Composition, form of production and packaging
The tablets covered with a film cover from pinkish-white to orange-white color, oval, biconcave, with engraving "VEM" on one side.
1 tab.
vemurafenib * 240 mg
Excipients: silicon dioxide colloidal anhydrous - 10.4 mg, croscarmellose sodium - 29.4 mg, giprolose (hydroxypropylcellulose) - 4.25 mg, magnesium stearate - 5.95 mg.
The composition of the film shell **: polyvinyl alcohol - 8 mg, titanium dioxide (E171) - 4.982 mg, macrogol 3350 - 4.04 mg, talc - 2.96 mg, iron oxide red (E172) 0.018 mg.
8 pcs. - blisters (7) - packs of cardboard.
* vemurafenib is contained in the form of co-precipitate vemurafenib and hypromellose acetate succinate - 800 mg.
** it is allowed to use the finished mixture Opadry II Pink 85F14411; the qualitative and quantitative composition of the mixture Opadry II Pink 85F14411 is similar to the composition of the film shell.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
PHARMACHOLOGIC EFFECT
Antitumor drug. Vemurafenib is an 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 BRAF gene, constitutive activation of the oncogenic BRAF protein occurs, and as a consequence, 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. This inhibitory effect was confirmed by the extracellular signal-regulating kinase phosphorylation and cell antiproliferation in available melanoma cell lines expressing the BRAF gene with V600 mutations. In antiproliferation tests in cell lines with V600 mutations (lines V600E, V600R, V600D and V600K), the half-maximal inhibition (IC 50 ) concentration ranged from 0.016 to 1.131 Ојmol, while the IC 50 for the wild-type cell lines of the BRAF gene was 12.06 and 14.32 Ојmol, respectively.
Patients with metastases in the brain
The total efficacy of the therapy (BORR, best overall response rate) of vemurafenib in patients with metastases in the brain was 17.8% and 17.9% in patients who had not previously received / received therapy, respectively (17.8% in the general population).
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 / 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 to 240 mg), the median time to achieve C max in blood plasma is approximately 4 hours. With repeated administration of vemurafenib at a dose of 960 mg 2 times / day, there is an accumulation of the drug, which is characterized by a high interindividual variability. Mean values ​​of AUC 0-8 h and C max (± 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 2 times / day, AUC on day 15 increased 15-17 times compared to AUC on day 1, C max increased by 13-14 times compared to C max in the 15th day 1 day. In the equilibrium state, AUC 0-8h 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. The average geometric parameters Cmax and AUC increased with taking vemurafenib with food as compared to fasting at 2.5 and 4.6 to 5.1 times, respectively. Median T max increased from 4 hours to 7.5 hours with a single dose of vemurafenib with food. Data on the effect of food intake on the exposure of vemurafenib in the equilibrium state is not available. Prolonged administration of vemurafenib on an empty stomach can lead to a significant reduction 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 basic studies have been studied in patients taking vemurafenib 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, 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 V d of vemuraphenib in patients with metastatic melanoma is 91 L (interindividual variability is 64.8%). Vemurafenib is characterized by a high degree of binding to human plasma proteins in vitro (more than 99%).
Metabolism
Isozyme CYP3A4 - the main enzyme involved in the metabolism of vemuraphenib 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 a 14 C-radioactive label. In plasma, the drug is contained predominantly in unchanged form (> 95%), while metabolites are ≥ 5%.
Excretion
According to the population analysis, the apparent clearance of vemurafenib in patients with metastatic melanoma is 29.3 l / day (interindividual variability is 31.9%), the median T 1/2 vemurafenib is 51.6 h (the range of individual values ​​between the 5th and 95th percentile is 29.8- 119.5 hours).
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 effect of hepatic and renal excretion on the clearance of the drug in an unchanged form can not be evaluated. Vemurafenib is a substrate and inhibitor of P-glycoprotein in vitro.
Pharmacokinetics in specific patient groups
According to the results of population pharmacokinetic analysis, the age of patients does not have a 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 V d - by 48% compared to women. However, the differences in the 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, BMI or body weight.
Studies of the pharmacokinetics of vemurafenib in children and adolescents have not been carried out.
According to the results of population pharmacokinetic analysis of patients with metastatic melanoma, mild and moderate renal insufficiency (CK> 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 the population pharmacokinetic analysis of patients with metastatic melanoma, an increase in the activity of ACT and ALT to a value 3 times that of UHN 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.
