capsules on an empty stomach.

In the case of taking Tasigna 30 minutes and 2 hours after meals, an increase in the bioavailability of nilotinib is observed, respectively, by 29 and 15%. In patients undergoing partial or total gastrectomy, the absorption of the drug (relative bioavailability) decreases by about 22 and 48%, respectively.

The bioavailability of the drug dissolved in applesauce does not change when compared with taking whole capsules.

The concentration ratio of nilotinib in blood and plasma is 0.71. In vitro, about 98% of the dose is bound to plasma proteins.

In the equilibrium state, the systemic exposure of the drug was dose-dependent. However, in the case of taking a daily dose of more than 400 mg, the dose dependence of the increase in exposure is less pronounced.

The daily equilibrium concentration (C _ss) in plasma is 35% higher when taking a dose of 400 mg twice a day than when taking a dose of 800 mg once a day. AUC after a dose of 400 mg 2 times a day is approximately 13.4% higher than after a dose of 300 mg 2 times a day. Against the background of therapy lasting 12 months, when using the drug at a dose of 400 mg 2 times a day, compared with a dose of 300 mg 2 times a day, an increase in C _min (minimum concentration) and C _max was noted, respectively, by 15.7 and 14.8% … With an increase in a single dose from 400 mg to 600 mg (with a two-time dose per day), a significant increase in C _{ss was} not observed.

C _{ss is} reached by the 8th day of taking Tasigna. Plasma exposure of nilotinib in the period between the use of the first dose and the achievement of C _ss when taking the drug once a day increases by about 2 times, when taken twice a day - 3.8 times.

In the blood plasma, nilotinib circulates mainly unchanged. In studies in healthy volunteers, the active substance was metabolized mainly by oxidation and hydroxylation with the formation of metabolites with insignificant pharmacological activity.

In healthy volunteers, after taking a single dose of the drug, more than 90% was excreted within 7 days, mainly with feces. At the same time, 69% was excreted unchanged.

The half-life (T _½) after repeated administration of Tasigna is approximately 17 hours.

In case of liver dysfunction, no significant changes in the pharmacokinetic characteristics of nilotinib were observed. Compared with individuals without liver dysfunction, in patients with mild, moderate and severe functional liver dysfunctions with a single dose of the drug, a decrease in the AUC of nilotinib was noted by 35, 35 and 19%, respectively. C _max in equilibrium increased by 29, 18 and 22%, respectively.

Individual differences in pharmacokinetic parameters among the general population were moderate to significant.

Indications for use

newly diagnosed Ph + CML in the chronic phase;
Ph + CML in the chronic phase and in the acceleration phase in case of intolerance to previous therapy (including imatinib) or resistance to it.

Contraindications

Absolute:

hereditary galactose intolerance, impaired absorption of glucose / galactose, lactase deficiency;
age up to 18 years;
period of pregnancy and lactation;
concomitant use of powerful inhibitors of the isoenzyme CYP3F4 (drugs and food, including grapefruit juice);
joint administration of drugs that lengthen the QT interval, especially with concomitant hypokalemia or hypomagnesemia;
hypersensitivity to drug components.

Relative (Tasigna capsules are used with caution, after assessing the benefits and risks):

pancreatitis (including a history);
liver dysfunction;
the presence of risk factors for prolongation of the QT interval (congenital prolongation of the QT interval, severe or drug-induced uncontrolled heart disease, including clinically significant bradycardia, unstable angina pectoris, chronic heart failure, myocardial infarction).

Tasigna, application instruction: method and dosage

Tasigna should be taken orally, between meals - not earlier than two hours after a meal and not later than one hour before the next meal. The capsules are swallowed whole with plenty of water. Patients who have difficulty swallowing are allowed to open the capsules immediately before taking and mix the contents with 1 teaspoon (no more) of applesauce.

The recommended dose is 400 mg (2 capsules of Tasigna 200 mg) 2 times a day.

