Nexavar

Nexavar is a drug that inhibits the proliferation of tumor cells.

The drug contains the component sorafenib, which slows down the action of a number of enzymes from the kinase subcategory. Among these are intracellular kinases, as well as those located on the cell surface (BRAF and c-CRAF with FLT-3, and also KIT with VEGFR-1, -2 and -3, as well as RET with PDGFR-β). Many kinases, the action of which is slowed by sorafenib, are involved in the movement of signals to neoplastic cells, as well as in the processes of angiogenesis and apoptosis.

Indications Nexavara

It is used to treat renal cell carcinoma of a widespread nature. For example, the drug is prescribed in the case of a progressive form of the disease in people who have not been helped by previous therapy using interferon-α or IL-2.

In addition, it is used for hepatocellular carcinoma (as a drug of choice for this pathology).

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Release form

The therapeutic agent is released in tablets - 28 pieces in a blister pack. There are 4 packs in a box.

Pharmacodynamics

In testing, sorafenib was shown to inhibit human hepatocellular carcinoma, renal cell carcinoma, and some other human tumor xenografts in thymus-ablated mice.

Models of renal cell carcinoma and liver carcinoma show decreased angiogenesis within tumor tissue and increased apoptosis within tumor cells. The liver cancer model also showed decreased signaling into tumor cells with sorafenib.

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Pharmacokinetics

Following oral administration of sorafenib, the bioavailability is approximately 38-49%. The half-life is in the range of 25-48 hours.

After repeated administration of sorafenib in a 7-day cycle, the accumulation of the drug inside the body increases by 2.5-7 times (compared to a single administration of the tablet). During a week of continuous use of the drug, an equilibrium serum level of sorafenib is achieved (the proportion of Cmax to Cmin is less than 2).

After oral administration, Cmax values of sorafenib are observed after 3 hours. When taken with food containing a moderate amount of fat, the bioavailability of the drug remains almost unchanged, but when administered with fatty food, it decreases by 29% (compared to taking on an empty stomach).

Administration of a dose greater than 0.4 g results in a non-linear increase in serum Cmax and AUC (the values obtained are lower than those expected in the case of linear kinetics).

In vitro testing showed that sorafenib was 99.5% synthesized into protein.

Sorafenib oxidation is carried out in the liver by the CYP3 A4 element. Along with this, glucuronidation occurs by UGT1 A9. It is necessary to take into account that in the gastrointestinal tract, the drug conjugates are broken down by bacterial glucuronidase action, as a result of which the unconjugated active component is reabsorbed (administration together with neomycin reduces the formation of the unconjugated element in the gastrointestinal tract, due to which the average level of bioavailability of the drug decreases by 54%).

After oral administration of the drug solution (0.1 g dose), about 96% of the substance was excreted within 14 days (77% through the intestines, and 19% through the kidneys in the form of derivatives). Approximately 51% of the drug is excreted unchanged - only through the intestines (no unchanged component is observed in the urine).

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Dosing and administration

Only doctors with experience in using antitumor agents can carry out treatment with the drug.

The daily dose required is 0.8 g of the medicine (2 tablets of 0.2 g, 2 times a day). The medicine should not be taken with food rich in fat. The tablets are swallowed whole, washed down with plenty of plain water.

The duration of the treatment cycle is selected by the doctor, taking into account the tolerance and the medicinal effect. If strong toxic signs are observed, the drug is discontinued; in case of weak or moderate negative manifestations, the dose of the drug is reduced or the treatment is discontinued for a while.

If necessary, the daily portion can be reduced to 0.4 g, which is divided into 2 doses.

