Zelborab® (Zelboraf®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceVemurafenibVemurafenib
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  • Zelborab®
    pills inwards 
    Hoffmann-La Roche Ltd.     Switzerland
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    1 tablet, film-coated, contains:

    active substance: vemurafenib1 240,000 mg;

    Excipients: silicon dioxide colloidal anhydrous 10,400 mg, croscarmellose sodium 29,400 mg, giprolose (hydroxypropyl cellulose) 4,250 mg, magnesium stearate 5,950 mg;

    film sheath2: polyvinyl alcohol 8,000 mg, titanium dioxide (E171) 4.982 mg, macrogol 3350 4.040 mg, talc 2.960 mg, iron oxide red oxide (E 172) 0.018 mg.

    1 Vemurafenib is contained in the form of co-precipitate vemurafenib and hypromellose acetate succinate 800 mg.

    2 It is allowed to use the finished mixture Opadry II Pink 85F14411. Qualitative and quantitative composition of the finished mixture Opadry II Pink 85F14411 is similar to the composition of the film shell, indicated in the section.
    Description:

    Oval biconvex tablets covered with a film membrane from pinkish white to orangeish white; on one side of the tablet engraving "VEAT".

    Pharmacotherapeutic group:antitumor agent
    ATX: & nbsp

    L.01.X.E   Protein kinase inhibitors

    L.01.X.E.15   Vemurafenib

    Pharmacodynamics:

    Vemurafenib is an inhibitor of serine-threonine kinase encoded by the gene BRAF (v-raf murine sarcoma viral oncogene homolog B1). As a result of mutations in the gene BRAF constitutive activation of the oncogenic protein occurs BRAF and, as a consequence, the proliferation of cells in the absence of growth factors.

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

    This andMr.the killing effect was confirmed during the phosphorylation of extracellular signal-regulating kinase and cell antiproliferation in available melanoma cell lines expressing the gene BRAF from V600 mutations. In antiproliferation tests in cell lines with V600 mutations (lines V600E, V600R, V600D and V600K) concentration of half maximal inhibition (IC50) varied from 0.016 to 1.131 μmol, while IC50 for cell lines with wild-type gene BRAF was 12.06 and 14.32 μmol, respectively.

    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 single dose of 960 mg (4 tablets 240 mg) median time until the maximum concentration in the blood plasma (TmOh) is approximately 4 hours. With repeated administration of vemurafenib in a dose of 960 mg twice a day, accumulation of the drug is observed, which is characterized by high interindividual variability. The average area under the "concentration-time" curve AUC0-8h and the maximum concentration in the blood plasma (CmOh) (± standard deviation) on day 1 was 22.1 ± 12.7 μg * h / ml and 4.1 ± 2.3 μg / ml, respectively. In the course of non-compartmental analysis, when taking vemurafenib in a dose of 960 mg twice daily AUC for 15 days increased by 15-17 times compared to AUC in 1 day, withmOh 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 Сmax and AUC increased when taking vemurafenib with food as compared with fasting at 2.5 and from 4.6 to 5.1 times, respectively. Median TmOh Increased from 4 hours to 7.5 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 the equilibrium state (achieved at day 15 in 80% of patients), the average exposure of vemurafenib in blood plasma is stable for 24 hours,as evidenced by the average ratio of plasma concentration 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

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

    Metabolism

    Isozyme of cytochrome P450 (CYP) 3A4 - 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 in unchanged form (> 95%), while metabolites are ≤5%.

    Excretion

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

    According to the study of the material balance in the average 95% of the dose is displayed vemurafenib for 18 days. Most (94%) vemurafenib unchanged and its metabolites derived intestine, less than 1% - 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

    Elderly patients

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

    Floor

    According to the results of population pharmacokinetic analysis in men, the apparent clearance of the drug is greater by 17%, and the apparent volume of distribution is 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.

    Patients of childhood and adolescents

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

    Patients with impaired renal function

    According to the results of the population pharmacokinetic analysis of patients with metastatic melanoma, mild to 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 failure are insufficient to determine the need for dose adjustment.

