Vemurafenib (Vemurafenibum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Antineoplastic agents

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    Hoffmann-La Roche Ltd.     Switzerland
    • АТХ:

    L.01.X.E   Protein kinase inhibitors

    L.01.X.E.15   Vemurafenib

    Pharmacodynamics:

    An antineoplastic agent, a protein kinase inhibitor. Vemurafenib is a low molecular weight oral inhibitor of serine-threonine kinase encoded by the BRAF gene (v-raf murine sarcoma viral oncogene homolog B1). As a result of mutations in the gene BRAF, leading to the replacement of the amino acid valine at position 600, constitutive activation of the oncogenic protein BRAF and, consequently, cell proliferation in the absence of growth factors.

    According to biochemical studies vemurafenib is a potent inhibitor of BRAF kinases with activating mutations in the codon 600.

    Pharmacokinetics:

    Vemurafenib is a substance with low solubility and low permeability (class 4 according to the biopharmaceutical classification system). The pharmacokinetic parameters of vemurafenib were assessed by non-compartmental analysis, as well as by population pharmacokinetic analysis. The pharmacokinetics of vemurafenib is dose-dependent in the dose range from 240 to 960 mg when taken 2 times a day. The linearity of pharmacokinetics is also confirmed by the data of population pharmacokinetic analysis.

    Suction

    Absolute bioavailability of vemurafenib for 240 mg tablets is unknown. When taking vemurafenib in a dose of 960 mg 2 times a day, the median time to achieve Cmax is approximately 4 hours. With repeated intake of vemurafenib in a dose of 960 mg twice a day, accumulation of the drug is observed, which is characterized by high interindividual variability. Average AUC0-8 hours and Cmax (± standard deviation) on day 1 were 22.1 ± 12.7 μg × h / ml and 4.1 ± 2.3 μg / ml, respectively. During non-compartmental analysis, when taking vemurafenib at a dose of 960 mg twice a day, the AUC increased 15-17 times on day 15 compared to AUC at 1 day, Cmax for 15 days increased by 13-14 times compared with Cmax in 1 day. In the equilibrium state AUC0-8h and Cmax were 380.2 ± 143.6 μg × h / ml and 56.7 ± 21.8 μg / ml, respectively.

    Food rich in fats increases the exposure of vemurafenib with a single dose of 960 mg. Average geometric parameters Cmax and AUC increased with taking vemurafenib with food as compared with fasting at 2.5 and 4.7 times, respectively. Median Tmax increased from 4 hours to 8 hours with a single dose of vemurafenib with food. There are no data on the effect of food intake on the exposure of vemurafenib in the equilibrium state.Prolonged administration of vemurafenib on an empty stomach can lead to a significant decrease in the exposure of vemurafenib in an equilibrium state compared to taking vemurafenib with food or shortly before meals. It is expected that with irregular reception of vemurafenib on an empty stomach the exposure of vemurafenib in an equilibrium state will change insignificantly due to the high degree of accumulation of vemurafenib in the equilibrium state. The safety and efficacy of vemurafenib in baseline studies have been studied in patients taking vemurafenib both with food, and separately from food intake.

    It is possible to change the exposure of vemurafenib depending on the composition, volume and acidity (pH) of the gastrointestinal fluid, motility and time of passage of food, the composition of bile.

    In an equilibrium state (achieved on day 15 in 80% of patients), the average exposure of vemurafenib in blood plasma is stable for 24 hours, as evidenced by the average plasma concentration ratio before and after 2-4 hours after the morning dose, equal to 1, 13.

    After oral administration, the rate constant of absorption in patients with metastatic melanoma is 0.19 h-1 (interindividual variability is 101%).

    Distribution

    Vemurafenib is characterized by a high degree of binding to human plasma proteins in vitro (more than 99%). According to population analysis, the apparent Vd vemurafenib in patients with metastatic melanoma is 91 liters (interindividual variability is 64.8%).

    Metabolism

    Isozyme CYP3A4 - the main enzyme involved in the metabolism of vemurafenib in vitro. In humans, products of conjugation with glucuronic acid and glycosylation products have also been found. The ratio of vemurafenib and its metabolites was studied in a clinical study of the material balance after a single dose of vemurafenib with 14C-radioactive label. In plasma, the drug is contained predominantly unchanged (> 95%), while metabolites are ≤ 5%.

