Zelboraf^® (Tablets) Instructions for Use

Marketing Authorization Holder

F. Hoffmann-La Roche, Ltd (Switzerland)

Manufactured By

Delpharm Milano, S.r.l. (Italy)

Quality Control Release

F.Hoffmann-La Roche, Ltd (Switzerland)

ATC Code

L01EC01 (Vemurafenib)

Active Substance

Vemurafenib (Rec.INN registered by WHO)

Dosage Form

Zelboraf®

Film-coated tablets, 240 mg: 56 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from pinkish-white to orange-white, oval, biconvex; engraved with “VEM” on one side.

Excipients: colloidal anhydrous silicon dioxide, croscarmellose sodium, hypromellose (hydroxypropylcellulose), magnesium stearate.

Film coating composition: polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, talc, red iron oxide dye (E172).

8 pcs. – blisters (7) – cardboard packs^×.

* Vemurafenib is contained as a co-precipitate of vemurafenib and hypromellose acetate succinate – 800 mg.
^× a protective holographic sticker is applied to the pack for first opening control.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent – protein kinase inhibitor

Pharmacological Action

Antitumor agent, protein kinase inhibitor. Vemurafenib is a low molecular weight oral inhibitor of serine-threonine kinase encoded by the BRAF gene (v-raf murine sarcoma viral oncogene homolog B1). Mutations in the BRAF gene leading to the substitution of the amino acid valine at position 600 result in constitutive activation of the oncogenic BRAF protein and, consequently, 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.

Pharmacokinetics

Vemurafenib is a substance with low solubility and low permeability (Biopharmaceutics Classification System class 4). The pharmacokinetics of vemurafenib are dose-dependent in the dose range from 240 mg to 960 mg twice daily. Linearity of pharmacokinetics was also confirmed by population pharmacokinetic analysis data.

When vemurafenib is taken at a dose of 960 mg twice daily, the median time to reach C_max is approximately 4 hours. With repeated administration of vemurafenib at a dose of 960 mg twice daily, accumulation is observed, characterized by high interindividual variability. The mean 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. In a non-compartmental analysis with vemurafenib at a dose of 960 mg twice daily, AUC on day 15 increased 15-17 times compared to AUC on day 1, C_max on day 15 increased 13-14 times compared to C_max on day 1. At steady state, AUC_0-8h and C_max were 380.2 ± 143.6 µg×h/ml and 56.7 ± 21.8 µg/ml, respectively.

A high-fat meal increases the exposure of vemurafenib after a single 960 mg dose. The geometric mean C_max and AUC increased when vemurafenib was taken with food compared to fasting by 2.5 and 4.7 times, respectively. The median T_max increased from 4 hours to 8 hours after a single dose of vemurafenib with food. Prolonged administration of vemurafenib on an empty stomach may lead to a significant decrease in vemurafenib exposure at steady state compared to taking vemurafenib with food or shortly before a meal.

Changes in vemurafenib exposure are possible depending on the composition, volume, and acidity (pH) of the gastrointestinal fluid, motility and transit time of food, and bile composition.

At steady state (achieved by day 15 in 80% of patients), the average exposure of vemurafenib in plasma is stable over 24 hours, as evidenced by the mean ratio of plasma concentration before and 2-4 hours after the morning dose, equal to 1.13.

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

Plasma protein binding is high – more than 99%. According to population analysis, the apparent V_d of vemurafenib in patients with metastatic melanoma is 91 L (interindividual variability is 64.8%).

The CYP3A4 isoenzyme is the main enzyme involved in the metabolism of vemurafenib in vitro. Glucuronic acid conjugation products and glycosylation products have also been found in humans. The ratio of vemurafenib and its metabolites was studied in a clinical material balance study after a single dose of vemurafenib with a ¹⁴C-radioactive label. In plasma, the drug is predominantly present unchanged (>95%), while metabolites account for ≤5%.

According to 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 of vemurafenib is 51.6 hours (range of individual values between the 5th and 95th percentile is 29.8-119.5 hours).

According to the material balance study, on average 95% of the vemurafenib dose is excreted within 18 days. The majority (94%) of vemurafenib unchanged and its metabolites is excreted via the intestine, less than 1% via the kidneys. Excretion of the drug unchanged in bile may be an important route of elimination. However, since the absolute bioavailability of the drug is unknown, the significance of the influence of hepatic and renal excretion on the clearance of the unchanged drug also cannot be assessed. Vemurafenib is a substrate and inhibitor of P-glycoprotein in vitro.