    Patients with impaired hepatic function

    Vemurafenib is mainly excreted with bile. According to the results of population pharmacokinetic analysis of patients with metastatic melanoma, an increase in activity of aspartate aminotransferaseACT) and alanine aminotransferase (ALT) 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.

    Contraindications:

    Hypersensitivity to vemurafenib and to other components of the drug in the anamnesis.

    Pregnancy and the period of breastfeeding.

    Children under 18 years of age (efficacy and safety of use not established).

    Unviable correction of water-electrolyte balance (including magnesium balance), long interval syndrome QT, taking medications that promote the lengthening of the interval QT, corrected interval QT (QTc)> 500 ms before the start of therapy.

    Severe degree of renal and hepatic insufficiency.

    Carefully:

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

    Care should be taken when using together vemurafenib and isoenzyme substrates CYP2C8 with a narrow therapeutic range (see section "Interaction with other drugs").

    Dosing and Administration:

    Treatment with Zelboraf® should be performed under the supervision of an oncologist.

    Before using Zelboraf®, a validated test should be performed BRAF V600 mutations.

    The recommended dose of Zelboraf® is 960 mg (four 240 mg tablets) a day and a half a day (daily dose is 1920 mg), inside. The drug Zelboraf® 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. To chew or grind a tablet it is impossible.

    Duration of the drug

    When there are signs of progression of the disease, Zelboraf® should be discontinued. If intolerable toxicity develops, Zelboraf® should be suspended or discontinued (see Tables 1 and 2).

    Missed doses

    If the next dose is missed, it can be taken later to maintain the regimen twice a day, but the interval between taking the missed dose and taking the next dose should be at least 4 hours. Do not take both doses simultaneously.

    Vomiting

    In the event of vomiting after taking Zelboraf® Do not take an extra dose, and then continue the treatment as usual.

    Dose change

    When unwanted reactions appear or when the interval is extended QT, adjusted in accordance with the heart rate (QTc), a dose reduction, temporary interruption or discontinuation of Zelboraf® preparation may be required (see Tables 1 and 2).

    He should reduce the dose of the drug below 480 mg twice a day.

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

    Table 1. Dose change depending on severity of adverse events

    Severity of adverse events *

    Recommended tactics for the vine of Zelboraf® during the current treatment period

    The recommended tactic for the dose of Zelboraf® with the resumption of treatment

    Degree 1 or degree 2 (portable)

    Accept unchanged.

    Not applicable.

    Degree 2 (intolerable) or degree 3

    The first manifestation of any undesirable phenomena of 2 or 3 severity

    Discontinue taking the drug until the severity of adverse events is reduced to 0-1.

    Reduce the dose by 240 mg twice a day.

    The second manifestation of any undesirable phenomena is ^ 2 or 3 degrees of severity or their retention after the suspension of therapy

    Interrupt drug intake until the severity of adverse events is reduced to a degree of 0-1

    Reduce the dose by 240 mg twice a day.

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

    Stop taking the drug.

    Not applicable.

    Degree 4

    The first manifestation of any undesirable phenomena of the 4th degree of severity

    Stop taking the drug or interrupt before reducing the severity of adverse events to grade 0-1.

    Reduce the dose to 480 mg twice daily.

    The second manifestation of any undesirable phenomena of 4 severity after the first dose reduction

    Pto reduce the reception of the drug.

    Not applicable.

    * The severity of the adverse event in accordance with the General Unwanted Tension Criteria of the National Cancer Institute, USA, version 4.0.

    Any undesirable phenomenon in which the dose was reduced or the medication was interrupted for medical reasons.

    When using Zelboraf® lengthening of the interval was observed QT, proportional to the exposure of vemurafenib. With elongation QTc monitoring may be required (see section "Special instructions").

    Table 2. Variation of dose with QT interval prolongation

    Value QTc

    Recommended tactics for the dose of Zelboraf®

    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, 60 ms or less

    Temporarily stop taking the drug before the decrease QTc below 500 ms.