    Excretion

    According to the population analysis, the apparent clearance of vemurafenib in patients with metastatic melanoma is 29.3 liters per day (interindividual variability is 31.9%), median The half-life of vemurafenib is 51.6 hours (the range of individual values ​​between the 5th and 95th percentiles is 29.8-119.5 h).

    According to the study of material balance, on average 95% of the dose of vemurafenib is excreted within 18 days. Most (94%) of vemurafenib in unchanged form and its metabolites are excreted through the intestine, less than 1% by the kidneys. Removal of the drug unchanged with bile may be an important way of excretion. However, since the absolute bioavailability of the drug is unknown, the value of the influence hepatic and renal excretion on the clearance of the drug in an unchanged form also can not be estimated. Vemurafenib is a substrate and an inhibitor of P-glycoprotein in vitro.

    Pharmacokinetics in specific patient groups

    According to the results of a population pharmacokinetic analysis of patient age has no statistically significant effect on the pharmacokinetic parameters of vemurafenib.

    According to the results of population pharmacokinetic analysis in men, the apparent clearance of the drug is greater by 17%, and the apparent Vd - by 48% compared to women. However, the differences in exposure of vemurafenib are relatively small, indicating that there is no need to adjust the dose of the drug depending on the patient's sex, body mass index or body weight.

    Studies of the pharmacokinetics of vemurafenib in children and adolescents have not been conducted.

    According to the results of population pharmacokinetic analysis of patients with metastatic melanoma, mild and moderate renal insufficiency (creatinine clearance> 40 ml / min) does not affect the apparent clearance of vemurafenib. Clinical data and pharmacokinetic data in patients with severe renal insufficiency are insufficient to determine the need for dose adjustment.

    Vemurafenib is mainly excreted with bile. According to the results of population pharmacokinetic analysis of patients with metastatic melanoma, an increase in activity aspartate aminotransferase and alanine aminotransferase up to a value 3 times higher than the upper limit of the norm, does not affect the apparent clearance of vemurafenib. Clinical data and data on pharmacokinetics in patients with severe hepatic insufficiency is not sufficient to determine the effect of metabolic or excretory liver imbalance on the pharmacokinetics of vemurafenib.

    Indications:

    Inoperable or metastatic melanoma with BRAF V600 mutation in adult patients in the form of monotherapy.

    ICD-10

    II.C43-C44.C43   Malignant skin melanoma

    Contraindications:

    - Hypersensitivity to vemurafenib and to other components of the drug in the anamnesis;

    - severe renal failure;

    - severe degree of hepatic insufficiency;

    - non-amenable correction of the water-electrolyte balance (including the balance of magnesium);

    - syndrome of prolonged QT interval;

    - Corrected QT interval (QTc)> 500 ms before the start of therapy;

    - taking medications that promote the prolongation of the QT interval;

    - Pregnancy;

    - the period of breastfeeding;

    - children and adolescents under 18 years of age (efficacy and safety of use not established).

    Carefully:

    Simultaneous administration with warfarin, potent inhibitors and inductors of CYP3A4 isoenzyme, glucuronation and / or transport proteins (including P-glycoprotein), drugs that are substrates of the isoenzyme CYP1A2.

    Pregnancy and lactation:

    Contraindicated in pregnancy and lactation.

    Dosing and Administration:

    The recommended dose of the drug is 960 mg (4 tablets of 240 mg) 2 times a day (daily dose is 1920 mg), inside. A drug can be taken both during meals and separately from food intake, however, long-term administration of both fasting doses should be avoided.

    The tablet should be swallowed whole, washed down with water. Do not chew or grind the tablet.

    Duration of the drug

    When there are signs of progression of the disease, drug therapy should be discontinued. In case of development of intolerable toxicity, drug therapy should be suspended or discontinued (Tables 1 and 2).

    Missed doses

    If the next dose is missed, it can be taken later to maintain the regimen 2 times a day, but the interval between taking the missed dose and taking the next dose should be at least 4 hours. Take both doses of the drug at the same time.

    Vomiting

    If vomiting occurs after taking vemurafenib, do not take an additional dose, and then continue the treatment as usual.

    Dose change

    When unwanted reactions appear or when the QT interval is extended, corrected according to the heart rate (QTc), a dose reduction, temporary interruption or discontinuation of the drug may be required vemurafenib (tables 1 and 2).

    Do not reduce the dose of the drug below 480 mg 2 times a day.