If you miss the next appointment, you do not need to take a double dose, you should adhere to the standard treatment regimen.

Drug therapy is carried out as long as the clinical effect persists.

Before prescribing the drug, hypokalemia / hypomagnesemia, increased uric acid concentration and clinically significant dehydration (if any) should be corrected. Before taking Tasigna, after 7 days and periodically during treatment, an electrocardiogram (ECG) control is indicated. Also, during therapy, it is necessary to monitor the level of magnesium and potassium in the blood serum, especially in patients at risk of developing metabolic disorders.

Dose adjustment for neutropenia and thrombocytopenia

With Ph + CML in the chronic phase, in the case of a decrease in the absolute number of neutrophils <1 × 10 ⁹ / L and / or the number of platelets <50 × 10 ⁹ / L, Tasigna should be canceled and clinical blood tests should be performed. If within 2 weeks the number of neutrophils increases> 1 × 10 ⁹ / L and / or platelets> 50 × 10 ⁹ / L, the treatment is resumed at the dose used before the interruption of therapy. If cytopenia persists, a dose reduction to 400 mg once a day may be required.

With Ph + CML in the acceleration phase, in the case of a decrease in the absolute number of neutrophils <0.5 × 10 ⁹ / L and / or the number of platelets <10 × 10 ⁹ / L, Tasigna should be canceled and clinical blood tests should be performed. If within 2 weeks the number of neutrophils increases> 1 × 10 ⁵ / l and / or platelets> 20 × 10 ⁹ / l, treatment is resumed at the dose used before the interruption of therapy. If cytopenia persists, a dose reduction to 400 mg once a day may be required.

Dose adjustments for non-hematological side effects

If moderate or severe non-hematological reactions appear, Tasigna is canceled.

Treatment can be resumed after the disappearance of unwanted disorders, but at a dose of 400 mg 1 time per day. In the future, it is possible to increase the frequency of administration up to 2 times a day, 400 mg.

If the upper limit of the norm (UHN) of lipase activity in the blood is 2 times, the concentration of bilirubin is 3 times, or hepatic transaminases is 5 times, the dose of Tasigna should be reduced to 400 mg once a day or the drug should be temporarily interrupted.

Side effects

Tasigna can cause the following side effects (according to the frequency of occurrence, they are classified as follows: very often - ≥ 1/10, often - from ≥ 1/100 to <1/10, infrequently - from ≥ 1/1000 to <1/100, the frequency is unknown - some undesirable reactions with an unknown frequency):

