Zelboraf

General characteristics. Structure:

Active ingredient: 240,0 mg of a vemurafenib in a look to - precipitated calcium superphosphate of a vemurafenib and a gipromelloza of acetate of succinate (800,0 mg). 

Excipients: silicon dioxide colloid anhydrous, croscarmellose sodium, hypro rod (hydroxypropyl cellulose), magnesium stearate.

Film cover: polyvinyl alcohol, titanium dioxide (E171), macrogoal 3350, talc, dye ferrous oxide red (E172).

The antineoplastic means applied generally to treatment of an inoperable or metastatic melanoma with BRAF V600 a mutation at adult patients in the form of monotherapy.

Pharmacological properties:

Pharmacodynamics. Action mechanism. Вемурафениб serine-threonine of the kinase coded by a gene of BRAF (v-raf murine sarcoma viral oncogene homolog B1) is low-molecular peroral inhibitor. As a result of mutations in a gene of BRAF leading to amino acid replacement valine in situation 600 there is a constitutive activation of BRAF oncoprotein and, as a result, proliferation of cells in the absence of growth factors.

According to the conducted biochemical researches вемурафениб is powerful inhibitor of BRAF kinases with the activating mutations in a codon 600.

Pharmacokinetics. Вемурафениб - substance with low solubility and low-permeability (a class 4 on system of biopharmaceutical classification). Pharmacokinetic parameters of a vemurafenib estimated by method of the nekompartmentny analysis, and also by means of the population pharmacokinetic analysis. The pharmacokinetics of a vemurafenib has dozozavisimy character in the range of doses from 240 to 960 mg at reception 2 times a day. Linearity of pharmacokinetics is also confirmed with data of the population pharmacokinetic analysis.

Absorption. Absolute bioavailability of a vemurafenib for tablets of 240 mg is unknown. At reception of a vemurafenib in a dose of 960 mg twice a day time median before achievement of the maximum concentration in a blood plasma (Tmax) makes about 4 hours. At multiple dose of a vemurafenib in a dose of 960 mg drug accumulation which is characterized by high interindividual variability is twice a day observed. "Concentration time" of AUC0-8ch and the maximum concentration in a blood plasma (Cmax) (±стандартное a deviation) in 1 days made average values of the area under a curve 22.1±12.7 ¼¬ú*þ/ml and 4.1±2.3 mkg/ml, respectively. During the nekompartmentny analysis at reception of a vemurafenib in a dose of 960 mg twice a day AUC for the 15th days increased at 15-17 times in comparison with AUC in 1 days, Cmax for the 15th days increased at 13-14 times in comparison with Cmax in 1 days. In an equilibrium condition of AUC0-8ch and Cmax made 380.2±143.6 ¼¬ú*þ/ml and 56.7±21.8 mkg/ml, respectively.

The food rich with fats increases exposure of a vemurafenib at single use in a dose of 960 mg. Average geometrical values of Cmax and AUC increased at reception of a vemurafenib with food in comparison with inclusion on an empty stomach in 2.5 and 4.7 times, respectively. The median of Tmax increased from 4 to 8 o'clock at a single dose of a vemurafenib with food. There are no data on influence of meal on exposure of a vemurafenib in an equilibrium state. Long reception of a vemurafenib on an empty stomach can lead to significant decrease in exposure of a vemurafenib in an equilibrium state in comparison with reception of a vemurafenib with food or shortly before meal. It is expected that at irregular reception of a vemurafenib on an empty stomach exposure of a vemurafenib in an equilibrium state will change slightly in view of high extent of accumulation of a vemurafenib in an equilibrium state. Safety and efficiency of a vemurafenib in basic researches were studied at the patients accepting вемурафениб as with food, and separately of meal.

Change of exposure of a vemurafenib depending on composition, volume and acidity (рН) of liquid of digestive tract, motility and time of passing of food, composition of bile is possible.

In an equilibrium state (it is reached for the 15th days at 80% of patients) average exposure of a vemurafenib in a blood plasma is characterized by stability for 24 hours what the average ratio of concentration in a blood plasma to and in 2–4 hours after reception of a morning dose, equal 1.13 testifies to.

After oral administration the absorption speed constant at patients with a metastatic melanoma makes 0.19 p-1 (interindividual variability makes 101%).