    With the development of squamous cell carcinoma of the skin, it is recommended to continue treatment without dose adjustment.

    Table 1. Change in dose depending on the degree of severity of adverse reactions

    Severity of adverse reactions *

    Recommended tactics for the dose of the drug

    Degree 1 or degree 2 (portable)

    Continue taking the drug at a dose of 960 mg 2 times a day.

    Degree 2 (intolerable) or degree 3

    The first manifestation of any adverse reactions of 2 or 3 severity

    Discontinue taking the drug until the severity of adverse reactions is reduced to 0-1. Resume the drug at a dose of 720 mg 2 times a day (or at a dose of 480 mg 2 times a day, if the dose was previously reduced).

    The second manifestation of any adverse reactions of 2 or 3 severity degree or their retention after the suspension of therapy

    Discontinue taking the drug until the degree of severity of adverse reactions is reduced to a grade of 0-1. Resume the drug at a dose of 480 mg 2 times a day (or stop taking the drug if the dose was previously reduced to 480 mg 2 times a day).

    The third manifestation of any adverse reactions of 2 or 3 severity degree or their preservation after the 2nd dose reduction

    Stop taking the drug.

    Degree 4

    The first manifestation of any adverse reactions of the 4th degree of severity

    Stop taking the drug or interrupt before reducing the severity of adverse reactions to grade 0-1. Resume the drug at a dose of 480 mg 2 times a day (or discontinue if the dose has previously been reduced to 480 mg 2 times a day).

    The second manifestation of any adverse reactions of 4 severity after the first dose reduction

    Stop taking the drug.

    * Severity of adverse events in accordance with the United States National Cancer Institute's General Unwanted Criteria for Toxicity, version 4.0.

    When using the drug an elongation of the QT interval, proportional to the exposure of vemurafenib, was observed. With an extension of QTc monitoring may be required.

    Table 2. Variation of dose with QT interval prolongation

    Value QTc

    Recommended tactics for the dose of the drug

    QTc > 500 ms before the start of therapy

    The drug is not recommended.

    QTc > 500 ms and differs from the initial value recorded before the start of the drug, more than 60 ms

    The drug should be discontinued.

    First detection
    QTc > 500 ms during treatment, contrast QTc from the initial value recorded before the start of the drug, less than 60 ms

    Temporarily stop taking the drug before QT decreasesc below 500 ms.
    Monitoring.
    Resume the drug at a dose of 720 mg     2 times a day (or at a dose of 480 mg 2 times a day, if the dose was previously reduced).

    The second identification
    QTc > 500 ms during treatment, contrast QTc from the initial value recorded before the start of the drug, less than 60 ms

    Temporarily stop taking the drug before QT decreasesc below 500 ms.
    Monitoring.
    Resume the drug at a dose of 480 mg     2 times a day (or stop taking the drug if the dose was previously reduced to 480 mg 2 times a day).

    Third detection
    QTfrom > 500 ms during treatment, contrast QTc from the initial value recorded before the start of the drug, less than 60 ms

    Stop taking the drug.

    In elderly patients 65 years of age and older, dose adjustment is not required.

    In patients with mild or moderate renal failure, correction of the initial dose is not required. There is insufficient data to determine the need for dose adjustment in patients with severe renal insufficiency.

    In patients with mild to moderate hepatic insufficiency, dose adjustment is not required. There is insufficient data to determine the need for dose adjustment in patients with severe hepatic impairment.

    The safety and effectiveness of the drug in patients not belonging to the Europoid race is not established.

    Side effects:

    Determination of the frequency of adverse reactions: very often (≥ 10%), often (≥ 1% and <10%), infrequently (≥ 0.1% and <1%), rarely (≥ 0.01% and <0.1% ), very rarely (<0.01%).

    Most often (> 30%): arthralgia, fatigue, rash, photosensitivity reaction, nausea, diarrhea, alopecia, itching and papilloma of the skin. There were reports of very frequent cases of squamous cell carcinoma of the skin, the treatment, as a rule, was surgical.

    Benign, malignant and unspecified neoplasms (including cysts and polyps): very often - squamous cell carcinoma of the skin, seborrheic keratosis, papilloma of the skin; often - basal cell carcinoma, new primary melanomas; infrequently - squamous cell carcinoma of non-localization.

    From the side of metabolism: very often - a decrease in appetite, weight loss.