DOSING MODE
Treatment with Zelboraf В® should be performed under the supervision of an oncologist.
Before using Zelboraf В® , a validated BRAF V600 mutation test should be performed.
The recommended dose of Zelboraf В® is 960 mg (4 tablets to 240 mg) 2 times / day (daily dose is 1920 mg), inside. Zelborab В® can be taken either during meals or separately from meals, 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
If signs of disease progression appear, Zelboraf В® therapy should be discontinued. If intolerable toxicity develops, Zelboraf В® 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 2 times / 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
In the event of vomiting after taking Zelboraf В®, do not take an additional dose, and then continue the treatment as usual.
Dose change
If unwanted reactions occur or if the QT interval corrected according to the heart rate (QT c ) is prolonged, a dose reduction, temporary interruption or discontinuation of Zelboraf В® preparation may be required (see Tables 1 and 2).
Do not reduce the dose of the drug below 480 mg 2 times / day.
With the development of squamous cell carcinoma of the skin, it is recommended to continue treatment without dose adjustment.
Table 1. Dose variation depending on severity of adverse events
Severity of adverse events * Recommended tactics for the dose of Zelboraf В® during the current treatment period The recommended tactic for the dose of Zelboraf В® at 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 adverse events ** 2 or 3 degrees of severity Interrupt drug intake to reduce the severity of adverse events to 0-1. Reduce the dose by 240 mg 2 times / day.
The second manifestation of any undesirable phenomena of 2 or 3 severity or their retention after the suspension of therapy Discontinue taking the drug until the severity of adverse events decreases to a degree of 0-1. Reduce the dose by 240 mg 2 times / day.
The third manifestation of any undesirable phenomena of 2 or 3 severity or their retention after the second dose reduction. Stop taking the drug. Not applicable.
Degree 4
The first manifestation of any undesirable phenomena of 4 degrees 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 2 times / day
The second manifestation of any adverse reactions of 4 severity after the first dose reduction. Stop the drug. Not applicable.
* Severity of adverse events in accordance with the United States National Cancer Institute's General Unwanted Criteria for Toxicities, version 4.0.
** Any undesirable phenomenon in which the dose or treatment was reduced was interrupted by medical reasons.
When Zelboraf В® was used, the QT interval was prolonged, proportional to the exposure of vemurafenib. When extending QT c , monitoring may be required.
Table 2. Variation of dose with QT interval prolongation
QT value c Recommended tactic for the dose of Zelboraf В®
QT c > 500 ms prior to initiation of therapy. Drug administration is not recommended.
QT c > 500 ms and differs from the initial value recorded before the start of the drug, more than 60 ms. The drug should be discontinued.
The first detection of QT> 500 ms during treatment, the difference between QT c from the initial value recorded before the start of the drug intake, by 60 ms or less. Interrupt the drug intake until the QT c decreases below 500 ms. Monitoring. Reduce the dose by 240 mg 2 times / day.
The second detection of QT c > 500 ms during treatment, the difference between QT c and the initial value recorded before the start of the drug intake, by 60 ms or less. Interrupt the drug intake until the QT c decreases below 500 ms. Monitoring. Resume the drug at a dose of 480 mg 2 times / day (or stop taking the drug if the dose was previously reduced to 480 mg 2 times / day).
The third detection of QT with > 500 ms during treatment, the difference of QT c from the initial value recorded before the start of the drug intake, by 60 ms or less Stop taking the drug.
In elderly patients (65 years 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 inpatients with severe renal insufficiency .
In patients with mild to moderate hepatic insufficiency, correction of the initial dose is not required. There is insufficient data to determine the need for dose adjustment in patients with severe hepatic impairment.
The safety and efficacy of Zelboraf В® in patients not belonging to the Europoid race is not established.
SIDE EFFECT
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 Zelboraf В® were arthralgia, fatigue, rashes, photosensitivity reactions, nausea, diarrhea, alopecia, pruritus 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, skin papilloma;often - basal cell carcinoma, new primary melanomas; infrequently - squamous cell carcinoma of non-localization.
From the side of metabolism: very often - weight loss.
From the nervous system: very often - headache, dysgeusia, 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 cardiovascular system: infrequently - vasculitis.
From the respiratory system: very often - cough.
