Zelboraf tablets coated film.ob. 240 mg, 56 pcs.

Pharmacodynamics

Mechanism of action

Vemurafenib is an inhibitor of serine threonine kinase encoded by the BRAF gene (v-raf murine sarcoma viral oncogene homolog B1). Mutations in the BRAF gene result in constitutive activation of the oncogenic BRAF protein 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 codon 600.

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

Pharmacokinetics

Vemurafenib is a low solubility, low permeability substance (Biopharmaceutical Classification System Class 4). The pharmacokinetic parameters of vemurafenib were assessed by noncompartmental 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 administered 2 times daily. Linearity of pharmacokinetics has also been confirmed by population pharmacokinetic analysis.

Intestinal absorption

The absolute bioavailability of vemurafenib for 240 mg tablets is unknown. When vemurafenib is taken in a single dose of 960 mg (4 tablets of 240 mg), the median time to reach maximum plasma concentration (Tmax) is approximately 4 hours. When receiving vemurafenib in a dose of 960 mg twice a day repeatedly, accumulation of the drug is observed, which is characterized by high interindividual variability. AUC0-8h and maximum plasma concentration (Cmax) (±standard deviation) averaged 22.1±12.7 µg*h/ml and 4.1±2.3 µg/ml at 1 day, respectively, under the “concentration-time” curve. In a non-comparison analysis, when vemurafenib was administered at a dose of 960 mg twice daily, the AUC on day 15 increased 15-17 times the AUC on day 1, the Cmax on day 15 increased 13-14 times the Cmax on day 1. At equilibrium, AUC0-8h and Cmax were 380.2±143.6 µg*h/ml and 56.7±21.8 µg/ml, respectively.

Fat-rich foods increased exposure to vemurafenib at a single dose of 960 mg. The geometric mean Cmax and AUC were increased by 2.5 and 4.6 to 5.1-fold, respectively, when vemurafenib was taken with food compared to fasting food. Median Tmax increased from 4 hours to 7.5 hours when vemurafenib was administered with food alone. There are no data on the effect of food intake on the exposure of vemurafenib in equilibrium. Prolonged intake of vemurafenib on an empty stomach may result in a significant decrease in the exposure of vemurafenib at equilibrium compared to intake of vemurafenib with food or shortly before a meal. It is expected that the exposure of vemurafenib in the equilibrium state will not change significantly when vemurafenib is not routinely taken on an empty stomach due to the high degree of accumulation of vemurafenib in the equilibrium state. The safety and efficacy of vemurafenib in reference studies have been studied in patients taking vemurafenib both with food and alone.

Vemurafenib exposure may vary depending on the composition, volume and acidity (pH) of the gastrointestinal tract fluid, motility and timing of food passage, and bile composition.

At equilibrium (reached on day 15 in 80% of patients), the average plasma exposure of vemurafenib is characterized by stability over 24 hours, as evidenced by an average plasma concentration ratio before and 2-4 hours after the morning dose of 1.

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

Distribution

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

Metabolism

The cytochrome P450 (CYP) 3A4 isoenzyme is the main enzyme involved in the metabolism of vemurafenib in vitro. In humans, products of conjugation to glucuronic acid and glycosylation products are also found. The ratio of vemurafenib to its metabolites was studied in a clinical study of the material balance after a single administration of vemurafenib with a 14C-radioactive label. In plasma, the drug was found predominantly unchanged (>95%), whereas metabolites were ≤5%.

Elevation

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

According to a material balance study, 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 by the intestine, less than 1% – by the kidneys. Excretion of the drug unchanged with bile may be an important route of excretion. However, since the absolute bioavailability of the drug is unknown, the significance of the effect of hepatic and renal excretion on the clearance of the drug in unchanged form also cannot be assessed. Vemurafenib is a substrate and inhibitor of P-glycoprotein in vitro.

Pharmacokinetics in special patient groups

Patients in the elderly

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

Population pharmacokinetic analysis showed that males had a 17% greater apparent clearance of the drug and a 48% greater apparent volume of distribution compared to females. At the same time, the differences in vemurafenib exposure are relatively small, indicating that there is no need to adjust the drug dose according to patient gender, body mass index, or body weight.

In pediatric patients and adolescents

There have been no studies of the pharmacokinetics of vemurafenib in pediatric patients and adolescents.

