Description of the drug ZELBORAF®
Vemurafenib is a substance with low solubility and low permeability (class 4 according to the biopharmaceutical classification system). The pharmacokinetics of vemurafenib is dose-dependent in the dose range from 240 to 960 mg when taken 2 times a day. The linearity of pharmacokinetics was also confirmed by data from population pharmacokinetic analysis.
When taking vemurafenib at a dose of 960 mg 2 times / day, the median time to reach Cmax is approximately 4 hours. With repeated administration of vemurafenib at a dose of 960 mg 2 times / day, accumulation is observed, which is characterized by high interindividual variability. The average AUC0-8 h and Cmax (±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, when taking vemurafenib at a dose of 960 mg 2 times / day, AUC on day 15 increased by 15-17 times compared to AUC on day 1, Cmax on day 15 increased by 13-14 times compared to Cmax on day 1 . At steady state, AUC0-8h and Cmax were 380.2±143.6 µg×h/ml and 56.7±21.8 µg/ml, respectively.
A meal rich in fat increases the exposure of vemurafenib when administered as a single 960 mg dose. Geometric mean Cmax and AUC increased when vemurafenib was taken with food compared to fasting by 2.5 and 4.7 times, respectively. The median Tmax increased from 4 hours to 8 hours with a single dose of vemurafenib with food. Chronic administration of vemurafenib in a fasted state may result in a significant reduction in vemurafenib exposure at steady state compared to administration of vemurafenib with or shortly before food.
The exposure of vemurafenib may change depending on the composition, volume and acidity (pH) of the gastrointestinal fluid, motility and transit time of food, and bile composition.
At steady state (reached by day 15 in 80% of patients), the average plasma exposure of vemurafenib is stable over 24 hours, as evidenced by the average plasma concentration ratio before and 2-4 hours after the morning dose of 1.13.
After oral administration, the absorption rate constant in patients with metastatic melanoma is 0.19 h-1 (interindividual variability is 101%).
Binding to blood plasma proteins is high - more than 99%. Based on a population-based analysis, the apparent Vd 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. Conjugation products with glucuronic acid and glycosylation products have also been found in humans. The ratio of vemurafenib to its metabolites was studied in a clinical material balance study following a single dose of 14C radiolabeled vemurafenib. In blood plasma, the drug is found predominantly unchanged (>95%), while metabolites account for ≤5%.
According to a population analysis, the apparent clearance of vemurafenib in patients with metastatic melanoma is 29.3 L/day (interindividual variability is 31.9%), the median T1/2 of vemurafenib is 51.6 hours (the range of individual values between the 5th and 95th percentile is 29.8-119.5 h).
According to the material balance study, on average, 95% of the vemurafenib dose was eliminated within 18 days. The majority (94%) of vemurafenib unchanged and its metabolites are excreted through the intestines, less than 1% by 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 effect of hepatic and renal excretion on the clearance of the unchanged drug cannot be assessed. Vemurafenib is a substrate and inhibitor of P-gp in vitro.
According to the results of a population pharmacokinetic analysis, the apparent clearance of the drug is 17% greater in men and the apparent Vd is 48% greater than in women. However, the differences in vemurafenib exposure are relatively small.
Zelboraf
Before use, patients must undergo a validated test for the presence of the BRAF V600 mutation. The efficacy and safety of the drug in patients whose tumors carry rare BRAF V600 mutations other than V600E and V600K have not been convincingly proven. Should not be used in patients with malignant melanoma expressing wild-type BRAF.
Hypersensitivity reactions
Cases of serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of the drug. Severe hypersensitivity reactions may include generalized rash, erythema, or hypotension. If severe hypersensitivity reactions develop, further use of the drug should be discontinued.
Dermatological reactions
Severe dermatologic reactions have been reported with use, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in a pivotal clinical trial. If severe dermatological reactions develop, further use of the drug should be discontinued.
QT prolongation
QT interval prolongation proportional to vemurafenib exposure was observed with use. Prolongation of the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes (TdP). The use of the drug is not recommended in patients with uncorrectable fluid and electrolyte imbalances (including magnesium balance), long QT syndrome, as well as in patients receiving medications that prolong the QT interval.
An ECG and a study of water and electrolyte balance (including magnesium balance) must be performed before starting the drug and after changing its dose. Subsequently, ECG recording and determination of electrolyte levels are recommended to be carried out monthly during the first 3 months of taking the drug, and then every 3 months or more often in the presence of clinical symptoms. If the QTc interval is >500 ms, it is not recommended to start taking the drug. If during treatment the QTc interval is more than 500 ms, it is necessary to temporarily interrupt the drug, eliminate water and electrolyte disturbances (including magnesium balance) and achieve correction of risk factors for prolongation of the QT interval (for example, chronic heart failure, bradyarrhythmia). Once 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 adjustment for concomitant risk factors, the QTc interval is >500 ms and differs from the baseline value recorded before When you start taking the drug, you must stop taking it more than 60 ms.
