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The convex tablet contains 274 mg of a sorafenib in the form of a tonzilat in a red film cover that corresponds to 200 mg of pure active agent.
Additional components: magnesium stearate, croscarmellose sodium, microcrystallic cellulose, sodium lauryl sulfate, gipromelloza.
Structure of a red film cover: titanium dioxide, gipromelloz, Fe oxide red, macrogoal.
Neksavar is issued in the tableted form. On one party of a tablet figure "200" is engraved that corresponds to a dose of active component, and on other party it is possible to see a logo of the company. Red tablets are packed into blisters on 7 pieces. In a pack from a cardboard there is 1 instruction and 4 blisters.
Active agent — multikinazny inhibitor. The operating component is capable to reduce an indicator of proliferation of oncological, tumor cells of in vitro.
It is proved that active agent sorafenib suppresses activity of kinases which are located on a cellular surface (PDGFR-betta, VEGFR-l-2-3, FLT-3, KIT, RET), and also suppresses mutant BRAF, with-CRAF and other numerous intracellular kinases. It is supposed that the listed above kinases take part in alarm system an onkokletok, in processes of apoptosis and an angiogenesis.
At nephrocellular and hepatocellular cancer sorafenib it is capable to suppress activity of tumoral process.
Pharmacodynamics and pharmacokinetics
The average value of relative biological availability of active agent fluctuates in the range from 38 to 49%. The elimination half-life is equal 25-48ch. Increase in accumulation (by 2,5-7 times) is observed after repeated receptions of a sorafenib within one week in comparison with reception of a single dose.
Absorption of active component and its distribution
In 3 hours after reception of per os the maximum concentration of active agent of a sorafenib is registered. Biological availability at reception on an empty stomach and at reception with food with the moderate content of fat identical. High content of fat in food lowers an indicator of biological availability by 29%. Contacts plasma proteins for 99.5%.
Metabolites are formed as a result of oxidizing processes with participation of a specific isoenzyme of CYP3A4. UGT1A9 takes part in reactions of a glyukuronirovaniye.
Conjugates of the operating component are split in a gleam of a digestive tract due to activity of bacterial glucuronidase, allowing not conjugated medicine to reabsorbirovatsya completely. Neomycinum is capable to lower an indicator of average biological availability of active ingredient of a sorafenib by 46%.
8 active metabolites are known, 5 of them are found in a blood plasma. The main metabolite — the pyridine-N-oxide possessing activity of in vitro. After medicine solution reception in a dose of 100 mg of 96% of drug it is removed within 2 weeks (77% — with a fecal masses, 19% — through renal system in the form of glucuronides). Not changed active component (51% of the accepted dose) is found in fecal masses.
Indications to use
Drug Neksavar is used in oncological practice:
- hepatocellular form of cancer;
- metastatic nephrocellular cancer.
Drug is not used in pediatric medical practice due to the lack of adequate evidential base on safety of use of Neksavar and his efficiency at children.
- bleedings in the anamnesis, the raised bleeding;
- arterial hypertension;
- skin diseases;
- myocardial infarction;
- treatment by Dotsetaksel, Irinotekan;
- unstable course of stenocardia.
- ischemic changes in a myocardium;
- increase of a blood pressure;
- lengthening of QT on an ECG;
- hypertensive crisis;
- heart failure (chronic current);
- myocardial infarction.
- respiratory distress syndrome (acute form);
- beam pneumonitis;
- intersticial pneumonia.
- exfoliative dermatitis;
- skin rash;
- skin peeling;
- keratoacanthoma (kartsioma, planocellular form);
- bottom and palmar eritrodizesteziya;
- skin itch;
- epidermal necrolysis (toxic form);
- gastroesophageal reflux;
- bilirubin increase;
- dryness in a mouth;
- medicamentous hepatitis;
- diarrheal syndrome;
- syndrome of reversible back encephalopathy;
- touch peripheral neuropathy;
- ring in ears;
- nephrotic syndrome;
- renal failure;
- erectile dysfunction;
- small tortoiseshell;
- Quincke's disease;
- tranzitorny increase of nuclear heating plant, ALT;
- anaphylactic reactions;
- accession of consecutive infection;
- fast fatigue;
- grippopodobny syndrome;
- pain syndrome (headaches, ostealgias, epigastriums, etc.);
- decrease in body weight.
Neksavar, application instruction (Way and dosage)
The medicine is intended for reception of per os during food. The producer recommends to take a pill together with foodstuff which contains moderate amount of fat. Tablets need to be washed down with water.