According to the results of population pharmacokinetic analysis, the apparent clearance of the drug in men is 17% greater, and the apparent V_d is 48% greater compared to women. However, the differences in vemurafenib exposure are relatively small.

Indications

Unresectable or metastatic melanoma with BRAF V600 mutation in adult patients – as monotherapy.

ICD codes

Dosage Regimen

Treatment should be carried out under the supervision of an oncologist.

Before using vemurafenib, a validated test for the presence of a BRAF V600 mutation should be performed.

Take orally. The recommended dose is 960 mg twice daily. The daily dose is 1920 mg.

If signs of disease progression appear, therapy should be discontinued. In case of intolerable toxicity, therapy should be interrupted or discontinued.

Adverse Reactions

Benign, malignant and unspecified neoplasms (including cysts and polyps) very common – cutaneous squamous cell carcinoma, seborrheic keratosis, skin papilloma; common – basal cell carcinoma, new primary melanoma lesion; uncommon – non-cutaneous squamous cell carcinoma.

Metabolism and nutrition disorders very common – decreased appetite, weight loss.

Nervous system disorders very common – headache, dysgeusia (taste perception disorder), peripheral neuropathy; common – facial palsy, dizziness.

Eye disorders common – uveitis; uncommon – retinal vein occlusion.

Vascular disorders uncommon – vasculitis.

Respiratory, thoracic and mediastinal disorders very common – cough.

Gastrointestinal disorders: very common – diarrhea, vomiting, nausea, constipation.

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

Musculoskeletal and connective tissue disorders very common – arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain, arthritis.

Investigations very common – increased GGT activity (grade 3 or 4); common – increased ALT activity (grade 3), ALP activity (grade 3), increased bilirubin concentration (grade 3); uncommon – increased AST activity (grade 3 or 4).

General disorders and administration site conditions very common – fatigue, pyrexia, peripheral edema, asthenia.

Contraindications

Severe renal failure; severe hepatic failure; uncorrectable disturbances of water-electrolyte balance (including magnesium balance); long QT syndrome; corrected QT interval (QT_c) >500 ms before starting therapy; use of drugs that prolong the QT interval; pregnancy; lactation (breastfeeding); children and adolescents under 18 years of age; hypersensitivity to vemurafenib.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Women of reproductive potential and men should use reliable methods of contraception throughout the course of treatment with vemurafenib and for at least 6 months after discontinuation. Vemurafenib may reduce the effectiveness of hormonal contraceptives, therefore it is recommended to use an alternative or additional method of contraception.

Special Precautions

With caution: concomitant use with warfarin, potent inhibitors and inducers of the CYP3A4 isoenzyme, glucuronidation and/or transport proteins (including P-glycoprotein), drugs that are substrates of the CYP1A2 isoenzyme.

The efficacy and safety of vemurafenib in tumors carrying rare BRAF V600 mutations other than V600E and V600K have not been convincingly proven. Vemurafenib should not be used in patients with malignant melanoma expressing wild-type BRAF.

If severe hypersensitivity reactions or severe dermatological reactions occur, further use of vemurafenib should be discontinued.

Not recommended in patients with uncorrectable disturbances of water-electrolyte balance (including magnesium balance), long QT syndrome, as well as in patients receiving drugs that prolong the QT interval. During treatment, ECG and water-electrolyte balance (including magnesium balance) should be regularly monitored. If, after correction of concomitant risk factors, the QT_c interval value is >500 ms and differs from the baseline value recorded before the start of treatment by more than 60 ms, Vemurafenib should be discontinued.

The treating physician is recommended to regularly monitor the patient for the development of ophthalmological reactions.

Before starting treatment, all patients are recommended to be examined by a dermatologist. If any suspicious skin lesions occur, an appropriate investigation should be performed. Examination should be performed monthly during therapy and for 6 months after treatment with vemurafenib or until the start of another antitumor therapy. Patients should be informed to report any skin changes to their doctor.

Cases of non-cutaneous squamous cell carcinoma have been registered in patients taking Vemurafenib. Before starting vemurafenib, an examination of the head and neck should be performed, consisting of at least a visual examination of the oral mucosa and palpation of the lymph nodes, and this examination should be repeated every 3 months during the drug intake. In addition, before starting the intake, a CT scan of the chest organs should be performed and this examination should be repeated every 6 months. Before starting and upon completion of therapy or in the presence of clinical symptoms, examinations of the rectum and pelvic organs (in women) are recommended. After discontinuation of vemurafenib treatment, examinations to detect non-cutaneous squamous cell carcinoma should be continued for 6 months or until the start of another antitumor therapy. Identified pathological changes should be managed according to clinical practice.

