Nexavar
Active material: Sorafenib
When ATH: L01XE05
CCF: Anticancer drug. An inhibitor of protein tyrosine kinase
ICD-10 codes (testimony): C22.0, C64
When CSF: 22.06
Manufacturer: BAYER HealthCare AG (Germany)
Pharmaceutical form, composition and packaging
Pills, Film-coated of red color, round, lenticular, One side of the tablet embossed logo, with another – figure “200”.
| 1 tab. | |
| sorafeniʙa tozilat | 274 mg, |
| that corresponds to the content of sorafenib | 200 mg |
Excipients: microcrystalline cellulose, sodium croscarmellose, gipromelloza (5 cP, 15 cP), magnesium stearate, sodium lauryl.
The composition of the shell: gipromelloza, macrogol 3350, Titanium dioxide, iron oxide red.
28 PC. – blisters (4) – packs cardboard.
Pharmacological action
Anticancer drug. Sorafenib is a multi-kinase inhibitor. Reduces the proliferation of tumor cells in vitro.
Displaying, that sorafenib inhibits multiple intracellular kinases (с-CRAF, Nice nice и мутантную) and kinase, located at the cell surface (KIT, FLT-3, RIGHT, VEGFR-1, VEGFR-2, VEGFR-3 и PDGFR-b). It is believed, that some of these kinases involved in tumor cell signaling systems, in angiogenesis and apoptosis. Sorafenib inhibits tumor growth in the hepatocellular carcinoma and renal cell carcinoma in humans.
Pharmacokinetics
Absorption
After oral administration the mean relative bioavailability is 38-49%. Cmax sorafenib in plasma is reached after about 3 h after administration. When taken with food fat with moderate bioavailability sorafenib approximates the bioavailability in the fasting. When taken with a meal high in fat reduced bioavailability by approximately 29% versus drug-fasting.
In appointing the drug orally at doses, exceeding 400 mg 2 times / day, middle Cmax iAUC increase is not proportional.
Distribution
It is receiving repeated doses of sorafenib for 7 days resulted in 2.5 -7-fold increase in storage, compared with a single dose.
Css sorafenib plasma levels are reached within 7 d, отношение Cmax to Cmin is less than 2.
The binding to plasma proteins – 99.5%.
Metabolism and excretion
Metabolism of sorafenib made, mainly, in the liver by oxidation, mediated by CYP3A4 isoenzyme, and by glyukuronirovaniya, mediated by UGT1A9.
Upon reaching equilibrium in the sorafenib accounted for approximately 70-85%. Identified 8 metabolites of sorafenib, 5 They are found in plasma. The main circulating metabolite of sorafenib in plasma – pyridine N-oxide possesses in vitro activity, similar to the activity of sorafenib, and approximately 9-16%.
After oral administration of sorafenib at a dose 100 mg for 14 days displayed 96% of the administered dose, 77% excreted in the feces, 19% – the urine in the form of glucuronides. Unchanged sorafenib, in an amount 51% of the administered dose, determined in the stool.
T1/2 sorafenib is approximately 25-48 no.
Pharmacokinetics in special clinical situations
Analysis of demographic data indicates, that the correction of the dose depends on the age or sex not required.
The data on the pharmacokinetics of the drug in children missing.
Sorafenib pharmacokinetics was studied after administration of the drug in a single dose 400 mg in patients with normal renal function and patients with mild renal insufficiency (CC 50-80 ml / min), average (KK from 30 to < 50 ml / min) and severe (CC < 30 ml / min) degrees, not requiring dialysis. The impact of renal impairment on the pharmacokinetics of sorafenib were found. For patients with mild renal insufficiency, moderate and severe, not
requiring hemodialysis, the need to reduce the dose missing.