benign and malignant neoplasms: often - skin papilloma; frequency unknown - papilloma of the oral mucosa;
infections: often - folliculitis; infrequently - candidiasis (including oral), herpes infection, urinary tract infections, gastroenteritis, upper respiratory tract infections (including rhinitis, pharyngitis, nasopharyngitis), bronchitis, pneumonia; frequency unknown - furuncle, subcutaneous abscess, abscess of the perianal region, sepsis, mycosis of smooth skin of the feet;
from the hematopoietic system: very often - thrombocytopenia, neutropenia, anemia; often - lymphopenia, pancytopenia, febrile neutropenia; frequency unknown - leukocytosis, thrombocythemia, eosinophilia;
from the side of metabolism: often - anorexia, decreased appetite, hypercholesterolemia, hyperglycemia, hyperlipidemia, diabetes mellitus, electrolyte disturbances (hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hyperphosphatemia, hypophosphatemia, hyponatremia, hypomagnesemia); infrequently - increased appetite, dehydration; frequency unknown - dyslipidemia, hyperuricemia, hypoglycemia, gout;
on the part of the cardiovascular system: often - a feeling of palpitations, hot flushes, prolongation of the QT interval on the electrocardiogram, angina pectoris, increased blood pressure, arrhythmias (including bradycardia, tachycardia, extrasystole, atrial flutter, atrial fibrillation, AV block); infrequently - cyanosis, hypertensive crisis, the appearance of a murmur in the heart, ischemic heart disease, pericardial effusion, heart failure, the formation of hematomas, occlusion of peripheral arteries; frequency unknown - lowering blood pressure, dysfunction of the ventricles, decreased ejection fraction, pericarditis, thrombosis, hemorrhagic shock, myocardial infarction;
from the digestive system: very often - nausea, vomiting, constipation, diarrhea; often - abdominal pain (including in the epigastric region), flatulence, bloating, abdominal discomfort, dyspepsia, liver dysfunction, pancreatitis; infrequently - dry mouth, ulceration of the oral mucosa, stomatitis, pain in the esophagus, gastroesophageal reflux, melena, gastrointestinal bleeding, toxic liver damage, jaundice, hepatitis; frequency unknown - increased sensitivity of tooth enamel, gingivitis, enterocolitis, gastritis, retroperitoneal hemorrhage, vomiting with blood, perforation of gastrointestinal ulcers, gastric ulcer, partial intestinal obstruction, hiatal hernia, ulcerative esophagitis, hepatomegaly, cholangitis;
from the respiratory system: often - nosebleeds, dysphonia, cough, shortness of breath at rest and during exercise; infrequently - irritation of the pharyngeal mucosa, pain in the pharynx and / or larynx, chest pain, interstitial lung disease, pleurisy, pleural pain, pleural effusion, pulmonary edema; frequency unknown - wheezing, pulmonary hypertension;
from the nervous system: very often - headache; often - a violation of taste, paresthesia, hypesthesia, peripheral neuropathy, dizziness; infrequently - impaired concentration, migraine, hyperesthesia, tremor, loss of consciousness, intracranial hemorrhage; frequency unknown - dysesthesia, lethargy, optic neuritis, restless legs syndrome, cerebral edema;
on the part of the psyche: often - anxiety, insomnia, depression; frequency unknown - confusion, dysphoria, disorientation, amnesia;
from the endocrine system: infrequently - hypo- or hyperthyroidism; frequency unknown - thyroiditis, secondary hyperparathyroidism;
from the immune system: the frequency is unknown - hypersensitivity;
from the urinary system: often - pollakiuria; infrequently - an imperative urge to urinate, dysuria, nocturia; frequency unknown - urinary incontinence, hematuria, chromaturia, renal failure;
from the reproductive system: infrequently - erectile dysfunction, gynecomastia, pain in the mammary gland; frequency unknown - menorrhagia, swelling of the nipples, breast lumps;
from the musculoskeletal system: very often - myalgia; often - bone pain, muscle spasms, pain in the extremities, arthralgia, musculoskeletal pain (including in the chest), pain in the iliac region, pain in the side; infrequently - muscle weakness, stiffness, joint swelling; frequency unknown - arthritis;
from the organ of hearing: often - vertigo; frequency unknown - noise / pain in the ears, hearing loss;
on the part of the organ of vision: often - dry eye syndrome, itchy eyes, periorbital edema, intraocular hemorrhage, conjunctivitis; infrequently - eye irritation, eyelid edema, deterioration / blurred vision, hyperemia (conjunctiva, sclera, eyeball), photopsia, decreased visual acuity; frequency unknown - pain in the eye, swelling of the eyelids, diplopia, blepharitis, edema of the optic nerve head, hemorrhage in the conjunctiva, chorioretinopathy, photophobia, diseases of the mucous membrane of the eye, allergic conjunctivitis;
dermatological reactions: very often - rashes, itching; often - dry skin, urticaria, acne, hyperhidrosis, increased sweating at night, dermatitis (allergic and acneform), erythema, eczema, subcutaneous hemorrhages; infrequently - soreness of the skin, swelling of the face, exfoliative rash, ecchymosis, drug rash; frequency unknown - skin peeling, skin discoloration, skin hyperpigmentation, skin atrophy / hypertrophy, skin cysts, blisters, hyperplasia of the sebaceous glands, skin ulcers, petechiae, palmar-plantar erythrodysesthesia syndrome, increased photosensitivity, erythema nodosum, erythema multiforme;
laboratory parameters: often - increase / decrease in body weight, decrease in hemoglobin, increase in plasma alkaline phosphatase, creatine phosphokinase, amylase and gamma-glutamyl transpeptidase activity; infrequently - an increase in the concentration of urea and the activity of lactate dehydrogenase in the blood plasma; the frequency is unknown - an increase in the blood plasma level of parathyroid hormone, the concentration of troponin, insulin, unconjugated bilirubin, very low density lipoproteins and high density lipoproteins;
others: very often - increased fatigue; often - fluid retention and edema, asthenia, general malaise, fever, chest discomfort, neck and back pain, chest pain (including non-cardiological), alopecia; infrequently - a change in body temperature (alternation of sensations of heat and cold), chills, flu-like syndrome, facial edema, peripheral edema; the frequency is unknown - localized edema, as well as tumor lysis syndrome (the connection with the use of nilotinib has not been established).