    Monitoring (see section "Special instructions").

    Reduce the dose by 240 mg twice a day.

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

    Temporarily stop taking the drug before the decrease QTc below 500 ms.

    Monitoring (see section "Special instructions").

    Reduce the dose by 240 mg twice a day.

    Third detection QTwith> 500 ms during treatment, contrast QTc from the initial value, registered before the start of the drug, 60 ms or less

    Stop taking the drug.

    Dosing in special cases

    Elderly patients

    Dose adjustments in patients aged ≥65 years are not required.

    Patients with impaired renal function

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

    Patients with impaired hepatic function

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

    Patients not belonging to the Europoid race

    The safety and efficacy of Zelboraf® in patients not belonging to the Europoid race has not been established.

    Side effects:

    To describe the frequency of undesired reactions, the following classification is used: very often (≥10%), often (> 1% and <10%), infrequently (≥0.1% and <1%), rarely (≥0.01% and < 0.1%), very rarely (<0.01%).

    The most frequent adverse reactions (> 30%) with the use of the drug Zelboraf® were arthralgia, fatigue, rashes, photosensitization reaction, nausea, diarrhea, alopecia, itching and papilloma of the skin. Very frequent cases of squamous cell carcinoma of the skin have been reported; 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, skin papilloma; often - basal cell carcinoma, new primary melanomas; infrequently - squamous cell carcinoma of non-localization.

    Disorders from the metabolism: very often - a decrease in appetite, weight loss.

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

    Disorders from the side of the organ of vision: often uveitis, including iritis; infrequently, retinal vein occlusion.

    Vascular disorders: infrequently - vasculitis.

    Disturbances from the respiratory system, chest and mediastinal organs: very often - a cough.

    Disorders from the gastrointestinal tract: very often - diarrhea, vomiting, nausea, constipation.

    Disturbances 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, syndrome palmar-plantar erythrodysesthesia; often - panniculitis, including erythema nodosum, follicular keratosis, folliculitis; infrequently - toxic epidermal necrolysis, Stevens-Johnson syndrome.

    Ondestruction from the musculoskeletal and connective tissue: very often - arthralgia, myalgia, pain in the extremities, musculoskeletal pain, back pain, arthritis.

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

    Laboratory and instrumental data: very often - increased activity of gamma glutamyltranspeptidase **; often - increased ALT * activity, alkaline phosphatase *, increased bilirubin concentration *; infrequently - increased ACT activity **.

    * - 3 degrees of severity

    ** - 3 or 4 degrees of severity

    Hypersensitivity reactions

    With the use of the drug Zelboraf ® 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 use of Zelboraf® should be discontinued.

    Post-registration application of

    Benign, malignant and unspecified neoplasms (including cysts and polyps): progression of a previous chronic myelomonocytic leukemia with a mutation in the NRAS gene (the frequency is unknown); progression of the previous pancreatic adenocarcinoma with a mutation in the KRAS gene (the frequency is unknown).

    Disturbances from the skin and subcutaneous tissues: drug rash with eosinophilia and systemic symptoms (DRESS-syndrome) (frequency is unknown).

    Disturbances from the liver and bile ducts: liver damage (infrequently).

    Disorders from the gastrointestinal tract: pancreatitis (infrequently).

    Disorders from the side of the coryza and lymphatic system: neutropenia (infrequently).

    Trauma, intoxication and complications of manipulation: radiation sickness (frequency unknown), including radiation dermatitis, radiation damage to the skin, radiation pneumonitis, radiation esophagitis, radiation proctitis,radiation hepatitis, radiation cystitis and radiation necrosis (see section "Special instructions").

    Laboratory and instrumental data: deviations in laboratory parameters characterizing liver function, including an increase in ALT activity 5 or more times higher than the upper limit of the norm (UGN), an increase in the activity of alkaline phosphatase is 2 and more times higher than UGN, an increase in ALT activity is 3 or more times higher than UGN with simultaneous an increase in the concentration of bilirubin is more than 2 times higher than UGN.