Ophthalmic reactions
Serious ophthalmic reactions have been reported with the use of the drug, including uveitis (including iritis) and retinal vein occlusion. The attending physician is recommended to regularly monitor the patient for the development of ophthalmic reactions.
Squamous cell carcinoma of the skin
Cases of the development of squamous cell carcinoma of the skin have been described in patients receiving the drug, including cases classified as keratoacanthoma and mixed keratoacanthoma. All patients are recommended to be examined by a dermatologist before starting to take 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 a patient develops squamous cell carcinoma of the skin, it is recommended to continue treatment with the drug without dose adjustment. The physician should evaluate the patient monthly during therapy and for 6 months after treatment with the drug or before starting other anticancer therapy. Patients should be informed that if any skin changes occur, they should notify their doctor.
Squamous cell carcinoma of another (non-cutaneous) location
Cases of development of squamous cell carcinoma of other localizations have been reported in patients receiving the drug. Before starting to take the drug, it is necessary to conduct an examination of the head and neck, consisting of, at a minimum, a visual examination of the oral mucosa and palpation of the lymph nodes, and repeat this examination every 3 months while taking the drug. In addition, before starting to take the drug, it is necessary to perform a CT scan of the chest, and while taking the drug, repeat this examination every 6 months.
Before starting the drug and upon completion of therapy or in the presence of clinical symptoms, it is recommended to conduct examinations of the rectum and pelvic organs (in women).
After discontinuation of treatment, screening for squamous cell carcinoma of other sites should be continued for 6 months or until other antitumor therapy is started. Identified pathological changes should be managed in accordance with clinical practice.
New focus of primary melanoma
With use, cases of new lesions of primary melanoma have been reported. In all cases, treatment was surgical, and patients continued treatment without dose adjustment. Screening for skin lesions should follow the recommendations above for cutaneous squamous cell carcinoma.
Other malignancies
Based on its mechanism of action, vemurafenib may cause the progression of malignancies associated with mutations in the RAS gene. It is necessary to carefully consider the balance between the expected benefit and the possible risk of using the drug in patients with previous or concomitant malignant neoplasms associated with mutations in the RAS gene.
Pathological changes in laboratory parameters characterizing liver function
While taking it, pathological changes in laboratory parameters characterizing liver function may occur. Before starting to take the drug, it is necessary to evaluate the activity of liver enzymes (transaminases and alkaline phosphatase), as well as the concentration of bilirubin, and while taking the drug, these parameters should be monitored monthly or more often if clinical symptoms occur. If pathological changes in laboratory parameters are detected, the dose should be reduced, interrupted or discontinued taking the drug.
Patients with impaired renal function
No adjustment of the starting dose is required in patients with mild to moderate renal failure. There are insufficient data to determine the need for dose adjustment in patients with severe renal impairment.
Photosensitivity
Mild to severe photosensitivity reactions have been reported in patients receiving the drug. All patients should avoid exposure to the sun while taking the drug. Patients taking the drug should wear sun-protective clothing and use UVA (ultraviolet A) and UVB (ultraviolet B) sunscreen filters and lip balm (sun protection factor ≥) when outdoors. 30) to protect against sunburn. For photosensitivity reactions of grade 2 (intolerance) and higher, it is recommended to change the dose of the drug.
Effect of vemurafenib on other drugs
Vemurafenib may increase the exposure of drugs primarily metabolized by CYP1A2 and decrease the exposure of drugs primarily metabolized by CYP3A4, including oral contraceptives.
The need for dose adjustment of drugs metabolized primarily by the CYP1A2 and CYP3A4 isoenzymes should be assessed before starting drug therapy, depending on the therapeutic index of the drug.
When used concomitantly with warfarin, caution should be exercised and the INR should be taken into account.
Effect of drugs on vemurafenib
The pharmacokinetic parameters of vemurafenib may be influenced by drugs that inhibit or affect P-glycoprotein (for example, verapamil, clarithromycin, cyclosporine, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine). If possible, simultaneous use with strong inducers of P-glycoprotein, glucuronidation, and CYP3A4 isoenzyme (for example, rifampicin, rifabutin, carbamazepine, phenytoin, St. John's wort) should be avoided. In order to maintain the effectiveness of Zelboraf, alternative treatment options with drugs with less inducing potential should be considered.