Patients with impaired renal function

According to a population-based pharmacokinetic analysis of data from patients with metastatic melanoma, mild to moderate renal impairment (creatinine clearance >40 ml/min) has no effect on the apparent clearance of vemurafenib. Clinical and pharmacokinetic data in patients with severe renal impairment are insufficient to determine the need for dose adjustment.

Patients with impaired hepatic function

Vemurafenib is primarily excreted with bile. According to the results of population pharmacokinetic analysis of data from patients with metastatic melanoma, increasing aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity to a value 3 times the upper limit of normal has no effect on the apparent clearance of vemurafenib. Clinical and pharmacokinetic data in patients with severe hepatic impairment are insufficient to determine the effect of impaired metabolic or excretory hepatic function on the pharmacokinetics of vemurafenib.

Indications

Inoperable or metastatic melanoma with a BRAF V600 mutation in adult patients as monotherapy.

Active ingredient

Composition

Active substance:

Vemurafenib 240 mg;

Associates:

colloidal anhydrous silica – 10.4 mg,

croscarmellose sodium – 29.4 mg,

hyprolose (hydroxypropyl cellulose) – 4.25 mg,

magnesium stearate – 5.95 mg

How to take, the dosage

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

Before using Zelboraf, a validated test for the BRAF V600 mutation must be performed.

The recommended dose of Zelboraf is 960 mg (4 tablets of 240 mg) 2 times daily (daily dose is 1920 mg), oral. Zelboraf can be taken with or without meals, but prolonged use of both doses on an empty stomach should be avoided.

The tablet should be swallowed whole with water. The tablet should not be chewed or crushed.

Interaction

Cytochrome P450 isoenzyme substrates

The results of in vivo drug interaction studies conducted with patients with metastatic melanoma indicate that vemurafenib is a moderate inhibitor of CYP1A2 and inducer of CYP3A4 isoenzyme. Vemurafenib may reduce the exposure of substances metabolized primarily by the CYP3A4 isoenzyme. In this regard, the effectiveness of contraceptive drugs metabolized with the participation of CYP3A4 isoenzyme may be reduced.

The concomitant use of vemurafenib with drugs with a narrow therapeutic index, which are metabolized with the participation of CYP1A2 and CYP3A4, is not recommended, because vemurafenib may alter their concentration. If coadministration cannot be avoided, caution should be exercised and the dose of the drug that is a substrate of CYP1A2 isoenzyme should be reduced. Co-administration with vemurafenib increases AUC of caffeine (CYP1A2 substrate) by 2.6 times on average (maximum 5 times), while AUC of midazolam (CYP3A4 substrate) decreases by 39% on average (maximum 80%). The AUC of dextromethorphan (a CYP2D6 substrate) and its metabolite dextrophan increased by approximately 47% due to effects on dextromethorphan kinetics that may not be mediated by CYP2D6 isoenzyme inhibition. In an in vitro study, vemurafenib at a concentration of 10 μM caused weak inhibition of the CYP2B6 isoenzyme. It is not known whether vemurafenib, when reaching an equilibrium concentration of 100 µM in the blood of patients (approximately 50 µg/mL), will decrease CYP2B6 isoenzyme substrates such as bupropion when administered simultaneously.

The concomitant use of vemurafenib and warfarin (a substrate of the CYP2C9 isoenzyme) may lead to an 18% increase in the AUC of the latter. Caution should be exercised and additional MHO monitoring should be considered if vemurafenib is used in combination with warfarin.

In an in vitro study, vemurafenib inhibited the CYP2C8 isoenzyme. The significance of this observation in humans is unknown, but the risk of clinically significant effects on CYP2C8 isoenzyme substrates when used together cannot be excluded.

In order to avoid drug interactions, a washout period of 8 days may be required after discontinuation of vemurafenib.

Drug carriers

Vemurafenib has been shown in in vitro studies to be an inhibitor of P-glycoprotein and BCRP (breast cancer resistance protein). The clinical significance of these data is unknown. A possible increase in exposure to drugs transported by P-glycoprotein cannot be ruled out when used simultaneously with vemurafenib (e.g., aliskiren, colchicine, digoxin, everolimus, fexofenadine) or BCRP (e.g., methotrexate, mitoxantrone, rosuvastatin). There are no data on the effect of vemurafenib on other carriers.

The effect of drugs on vemurafenib

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

The concomitant use of vemurafenib with potent inducers of P-glycoprotein, glucuronidation, CYP3A4 isoenzyme (for example, with rifampicin, rifabutin, carbamazepine, phenytoin or St. John’s wort) should be avoided because of possible reduced exposure to vemurafenib.