    From the nervous system: very often - headache, dysgeusia (distortion of taste perception), peripheral neuropathy; often paralysis of the facial nerve, dizziness.

    From the side of the organ of vision: often uveitis; infrequently, retinal vein occlusion.

    From the side of the vessels: infrequently - vasculitis.

    From the respiratory system: very often - a cough.

    From the digestive system: very often - diarrhea, vomiting, nausea, constipation.

    From the skin and subcutaneous tissues: very often - the reaction of photosensitization, actinic keratosis, rash, maculopapular rash, papular rash, itching, hyperkeratosis, erythema, alopecia, dry skin, sunburn, palmar-plantar erythrodysesthesia syndrome; often - erythema nodosum, follicular keratosis, folliculitis; infrequently - toxic epidermal necrolysis, Stevens-Johnson syndrome.

    From the musculoskeletal system: very often - arthralgia, myalgia, pain in the extremities, musculoskeletal pain, back pain, arthritis.

    Other: very often - fatigue, fever, peripheral edema, asthenia.

    Special populations of patients

    Elderly patients

    Patients aged 65 years or more are more likely to develop adverse reactions, including squamous cell carcinoma of the skin, decreased appetite and heart problems.

    Floor

    When using the drug Among the adverse reactions of the 3rd degree of severity observed more often in women than in men, there was rash, arthralgia, and photosensitivity.

    Overdose:

    Symptoms: dose-limiting toxicity of the drug manifested as a rash with itching and fatigue.

    Treatment: In case of suspected overdose, you must stop taking and prescribe supportive therapy. If any adverse reactions occur, appropriate symptomatic treatment should be given. Specific antidote, which could be used in cases of drug overdose, does not exist.

    Interaction:

    Substrates of cytochrome P450 isoenzymes

    Results of the study of drug interaction in vivo, conducted with the participation of patients with metastatic melanoma, suggest that vemurafenib is a moderate inhibitor of the isoenzyme CYP1A2 and inducer of the isoenzyme CYP3A4. Vemurafenib can reduce the exposure of substances metabolized predominantly with the participation of the CYP3A4 isoenzyme. In this regard, it is possible to reduce the effectiveness of contraceptive drugs metabolized with the participation of the CYP3A4 isoenzyme.

    Vemurafenib simultaneous use with drugs with a narrow therapeutic index, which is metabolized by the participation not recommended isozymes CYP1A2 and CYP3A4, since vemurafenib can change their concentration. If it is not possible to avoid their joint use, care should be taken and the dose of the drug, which is the substrate of the CYP1A2 isoenzyme, should be reduced. Joint application with vemurafenib caffeine increases AUC (substrate isoenzyme CYP1A2) by an average of 2.6 times (up to 5 fold), whereas midazolam AUC (substrate isoenzyme CYP3A4) decreases on average by 39% (to a maximum of 80%). Dextromethorphan AUC (substrate CYP2D6) Dextrorphan and its metabolite increased by approximately 47% due to the effect on the kinetics of dextromethorphan which may be mediated by inhibition of isozyme CYP2D6. In the study in vitro vemurafenib in a concentration of 10 μM caused a slight inhibition of the CYP2B6 isoenzyme. It is not known whether vemurafenib when it reaches an equilibrium concentration of 100 .mu.M in the blood of patients (approximately 50 ug / ml) to reduce the content of substrates isoenzyme CYP2B6, such as bupropion, with their simultaneous application.

    The simultaneous use of vemuraphhene and warfarin (the substrate of the isoenzyme CYP2C9) can lead to an increase in the AUC of the latter by 18%. Care should be taken and additional monitoring of MHO should be envisaged if vemurafenib is used in combination with warfarin.

    In the study in vitro vemurafenib inhibited the isoenzyme CYP2C8. The significance of this observation for a person is unknown, but the risk of a clinically significant effect on the substrates of the CYP2C8 isoenzyme in a joint application can not be ruled out.

    To avoid interaction with medications, after the termination of vemurafenib, a washout period of 8 days may be required.

    Carriers of medicines

    During the research in vitro it was shown that vemurafenib is an inhibitor of P-glycoprotein and BCRP (a breast cancer resistance protein, a protein of resistance to breast cancer). The clinical significance of this data is not known. It is impossible to exclude the possible increase in exposure of drugs transported with P-glycoprotein, while using with vemurafenib (for example, aliskiren, colchicine, digoxin, everolimus, fexofenadine) or BCRP (for example, methotrexate, mitoxantrone, rosuvastatin). Data on the effect of vemurafenib on other vectors are not available.