Distribution. According to the population analysis the seeming volume of distribution of a vemurafenib at patients with a metastatic melanoma makes 91 l (interindividual variability makes 64.8%). Вемурафениб it is characterized by high extent of linkng with proteins of a blood plasma of the person of in vitro (more than 99%).

Metabolism. An isoenzyme of P450 (CYP) cytochrome 3A4 – the main enzyme participating in metabolism of a vemurafenib of in vitro. Conjugation products with glucuronic acid and glycosylation products are also found in the person. The ratio of a vemurafenib and its metabolites was studied during clinical trial of a material balance after a single dose of a vemurafenib with a 14C-radioactive label. In a blood plasma drug contains preferential in not changed look (> 95%) whereas metabolites make ≤5%.

Removal. According to the population analysis the seeming clearance of a vemurafenib at patients with a metastatic melanoma makes 29.3 l/day (interindividual variability makes 31.9%), the median of an elimination half-life of a vemurafenib makes 51.6 hours (range of individual values between the 5th and 95th percentile makes 29.8–119.5 hours).

According to a research of a material balance on average 95% of a dose of a vemurafenib are removed within 18 days. The most part (94%) of a vemurafenib in an invariable look and its metabolites is removed by intestines, less than 1% - kidneys. Removal of drug in an invariable view with bile can be an important way of removal. However as absolute bioavailability of drug is unknown, value of influence of hepatic and renal excretion on clearance of drug in an invariable look cannot be also estimated. Вемурафениб is substrate and inhibitor of the R-glycoprotein in vitro.

Pharmacokinetics at special groups of patients. Patients of advanced age. According to results of the population pharmacokinetic analysis the age of patients does not exert statistically significant impact on pharmacokinetic parameters of a vemurafenib.

Floor. According to results of the population pharmacokinetic analysis at men the seeming clearance of drug is 17% more, and the seeming distribution volume – for 48% in comparison with women. At the same time distinctions in exposure of a vemurafenib are rather small that indicates lack of need to adjust a drug dose depending on a sex of the patient, an index of body weight or body weight.

Patients of children's age and teenagers. Researches of pharmacokinetics of a vemurafenib at patients of children's age and teenagers were not conducted.

Patients with a renal failure. According to results of the population pharmacokinetic analysis of these patients with a metastatic melanoma easy and average degree of a renal failure (clearance of creatinine> of 40 ml/min.) does not exert impact on the seeming clearance of a vemurafenib. Clinical data and data on pharmacokinetics at patients with heavy degree of a renal failure are insufficient for definition of need for dose adjustment.

Patients with an abnormal liver function. Вемурафениб it is preferential removed with bile. According to results of the population pharmacokinetic analysis of these patients with a metastatic melanoma increase in activity of aspartate aminotransferase (nuclear heating plant) and alaninaminotranspherase (ALT) to the value, by 3 times exceeding the upper bound of norm does not exert impact on the seeming clearance of a vemurafenib. Patients with heavy degree of a liver failure have not enough clinical data and data on pharmacokinetics for definition of influence of disturbance of metabolic or excretory function of a liver on pharmacokinetics of a vemurafenib.

Indications to use:

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

Route of administration and doses:

Treatment by the drug Zelboraf® should be carried out under observation of the oncologist.
Before use of the drug Zelboraf® the validirovanny test for existence of BRAF V600 of a mutation has to be carried out.

The recommended dose of the drug Zelboraf® makes 960 mg (four tablets on 240 mg) twice a day (the daily dose makes 1920 mg), inside. The drug Zelboraf® can be accepted as during food, and separately of meal, however it is necessary to avoid long reception of both doses on an empty stomach. 

The tablet should be swallowed entirely, washing down with water. It is impossible to chew or crush a tablet.

Duration of administration of drug. At emergence of signs of progressing of a disease therapy of the drug Zelboraf® should be stopped. In case of development of intolerable toxicity therapy by the drug Zelboraf® should be suspended or stopped (see tables 1 and 2).

The passed doses. If reception of the next dose is missed, it can be accepted later for maintenance of the mode of reception twice a day, however the interval between reception of the passed dose and reception of the following dose has to make not less than 4 hours. It is not necessary to accept both doses of drug at the same time.