Average daily dosage – 4 tablets on 200 mg that corresponds to the general dose of active agent of 800 mg of a sorafenib. Therapy continues until accurate clinical performance of medicine, or before emergence of the first symptoms of the expressed toxic influence is registered.
At registration of negative reactions the dosage of a medicine is reduced (to 200-400 mg a day). At the expressed by-effects drug Neksavar is temporarily cancelled. At pathology of renal system monitoring of indicators of water and electrolytic balance is required.
High concentration of a sorafenib can provoke skin reactions, a diarrheal syndrome, strengthening of expressiveness of the reactions described in the section "Side effect".
The specific antidote is not issued. Timely therapy depending on clinical displays of poisoning is carried out.
Substrates of specific group of enzymes of P450 cytochrome
Dextromethorphan, Midazolam and Omeprazol which are substrates of isoenzymes CYP2D6, CYP3A4, CYP2C19 at simultaneous therapy with sorafeniby within 4 weeks did not lead to fluctuations of exposures of above-mentioned medicines. It is the certificate that Neksavar is not capable to induce and inhibit isoenzymes of group of P450 cytochrome.
Simultaneous use with Paklitaksel was observed increase of exposure of an active metabolite 6-ON-paklitaksela, formed by means of CYP2C8. It is the certificate that active component of Neksavar in vivo does not inhibit CYP2C8.
Warfarin together with sorafeniby has no significant effect on averages MNO and PTI value in comparison with group of placebo. However it does not cancel requirement to watch regularly MNO indicator at all patients who at the same time accept Neksavar and Warfarin.
Significant clinically medicinal interactions of Neksavar with CYP3A4 inhibitors are not revealed.
The medicines capable to induce activity of CYP3A4 (Phenytoinum, Rifampicin, Phenobarbital, Carbamazepine, Dexamethasone, St. John's Wort extract) strengthen Neksavar's metabolism, reducing the level of concentration of active agent of a sorafenib in a human body. The indicator of AUC of active ingredient decreases by 37% at long and simultaneous therapy of Neksavar and Rifampicin.
Other antineoplastic means
The three-day interval between receptions of medicines allows to avoid interaction of active agents, without changing pharmacokinetics.
Essential changes in Neksavar's exposure were not observed, however, the indicator of exposure of a 5-ftoruratsil (one of products of a metabolism of Kapetsitabin) increased by 0-52%, and Kapetsitabin's exposure increased by 15-50%. Clinical value of such fluctuations of exposures of medicines is still unknown.
Irinotekan / Doxorubicine
Increase of an indicator of AUC Doxorubicine for 21% is observed at simultaneous therapy with Sorafenib. The active metabolite of Irinotekan of SN-38 passes a metabolism with the participation of UGT1A1, the indicator of AUC of Irinotekan increases by 26-42%, and AUCSN-38 increases by 67-120%. Clinical value of these supervision is still unknown.
At observance of a three-day interval indicators of AUC and Dotsetaksel's Cmax increase by 36-80% and 16-32% respectively. Dotsetaksel and Neksavar's combination demands care in need of simultaneous therapy.
The antibacterial, not system medicine applied to an eradikation of flora of a digestive tract is capable to reduce exposure of active agent of Neksavar by impact on enterogepatichesky circulation of the operating component of a sorafenib. 5-day therapy by Neomycinum lowers an indicator of average biological availability of a sorafenib by 46%. Clinical value of these changes is unknown. Influence of other antibiotics is not studied yet, but it is supposed that their influence will depend on ability to suppress activity of glucuronidase.
Terms of sale
It is possible to buy Neksavar in pharmaceutical point, having shown the medical prescription form.
Transportation and storage of tablets Neksavar demand observance of temperature condition – to 25 degrees.
Period of validity
The medicine can be stored 3 years without efficiency loss.
Therapy by Neksavar is carried out under control of the specialist doctor which has a treatment vast experience antineoplastic medicines. Regular carrying out analyses and control over indicators of a condition of peripheral blood (thrombocytes, a leukocytic formula) is recommended. At emergence of undesirable skin, toxic reactions during therapy it is recommended to use symptomatic drugs of local appointment. In the absence of effect and aggravation of symptomatology Neksavar temporarily cancel.
Rather often hypertensive crises against treatment sorafeniby were registered. The arterial hypertension had easy or moderate temper, and responded to treatment standard hypotensive therapy. Medicine is capable to cause bleedings. Seldom heavy bleedings are registered (against simultaneous therapy by Warfarin). At a heart attack and/or ischemia the medicine is cancelled.
Structural analogs of Neksavar are not developed.
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