    The effect of drugs on vemurafenib

    In studies in vitro It is shown that the metabolism of vemurafenib occurs with the participation of the CYP3A4 isoenzyme and by glucuronation. Caution should be exercised when using simultaneously vemurafenib and potent inhibitors of the CYP3A4 isoenzyme, glucuronation and / or transport proteins (eg ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir).

    It should be avoided simultaneous use of vemurafenib with powerful inducers of P-glycoprotein, glucuronation, isoenzyme CYP3A4 (for example, with rifampicin, rifabutin, carbamazepine, phenytoin or St. John's wort) due to a possible decrease in vemurafenib exposure.

    In studies in vitro shown, that vemurafenib is a substrate of P-glycoprotein and BCRP. Data on the effect of inducers or inhibitors of P-glycoprotein and BCRP on the exposure of vemurafenib is not available.It can not be ruled out that the pharmacokinetic parameters of vemurafenib may be influenced by drugs that inhibit or affect the P-glycoprotein (for example, verapamil, clarithromycin, ciclosporin, ritonavir, quinidine, dronedaron, amiodarone, itraconazole, ranolazine) and BCRP (ciclosporin, gefitinib).

    Data on whether vemurafenib substrate for other vectors.

    Special instructions:

    Before using the drug, patients should undergo a validated test for the presence of a BRAF V600 mutation. Efficacy and safety of the drug In patients whose tumors carry rare BRAF V600 mutations other than the V600E and V600K, it has not been conclusively proven. Do not use in patients with a malignant melanoma expressing wild-type BRAF.

    Hypersensitivity reactions

    When using the drug reported cases of serious hypersensitivity reactions, including anaphylaxis. Severe hypersensitivity reactions may include generalized rash, erythema, or arterial hypotension. With the development of severe hypersensitivity reactions, further administration of the drug should be discontinued.

    Dermatological reactions

    When using the drug reported severe dermatological reactions, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in a basic clinical study. With the development of severe dermatological reactions, further administration of the drug should be discontinued.

    QT interval extension

    When using the drug an elongation of the QT interval, proportional to the exposure of vemurafenib, was observed. Elongation of the QT interval may increase the risk of ventricular arrhythmias, including ventricular pirouette tachycardia. Application of the drug It is not recommended in patients with unrecoverable water-electrolyte balance disorders (including magnesium balance), QT prolonged interval syndrome, and also in patients receiving medications that promote QT interval prolongation.

    ECG and the study of the water-electrolyte balance (including the balance of magnesium) must be performed before starting the drug and after changing the dose of the drug. Further ECG registration and determination of the electrolyte content is recommended to be carried out monthly induring the first 3 months of taking the drug, and then every 3 months or more often if there are clinical symptoms. If the interval QTc > 500 ms, start taking the drug Not recommended. If during the treatment interval QTc (including the balance of magnesium) and to correct the risk factors for prolongation of the QT interval (for example, chronic heart failure, bradyarrhythmia), it will be more than 500 msec, it is necessary to temporarily interrupt the intake of the drug, eliminate water-electrolyte disturbances. After decreasing the QT intervalc up to a value of less than 500 ms, the drug should be resumed at a lower dose as described in Tables 1 and 2. If, after correcting the attendant risk factors, the QT intervalc is> 500 ms and differs from the initial value recorded before the start of the drug, more than 60 ms, the drug should be discontinued.

    Ophthalmic reactions

    Serious ophthalmic reactions including uveitis (including iritis) and occlusion of retinal veins were registered with the use of the drug. The attending physician should regularly monitor the patient for the development of ophthalmic reactions.

    Squamous cell carcinoma of the skin

    In patients who received vemurafenib, cases of development of squamous cell carcinoma of the skin are described, including cases classified as keratoacanthoma and mixed keratoacanthoma. All patients are recommended to undergo examination at a dermatologist before starting the drug. If any suspicious skin lesions occur, they must be excised, sent to a dermatopathological examination and treated in accordance with local medical care standards. When the patient develops squamous cell carcinoma of the skin, it is recommended to continue treatment with the drug without dose correction. A doctor should conduct a monthly examination during therapy and for 6 months after treatment with the drug or before the start of another antitumor therapy. Patients should be informed that if any skin changes occur, the doctor should be informed.