Vomiting. In case of developing of vomiting after administration of drug of Zelboraf® it is not necessary to accept an additional dose, and further to continue treatment, as usual.

Change of a dose. At emergence of undesirable reactions or when lengthening an interval of QT, korrigirovanny according to the heart rate (QTc), reduction of a dose, temporary interruption or the termination of administration of drug of Zelboraf® can be required (see tables 1 and 2).

It is not necessary to reduce a drug dose lower than 480 mg twice a day. At development of a planocellular carcinoma of skin it is recommended to continue treatment without dose adjustment.

Table 1. Change of a dose depending on severity of the undesirable phenomena.

Severity of the undesirable phenomena *	The recommended tactics concerning a drug Zelboraf® dose
Degree 1 or degree 2 (transferable)	To continue administration of drug in a dose of 960 mg twice a day.
Degree 2 (intolerable) or degree 3
First manifestation of any undesirable phenomena 2 or 3 severity	To interrupt administration of drug before reduction of severity of the undesirable phenomena to 0–1. To resume administration of drug in a dose of 720 mg twice a day (or in a dose of 480 mg twice a day if the dose was lowered earlier).
The second manifestation of any undesirable phenomena 2 either 3 severity or their preservation after therapy suspension	To interrupt administration of drug before reduction of severity of the undesirable phenomena to degree 0–1. To resume administration of drug in a dose of 480 mg twice a day (or to stop administration of drug if the dose was lowered to 480 mg twice a day earlier).
The third manifestation of any undesirable phenomena 2 either 3 severity or their preservation after the 2nd dose decline	To stop administration of drug.
Degree 4
First manifestation of any undesirable phenomena 4 severity	To stop administration of drug or to interrupt before reduction of severity of the undesirable phenomena to degree 0–1. To resume administration of drug in a dose of 480 mg twice a day (or to stop if the dose was lowered to 480 mg two times a day earlier).
The second manifestation of any undesirable phenomena 4 severity after the 1st dose decline	To stop administration of drug.

* Severity of the undesirable phenomena according to the General criteria of toxicity of the undesirable phenomena of National institute of cancer of the USA, version 4.0.

At use of the drug Zelboraf® the lengthening of an interval of QT proportional to exposure of a vemurafenib was observed. When lengthening QTS carrying out monitoring can be required (see the section "Special Instructions").

Table 2. Change of a dose when lengthening an interval of QT.

QTc value	The recommended tactics concerning a drug Zelboraf® dose
QTc> 500 ms prior to therapy	Administration of drug is not recommended.
QTc> 500 ms also differ from the reference value registered before administration of drug, more than on 60 ms	Administration of drug needs to be stopped.
The first identification of QTc> 500 ms during treatment, difference of QTc from the reference value registered before administration of drug, less than on 60 ms	It is temporary to interrupt administration of drug before decrease in QTc lower than 500 ms. Monitoring (see the section "Special Instructions"). To resume administration of drug in a dose of 720 mg twice a day (or in a dose of 480 mg twice a day if the dose was lowered earlier).
The second identification of QTc> 500 ms during treatment, difference of QTc from the reference value registered before administration of drug, less than on 60 ms	It is temporary to interrupt administration of drug before decrease in QTc lower than 500 ms. Monitoring (see the section "Special Instructions"). To resume administration of drug in a dose of 480 mg twice a day (or to stop administration of drug if the dose was lowered to 480 mg twice a day earlier).
The third identification of QTc> 500 ms during treatment, difference of QTc from the reference value registered before administration of drug, less than on 60 ms	To stop administration of drug.

Dosing in special cases. Patients of advanced age. Dose adjustment at the age of ≥65 years is not required from patients.

Patients with a renal failure. Correction of a starting dose with easy or average degree of a renal failure is not required from patients. There are not enough data for definition of need for dose adjustment at patients with heavy degree of a renal failure.

Patients with an abnormal liver function. Correction of a starting dose with easy or average degree of a liver failure is not required from patients. There are not enough data for definition of need for dose adjustment at patients with heavy degree of a liver failure.

The patients who are not belonging to Caucasian race. Safety and efficiency of the drug Zelboraf® at the patients who are not belonging to Caucasian race is not established.