Sorafenib appears, mainly, liver. Patients with mild (Class A classification Child-Pugh) or moderately (Class B classification Child-Pugh) impaired liver function, The pharmacokinetic parameters were the same sorafenib, both in patients with normal liver function. In patients with severely impaired hepatic function (Class C classification Child-Pugh) The pharmacokinetics of sorafenib has not been studied.
Testimony
- Metastatic renal cell carcinoma;
- Hepatocellular carcinoma.
Dosage regimen
The recommended daily dose of sorafenib 800 mg (4 tab. by 200 mg). The daily dose is administered in 2 admission (2 tab. 2 times / day), or between meals, or together with food, containing low or moderate amount of fat. The tablets swallowed, with a glass of water.
Treatment is continued until, As long as the clinical efficacy of the drug, or until its unacceptable toxic effect.
Development of possible adverse drug reactions may require temporary interruption and / or dose reduction of sorafenib. If necessary, the dose sorafenib can be reduced to 400 mg 1 time / day.
Recommendations to reduce the dose of sorafenib in the development of skin toxicity
| Episodes | Recommendations for corrective doses of sorafenib |
| 1 the degree of skin toxicity numbness, dysesthesia, paraesthesia, painless swelling, erythema or discomfort in the arms or legs, which do not interfere with the normal activity of the patient | |
| Anyone in a row | Treatment continued with local symptomatic treatment |
| 2 the degree of skin toxicity erythema and swelling of the hands or feet, accompanied by pain and / or discomfort, that restrict normal activity of the patient | |
| The first occurrence | Treatment continued with the use of Nexavar® at a reduced dose (400 mg / day 28 days) and using the local symptomatic therapy. If there is no improvement within 7 See days. below. If after a dose reduction level of toxicity returns to 0-1 degrees, through 28 sorafenib day dose was increased to full dose |
| The absence of cutaneous symptoms decrease in intensity during 7 days | Suspend therapy Nexavar® until, dermal toxicity is not docked or its severity is reduced to 1-st degree of toxicity. With the resumption of therapy to reduce the dose of Nexavar® to 400 mg / day |
| 2-second or third episode of skin toxicity | Suspend therapy Nexavar® until, dermal toxicity is not docked or its severity is reduced to 1-st degree of toxicity. With the resumption of therapy to reduce the dose of Nexavar® to 400 mg / day |
| At the 4th episode of skin toxicity | Treatment with Nexavar® discontinue. The decision to cancel sorafenib therapy should be based on clinical evaluation of the patient and his preferences |
| 3 the degree of skin toxicity moist desquamation, ulceration, Blisters, severe pain in hands or feet, expressed discomfort, do not allow the patient to carry out their professional duties, or take care of themselves | |
| The first occurrence | Suspend therapy Nexavar® on 7 or more days (until, dermal toxicity is not docked or its severity is reduced to 1 toxicity). Immediately appoint a local symptomatic therapy. With the resumption of therapy to reduce the dose of Nexavar® to 400 mg / day. If after a dose reduction level of toxicity returns to 0-1 degrees, through 28 sorafenib day dose was increased to full dose |
| At the 2nd episode of skin toxicity | Suspend therapy Nexavar® on 7 or more days (until, dermal toxicity is not docked or its severity is reduced to 1 toxicity). Immediately appoint a local symptomatic therapy. With the resumption of therapy to reduce the dose of Nexavar® to 400 mg / day |
| At the 3rd episode of skin toxicity | Treatment with Nexavar® discontinue. The decision to cancel sorafenib therapy should be based on clinical evaluation of the patient and his preferences |
Dose adjustments depending on the the patient's age (senior 65 years), sex or body weight is not required.
In patients with impaired liver function class A and B on the Child-Pugh classification correction dose is not required. The use of sorafenib in patients with impaired liver function P on the Child-Pugh classification not known.
At light, moderate or severe renal impairment (hemodialysis) sorafenib dose adjustment is not required. The use of sorafenib in patients, hemodialysis, not known.