    Special populations of patients

    Elderly patients

    Patients aged 65 and over are more likely to develop unwanted reactions, including such as squamous cell carcinoma of the skin, decreased appetite and heart problems.

    Floor

    When Zelboraf ® was used, among undesirable reactions of the 3rd degree of severity observed more often in women than in men, there was rash, arthralgia and photosensitivity.

    Overdose:

    A specific antidote that could be used in cases of an overdose of Zelboraf®, does not exist. If unwanted reactions occur, appropriate symptomatic treatment should be given.The dose-limiting toxicity of Zelboraf® was manifested as a rash with itching and fatigue. In case of suspicion of overdose, you should stop taking Zelboraf® and prescribe maintenance therapy.

    Interaction:

    The interaction of vemurafenib and cytochrome P450 substrates (CYR)

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

    Simultaneous use of vemurafenib with drugs metabolized by isoenzymes CYP1A2 and CYP3A4, and having a narrow therapeutic index is not recommended. Care should be taken when it is not possible to avoid their joint application, since vemurafenib can increase the exposure of substrate-drug isoenzyme CYP1A2 and reduce the exposure of substrate-preparation isoenzyme CYP3A4 in the blood plasma. If necessary, a reduction in the dose of the drug, which is the substrate of the isoenzyme CYP1A2. During the clinical trial, it was found that joint use with vemurafenib increases AUC caffeine (substrate isoenzyme CYP1A2) an average of 2.6 times (a maximum of 5 times), whereas AUC midazolam (substrate isoenzyme CYP3A4) is reduced by an average of 39% (up to 80%). AUC dextromethorphan (substrate CYP2D6) and its dextrophane metabolite increased by approximately 47% due to the effect on the kinetics of dextromethorphan, which may not be mediated by inhibition of the isoenzyme CYP2D6.

    In the study in vitro vemurafenib at a concentration of 10 μM caused a slight inhibition of the isoenzyme CYP2B6. It is not known whether vemurafenib when the equilibrium concentration of 100 μM in the blood of patients (approximately 50 μg / ml) is reached, the content of isoenzyme substrates CYP2B6, such as bupropion, with their simultaneous application.

    The simultaneous use of vemurafenib and warfarin (substrate isoenzyme CYP2C9) can lead to an increase AUC the latter by 18%. Care should be taken and additional monitoring of the international normalized relationship (MBUT) in the event that vemurafenib It is used concomitantly with warfarin. During the research in vitro it was shown that vemurafenib is a moderate inhibitor of isoenzyme CYP2C8. The significance of this observation for a person is unknown, but the risk of a clinically significant effect on isoenzymatic substrates CYP2C8 in joint application can not be ruled out. Care should be taken when using together vemurafenib and isoenzyme substrates CYP2C8 with a narrow therapeutic range, since vemurafenib can increase the concentration of the latter.

    To avoid drug interactions, after the termination of vemurafenib, a washout period of 8 days may be required.

    Interaction of vemurafenib with vectors of medications

    AT research in vitro it was shown that vemurafenib is a substrate and inhibitor of P-glycoprotein and BCRP (breast cancer resistance protein, protein resistance of breast cancer). The clinical significance of this data is not known.

    It can not be ruled out that with simultaneous use with vemurafenib, an increase in the exposure of drugs transported with P-glycoprotein (for example, aliskiren, colchicine, digoxin, everolimus, fexofenadine) or inCRP (eg, methotrexate, mitoxantrone, rosuvastatin). In a clinical trial drug interaction with the use of digoxin (drug-substrate P-glycoprotein) it was found that with the use of multiple oral doses of vemurafenib (960 mg 2 times a day), the exposure of a single oral dose of digoxin increased (an increase in the total system exposure (AUFROMlast) and CmOh digoxin 1.8 and 1.5 times, respectively).

    Care should be taken when using simultaneously vemurafenib and P-glycoprotein substrates. If necessary, it is recommended to reduce the dose of the concomitant drug-substrate P-glycoprotein.