Features of use:

Before drug Zelboraf® use patients have to pass a validirovanny test for existence of BRAF V600 of a mutation. Efficiency and safety of the drug Zelboraf® at patients whose tumors bear the rare BRAF V600 of a mutation other than V600E and V600K was not convincingly proved. The drug Zelboraf® should not be used at patients with the malignant melanoma expressing BRAF of wild type.

Hypersensitivity reactions. At use of the drug Zelboraf® it was reported about cases of serious reactions of hypersensitivity, including about an anaphylaxis. Heavy reactions of hypersensitivity can include generalized rash, an erythema or arterial hypotension. At development of heavy reactions of hypersensitivity further administration of drug of Zelboraf® should be stopped.

Dermatological reactions. At use of the drug Zelboraf® it was reported about heavy dermatological reactions, including exceptional cases of a syndrome of Stephens-Johnson and a toxic epidermal necrolysis in basic clinical trial. At development of heavy dermatological reactions further administration of drug of Zelboraf® should be stopped.

Lengthening of an interval of QT. At use of the drug Zelboraf® the lengthening of an interval of QT proportional to exposure of a vemurafenib was observed. Lengthening of an interval of QT can promote increase in risk of developing of ventricular arrhythmias, including ventricular tachycardia like "pirouette". Use of the drug Zelboraf® is not recommended at patients with the disturbances of water and electrolytic balance which are not giving in to correction (including balance of magnesium), a syndrome of the extended QT interval, and also at the patients receiving the medicines promoting lengthening of an interval of QT.

The ECG and research of water and electrolytic balance (including balance of magnesium) needs to be executed before administration of drug and after change of a dose of the drug Zelboraf®. Further registration of an ECG and determination of content of electrolytes is recommended to be carried out monthly within the first 3 months of administration of drug, and then every 3 month or more often in the presence of clinical symptoms. If QTS interval> 500 ms, is not recommended to begin administration of drug of Zelboraf®. If during treatment the interval of QTS makes more than 500 ms, it is necessary to interrupt temporarily administration of drug of Zelboraf®, to eliminate disturbances of water and electrolytic balance (including balance of magnesium) and to achieve correction of risk factors of lengthening of an interval of QT (for example, chronic heart failure, a bradyarrhythmia). After reduction of an interval of QTS to the value making less than 500 ms it is necessary to resume administration of drug in lower dose as it is described in tables 1 and 2. If after correction of concurrent factors of risk value of an interval of QTS makes> 500 ms and differs from the reference value registered before administration of drug, more than on 60 ms, administration of drug of Zelboraf® needs to be stopped.

Ophthalmologic reactions. At use of the drug Zelboraf® the serious ophthalmologic reactions including a uveitis (including an iritis) and occlusion of veins of a retina were registered. The attending physician is regularly recommended to watch the patient regarding development of ophthalmologic reactions.

Planocellular carcinoma of skin. At the patients receiving the drug Zelboraf® cases of development of a planocellular carcinoma of skin, including the cases classified as a keratoacanthoma and the mixed keratoacanthoma are described. All patients are recommended to undergo inspection at the dermatologist before administration of drug. At emergence of any suspicious damages of skin they need to be exsected, directed to a dermatopatologichesky research and to carry out therapy according to local standards of delivery of health care. At development in the patient of a planocellular carcinoma of skin it is recommended to continue treatment by the drug Zelboraf® without dose adjustment. The doctor has to conduct examination of the patient monthly during therapy and within 6 months after treatment by drug or prior to other antineoplastic therapy. Patients have to be instructed about need to inform the doctor on emergence of any changes on skin.

Planocellular carcinoma of other (not skin) localization. At the patients receiving the drug Zelboraf® cases of development of a planocellular carcinoma of other localization are registered. Before administration of drug it is necessary to conduct the examination of the head and neck consisting, at least, of visual survey of a mucous membrane of an oral cavity and a palpation of lymph nodes and to repeat this inspection every 3 month during administration of drug. Besides, before administration of drug it is necessary to execute a computer tomography of bodies of a thorax, and during administration of drug to repeat this inspection every 6 months. 
Before administration of drug and upon completion of therapy or in the presence of clinical symptoms it is recommended to conduct researches of a rectum and bodies of a small pelvis (at women).