Contraception in women and men
Women of reproductive age and men should use reliable methods of contraception throughout the course of taking the drug and for at least 6 months after stopping the drug. The drug may reduce the effectiveness of hormonal contraceptives, and therefore the use of an alternative or additional method of contraception is recommended.
Disposal of unused or expired drugs must be carried out in accordance with local requirements.
Impact on the ability to drive vehicles and operate machinery
Studies of the effect of the drug on the ability to drive vehicles and work with machines and mechanisms have not been conducted. Patients should be warned about the possible development of dizziness, eye disturbances and fatigue, which may be grounds for refusing to drive.
Zelboraf®
Before using Zelboraf®, patients must undergo a validated test for the presence of the BRAF V600 mutation. The efficacy and safety of Zelboraf® in patients whose tumors carry rare BRAF V600 mutations other than V600E and V600K have not been convincingly 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® use.
Severe hypersensitivity reactions may include generalized rash, erythema, or hypotension.
If severe hypersensitivity reactions develop, further use of Zelboraf® should be discontinued.
Dermatological reactions
Severe dermatological reactions have been reported with Zelboraf®, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in a pivotal clinical trial. Cases of drug rash with eosinophilia and systemic symptoms (DRESS syndrome) have been reported with the use of Zelboraf®.
If severe dermatological reactions develop, further use of Zelboraf® should be discontinued.
Enhancing the effects of radiation therapy
In patients receiving radiation therapy before, during or after the use of vemurafenib, cases of increased sensitivity to radiation therapy and radiation dermatitis have been observed (see sections "Interaction with other drugs" and "Side effects", subsection "Post-marketing use"). Most of these cases were skin disorders, but some cases of visceral organ involvement were fatal. Caution should be exercised when vemurafenib is used concomitantly or sequentially with radiation therapy.
QT prolongation
Prolongation of the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes (TdP).
The use of Zelboraf® is not recommended in patients with uncorrectable fluid and electrolyte imbalances (including magnesium balance), long QT syndrome, or in patients receiving medications that prolong the QT interval.
An ECG and a study of water and electrolyte balance (including magnesium balance) must be performed before starting the drug and after changing the dose of Zelboraf®. Subsequently, ECG recording and determination of electrolyte levels are recommended to be carried out monthly during the first 3 months of taking the drug, and then every 3 months or more often in the presence of clinical symptoms. If the QTc interval is >500 ms, it is not recommended to start taking Zelboraf®. If during treatment the QTc interval is more than 500 ms, it is necessary to temporarily interrupt the use of Zelboraf®, eliminate disturbances in water and electrolyte balance (including magnesium balance) and achieve correction of risk factors for prolongation of the QT interval (for example, chronic heart failure, bradyarrhythmia). Once 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 adjustment for concomitant risk factors, the QTc interval is >500 ms and differs from the baseline value recorded before the start of taking the drug for more than 60 ms, Zelboraf® should be discontinued.
Ophthalmic reactions
Serious ophthalmic reactions, including uveitis (including iritis) and retinal vein occlusion, have been reported with the use of Zelboraf®. The attending physician is recommended to regularly monitor the patient for the development of ophthalmic reactions.
Concomitant use with ipilimumab
When vemurafenib (960 mg or 720 mg twice daily) was co-administered with ipilimumab (3 mg/kg), asymptomatic increases in transaminases and grade 3 bilirubin concentrations were reported. Based on these data, coadministration of vemurafenib and ipilimumab is not recommended.
Malignant neoplasms
Squamous cell carcinoma of the skin
Potential risk factors for developing cutaneous squamous cell carcinoma include age (≥65 years), a history of skin cancer, and chronic sun exposure.
All patients are recommended to be examined by a dermatologist before starting to take 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 a patient develops squamous cell carcinoma of the skin, it is recommended to continue treatment with Zelboraf® without dose adjustment. The physician should evaluate the patient monthly during therapy and for 6 months after treatment with the drug or before starting other anticancer therapy. Patients should be instructed to inform the physician of any changes in the skin.
Squamous cell carcinoma of another (non-cutaneous) location
Cases of development of squamous cell carcinoma of other localizations have been reported in patients receiving Zelboraf®.
Before starting to take the drug, it is necessary to conduct an examination of the head and neck, consisting of, at a minimum, a visual examination of the oral mucosa and palpation of the lymph nodes, and repeat this examination every 3 months while taking the drug. In addition, before starting to take the drug, it is necessary to perform a computed tomography scan of the chest, and while taking the drug, repeat this examination every 6 months.
Before starting the drug and upon completion of therapy or in the presence of clinical symptoms, it is recommended to conduct examinations of the pelvic organs (in women) and the rectum.