Taking into account the severity of the toxicity indicator, the dosage is changed according to the following schemes:

• 1st degree of epidermal toxicity – therapy continues without adjusting the dose of the medication; additional symptomatic substances are prescribed;
• 2nd degree (1st episode) - the daily dose of the drug is reduced to 0.4 g, and symptomatic measures are also prescribed. If toxic signs disappear or decrease to the 1st degree of toxicity after 28 days, the dose is increased to 0.8 g. If there is no effect, the therapy is stopped until the symptoms disappear or weaken to the 1st degree. Then the treatment is resumed with a daily dose of 0.4 g (28-day cycle). If there is no toxicity or its 1st degree, the dose is increased to 0.8 g;
• 2nd degree (2/3rd episode) – the dose is changed according to the scheme used in the case of the 1st episode, but during the course restoration, a dosage of 0.4 g should be used for an indefinite period;
• Grade 2 (4th episode) – taking into account the patient’s condition and personal response to treatment, sorafenib should be discontinued;
• Grade 3 (1st episode) – symptomatic measures are taken immediately, and sorafenib administration is stopped for 7+ days (until signs of toxicity weaken to Grade 1 or disappear completely). After this, treatment is resumed in a dose of 0.4 g (28-day intake), and later, if toxicity does not develop more than Grade 1 or does not appear at all, the dosage is increased to 0.8 g;
• 3rd degree (2nd episode) – the dose is changed in the regimen used during the 1st episode, but during the restoration of the treatment cycle, the daily dose of 0.4 g is taken within the limits of an indefinite period;
• Grade 3 (3rd episode) – complete discontinuation of Nexavar treatment is required.

Individuals with kidney impairment or risk factors for kidney failure should have their EBV levels monitored while taking this medication.

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Use Nexavara during pregnancy

Sorafenib impaired reproductive activity in animals (regardless of their sex) during testing.

Adequate testing of the drug during pregnancy has not been performed. Information obtained from animal tests showed significant reproductive toxicity of the drug - for example, Nexavar, when administered to pregnant women, can cause congenital anomalies in the fetus or its intrauterine death.

Tests in rats have shown that sorafenib crosses the placenta, suggesting that the drug may be inhibiting angiogenesis in the fetus.

During the use of sorafenib, reliable contraception must be used. Given the possible risk, pregnancy should not be planned during therapy (women of childbearing age should be informed about the toxic effect of the drug). Reliable contraception must also be used for at least 14 days after discontinuing the drug.

During pregnancy, the medication is prescribed only for strict indications; the decision on this is made by the attending physician.

There is no information regarding the excretion of the drug in human breast milk. In animal studies, unchanged sorafenib and its derivatives were found to be secreted in milk.

Breastfeeding should be discontinued when using Nexavar.

Contraindications

Main contraindications:

• severe hypersensitivity associated with sorafenib or excipients of the drug;
• administration to individuals with squamous cell lung carcinoma receiving treatment with carboplatin and paclitaxel.

Caution is required in the event of such violations:

• coronary syndrome in the active phase or a recent history of myocardial infarction (the safety of the drug has not been studied in such groups of patients; an increased risk of developing myocardial ischemia was observed in volunteers);
• prolongation of QT interval indicators, which has a different nature (for example, the use of drugs that affect this indicator, a congenital disorder or pathologies in which such changes in ECG readings are observed);
• severe hepatobiliary dysfunction (because sorafenib is excreted primarily through the liver; testing in people with such disorders has not been performed).

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Side effects Nexavara

Among the most severe side effects of sorafenib are: myocardial infarction or ischemia, hypertensive crisis, perforation in the gastrointestinal tract, as well as drug-induced hepatitis and hemorrhage.

Often, the use of the drug led to the appearance of such symptoms as bowel disorders, alopecia, epidermal rashes and LPS.

