Neksavar

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

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

Indications Neksavara

It is used to treat common renal cell carcinoma. For example, the drug is prescribed in the case of a progressive form of the disease in persons who were not helped by previous therapy with interferon-α or IL-2.

In addition, hepatocellular character is used in carcinoma (as a means of choice in this pathology).

[1], [2],

Release form

The release of therapeutic agent is implemented in tablets - 28 pieces inside the cell packaging. In the box - 4 packs.

Pharmacodynamics

During testing, sorafenib suppressed neoplasms of hepatocellular carcinoma in humans, as well as renal cell carcinoma and some other human tumor xenografts in experimental mice that had their thymus removed.

On models that demonstrate renal cell carcinoma and liver carcinoma, there is a decrease in angiogenesis inside the tumor tissue, as well as an increase in apoptosis inside the cells of the neoplasms. The liver cancer model also showed a weakening of the movement of signals to the neoplasm cells when sorafenib was used.

[3], [4], [5]

Pharmacokinetics

After ingestion of sorafenib inside the level of bioavailability is approximately 38-49%. The term half-life is in the range of 25-48 hours.

After repeated use of sorafenib 7-day cycle, the cumulation of drugs inside the body increases by 2.5-7 times (compared with a single administration of the tablet). During the weekly period of constant use of the drug, an equilibrium serum indicator of sorafenib is reached (the proportion of Cmax to Cmin is less than 2).

After oral administration, Cmax values of sorafenib are noted after 3 hours. When used together with food, which contains a moderate amount of fat, the bioavailability index of the drug almost does not change, but when administered with a fatty food, it decreases by 29% (compared to eating on an empty stomach).

The introduction of a portion of more than 0.4 g leads to a nonlinear increase in serum Cmax and AUC (the values obtained are less than expected in the case of linear kinetics).

In vitro testing, sorafenib was 99.5% synthesized with protein.

Oxidation of sorafenib is realized inside the liver using the element CYP3 A4. Along with this, glucuronization occurs with the help of UGT1 A9. It is necessary to take into account that within the gastrointestinal tract the drug conjugates are split under the bacterial glucuronidase effect, as a result of which the unconjugated active component is reabsorbed (administration together with neomycin reduces the formation of the unconjugated element inside the gastrointestinal tract, resulting in an average drug bioavailability level of 54%).

After ingestion of the medication into the solution (a portion of 0.1 g) for 14 days, about 96% of the substance excreted (77% through the intestines, and 19% through the kidneys as derivatives). Approximately 51% of drugs are excreted unchanged - only through the intestines (no unchanged component is observed inside the urine).

[6], [7], [8]

Dosing and administration

To conduct drug treatment can only doctors with experience in the use of anticancer agents.

During the day it is required to apply 0.8 g of the drug (2 tablets with a volume of 0.2 g, 2 times a day). You can not use the drug with a meal rich in fats. The tablets are swallowed whole, while squeezing it down with plenty of plain water.

The duration of the treatment cycle is selected by the doctor, taking into account the tolerability and the medical effect exerted. If strong toxic signs are observed, the medication is withdrawn; in the case of weak or moderate negative manifestations, reduce the dose of the drug or cancel the treatment for a while.

When required, the portion per day can be reduced to 0.4 g, which is divided into 2 uses.

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

• 1st degree of epidermal toxicity - therapy continues without adjusting a portion of the drug; additional prescription of symptomatic substances is performed;
• 2nd degree (1st episode) - a daily dose of drugs is reduced to 0.4 g, and in addition, symptomatic measures are prescribed. With the disappearance of toxic signs or reduction to 1st degree of toxicity after 28 days, the portion is increased to 0.8 g. In the absence of effect, therapy is stopped until the symptoms disappear or weaken to 1st degree. Next, the treatment is restored with a daily dosage of 0.4 g (28-day cycle). In the absence of toxicity or its 1st degree, the portion is increased to 0.8 g;
• 2nd degree (2/3rd episode) - a portion is changed according to the scheme used in the case of the 1st episode, but during recovery of the course, a dosage of 0.4 g is needed for an indefinite term;
• 2nd degree (4th episode) - taking into account the condition of the patient and the personal response to treatment, the administration of sorafenib should be canceled;
• 3rd degree (1st episode) - symptomatic actions are immediately carried out, and the introduction of sorafenib is stopped for 7+ days (until signs of toxicity diminish to 1st degree or disappear completely). After this treatment, they restore 0.4 g per serving (28-day intake), and later, if the toxicity does not develop more than 1st degree or does not appear at all, the dosage is increased to 0.8 g;
• 3rd degree (2nd episode) - the portion is changed in the mode used in the 1st episode, but during the restoration of the treatment cycle the daily portion of 0.4 g is taken within an indefinite term;
• 3rd degree (3rd episode) - the complete abolition of treatment using Nexavar is required.

Persons with renal impairment or the presence of risk factors for kidney failure, should be monitored for EBV during treatment with this medication.

[13], [14], [15]

Use Neksavara during pregnancy

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

Adequate testing of the drug during pregnancy has not been performed. Information that was obtained from tests with animals, showed significant reproductive toxicity of drugs - for example, Nexavar when administered to pregnant women can cause the appearance of congenital abnormalities in the fetus or its fetal death.

Testing with rats showed that sorafenib overcomes the placenta. There is a possibility that the drug inhibits the process of angiogenesis in the fetus.

When using sorafenib, you need to use reliable contraception. Taking into account the possible risk, it is impossible to plan pregnancy during therapy (women who are in childbearing age should be notified about the toxic effects of drugs). Reliable contraception must be applied for at least 14 days from the moment of discontinuation of the drug.