After the termination of administration of drug of Zelboraf® of inspection for the purpose of identification of a planocellular carcinoma of other localization it is necessary to continue within 6 months or prior to other antineoplastic therapy. The revealed pathological changes should be conducted according to clinical practice.

New center of primary melanoma. At use of the drug Zelboraf® cases of emergence of the new centers of primary melanoma were registered. In all cases treatment was surgical, and patients continued treatment without dose adjustment. Examination regarding damages of skin should be conducted according to the recommendations which are stated above for a planocellular carcinoma of skin.

Other malignant new growths. Proceeding from the action mechanism, вемурафениб can cause progressing of the malignant new growths associated with mutations in RAS gene. It is required to consider carefully a question of the attitude of the expected advantage towards possible risk of use of drug for patients with earlier postponed or accompanying malignant new growths associated with mutations in RAS gene.

Pathological changes of the laboratory parameters characterizing functions of a liver. Against the background of administration of drug of Zelboraf® there can be pathological changes of the laboratory parameters characterizing functions of a liver. Before administration of drug it is necessary to estimate activity of "hepatic" enzymes (transaminases and an alkaline phosphatase), and also concentration of bilirubin, and during administration of drug it is necessary to control these parameters monthly or more often at emergence of clinical symptoms. At identification of pathological changes of laboratory parameters it is necessary to reduce a dose, to interrupt or stop administration of drug (see table 1).

Patients with a renal failure. Correction of a starting dose with easy or average degree of a renal failure is not required from patients. There are not enough data for definition of need for dose adjustment at patients with heavy degree of a renal failure.

Photosensitization. At the patients receiving the drug Zelboraf® reactions of a photosensitization from easy to heavy severity were registered. All patients during administration of drug of Zelboraf® should avoid stay in the sun. The patients accepting drug during stay should wear the clothes protecting from the sun in the open air and to use sun-protection means with UFA (ultraviolet radiation of range And) - and UFV (ultraviolet radiation of range In) - filters and lip balm (a sun-protection factor ≥30) for protection against sunblisters.

At reactions of a photosensitization 2 degrees (intolerance) are recommended to change a drug dose above (see table 1).

Influence of a vemurafenib on other medicines. Вемурафениб can increase exposure of medicines which are preferential metabolized with the participation of CYP1A2 isoenzyme and to reduce exposure of drugs which are preferential metabolized with the participation of CYP3A4 isoenzyme, including oral contraceptives.

Need of dose adjustment of the drugs which are metabolized preferential with the participation of isoenzymes of CYP1A2 and CYP3A4 should be estimated prior to therapy by the drug Zelboraf® depending on a therapeutic index of drug.

At simultaneous use of the drug Zelboraf® and warfarin it is necessary to be careful and take into account to MNO.

Influence of medicines on вемурафениб. The drugs inhibiting or influencing the R-glycoprotein can exert impact on pharmacokinetic parameters of a vemurafenib (for example, verapamil, кларитромицин, cyclosporine, ритонавир, quinidine, дронедарон, Amiodaronum, итраконазол, ранолазин).

Whenever possible it is necessary to avoid simultaneous use of the drug Zelboraf® with powerful inductors of the R-glycoprotein, glyukuronirovaniye, CYP3A4 isoenzyme (for example, rifampicin, rifabutiny, the carbamazepine, Phenytoinum, a St. John's Wort which is made a hole). For the purpose of preservation of efficiency of the drug Zelboraf® it is necessary to consider alternative options of treatment by drugs with the smaller inducing potential.

Contraception at women and men. Women of reproductive age and men have to use reliable methods of contraception throughout all course of administration of drug Zelboraf® and at least within 6 months after the termination of administration of drug. The drug Zelboraf® can reduce efficiency of hormonal contraceptives in this connection it is recommended to use an alternative or additional method of contraception.

Destruction of unused drug or drug expired has to be carried out according to local requirements.

Influence on ability to driving of vehicles and work with cars and mechanisms. Researches of influence of the drug Zelboraf® on ability to driving of vehicles and work with cars and mechanisms were not conducted. Patients should be warned about possible development of dizziness, disturbances from eyes and fatigue which can become the basis for refusal of driving.

Side effects:

For the description of frequency of undesirable reactions the following classification is used: very often (≥10%), it is frequent (≥1% and <10%), infrequently (≥0.1% and <1%), is rare (≥0.01% and <0.1%), is very rare (<0.01%).