On the part of the digestive system: very often - decreased appetite, 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 - panniculitis, including 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.
Laboratory and instrumental data: very often - increase in GGT activity **, increase in creatinine concentration (including in 3% or 4% of cases in 1.2% of cases);often - increased ALT activity *, APF *, increased bilirubin concentration *; infrequently - increased ACT activity **.
Allergic reactions: when using the drug Zelboraf В® reported cases of serious hypersensitivity reactions, including. about anaphylaxis. Severe hypersensitivity reactions may include generalized rash, erythema, or arterial hypotension. With the development of severe hypersensitivity reactions, further use of Zelboraf В® should be discontinued.
Other: very often - fatigue, fever, peripheral edema, asthenia.
* - 3 degrees of severity
** - 3 or 4 degrees of severity
Post-registration application
Benign, malignant and unspecified neoplasms (including cysts and polyps): frequency unknown - progression of a previous chronic myelomonocytic leukemia with a mutation in the NRAS gene, progression of a previous pancreatic adenocarcinoma with a mutation in the KRAS gene.
From the skin and subcutaneous tissues: the frequency is unknown - a drug rash with eosinophilia and systemic symptoms (DRESS syndrome).
From the digestive system: infrequently - liver damage, pancreatitis.
On the part of the hematopoiesis system: infrequently neutropenia.
From the side of the urinary tract: the frequency is unknown - acute damage to the kidneys.
Injury, poisoning and complications of manipulation: the frequency is unknown - radiation sickness, including radiation dermatitis, radiation skin lesions, radiation pneumonitis, radiation esophagitis, radiation proctitis, radiation hepatitis, radiation cystitis and radiation necrosis.
Laboratory and instrumental data: abnormal laboratory parameters characterizing liver functions, including increased ALT activity is 5 times or more higher than the ULN, increased AP activity in 2 and more times higher than the ULN, increased ALT activity in the 3 or more times the ULN while increasing the concentration of bilirubin more than 2 times the ULN, the pathological changes of creatinine concentration.
Special patient populations
In patients aged 65 or older more likely to develop adverse reactions, including squamous cell carcinoma of the skin, loss of appetite and disorders of the heart.
In applying the drug Zelboraf В® among the side reactions 3 severity observed more frequently in women than in men, were rash, arthralgia and photosensitivity.
Patients with brain metastases (with / without symptoms) vemurafenib therapy was safe and generally well tolerated. The safety profile was comparable to the previous study, the new safety data have been identified.
CONTRAINDICATIONS
- severe renal failure;
- severe degree of liver failure;
- not amenable to correction of violations of water-electrolyte balance (balance including magnesium);
- an elongated QT interval syndrome;
- correct the interval QT (QT c )> 500 ms before the start of therapy;
- medication facilitating lengthening QT interval;
- Pregnancy;
- the period of breastfeeding;
- child and adolescence to 18 years (effectiveness and safety have not been established);
- Hypersensitivity to vemurafenib and to other components of the drug in history.
With caution should be prescribed with the concomitant use of warfarin, potent inhibitors and inducers isoenzyme CYP3A4, glyukuronirovaniya and / or transport proteins (including P-glycoprotein), drugs that are substrates isoenzyme CYP1A2, drugs that are substrates isoenzyme CYP2C8 with a narrow therapeutic range.
PREGNANCY AND LACTATION
Do not use this drug during pregnancy and lactation.
Women of childbearing age and men should use reliable methods of contraception throughout the course of treatment with the drug Zelboraf В® and for at least 6 months after stopping treatment. The drug Zelboraf В® may reduce the effectiveness of hormonal contraceptives, in connection with which it is recommended to use an alternative or additional method of contraception.
APPLICATION FOR FUNCTIONS OF THE LIVER
Contraindicated in severe renal insufficiency.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Contraindicated in severe hepatic impairment.
APPLICATION FOR CHILDREN
Contraindicated for children and adolescents under the age of 18 years (effectiveness and safety have not been established).
APPLICATION IN ELDERLY PATIENTS
No dose adjustment in patients aged> 65 years is required.
SPECIAL INSTRUCTIONS
Before using the drug Zelboraf В® , patients should undergo a validated test for the BRAF V600 mutation. The efficacy and safety of the drug Zelboraf В® in patients whose tumors carry the BRAF V600 mutations are rare, other than V600E and V600K, has not been conclusively proved. Zelboraf В® should not be used in patients with malignant melanoma expressing wildtype BRAF.