The benefit-risk ratio of using the drug in patients with previous or concomitant malignant neoplasms associated with RAS gene mutations should be carefully considered.

Before starting treatment, the activity of liver enzymes (transaminases and ALP) and bilirubin concentration should be assessed; during treatment, these parameters should be monitored monthly or more often if clinical symptoms occur. If pathological changes in laboratory parameters are detected, the dose of vemurafenib should be reduced, or treatment should be interrupted or discontinued.

During treatment, patients should avoid sun exposure to prevent photosensitivity.

In patients aged 65 and over, adverse reactions are more likely to occur, including cutaneous squamous cell carcinoma, decreased appetite, and cardiac disorders.

Effect on ability to drive vehicles and operate machinery

Studies on the effect of vemurafenib on the ability to drive vehicles and operate machinery have not been conducted. Patients should be warned about the possible development of dizziness, eye disorders and fatigue, which may be grounds for refraining from driving.

Drug Interactions

Vemurafenib is a moderate inhibitor of the CYP1A2 isoenzyme and an inducer of the CYP3A4 isoenzyme. Vemurafenib may reduce the bioavailability of drugs metabolized primarily by the CYP3A4 isoenzyme. In this regard, a decrease in the effectiveness of contraceptive drugs metabolized by the CYP3A4 isoenzyme is possible.

Concomitant use of vemurafenib with drugs with a narrow therapeutic index that are metabolized by the CYP1A2 and CYP3A4 isoenzymes is not recommended, as Vemurafenib may change their concentration. If concomitant use cannot be avoided, then a dose reduction of the drug that is a substrate of the CYP1A2 isoenzyme should be considered.

Concomitant use with vemurafenib increases the AUC of caffeine (a substrate of the CYP1A2 isoenzyme) on average by 2.6 times (maximum by 5 times), while the AUC of midazolam (a substrate of the CYP3A4 isoenzyme) decreases on average by 39% (maximum up to 80%).

The AUC of dextromethorphan (a CYP2D6 substrate) and its metabolite dextrorphan increased by approximately 47% due to an effect on the kinetics of dextromethorphan, which may not be mediated by inhibition of the CYP2D6 isoenzyme. In an in vitro study, Vemurafenib at a concentration of 10 µM caused weak inhibition of the CYP2B6 isoenzyme. It is unknown whether Vemurafenib, at a steady-state concentration of 100 µM in patient blood (approximately 50 µg/ml), would reduce the levels of CYP2B6 isoenzyme substrates, such as bupropion, when used concomitantly.

Concomitant use of vemurafenib and warfarin (a substrate of the CYP2C9 isoenzyme) may lead to an increase in the AUC of the latter by 18%. Caution should be exercised and additional INR monitoring should be provided in case of using vemurafenib in combination with warfarin.

In an in vitro study, Vemurafenib inhibited the CYP2C8 isoenzyme. The significance of this observation for humans is unknown, but the risk of a clinically significant effect on CYP2C8 isoenzyme substrates when used concomitantly cannot be excluded.

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

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

In vitro studies have shown that Vemurafenib is a substrate of P-glycoprotein and BCRP. There are no data on the effect of inducers or inhibitors of P-glycoprotein and BCRP on vemurafenib exposure. It cannot be excluded that drugs inhibiting or affecting P-glycoprotein (e.g., verapamil, clarithromycin, cyclosporine, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine) and BCRP (cyclosporine, gefitinib) may influence the pharmacokinetic parameters of vemurafenib. A possible increase in the exposure of drugs transported by P-glycoprotein when used concomitantly with vemurafenib (e.g., aliskiren, colchicine, digoxin, everolimus, fexofenadine) or BCRP (e.g., methotrexate, mitoxantrone, rosuvastatin) cannot be excluded. Concomitant use of vemurafenib with potent inducers of P-glycoprotein, glucuronidation, and the CYP3A4 isoenzyme (e.g., rifampicin, rifabutin, carbamazepine, phenytoin, or St. John’s wort) should be avoided due to a possible decrease in the bioavailability of vemurafenib.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.