In patients at risk for impaired renal function should be monitored fluid and electrolyte balance.
Side effect
Determination of the frequency of adverse reactions: Often (≥1/10), often (of ≥1 / 100 to <1/10), sometimes (by ≥1 / 1,000 to <1/100).
From the hematopoietic system: Often – lymphopenia; often – leukopenia, neutropenia, anemia, thrombocytopenia.
Cardio-vascular system: Often – bleeding (incl. bleeding from the gastrointestinal tract, respiratory and cerebral hemorrhage), increased blood pressure; often – flushing; sometimes – hypertensive crisis, myocardial ischemia and / or myocardial infarction, congestive heart failure.
The respiratory system: often – hoarseness; sometimes – rhinorrhea.
Dermatological reactions: Often – skin rash, alopecia, palmar-plantar eritrodizesteziya, эritema, itching; often – exfoliative dermatitis, acne, xerosis, peeling of the skin; sometimes – folliculitis, eczema, erythema multiforme, keratoacanthomas / ploskokletočnaâ skin cancer.
On the part of the digestive system: Often – diarrhea, nausea, vomiting, stomach ache; often – stomatitis, dryness of the oral mucosa, glossodiniya, dyspepsia, dysphagia, anorexia, constipation; sometimes – hastroэzofahealnыy reflux, gastritis, pancreatitis, perforation of the gastrointestinal tract, increased levels of bilirubin (including jaundice), cholecystitis, kholangit.
From the nervous system: often – perifericheskaya sensornaya neuropathy, reversible encephalopathy syndrome, depression.
On the part of the organ of hearing: often – tinnitus.
On the part of the musculoskeletal system: often – arthralgia, myalgia.
From the urinary system: often – renal failure.
Reproductive function: often – erectile dysfunction; sometimes – gynecomastia.
On the part of the endocrine system: sometimes – gipotireoz.
Allergic reactions: sometimes – skin reactions, hives.
From the laboratory parameters: Often – gipofosfatemiя, increase in the level of lipase and amylase; often – transient increase in transaminases (ACT, GOLD); sometimes – degidratatsiya, giponatriemiya, transient elevation of alkaline phosphatase, improving MHO and prothrombin.
Other: Often – fatigue, pain of various localization (incl. pain in the oral cavity, abdominal pain, pain in the swelling, headache, pain in the extremities); often – asthenia, flu-like symptoms, fever, weight loss; sometimes – the accession of secondary infections.
Contraindications
- Pregnancy;
- Lactation (breast-feeding);
- Children's age (efficacy and safety have not been established);
- Hypersensitivity to sorafenib or any other component of the drug.
FROM caution should be prescribed for skin diseases, with hypertension, when increased bleeding or a history of bleeding, unstable angina, myocardial infarction, odnovremenno with irinotekanom and dotsetakselom.
Pregnancy and lactation
Research on the use of sorafenib in pregnant women were not conducted.
You should avoid becoming pregnant during treatment with sorafenib. During and for at least 2 weeks after treatment with sorafenib must use reliable methods of contraception.
Women of reproductive age We must be informed of the potential hazard to the fetus sorafenib, which includes teratogenicity, challenges to the survival of the fetus and embryotoxicity.
Unknown, stands whether sorafenib in breast milk. Because many drugs are excreted in breast milk and the effect of sorafenib on infants have not been studied, women should abandon breastfeeding during treatment with sorafenib.
IN experimental studies Animal studies have shown reproductive toxicity of sorafenib, including the ability of a substance to cause malformations. In experiments in rats show, that sorafenib and its metabolites cross the placenta. Expected, that sorafenib inhibits angiogenesis in the fetus. Do animals have a selection of milk sorafenib and / or its metabolites.
Cautions
Treatment with sorafenib should be under the supervision of a specialist, having experience of anticancer drugs.
During therapy with sorafenib should periodically monitor the performance of peripheral blood (including differential blood count and platelets).