In pregnancy, the medication is prescribed only with strict indications; The decision of this is made by the attending doctor.

There is no information regarding the allocation of the drug along with human breast milk. In tests involving animals, it was found that unchanged sorafenib and its derivatives are secreted with milk.

It is required to cancel breastfeeding when using the drug Nexavar.

Contraindications

The main contraindications:

• strong sensitivity associated with sorafenib or auxiliary elements of the drug;
• Reception for individuals with pulmonary carcinoma of a squamous nature who are treated with carboplatin and paclitaxel.

Caution is required in the event of such violations:

• coronary syndrome in the active phase or a myocardial infarction existing in a recent history (in such groups, the safety of the drug was not studied; volunteers showed an increase in the risk of myocardial ischemia);
• prolongation of the QT-interval, having a different nature (for example, the use of drugs affecting this indicator, congenital disorder or pathology, in which there are such changes in ECG indications);
• disorders of the hepatobiliary function, which are pronounced (because sorafenib is mainly excreted through the liver; tests have not been performed on people with similar disorders).

[9], [10]

Side effects Neksavara

Among the most serious side effects of sorafenib are: heart attack or myocardial ischemia, hypertensive crisis, perforation in the gastrointestinal tract, as well as drug-induced hepatitis and hemorrhages.

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

During clinical tests, the following negative symptoms developed:

• lesions with an infectious or invasive form: folliculitis or complications caused by infection;
• impaired blood function: neutro, leuko-, thrombocyto or lymphopenia, as well as anemia;
• problems with the work of the central nervous system: depressive episodes, ear ringing, sensory polyneuropathy, as well as treatable leukoencephalopathy of posterior character;
• disorders affecting the cardiovascular system: CHF, hypertensive crisis, ischemia or myocardial infarction, prolongation of the QT-gap and bleeding (affecting the gastrointestinal tract or cerebral);
• symptoms associated with the respiratory system: pneumonitis or pneumonia (also interstitial), rhinorrhea, hoarseness or respiratory distress;
• violations of the gastrointestinal tract: vomiting, stomatitis, disorders of the chair, GERD, signs of dyspepsia and nausea, and in addition to this perforation in the area of the gastrointestinal tract, gastritis, dysphagia or pancreatitis;
• problems with hepatobiliary function: jaundice, drug hepatitis, hyperbilirubinemia, cholangitis or cholecystitis;
• lesions affecting the ODA system: myalgia, rhabdomyolysis, or arthralgia;
• disorders associated with the urogenital system: gynecomastia, renal failure or erectile dysfunction;
• metabolic disorders: anorexia, hypocalcemia or natriemia, hypo or hyperthyroidism, dehydration, increased ALT or AST, as well as lipase with amylase and alkaline phosphatase, and in addition a decrease in serum phosphorus values, changes in the level of INR or prothrombin;
• other negative symptoms: flu-like symptoms, weight change, increased fatigue, pain in different places and weakness;
• allergy symptoms: anaphylaxis, urticaria, angioedema, and epidermal manifestations (including pruritus, eczema, alopecia, LPS, SJS, acne, squamous cell epidermal carcinoma, erythema, PET, radiation-induced dermatitis, and leukocyto-clastic vasculitis).

In the case of an increase in blood pressure values that is resistant to treatment while taking a drug, it may be necessary to cancel it. In addition, the termination of the use of Nexavar may be necessary when the appearance of severe bleeding.

[11], [12]

Overdose

Testing was carried out with the use of medication in a portion of 0.8 g, with a 2-time dose per day. In such cases, individual patients had epidermal symptoms and diarrhea. Studies with the introduction of higher dosages were not performed. If an overdose is suspected in a patient, it is necessary to suspend therapy and conduct a course using symptomatic substances.

To the present moment there is no information regarding the specific treatment in case of sorafenib poisoning.

[16], [17]

Interactions with other drugs

It is extremely necessary to administer the drug along with docetaxel or irinotecan.

The substances that induce the action of CYP3 A4, when combined with sorafenib, enhance its metabolic processes and reduce the serum indices of the unchanged element. Nexavar should be very carefully combined with dexamethasone, phenytoin and rifampicin, and in addition, with Hypericum, phenobarbital and carbamazepine.

When testing, ketoconazole had no effect on the AUC level of sorafenib in the case of their combination. When administered together with drugs that slow down the activity of CYP3 A4, the likelihood of changes in the pharmacokinetics of drugs is extremely low.

During the tests, the drug had almost no effect on the INR level in people using warfarin, but their joint administration requires careful monitoring of the PTV and INR values.

Combining 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 use of carboplatin with paclitaxel, there were no significant changes in the pharmacokinetics of these drugs. It is required to interrupt the use of Nexavar for 3 days in case of the need to administer paclitaxel with carboplatin.

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

The combination with neomycin causes a decrease in the bioavailability of sorafenib (due to exposure to metabolic processes of drugs inside the liver with intestines, as well as the gastrointestinal microflora).

[18], [19]

Storage conditions

Nexavar is required to be kept at standard temperature indicators, in a closed place from small children.

[20]

Shelf life

Nexavar can be used within a 36-month period from the date of sale of the pharmaceutical product.

Application for children

The use of drugs in pediatrics is prohibited.

[21], [22], [23]

Analogs

Analogues of drugs are substances Tayverb, Votrient, Sutent with Giotrifom, Sprysel and Ibrans with Tufinlar, and in addition to this, Imatero, Tasigna and Imatinib.

[24], [25], [26], [27]