During clinical tests, the development of the following negative symptoms was noted:

• lesions that have an infectious or invasive form: folliculitis or complications caused by infection;
• blood function disorders: neutro-, leukopenia, thrombocyto- or lymphopenia, as well as anemia;
• problems with the functioning of the central nervous system: depressive episodes, tinnitus, sensory polyneuropathy, as well as curable leukoencephalopathy of a posterior nature;
• disorders affecting the cardiovascular system: CHF, hypertensive crisis, ischemia or myocardial infarction, prolongation of the QT interval and bleeding (affecting the gastrointestinal tract or cerebral);
• symptoms related to the respiratory system: pneumonitis or pneumonia (also interstitial), rhinorrhea, hoarseness or respiratory distress;
• gastrointestinal disorders: vomiting, stomatitis, bowel disorders, GERD, signs of dyspepsia and nausea, as well as perforations in the gastrointestinal tract, gastritis, dysphagia or pancreatitis;
• problems with hepatobiliary function: jaundice, drug-induced hepatitis, hyperbilirubinemia, cholangitis or cholecystitis;
• lesions affecting the musculoskeletal system: myalgia, rhabdomyolysis or arthralgia;
• disorders associated with the urogenital system: gynecomastia, renal failure or erectile dysfunction;
• metabolic disorders: anorexia, hypocalcemia or -natremia, hypo- or hyperthyroidism, dehydration, increased ALT or AST levels, as well as lipase with amylase and alkaline phosphatase, as well as a decrease in serum phosphorus values, changes in INR or prothrombin levels;
• other negative signs: flu-like symptoms, weight change, increased fatigue, pain in various places and weakness;
• allergy symptoms: anaphylaxis, urticaria, Quincke's edema and epidermal manifestations (including itching, eczema, alopecia, LPS, SJS, acne, squamous cell epidermal carcinoma, erythema, TEN, radiation dermatitis and leukocytoclastic vasculitis).

In case of treatment-resistant increase in blood pressure values while taking the drug, it may be necessary to discontinue it. In addition, discontinuation of Nexavar may be necessary if severe bleeding occurs.

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Overdose

Tests were conducted using the drug in a 0.8 g dose, taken twice a day. In such cases, epidermal symptoms and diarrhea were observed in individual patients. Studies with higher doses were not performed. If an overdose is suspected in a patient, it is necessary to suspend therapy and conduct a course using symptomatic substances.

At present, there is no information regarding specific treatment in case of sorafenib poisoning.

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Interactions with other drugs

Extreme caution is required when administering the drug together with docetaxel or irinotecan.

Substances that induce the action of CYP3 A4, when combined with sorafenib, increase its metabolic processes and decrease serum levels of the unchanged element. Nexavar should be combined with dexamethasone, phenytoin and rifampicin, as well as with St. John's wort, phenobarbital and carbamazepine, with great caution.

When tested, ketoconazole did not affect the AUC level of sorafenib when they were combined. When administered together with drugs that inhibit CYP3 A4 activity, the likelihood of changes in the pharmacokinetics of the drug is extremely low.

In tests, the drug had little effect on INR levels in people using warfarin, but their co-administration requires careful monitoring of PT and INR levels.

Combination of the drug and carboplatin with paclitaxel causes an increase in the exposure values of these substances. In the case of a 3-day break in the administration of sorafenib during the period of carboplatin with paclitaxel, no significant changes in the pharmacokinetics of these drugs were observed. It is necessary to interrupt the use of Nexavar for 3 days if paclitaxel with carboplatin is required.

The drug increases the level of exposure to capecitabine by 15-50% (but there is no information regarding the clinical significance of such activity).

The combination with neomycin causes a decrease in the bioavailability of sorafenib (due to the effect on the metabolic processes of the drug in the liver and intestines, as well as the gastrointestinal microflora).

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Storage conditions

Nexavar should be stored at standard temperatures, out of the reach of small children.

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Shelf life

Nexavar can be used within 36 months from the date of sale of the pharmaceutical product.

Application for children

The use of drugs in pediatrics is prohibited.

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Analogues

The analogs of the drug are Tyverb, Votrient, Sutent with Giotrif, Sprycel and Ibrance with Tafinlar, and in addition Imatero, Tasigna and Imatinib.

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