    Squamous cell carcinoma of other (non-local) localization

    In patients who received vemurafenib, cases of development of squamous cell carcinoma of other localization have been reported. Before starting taking the drug, you need to conduct a head and neck examination, consisting, as a minimum,from a visual examination of the oral mucosa and palpation of the lymph nodes, and repeat this examination every 3 months during the administration of the drug. In addition, before you start taking the drug you need to computed tomography organs of the chest, and at the time of taking the drug, repeat this test every 6 months.

    Before starting the drug and at the conclusion of therapy or in the presence of clinical symptoms, it is recommended to conduct studies of the rectum and pelvic organs (in women).

    After discontinuation of the drug the examination for the purpose of revealing squamous cell carcinoma of another localization should be continued for 6 months or until the beginning of other antitumor therapy. The revealed pathological changes should be conducted in accordance with clinical practice.

    New focus of primary melanoma

    When the drug was used, cases of new foci of primary melanoma were registered. In all cases, the treatment was surgical, and patients continued treatment without dose adjustment. Examination for skin lesions should be carried out in accordance with the recommendations given above for squamous cell carcinoma of the skin.

    Other malignant neoplasmsthe

    Proceeding from the mechanism of action, vemurafenib can cause progression of malignant tumors associated with mutations in the RAS gene. It is necessary to carefully consider the relationship between the expected benefit and the possible risk of using the drug in patients with previously transferred or concomitant malignant tumors associated with mutations in the RAS gene.

    Pathological changes in laboratory parameters characterizing liver function

    Against the background of taking the drug, pathological changes in laboratory parameters characterizing liver function may occur. Before the start of the drug, it is necessary to evaluate the activity of liver enzymes, as well as the concentration of bilirubin, and during the administration of the drug, these parameters should be monitored monthly or more often if there are clinical symptoms. When detecting pathological changes in laboratory parameters, it is necessary to reduce the dose, interrupt or stop taking the drug (Table 1).

    Patients with impaired renal function

    Correction of the starting dose in patients with mild and moderate renal insufficiency is not required.There is insufficient data to determine the need for dose adjustment in patients with severe renal insufficiency.

    Photosensitivity

    In patients receiving the drug, photosensitization reactions were recorded from mild to severe severity. All patients should avoid exposure to sunlight while taking the drug. Patients taking the drug while staying outdoors should wear clothing that protects from the sun and use sunscreen with UVA (ultraviolet A range) - and UVB (ultraviolet B range) -filter and lip balm (Sun Protection Factor ≥ 30) for protection from sunburn. In photosensitization reactions of the 2nd degree (intolerance) and above, it is recommended to change the dose of the drug (Table 1).

    Effect of vemurafenib on other drugs

    Vemurafenib may increase the exposure of drugs that are metabolized mainly involving CYP1A2 isoenzyme, and reduce the exposure of drugs that are metabolized mainly involving isoenzyme CYP3A4, including oral contraceptives.

    The need to correct the dose of drugs metabolized predominantly with the participation of isoenzymes CYP1A2 and CYP3A4, should be evaluated before the drug therapy begins depending on the therapeutic index of the drug.

    The effect of drugs on vemurafenib

    The pharmacokinetic parameters of vemurafenib may be influenced by drugs that inhibit or affect the P-glycoprotein (for example, verapamil, clarithromycin, ciclosporin, ritonavir, quinidine, dronedaron, amiodarone, itraconazole, ranolazine). If possible, simultaneous use of the drug with potent inducers of P-glycoprotein, glucuronation, isoenzyme CYP3A4 (for example, rifampicin, rifabutin, carbamazepine, phenytoin, St. John's wort) should be avoided. In order to maintain the effectiveness of the drug should consider alternative treatment options with drugs with a lower inducing potential.

    Contraception in women and men

    Women of reproductive age and men should use reliable methods of contraception throughout the course of taking the drug and at least 6 months after stopping the drug. A drug can reduce the effectiveness of hormonal contraceptives, so it is recommended to use an alternative or additional method of contraception.

    Destruction of an unused preparation or product with expired shelf life must be carried out in accordance with local requirements.

    Impact on the ability to drive vehicles and manage mechanisms

    Investigations of the drug on the ability to drive vehicles and work with machines and mechanisms were not carried out. Patients should be warned about the possible development of dizziness, eye disorders and fatigue, which can be the basis for refusing to drive.

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