Index of drugs

The drug is indicated in monotherapy of adult patients with unresectable or metastatic melanoma showing a BRAF V600 mutation.

1 tabl contains 240 mg of vemurafenib (coprecipitate of vemurafenib and hypromellose acetate succinate).

An anti-cancer drug, a protein kinase inhibitor. Vemurafenib is a small molecule inhibitor of the BRAF serine / threonine kinase. The mutations in the BRAF gene for codon 600 (valine) cause the constitutive activation of BRAF proteins, which can lead to cell proliferation in the absence of growth factors necessary under normal conditions. Vemurafenib can strongly inhibit BRAF kinases with codon 600 activating mutants. The absolute bioavailability of the preparation is unknown. Vemurafenib administered twice a day at a dose of 960 mg is absorbed with the median time T_max approximately 4 hours. Vemurafenib shows significant variability of parameters between patients. Drug accumulation occurs when repeatedly administered twice a day. Food (a meal rich in fat) increases the relative bioavailability of a single 960 mg dose. The effect of food on steady state exposure is unknown. Continuous intake of the drug on an empty stomach can lead to a significant reduction in steady state exposure compared to taking the drug with or shortly after a meal. Occasional intake of the drug on an empty stomach for a limited effect on stationary exposure. The drug exposure may vary depending on the composition, volume and pH of the fluid in the gastrointestinal tract, as well as the severity of peristalsis and time of passage and bile composition. At steady-state, the mean exposure to vemurafenib in plasma is stable at 24 h intervals between doses. The drug is highly bound to plasma proteins (> 99%). In conditionsin vitro the main enzyme responsible for the metabolism of vemurafenib is CYP3A4. In humans, conjugated metabolites (glucuronidation and glycolysis) were also detected. The parent compound was the major (95%) compound found in the plasma. Estimated T_0,5 vemurafenib is 51.6 h (range 29.8-119.5 h). Most vemurafenib (94%) derivatives are excreted in the faeces and <1% in the urine. In conditionsin vitro vemurafenib is a substrate and inhibitor of P-gp.

Hypersensitivity to the active substance or to any of the excipients.