(> 30%) at use of the drug Zelboraf® the arthralgia, fatigue, rash, reaction of a photosensitization, nausea, diarrhea, an alopecia, an itch and papilloma of skin were the most frequent undesirable reactions. It was reported about very frequent cases of a planocellular carcinoma of skin, treatment, as a rule, was surgical.

The high-quality, malignant and not specified new growths (including cysts and polyps): very often – a planocellular carcinoma of skin, a seborrheal keratosis, skin papilloma; often – bazalnokletochny cancer, new primary melanomas; infrequently – a planocellular carcinoma of not skin localization.

Disturbances from a metabolism: very often – a loss of appetite, decrease in body weight.

Disturbances from a nervous system: very often – a headache, a dysgeusia (distortion of flavoring perceptions), peripheral neuropathy; often – paralysis of a facial nerve, dizziness.

Disturbances from an organ of sight: often – a uveitis; infrequently – occlusion of veins of a retina.

Disturbances from vessels: infrequently – a vasculitis.

Disturbances from respiratory system, bodies of a thorax and a mediastinum: very often – cough.

Disturbances from digestive tract: very often – diarrhea, vomiting, nausea, a lock.

Disturbances from skin and hypodermic fabrics: very often – reaction of a photosensitization, an actinic keratosis, rash, makulo-papular rash, papular rash, an itch, a hyperkeratosis, an erythema, an alopecia, a xeroderma, a sunblister, a syndrome of a palmar and bottom eritrodizesteziya; often – a knotty erythema, a White's disease, a folliculitis; infrequently – a toxic epidermal necrolysis, Stephens-Johnson's syndrome.

Disturbances from skeletal and muscular and connecting fabric: very often – an arthralgia, a mialgiya, extremity pains, musculoskeletal pain, dorsodynias, arthritis.

Others: very often – fatigue, fever, peripheral hypostases, an adynamy.

Laboratory and tool data: very often – increase in activity of a gammaglutamiltranspeptidaza **; often – increase in activity of ALT *, an alkaline phosphatase *, increase in concentration of bilirubin *; infrequently – increase in activity of nuclear heating plant **.
* - 3 severity
** - 3 or 4 severity

Special populations of patients. Patients of advanced age. At patients at the age of 65 and more years development of undesirable reactions, including, such as planocellular carcinoma of skin, loss of appetite and disturbances is more probable from heart.

Floor. At use of the drug Zelboraf® among undesirable reactions 3 severity observed more often at women, than at men were rash, an arthralgia and a photosensitization.

Interaction with other medicines:

Interaction of a vemurafenib and substrates of P450 (CYP) cytochrome. Results of a research of medicinal interactions in vivo conducted with participation of patients with a metastatic melanoma demonstrate to what вемурафениб is moderate inhibitor of an isoenzyme CYP1A2 and the inductor of an isoenzyme CYP3A4.

Вемурафениб can reduce exposure of the substances which are metabolized preferential with the participation of CYP3A4 isoenzyme. In this regard reduction of efficiency of the contraceptive drugs which are metabolized with the participation of CYP3A4 isoenzyme is possible.

Simultaneous use of a vemurafenib with medicines with a narrow therapeutic index which are metabolized with the participation of isoenzymes of CYP1A2 and CYP3A4 is not recommended as вемурафениб can change their concentration. At impossibility to avoid their combined use it is necessary to be careful and provide a dose decline of the medicine which is CYP1A2 isoenzyme substrate. Combined use with vemurafeniby raises AUC caffeine (CYP1A2 isoenzyme substrate) on average by 2.6 times (as much as possible by 5 times) whereas AUC midazolam (CYP3A4 isoenzyme substrate) decreases on average by 39% (as much as possible to 80%). AUC dextromethorphan (CYP2D6 substrate) and its metabolite of a dekstrofan increased approximately by 47% owing to effect for kinetics of dextromethorphan which can be not mediated by CYP2D6 isoenzyme inhibition.

In the research in vitro вемурафениб in concentration of 10 microns caused low inhibition of an isoenzyme of CYP2B6. It is unknown whether will be вемурафениб at achievement of equilibrium concentration of 100 microns in blood of patients (about 50 mkg/ml) to reduce the content of substrates of an isoenzyme of CYP2B6, such as бупропион, at their simultaneous use.