In in vitro studies, vemurafenib has been shown to be a substrate of P-glycoprotein and BCRP. There are no data on the effect of inducers or inhibitors of P-glycoprotein and BCRP on the exposure of vemurafenib. It cannot be excluded that the pharmacokinetic parameters of vemurafenib may be affected by drugs that inhibit or affect P-glycoprotein (e.g., verapamil, clarithromycin, cyclosporine, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine) and BCRP (cyclosporine, gefitinib).

Special Instructions

Patients should undergo a validated test for the presence of a BRAF V600 mutation before using Zelboraf. The efficacy and safety of Zelboraf in patients whose tumors carry rare BRAF V600 mutations other than V600E and V600K have not been conclusively proven. Zelboraf should not be used in patients with malignant melanoma expressing wild-type BRAF.

Hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylaxis, have been reported with Zelboraf. Severe hypersensitivity reactions may include generalized rash, erythema or arterial hypotension. If severe hypersensitivity reactions develop, further use of Zelboraf should be discontinued.

Dermatologic reactions

Severe dermatologic reactions have been reported with Zelboraf, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in a reference clinical trial. If severe dermatologic reactions develop, further administration of Zelboraf should be discontinued.

Longening of the QT interval

In the use of Zelboraf, prolongation of the QT interval in proportion to the exposure to vemurafenib has been observed. QT interval prolongation may contribute to an increased risk of ventricular arrhythmias, including pirouette-type ventricular tachycardia. Zelboraf is not recommended in patients with non-correctable electrolyte and water balance disorders (including magnesium balance), prolonged QT syndrome and patients treated with medications known to prolong QT interval.

The ECG and electrolyte-water balance (including magnesium balance) test should be performed before starting the drug and after changing the dose of Zelboraf. It is recommended to record ECG and electrolyte balance monthly during the first 3 months of using the drug and then every 3 months or more frequently in case of clinical symptoms. If the QTc&gt interval is 500 ms, it is not recommended to start Zelboraf. If the QTc interval is greater than 500 ms during treatment, Zelboraf should be temporarily stopped, fluid and electrolyte disturbances (including magnesium balance) should be corrected, and risk factors for QT interval prolongation (e.g., chronic heart failure, bradyarrhythmia) should be corrected. After the QTc interval has decreased to less than 500 ms, the drug should be resumed at a lower dose as described in Tables 1 and 2. If, after correction of associated risk factors, the QTc interval is >500 ms and differs from the baseline value recorded before initiation of the drug by more than 60 ms, Zelboraf should be discontinued.

Ophthalmologic reactions

Serious ophthalmologic reactions have been reported with Zelboraf including uveitis (including iritis) and retinal vein occlusion. The treating physician is advised to monitor the patient regularly for ophthalmic reactions.

Squamous cell carcinoma of the skin

Squamous cell carcinoma of the skin, including cases classified as keratoacanthoma and mixed keratoacanthoma, have been described in patients treated with Zelboraf. All patients are advised to be examined by a dermatologist before starting the drug. If any suspicious skin lesions occur, they should be excised, referred for dermatopathological examination and treated according to local standards of care. If the patient develops squamous cell carcinoma of the skin, it is recommended to continue treatment with Zelboraf without dose adjustment. The physician should examine the patient monthly during therapy and for 6 months after treatment with the drug or before starting other antitumor therapy. Patients should be informed that if any skin changes occur, the physician should be informed.

Patients who have received Zelboraf have had cases of squamous cell carcinoma of other (non-squamous) locations. An examination of the head and neck, consisting of at least a visual examination of the oral mucosa and palpation of the lymph nodes, should be performed before starting the drug and should be repeated every 3 months while taking the drug. In addition, a chest CT scan should be performed before starting the drug, and repeated every 6 months while taking it.

Perior colon and pelvic examinations (in women) are recommended before starting the drug and at the end of therapy or in the presence of clinical symptoms.

After discontinuation of Zelboraf, examinations for other localized squamous cell carcinoma should continue for 6 months or until other antitumor therapy is initiated. The pathological changes detected should be managed according to clinical practice.

New foci of primary melanoma

Cases of new foci of primary melanoma have been reported with Zelboraf. In all cases, the treatment was surgical, and patients continued treatment without dose adjustment. Examination for skin lesions should follow the recommendations 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. Careful consideration must be given to the balance of expected benefit and possible risk of using the drug in patients with prior or concurrent malignancies associated with mutations in the RAS gene.