Before initiating treatment with vemurafenib, confirm the occurrence of BRAF V600 mutations in the cancer cells of the patient by means of a validated test. The efficacy and safety of the medicine in cancer patients with rare BRAF V600 E mutations other than BRAF V600E and V600K have not been established. Vemurafenib should not be used in patients with BRAF-deficient melanoma. In patients who have experienced severe hypersensitivity reactions or severe skin reactions (Stevens-Johnson syndrome, toxic epidermal epidermal necrosis, DRESS syndrome), vemurafenib treatment should be permanently discontinued. Treatment with vemurafenib is not recommended in patients with irreversible electrolyte disturbances (including those with impaired magnesium), long QT syndrome or patients taking medicines known to prolong the QT interval. Before starting treatment with vemurafenib, after 1 month of treatment and after a change in dosage, it should be performed in all ECG patients and check electrolyte concentrations (including magnesium). Further observation, every month for the first 3 months of treatment and then every 3 months or more, if clinically indicated, it is recommended in particular for patients with moderate to severe hepatic impairment. It is not recommended to start treatment with vemurafenib in patients with a QTc interval above 500 ms. If the QT interval exceeds 500 ms during treatment, temporarily stop vemurafenib treatment, compensate for electrolyte disturbances (including magnesium) and control cardiac risk factors for QT prolongation (eg congestive heart failure, bradyarrhythmia). If the QTc interval is less than 500 ms, treatment should be resumed at a lower dose, as indicated in the "Dosage" field.It is recommended that treatment with vemurafenib should be discontinued if the QTc interval is greater than 500 ms at the same time and has increased by more than 60 ms compared with pre-treatment values. During treatment, patients should be routinely monitored for ocular reactions (uveitis, iritis and retinal vein occlusion). Because of the risk of squamous cell carcinoma (cuSCC), it is recommended that all patients be dermatologically assessed and routinely monitored during treatment before starting treatment. All suspected skin lesions should be removed, the material should undergo dermatopathological evaluation and the treatment should be carried out in accordance with local standards of conduct. Every month during the treatment and up to 6 months after its completion, the patient should be examined to detect the cuSCC. Patients who develop cuSCC are advised to continue treatment without dose adjustment of vemurafenib. Patients should be monitored for 6 months after stopping treatment with vemurafenib or until the initiation of another anticancer treatment. Patients should be instructed to inform their physician of any skin lesions. There have been reports of squamous cell carcinoma in a non-cuSCC location in patients receiving vemurafenib. Patients should undergo head and neck examination, including at least visual assessment of the oral mucosa and palpation of the lymph nodes, before treatment and every 3 months during treatment. In addition, patients should undergo a chest CT examination before starting treatment and every 6 months during treatment. Before and after treatment, or when there are clinical indications for this, it is recommended to perform anus examination and examination of the pelvic organs (in women). After discontinuation of treatment with vemurafenib, the patient should be monitored for non-cuSCC development for up to 6 months or until other anticancer treatment commences. In the event of abnormal test results, follow clinical practice. Due to the risk of new primary melanoma lesions, monitoring should be performed to detect skin lesions as described above for cuSCC. The management of new primary melanoma lesions included resection of the lesion, and patients continued treatment without dose adjustment. Vemurafenib may cause progression of RAS-related cancers - the benefit / risk ratio should be carefully assessed before vemurafenib is used in patients with pre-existing or co-existing RAS mutations. Patients using vemurafenib have been reported with pancreatitis - a rapid diagnosis of abdominal pain with an unclear reason (including amylase and lipase activity) should be undertaken; Patients continuing treatment with vemurafenib after an episode of pancreatitis require close monitoring. Due to the risk of liver damage (including severe liver damage), before and during treatment every month, or more frequently, if there are clinical indications, liver enzymes (aminotransferases and alkaline phosphatases) and bilirubin should be checked. In the event of abnormal results, reduce the dose, temporarily discontinue treatment or permanently terminate treatment. Patients with mild hepatic impairment due to metastases to this organ without accompanying hyperbilirubinemia may be observed according to general recommendations. Limited data are available for the use of patients with moderate to severe hepatic impairment (increased exposure may occur) - close observation is necessary, especially after the first few weeks of treatment, because in the longer term (several weeks), drug accumulation. In addition, every month for the first 3 months patients should undergo ECG examination. Vemurafenib should be used with caution in patients with severe renal impairment; patients should be carefully monitored. Because of photosensitivity, all patients should be advised to avoid exposure to sunlight during treatment with vemurafenib (patients should wear protective clothing and use sunscreen with a wide UVA / UVB protection range and lip balm with sun protection factor ≥30 when they are staying outside). If you have hypersensitivity to Stage 2 light.(no tolerance) or higher, it is recommended to modify the dose of the drug. Vemurafenib may increase plasma exposure to medicinal products metabolised predominantly by CYP1A2 and reduce plasma exposure to medicinal products primarily metabolised by CYP3A4, including oral contraceptives - modifications of dosing with these drugs based on their therapeutic windows should be considered before use with vemurafenib. Exercise caution and consider additional monitoring of INR when vemurafenib and Warfarin are administered concomitantly. Pharmacokinetic parameters of vemurafenib may be influenced by drugs that inhibit or affect P-glycoprotein (eg Verapamil, Clarithromycin, cyclosporin, ritonavir, quinidine, dronedarone, Amiodarone, Itraconazole, ranolazine). If possible, concomitant use of strong P-glycoprotein, glucuronidation, CYP3A4 inducers (eg rifampicin, rifabutin, carbamazepine, phenytoin or St John's wort) should be avoided - medication with lower induction capacity should be considered. Co-administration of ipilimumab and vemurafenib is not recommended. There are no data on the safety and efficacy of vemurafenib in children and adolescents (under 18 years). There are no data on safety and efficacy in non-Caucasian subjects.

There are no data on the use of vemurafenib in pregnant women. Vemurafenib should not be used in pregnant women unless the likely benefits to the mother outweigh the risks to the fetus. Women of childbearing potential should use effective contraception during treatment and for at least 6 months afterwards. Vemurafenib may reduce the effectiveness of hormonal contraceptives. It is not known whether vemurafenib is excreted in human milk. A decision should be made to discontinue breast-feeding or to discontinue vemurafenib treatment, taking into account the benefits of breastfeeding for the baby and the benefits of treatment for the woman.