Overdose

There are isolated reports of overdose cases. The patients took an unspecified number of capsules together with other drugs and alcohol. Symptoms such as vomiting, drowsiness, and neutropenia were noted. Signs of toxic liver damage and ECG changes were not observed.

In case of taking an excessive dose of Tasigna, careful monitoring of the patient's condition is required. Treatment is symptomatic.

special instructions

Treatment with Tasigna can only be performed by medical specialists with appropriate experience in the treatment of CML. Liver function (bilirubin and transaminase levels) should be monitored monthly.

Against the background of anticancer therapy, anemia, thrombocytopenia and neutropenia may develop (especially in patients with CML in the acceleration phase), therefore, a clinical blood test should be performed regularly: in the first two months - every 2 weeks, then - once a month or in case of clinical need … The resulting myelosuppression is usually manageable and reversible. To normalize the number of platelets and neutrophils, a reduction in the dose of Tasigna or a temporary discontinuation of the drug is often sufficient.

In case of an increase in the plasma activity of lipase, accompanied by abdominal symptoms, you should temporarily stop taking the drug and conduct an additional examination to exclude pancreatitis.

The bioavailability of nilotinib may be reduced in patients who have undergone gastrectomy, so treatment should be carried out under close medical supervision.

Approximately 0.1–1% of patients with heart disease or a high risk of cardiovascular complications have reported sudden deaths in clinical trials. All patients had concomitant diseases or were simultaneously receiving therapy with other drugs. An additional risk factor may be impaired ventricular repolarization. According to post-marketing research data, the frequency of spontaneous reports of sudden death cases per year per patient was 0.02%.

Influence on the ability to drive vehicles and complex mechanisms

During the period of anticancer therapy, side effects (for example, visual impairment, dizziness) may develop, which can have a negative effect on the ability to concentrate and speed of reactions. In this regard, patients receiving Tasigna are advised to exercise caution when driving and engaging in potentially hazardous activities.

Application during pregnancy and lactation

Tasigna is contraindicated during pregnancy and lactation.

During the period of drug treatment, men and especially women should use reliable methods of contraception.

Pediatric use

Tasigna is not prescribed for children and adolescents under 18 years of age, since there is no experience in treating patients of this age group with the drug.

With impaired renal function

Nilotinib and its metabolites are not excreted by the kidneys, therefore, in patients with renal insufficiency, a decrease in the total clearance of Tasigna is not expected.

For violations of liver function

In hepatic impairment, no dosage adjustment is required, but Tasigna should be used with caution.

Use in the elderly

There is no need to adjust the drug therapy regimen for elderly patients.

Drug interactions

When nilotinib was combined with ketoconazole (a strong inhibitor of the CYP3A4 isoenzyme), a 3-fold increase in the bioavailability of nilotinib was observed in healthy volunteers. In this regard, it is recommended to avoid the simultaneous administration of strong inhibitors of the isoenzyme CYP3A4 (including ketoconazole, voriconazole, itraconazole, telithromycin, clarithromycin, ritonavir). If necessary, consider the possibility of conducting alternative therapy with drugs that do not inhibit or slightly inhibit the specified isoenzyme. If the use of these drugs is necessary, it is recommended to suspend treatment with Tasigna. If temporary withdrawal is not possible, possible prolongation of the QTcF interval should be carefully monitored.