Pathological changes in laboratory parameters of liver function

A pathological changes in laboratory parameters of liver function may occur while taking Zelboraf. Before taking the drug it is necessary to estimate the activity of liver enzymes (transaminases and ALP) and bilirubin concentration, and during the time of taking the drug these parameters should be controlled monthly or more often in case of clinical symptoms. If abnormal changes in laboratory parameters are detected, the dose should be reduced and the drug should be interrupted or discontinued (Table 1).

Patients with impaired renal function

There is no need to adjust the starting dose in patients with mild to moderate renal impairment. There is insufficient data to determine the need for dose adjustment in patients with severe renal impairment.

Photosensitization

Mild to severe photosensitization reactions have been reported in patients treated with Zelboraf. All patients should avoid sun exposure while taking Zelboraf. Patients taking the drug should wear clothes protecting against the sun and use sunscreens with UVA (UVA range A) – and UVB (UVB range B) filters and lip balm (sun protection factor ≥30) to protect against sunburn while outdoors. For photosensitization reactions of grade 2 (intolerance) or higher, we recommend changing the dose of the drug (Table 1).

The effect of vemurafenib on other medicinal products

Vemurafenib may increase the exposure of medicinal products that are primarily metabolized through the CYP1A2 isoenzyme, and decrease the exposure of drugs that are primarily metabolized through the CYP3A4 isoenzyme, including oral contraceptives.

The necessity of dose adjustment of drugs predominantly metabolized by CYP1A2 and CYP3A4 isoenzymes must be assessed before starting therapy with Zelboraf depending on the therapeutic index of the drug.

When Zelboraf and warfarin are used concomitantly, caution should be exercised and the INR should be considered.

The effect of drugs on vemurafenib

The pharmacokinetic parameters of vemurafenib may be affected by drugs that inhibit or affect P-glycoprotein (e.g., verapamil, clarithromycin, cyclosporine, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine). If possible, avoid concomitant use of Zelboraf with potent inducers of P-glycoprotein, glucuronidation, CYP3A4 isoenzyme (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, St. John’s wort). In order to maintain the efficacy of Zelboraf, alternative treatment options with drugs with less inducing potential should be considered.

Contraception in women and men

Women of childbearing age and men should use reliable contraception for the duration of Zelboraf and for at least 6 months after discontinuation. Zelboraf may decrease the effectiveness of hormonal contraceptives, so the use of an alternative or additional contraceptive method is recommended.

The disposal of unused or expired medication should be done according to local requirements.

The effect of Zelboraf on driving and operating machinery

There have been no studies of the effect of Zelboraf on driving and operating machinery. Patients should be cautioned about the possible development of dizziness, eye disorders and fatigue, which may be grounds for refusal to drive.

Contraindications

With caution

Side effects

Benign, malignant and unspecified neoplasms (including cysts and polyps): very common – skin squamous cell carcinoma, seborrheic keratosis, skin papilloma; common – basal cell cancer, new primary melanoma; infrequent – squamous cell carcinoma of localized skin.

Mechanical disorders: very common – decreased appetite, decreased body weight.

Nervous system disorders: very common – headache, dysgeusia (distortion of taste), peripheral neuropathy; common – facial nerve palsy, dizziness.

Overlooking organ: common – uveitis; infrequent – occlusion of retinal veins.

vascular disorders: infrequent – vasculitis.

Respiratory system: very common – cough.

Digestive system disorders: very common – diarrhea, vomiting, nausea, constipation.

Skin and subcutaneous tissue disorders: very common – photosensitization reaction, actinic keratosis, rash, maculopapular rash, papular rash, itching, hyperkeratosis, erythema, alopecia, dry skin, sunburn, palmar and plantar erythrodysesthesia syndrome; erythema nodosum, follicular keratosis, folliculitis; infrequent – toxic epidermal necrolysis, Stevens-Johnson syndrome.

Muscular system disorders: very common – arthralgia, myalgia, pain in extremities, musculoskeletal pain, back pain, arthritis.

Others: very common – fatigue, fever, peripheral edema, asthenia.

Overdose

Symptoms: dose-limiting toxicity of Zelboraf was manifested by rash with itching and fatigue.

Treatment: in case of suspected overdose the drug Zelboraf should be discontinued and supportive therapy should be prescribed. In case of adverse reactions an appropriate symptomatic treatment should be prescribed. There is no specific antidote that could be used in cases of Zelboraf overdose.

Pregnancy use

It is contraindicated in pregnancy and lactation.