    During the research in vitro it was shown that vemurafenib is a protein inhibitor BSEP (Bile Salt Export Pump, exporting the bile acid pump). The clinical significance of this data is not known.

    Data on the effect of vemurafenib on other vectors are not available.

    Effect of concomitant medications on vemurafenib

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

    It should avoid the simultaneous use of vemurafenib and with powerful inducers of P-glycoprotein, glucuronation, isoenzyme CYP3A4 (eg, 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 P-glycoprotein inhibitors and BCRP there is no exposure to vemurafenib. 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.

    Strengthening the action of radiation therapy

    In patients receiving vemurafenib, there was an increase in the toxic effect of radiation therapy (see sections "Special instructions" and "Side effect", subsection "Post-registration application"). In most cases, patients received radiotherapy in the ≥2 G modep/ day (hypofraction mode).

    Special instructions:

    Before using Zelboraf®, patients should undergo a validated test for BRAF V600 mutations. The efficacy and safety of Zelboraf® in patients whose tumors carry rare BRAF V600 mutations other than V600E and Y600K, has not been conclusively proven. Zelboraf® should not be used in patients with malignant melanoma expressing BRAF wild type.

    Hypersensitivity reactions

    When using Zelboraf® 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, the continued use of Zelboraf® should be discontinued.

    Dermatological reactions

    PWhen using Zelboraf® reported severe dermatological reactions, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in a basic clinical study. The cases of the appearance of a drug rash with eosinophilia and systemic symptoms (DRESS-syndrome) against the background of the use of Zelboraf ®.

    With the development of severe dermatological reactions, further use of Zelboraf® should be discontinued.

    Strengthening the action of radiation therapy

    In patients receiving radiotherapy before, during or after the use of vemurafenib, there have been cases of increased sensitivity to radiation therapy and radiation dermatitis (see the sections "Interaction with other drugs" and "Side effect", subsection "Post-registration application"). Caution should be exercised when using vemurafenib simultaneously or sequentially with radiotherapy.

    Interval lengthening QT

    With the use of Zelboraf®, an interval elongation was observed QT, proportional to the exposure of vemurafenib. Interval lengthening QT may contribute to an increased risk of ventricular arrhythmias, including ventricular pirouette tachycardia. Application of the drug Zelboraf® It is not recommended in patients with uncontrollable disturbances in the water-electrolyte balance (including the balance of magnesium), the syndrome of an elongated interval QT, as well as in patients receiving medications that promote lengthening of the interval QT.

    ECG and the study of the water-electrolyte balance (including the balance of magnesium) should be performed before starting the drug and after changing the dose of Zelboraf®. Further ECG registration and determination of the electrolyte content is recommended to be performed monthly during 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, it is not recommended to start taking Zelboraf ®. If during the treatment interval QTc will be more than 500 ms, it is necessary to temporarily interrupt the reception of the drug Zelboraf®, eliminate violations of the water-electrolyte balance (including the balance of magnesium) and achieve correction of risk factors for lengthening the interval QT (eg, chronic heart failure, bradyarrhythmia). After decreasing the interval QTc up to a value of less than 500 ms, the drug should be taken at a lower dose as described in Tables 1 and 2. If, after correcting the concomitant risk factors, the interval value QTc is> 500 ms and differs from the initial value recorded before the start of taking the drug, more than 60 ms, taking Zelboraf® it is necessary to stop.

    Ophthalmic reactions

    When using Zelboraf® Serious ophthalmic reactions including uveitis (including iritis) and occlusion of retinal veins were recorded. The attending physician should regularly monitor the patient for the development of ophthalmic reactions.

    Joint application with ipilimumab

    When the combined use of vemurafenib (960 mg or 720 mg twice daily) with ipilimumab (3 mg / kg), an asymptomatic increase in the activity of transaminases and a bilirubin concentration of 3 severity was recorded. Based on these data, the combined use of vemuraphhenib and ipilimumab is not recommended.