The most common adverse reactions while taking sorafenib were skin reactions in the extremities (palmar-plantar eritrodizesteziya) and rashes. In most cases they have been 1 and 2 severity and manifested, mainly, during the first 6 weeks of treatment. For treatment of dermal toxicity, local agents can be used with symptomatic effect. If you want to temporarily stop treatment and / or change the dose of sorafenib or, in severe or recurring cases of skin reactions, therapy sorafenib cancel.
Patients, treated with sorafenib, It was registered increase in the incidence of hypertension. Hypertension usually wore light or moderate, I observed at the beginning of treatment and treatable with standard antihypertensive drugs. During treatment with sorafenib should regularly monitor blood pressure and adjust its increase antihypertensive therapy. In cases of severe or persistent hypertension, or the appearance of hypertensive crisis, despite holding adequate antihypertensive therapy, should consider discontinuing treatment with sorafenib.
Sorafenib may increase the risk of bleeding. Heavy bleeding are rare. If you experience any bleeding, requiring medical intervention, It encouraged to consider discontinuing treatment with sorafenib. The joint appointment of warfarin and sorafenib patients had some rare episodes of bleeding or increase MHO. The joint appointment of sorafenib and warfarin need regular determination of prothrombin time, MHO, Clinical signs of bleeding.
In the case of surgical interventions recommended the suspension of treatment with sorafenib position precaution. Clinical observations, concerning the reintroduction of sorafenib after surgery, very few. Therefore, the decision to resume sorafenib therapy after surgery should be based on the clinical evaluation of the adequacy of wound healing.
In the event of ischemia and / or myocardial infarction should be temporarily or permanently discontinue treatment with sorafenib.
Perforation of the gastrointestinal tract is uncommon and described in less than 1% patients, sorafenib. In some cases, these events were associated with tumors in the peritoneal cavity. In the case of perforation of the gastrointestinal tract sorafenib treatment should be discontinued.
There are no data on the treatment of sorafenib in patients with severe hepatic impairment (Class C classification Child-Pugh). Since sorafenib is derived mainly by the liver, in patients with severe hepatic impairment may increase the effect of the drug.
Be wary appoint sorafenib with drugs, are metabolized / O mainly involving UGT1A1 (eg, Irinotecan).
Use in Pediatrics
The safety and efficacy of sorafenib purpose has not been established in children.
Overdose
In case of overdose may increase adverse events, especially diarrhea and skin reactions.
Treatment: symptomatic therapy. Antidote k sorafenibu not known.
Drug Interactions
Preparations, inducing CYP3A4 activity (eg, rifampicin, phenytoin, Carbamazepine, phenobarbital, dexamethasone and preparatы, containing extract of the herb St. John's wort), may increase metabolism of sorafenib and, thus, reduce its concentration in the body.
Clinically significant pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely isoenzyme.
Simultaneous treatment with sorafenib and warfarin (субстрат CYP2C9) It does not change the average values of prothrombin time and MHO versus placebo. However, we recommend regular determination of MHO in all patients, receiving concomitant treatment with sorafenib and warfarin.
Sorafenib did not inhibit or induce cytochrome P450 isoenzymes system.
Sorafenib has no effect on the pharmacokinetics of gemcitabine and oxaliplatin.
Co-administration of sorafenib and doxorubicin increases the Cmax doxorubicin in blood plasma 21%.
When concomitant administration of sorafenib and irinotecan, the active metabolite SN-38 is further metabolised involving UGT1A1, It noted an increase in Cmax SN-38 and irinotecan in blood plasma 67-120% and 26-42% respectively. The clinical significance of these observations is not known.
The joint appointment of docetaxel and sorafenib noted increase in AUC of docetaxel on 36-80% and an increase in Cmax docetaxel 16-32% (this combination should be used with caution).
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be stored out of reach of children at or above 25 ° C. Shelf life – 2.5 year.