Simultaneous use of a vemurafenib and warfarin (CYP2C9 isoenzyme substrate) can lead to increase in AUC of the last by 18%. It is necessary to be careful and provide additional monitoring of the international normalized relation (INR) if вемурафениб it is used along with warfarin.

In the research in vitro вемурафениб inhibited CYP2C8 isoenzyme. Value of this observation for the person is unknown, however the risk of clinically significant influence on CYP2C8 isoenzyme substrates at combined use cannot be excluded.

In order to avoid interactions with medicines after phase-out of a vemurafenib the period of washing away lasting 8 days can be required.

Influence of a vemurafenib on carriers of medicines. During the researches in vitro it was shown what вемурафениб is inhibitor of the R-glycoprotein and BCRP (breast cancer resistance protein, protein of stability of a breast cancer). Clinical value of these data is unknown. It is impossible to exclude that at simultaneous use with vemurafeniby increase in exposure of the drugs transported by means of the R-glycoprotein (for example, алискирен, colchicine, digoxin, эверолимус, фексофенадин) or BCRP is possible (for example, a methotrexate, митоксантрон, розувастатин). Data on influence of a vemurafenib on other carriers are absent.

Influence of the accompanying drugs on вемурафениб. In the researches in vitro it is shown that metabolism of a vemurafenib happens with the participation of an isoenzyme CYP3A4 and in the way of a glyukuronirovaniye. It is necessary to be careful at simultaneous use of a vemurafenib and powerful inhibitors of an isoenzyme CYP3A4, glyukuronirovaniye and/or transport proteins (for example, a ritonavira, a sakvinavira, a telitromitsina, a ketokonazola, an itrakonazola, a vorikonazola, a pozakonazola, a nefazodona, an atazanavira).

It is necessary to avoid simultaneous use of a vemurafenib and with powerful inductors of the R-glycoprotein, glyukuronirovaniye, CYP3A4 isoenzyme (for example, rifampicin, rifabutiny, the carbamazepine, Phenytoinum or a St. John's Wort which is made a hole) because of possible decrease in exposure of a vemurafenib.

In the researches in vitro it is shown what вемурафениб is substrate of the R-glycoprotein and BCRP. There are no inductors or inhibitors of the R-glycoprotein and BCRP given on influence on exposure of a vemurafenib. It is impossible to exclude that the drugs inhibiting or influencing the R-glycoprotein (for example, verapamil, кларитромицин, cyclosporine, ритонавир, quinidine, дронедарон, Amiodaronum, итраконазол, ранолазин) and BCRP can exert impact on pharmacokinetic parameters of a vemurafenib (cyclosporine, гефитиниб).

Data on whether is вемурафениб substrate for other carriers, no.

Contraindications:

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

Pregnancy and period of breastfeeding.

Children's age up to 18 years (efficiency and safety of use are not established).

Not giving in corrections of disturbance of water and electrolytic balance (including balance of magnesium), a syndrome of the extended QT interval, reception of the medicines promoting lengthening of an interval of QT, a korrigirovanny interval of QT (QTc)> 500 ms prior to therapy.

Heavy degree of a renal and liver failure.

With care. A concomitant use with warfarin, powerful inhibitors and inductors of an isoenzyme CYP3A4, glyukuronirovaniye and/or transport proteins (including the R-glycoprotein), the medicines which are CYP1A2 isoenzyme substrates.

Overdose:

The specific antidote which could be used in overdose cases the drug Zelboraf® does not exist. At emergence of undesirable reactions it is necessary to appoint the corresponding symptomatic treatment. Dozolimitiruyushchy toxicity of the drug Zelboraf® was shown in the form of rash with an itch and fatigues. In case of suspicion on overdose it is necessary to stop administration of drug of Zelboraf® and to appoint a maintenance therapy.

Storage conditions:

Period of validity 2 years. Not to use after the period of validity specified on packaging.

To store at a temperature not above 30 °C in the dry, protected from light place. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 240 mg. On 8 tablets in the blister manufactured of triplex (oriented polyamides/aluminia/films of polyvinyl chloride (OPA/AL/PVH)) and high-temperature aluminum foil. 7 blisters together with the application instruction place in a cardboard pack.