During the period of treatment with nilotinib, the use of grapefruit juice and other food products that are known inhibitors of the isoenzyme CYP3A4 should be avoided.

Inducers of the CYP3A4 isoenzyme (including St. John's wort, phenobarbital, phenytoin, carbamazepine, rifampicin) can increase the metabolism of nilotinib and, as a result, reduce its plasma concentration. For example, rifampicin (applied for 12 days at 600 mg per day) reduces systemic exposure of nilotinib by 80%. It is recommended to consider the possibility of prescribing other drugs that have less inducing effect on the specified isoenzyme.

Drugs affecting the P-glycoprotein and / or the CYP3A4 isoenzyme are capable of influencing the absorption and increasing the concentration of nilotinib in the blood plasma. In clinical studies of the combined use of nilotinib and imatinib, an increase in the AUC of nilotinib by 18-40%, and the AUC of imatinib by 18-39% was noted.

Tasigna should not be used in conjunction with antiarrhythmic drugs (such as disopyramide, sotalol, quinidine, procainamide, amiodarone) and other drugs that cause prolongation of the QT interval (such as haloperidol, clarithromycin, halofantrine, bepridil, pimozide, moxifloxacin, methadone), chloroquin.

With a single dose of Tasigna with midazolam in healthy individuals, an increase in the concentration of the latter by 30% was noted, however, the degree of its metabolism to the main metabolite (1-hydroxyimidazolam) did not change.

The solubility of nilotinib depends on the pH level, so when it rises, the solubility of the drug decreases. In healthy volunteers with a pronounced increase in pH due to the intake of esomeprazole (for 5 days, 40 mg once a day), the decrease in the absorption of nilotinib was moderate (a decrease in C _max and AUC by 27 and 34%, respectively). If necessary, Tasigna can be used in combination with proton pump inhibitors.

There were no drug interactions with the simultaneous use of hematopoietic stimulants (such as erythropoietins and granulocyte colony-stimulating factor), anagrelide, hydroxycarbamide.

In healthy volunteers, nilotinib had no clinically significant effect on the pharmacological properties of warfarin.

When Tasigna is taken with food, the absorption of the drug increases, as a result of which its plasma concentration increases.

Analogs

Tasigna's analogs are: Albitinib, Afinitor, Bosulif, Vargatef, Votrient, Giotrif, Glemihib, Gefitinib, Genfatinib, Gleevec, Gistamel, Jakavi, Zelboraf, Iglib, Ibransa, Imbruvika, Iressa, Inlistelta, Kaprelsa, Kaprelsa, Sutent, Tagrisso, Erlotinib, etc.

Terms and conditions of storage

Keep out of reach of children at a temperature not exceeding 30 ° C.

The shelf life is 3 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Tasigna

Reviews about Tasigna are few, which, most likely, is due to the specifics of its application. Doctors indicate that nilotinib is the drug of choice for the treatment of chronic myeloid leukemia, especially in the case of ineffectiveness of previous therapy with Glivec. Tasigna is effective even with prolonged use, but it is generally hard to tolerate. Various adverse reactions are mentioned, including nausea, lack of appetite, dizziness, headache, pain in joints and bones, swelling, etc.

Price for Tasigna in pharmacies

The cost of the drug depends on the dosage, the number of capsules in the package, as well as the pharmacy network and the region of sale. The approximate price for Tasigna 150 mg is 153,708 rubles. per pack of 112 capsules. A pack of 120 200 mg Tasigna capsules can be purchased for RUB 163,062. behind.

Anna Kozlova Medical journalist About the author

Education: Rostov State Medical University, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!