Hypersensitivity reaction
Using the drug Zelboraf В®reported cases of serious hypersensitivity reactions, including anaphylaxis. Severe hypersensitivity reactions may include generalized rash, erythema or hypotension. With the development of severe hypersensitivity reactions, further reception of the drug Zelboraf В® should be discontinued.
Dermatologic reactions
In applying the drug Zelboraf В® reported severe dermatological reactions, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the reference clinical study. Cases of occurrence of drug rash with eosinophilia and systemic symptoms (DRESS syndrome) during treatment with the drug Zelboraf В® .
With the development of severe dermatological reactions further reception of the drug Zelboraf В® should be discontinued.
Potentiation of radiation therapy
in patients receiving radiation therapy before, during or after the application of vemurafenib, there have been cases of increasing the sensitivity to radiation therapy and radiation dermatitis. Most of these cases were violations of the skin, but some cases of lesions of the visceral organs ended with a fatal outcome. Care must be taken when using vemurafenib simultaneously or sequentially with radiotherapy.
QT interval elongation
In applying the drug Zelboraf В®observed lengthening the interval QT, proportional vemurafenib exposure. Lengthening QT interval may increase the risk of ventricular arrhythmias, including ventricular tachycardia type "pirouette". Use of the drug Zelboraf В® is not recommended in patients with impaired not amenable to correction fluid and electrolyte balance (including the balance magnesium) QT syndrome elongate slot, and in patients receiving drugs that promote lengthening QT interval.
ECG research and water and electrolyte balance (including the balance magnesium) must be performed before the start of ingestion and after changing the dose of the drug Zelboraf В®. Subsequently registered ECG and determination of electrolytes recommended monthly for the first 3 months drug administration, and then every 3 months or more in the presence of clinical symptoms. If the interval QT c > 500 ms, start receiving Zelboraf preparation В® not recommended. If during treatment interval QT c will be more than 500 ms, is necessary to temporarily interrupt the drug Zelboraf В® , remove water and electrolyte abnormalities (including magnesium balance) and achieve QT interval elongation correction of risk factors (e.g., chronic heart failure, bradyarrhythmias ). After reducing the QT interval cto a value of less than 500 ms, the drug should be resumed at a lower dose, as described in Tables 1 and 2. If the correction value associated risk factors QT interval c is> 500 ms and different from the original values recorded before dosing more than 60 ms reception Zelboraf preparation В® must stop.
Ophthalmic reaction
Using the drug Zelboraf В® were reported serious ophthalmic reaction include uveitis (including iritis) and retinal vein occlusion. Doctor should regularly monitor the patient for the development of ophthalmic reactions.
Joint application with ipilimumab
When the joint application vemurafenib (960 mg or 720 mg of 2 times / day) with ipilimumab (3 mg / kg) were recorded asymptomatic increase in the activity of transaminases and bilirubin 3 degrees. Based on these data combined use vemurafenib and ipilimumab not recommended.
Squamous cell carcinoma of the skin
in patients receiving Zelboraf В®Described cases of squamous carcinomas of the skin, including cases classified as keratoacanthoma and mixed keratoacanthoma. All patients are advised to undergo an examination by a dermatologist before taking the drug. If you have any suspicious skin lesions need to be excised, dermatopatologicheskoe directed to study and carry out treatment in accordance with local standards of care. With the development of squamous skin carcinoma patient is encouraged to continue treatment with Zelboraf В®without dose adjustment. The doctor should carry out examination of the patient monthly during therapy and for 6 months after treatment and before the start of another anticancer therapy. Patients should be informed that in case of any skin changes, you must inform your doctor.
Squamous cell carcinoma of the other (nekozhnoy) localization
in patients receiving Zelboraf В®, Reported cases of squamous cell carcinoma of other sites. Before taking the drug to conduct a survey of the head and neck, consisting at least of a visual inspection of the mucous membranes of the mouth and palpation lymph nodes, and repeating this examination every 3 months during treatment. In addition, before taking the drug need to perform CT of the chest and during treatment to repeat this survey every 6 months.
Before the start of dosing and at the end of therapy or the presence of clinical symptoms is recommended to study the rectum and pelvic organs (in women).
After cessation of drug Zelboraf В®screening for squamous cell carcinoma of other sites should continue for 6 months or until the beginning of another anticancer therapy. Revealed pathological changes should be carried out in accordance with clinical practice.