    Evilqualitative neoplasms

    Squamous cell carcinoma of the skin

    Have patients who received Zelboraf ®, described cases of development of squamous cell carcinoma of the skin, 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 Zelboraf® without correction of the dose. 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 instructed about the need to inform the doctor about any changes to the skin.

    Squamous cell carcinoma of other (non-local) localization

    In patients who received Zelboraf ®, cases of development of squamous cell carcinoma of another localization were recorded.Before starting the drug, a head and neck examination should be performed, consisting, at a minimum, of visual examination of the oral mucosa and palpation of the lymph nodes, and repeat this test every 3 months while taking the drug. In addition, before starting taking the drug, you need to perform a computed tomography scan of the chest, and at the time of taking the drug, repeat this test every 6 months.

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

    After discontinuation of the Zelboraf ® drug, a check should be continued for 6 months or until the beginning of another antitumor therapy to detect squamous cell carcinoma of another location. The revealed pathological changes should be conducted in accordance with clinical practice.

    New focus of primary melanoma

    When Zelboraf ® 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 neoplasms

    Proceeding from the mechanism of action, vemurafenib can cause progression of malignant tumors associated with mutations in the gene RAS. 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 gene RAS.

    Lesion of the liver

    With the use of vemurafenib, cases of liver damage, including severe ones, have been reported. Against the background of taking Zelboraf®, pathological changes in laboratory parameters characterizing liver function may occur. Before starting the preparation, it is necessary to evaluate the activity of "liver" enzymes (transaminase and alkaline phosphatase), 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, you should reduce the dose, interrupt or stop taking the drug (see Table 1).

    Patients with impaired renal function

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

    Photosensitivity

    In patients treated with Zelboraf ®, photosensitization reactions were recorded from mild to severe severity. All patients during the drug Zelboraf® avoid exposure to the sun. Patients taking the drug should wear sun protection clothing and sunscreens with UVA (ultraviolet radiation from band A) and UVB (ultraviolet radiation from band B) during outdoor activities, - filters and lip balm (sun protection factor ≥30) to protect against sunburn.

    In photosensitivity reactions of the 2nd degree (intolerance) and above, it is recommended to change the dose of the drug (see Table 1).

    Effect of vemurafenib on other drugs

    Vemurafenib may increase the exposure of drugs that are predominantly metabolized with the participation of an isoenzyme CYP1A2, and to reduce the exposure of drugs that are predominantly metabolized by the participation of isoenzyme CYP3A4, including oral contraceptives.

    The need for correction of the dose of drugs metabolized predominantly with the participation of isoenzymes CYP1A2 and CYP3A4, should be assessed before starting therapy with Zelboraf®, depending on the therapeutic index of the drug.

    With the simultaneous use of the drug Zelboraf® and warfarin should be careful and take into account MNO.

    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 Zelboraf® with powerful P-glycoprotein inducers, glucuronation, isoenzyme CYP3A4 (for example, rifampicin, rifabutin, carbamazepine, phenytoin, St. John's wort pitted). In order to maintain the effectiveness of the drug Zelboraf ® 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 contraceptive methods throughout the course of Zelboraf® and for at least 6 months after stopping the drug. The drug Zelboraf® can reduce the effectiveness of hormonal contraceptives, and therefore 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.

    Effect on the ability to drive transp. cf. and fur:

    Studies of the effect of Zelboraf® on the ability to drive vehicles and work with machines and mechanisms have not been 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.

    Form release / dosage:Tablécoated with film, 240 mg.
    Packaging:

    8 tablets per blister, made from a triplex (oriented polyamid / aluminum / polyvinylchloride films (OPA / AL / PVC)) and aluminum high temperature foil.

    7 blisters together with instructions for use are placed in a cardboard box.

    Storage conditions:

    Store at a temperature of no higher than 30 ° C, in a dry, dark place.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002271
    Date of registration:04.10.2013
    Date of cancellation:2018-10-04
    The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland
    Manufacturer: & nbsp
    Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland
    Information update date: & nbsp13.12.2015
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