Very common: squamous cell carcinoma of the skin - cuSCC (incidence of about 20%, median time of first symptoms 7-8 weeks, in about 33% of patients who developed cuSCC more than 1 tumor outbreak at the median time between events 6 weekly), decreased appetite, headache, taste disorders, cough, diarrhea, vomiting, nausea, constipation, hypersensitivity reactions, actinic keratosis, rash, maculopapular rash, papular rash, pruritus, hyperkeratosis, erythema, alopecia, dry skin, sunburn, joint pain, muscle pain, limb pain, muscle and bone pain, back pain, fatigue, fever, peripheral edema, increased GGT activity. Common: folliculitis, basal cell carcinoma, new pervasive melanoma, VII cranial nerve palsy, dizziness, choroiditis, palmar plantar erythrodystesis, inflammation of the subcutaneous tissue (including erythema nodosum), bovine keratosis, arthritis, increased activity alanine aminotransferase, alkaline phosphatase, bilirubin, weight loss, QT prolongation. Uncommon: non-cuSCC (squamous cell carcinoma in a different location than the skin), peripheral neuropathy, retinal vein occlusion, vasculitis, pancreatitis, liver damage, toxic epidermal necrolysis, Stevens-Johnson syndrome, decrease in aspartate aminotransferase. Rare: chronic myelomocytic leukemia (previously diagnosed chronic myelomocytic leukemia with NRAS mutation), drug reaction with eosinophilia and systemic symptoms (DRESS). The drug may cause the progression of cancers associated with the RAS mutation.

Treatment with vemurafenib should be initiated and supervised by a qualified physician experienced in the use of anticancer medicines. Oral: the recommended dose is 960 mg (4 tablets) 2 times daily (equivalent to a daily dose of 1920 mg). The drug can be taken with or without food, however, it should be avoided to take both daily doses on an empty stomach. Treatment with vemurafenib should be continued until tumor progression or unacceptable toxicity. If you miss a dose, you can take it up to 4 hours before the Next one to keep your schedule of administration twice daily. Do not take both doses at the same time.If vomiting occurs after administration of vemurafenib, the patient should not take an additional dose - the treatment should be continued without modification.Dosage adjustment. If dose adjustment is not recommended, dose adjustment per dose less than 480 mg 2 times a day.Dose modification based on the degree of adverse reactions (CTC-AE). Grade 1 or Grade 2 (tolerated): continuation of the drug at a dose of 960 mg 2 times a day. Grade 2 (untolerated) or Grade 3: first occurrence of any Grade 2 or 3 adverse reaction - discontinue treatment until symptom relief to Grade 0-1; restart treatment at 720 mg twice daily (or 480 mg twice daily if the dose has already been reduced); second occurrence of any Grade 2 or 3 adverse reaction or persistence after discontinuation of treatment - discontinue treatment until symptom relief to Grade 0-1; restart 480 mg twice daily (or stop treatment if the dose has already been reduced to 480 mg twice daily); the third occurrence of any Grade 2 or 3 adverse reaction or its persistence after the second dose reduction - end the treatment. Grade 4: first occurrence of any Grade 4 adverse reaction - stop treatment or discontinue vemurafenib treatment to achieve symptom relief to Grade 0-1; restart 480 mg twice daily (or stop treatment if the dose has already been reduced to 480 mg twice daily); second occurrence of any Grade 4 adverse reaction or persistence after the first dose reduction - end treatment.Dose modification based on QT prolongation. QTc> 500 ms before treatment - no treatment is recommended. QTc> 500 ms and at the same time QTc interval increased by more than 60 ms compared to pre-treatment values ​​- end treatment. The first occurrence of QTc> 500 ms during treatment and QTc interval increased by less than 60 ms compared to pre-treatment values ​​- temporarily discontinue treatment until QTc is less than 500 ms; restart treatment at 720 mg twice daily (or 480 mg twice daily if the dose has already been reduced). Second occurrence of QTc> 500 ms during treatment and QTc interval increased by less than 60 ms compared to pre-treatment values ​​- temporarily discontinue treatment until QTc is reduced below 500 ms; resume administration at 480 mg twice daily (or stop treatment if the dose has already been reduced to 480 mg twice daily). The third occurrence of QTc> 500 ms during treatment and QTc interval increased by less than 60 ms compared to pre-treatment values ​​- termination of treatment. If the patient develops squamous cell carcinoma (cuSCC), it is recommended to continue treatment without dose adjustment of vemurafenib. Elderly patients (over 65 years) do not need to adjust their dose.
Table. should be swallowed whole, washed down with water. Do not chew or crush them.