A new focus of the primary melanoma
Using the drug Zelboraf В® have been reported cases of the emergence of new centers of primary melanoma. In all cases, treatment was surgery, and patients continued treatment without dose adjustment. Screening for skin lesions should be carried out in accordance with the guidelines given above for squamous cell carcinoma of the skin.
Other malignancies
Based on the mechanism of action, vemurafenib may cause progression of malignancies associated with mutations in the RAS gene. The question of the relationship between the expected benefits and potential risks of the drug require careful consideration in patients with a history or concomitant malignancies associated with mutations in the RAS gene.
Liver damage
When using vemurafenib reported cases of liver injury, including severe.
Patients with impaired renal function
Correction of the starting dose in patients with renal insufficiency mild to moderate severity is not required. Insufficient data to determine the need for dose adjustment in patients with severe renal insufficiency.
Laboratory data
on background therapy vemurafenib may occur abnormal changes in laboratory parameters that characterize hepatic function. Before taking the drug to evaluate the activity of hepatic enzymes (transaminases and alkaline phosphatase) and bilirubin concentration. During treatment should monitor these parameters on a monthly basis, or more frequently in case of clinical symptoms. In identifying the pathological changes in laboratory parameters should reduce the dose, interrupt or stop taking the drug (see. Table 1).
Was an increase in serum creatinine concentrations, in most cases, from mild (> 1-1.5? ULN) to moderate (> 1.5-3? ULN) degrees of severity. As a rule, increases in serum creatinine concentration was reversible. Before therapy is necessary to determine the concentration of plasma creatinine and control it during treatment in case of clinical symptoms (see. Table 1).
Photosensitivity
Patients treated with drug Zelboraf В® , photosensitivity reactions were recorded from mild to severe. All patients while receiving the drug Zelboraf В®Avoid exposure to the sun. 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 radiation range B) filters and lip balm (Sun Protection Factor? 30) to protect against sunburn. When photosensitization reactions of 2 degrees (intolerance) or higher recommended dose change (see. Table 1).
Effect vemurafenib 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 for correction of the dose of drugs metabolized mainly involving isozymes CYP1A2 and CYP3A4, should be assessed prior to drug therapy Zelboraf В®depending on the therapeutic index of the drug.
With the simultaneous use of the drug Zelboraf В® and warfarin should be careful and take into account the MNO.
The effect of drugs on vemurafenib
On vemurafenib pharmacokinetic parameters can be influenced by drugs that inhibit or influence the P-glycoprotein (e.g., verapamil, clarithromycin, cyclosporin, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine). If possible, avoid the simultaneous application of the drug Zelboraf В® with potent inducers of P-glycoprotein, glyukuronirovaniya, isoenzyme CYP3A4 (e.g., rifampicin, rifabutin, carbamazepine, phenytoin, Hypericum perforatum). In order to preserve efficacy Zelboraf В® should consider alternative treatment options for inducing drugs with less potential.
Destruction of unused preparation or expired It should be performed in accordance with local requirements.
Impact on the ability to drive vehicles and manage mechanisms
Studies of the effect of the drug Zelboraf В® on the ability to drive vehicles and working with machinery and mechanisms have not been conducted. Patients should be warned about the possible development of dizziness, disorders of the eyes and fatigue, which can be the basis for refusing to drive.
OVERDOSE
Symptoms: dose-limiting toxicity of drug Zelboraf В® manifested as a rash and itching fatigue.
Treatment: in case of suspected overdose must stop taking the drug Zelboraf В® and assign maintenance therapy. When side reactions necessary to assign appropriate symptomatic treatment. Specific antidote which can be used in cases of drug overdose Zelboraf В® , does not exist.
DRUG INTERACTION
Interaction vemurafenib substrates and cytochrome P450 (CYP)
Results of the study of drug interactions in vivo, carried out in patients with metastatic melanoma suggests that vemurafenib is a moderate inhibitor of isozyme CYP1A2 inducer and isoenzyme CYP3A4. Vemurafenib can reduce exposure of substances metabolized mainly involving isoenzyme CYP3A4. In this regard, may reduce the effectiveness of contraceptive drugs metabolized with the participation of isoenzyme CYP3A4.
Simultaneous application vemurafenib with drugs metabolized by from