After discontinuation of Zelboraf®, screening for squamous cell carcinoma of other sites should be continued for 6 months or until other antitumor therapy is started. Identified pathological changes should be managed in accordance with clinical practice.
New focus of primary melanoma
Cases of new lesions of primary melanoma have been reported with the use of Zelboraf®. In all cases, treatment was surgical, and patients continued treatment without dose adjustment. Screening for skin lesions should follow the recommendations above for cutaneous squamous cell carcinoma.
Other malignancies
Based on its mechanism of action, vemurafenib may cause the progression of malignancies associated with mutations in the RAS gene. It is necessary to carefully consider the relationship between the expected benefit and the possible risk of using the drug in patients with previous or concomitant malignancies associated with mutations in the RAS gene. Liver damage
Cases of liver damage, including severe cases, have been reported with the use of vemurafenib.
Patients with impaired renal function
No adjustment of the starting dose is required in patients with mild or moderate renal impairment. There are insufficient data to determine the need for dose adjustment in patients with severe renal impairment. Laboratory data
Liver tests
During therapy with vemurafenib, pathological changes in laboratory parameters characterizing liver function may occur. Before starting to take the drug, it is necessary to evaluate the activity of liver enzymes (transaminases and alkaline phosphatase), as well as the concentration of bilirubin. While taking the drug, these parameters should be monitored monthly or more often if clinical symptoms occur. If pathological changes in laboratory parameters are detected, the dose should be reduced, interrupted or discontinued taking the drug (see Table 1).
Creatinine
There was an increase in creatinine concentration, in most cases, from mild (>1-1.5 x ULN) to moderate (>1.5-3 x ULN) severity. As a rule, the increase in creatinine concentration was reversible (see section "Side effects"). Before starting therapy, it is necessary to determine the concentration of plasma creatinine and monitor it while taking the drug in case of clinical symptoms (see Table 1).
Photosensitivity
Mild to severe photosensitivity reactions have been reported in patients receiving Zelboraf®. All patients should avoid exposure to the sun while taking Zelboraf®. Patients taking the drug should wear sun-protective clothing and use UVA (ultraviolet A) and UVB (ultraviolet B) sunscreen filters and lip balm (sun protection factor ≥) when outdoors. 30) to protect against sunburn.
For photosensitivity reactions of grade 2 (intolerance) and higher, it is recommended to change the dose of the drug (see Table 1).
Palmar fascial fibromatosis and Dupuytren's contracture
Cases of palmar fascial fibromatosis and Dupuytren's contracture have been reported during treatment with Zelboraf®. Most cases were mild to moderate in severity; Severe, disabling cases of Dupuytren's contracture have been reported.
To relieve symptoms, you should reduce the dose of the drug, interrupt therapy or completely stop treatment (see section “Method of administration and dosage”, subsection “Changing the dose”).
Effect of vemurafenib on other drugs
Vemurafenib may increase the plasma exposure of drugs that are primarily metabolized by CYP1A2 and decrease the plasma exposure of drugs that are primarily metabolized by CYP3A4. Concomitant use of vemurafenib with drugs that are metabolized by the CYP1A2 and CYP3A4 isoenzymes and have a narrow therapeutic index is not recommended. The need for dose adjustment of drugs metabolized primarily by CYP1A2 or CYP3A4 isoenzymes should be assessed before initiating vemurafenib therapy depending on their therapeutic range (see section "Special Instructions").
When vemurafenib and warfarin are used concomitantly, caution should be exercised and additional INR (international normalized ratio) monitoring should be considered.
Vemurafenib may increase plasma exposure to drugs that are P-glycoprotein (P-gp) substrates. Caution should be exercised when using vemurafenib concomitantly with P-gp substrates. Consideration should be given to dose reduction and/or additional level monitoring for a drug that is a P-gp substrate and has a narrow therapeutic index (NTI) (eg, digoxin, dabigatran etexilate, aliskiren) (see Interactions with Other Drugs section) ) when used concomitantly with vemurafenib.
Effect of other drugs on vemurafenib
Concomitant use of strong CYP3A4 inducers, P-gp substrates, and glucuronidation (e.g., rifampicin, rifabutin, carbamazepine, phenytoin, or St. John's wort [hypericin]) may result in decreased vemurafenib exposure and should be avoided if possible (see section " Interaction with other drugs"). To maintain the effectiveness of vemurafenib, alternative drugs with lower inducing potential should be considered. Caution must be exercised when vemurafenib is used concomitantly with potent inhibitors of the CYP3A4/P-rn isoenzyme. Patients should be carefully monitored for safety and the dose adjusted if clinically necessary (see Dosage and Administration, Table 1).
Disposal of unused or expired drugs must be carried out in accordance with local requirements.
