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Sorafenib

Pharmacotherapeutic group:

The antitumor agent is an inhibitor of protein kinase.

Pharmacological action

Pharmacodynamics 
Sorafenib is an inhibitor multikinase. Reduces the proliferation of tumor cells in vitro. 
It was shown that sorafenib inhibits many kinase intracellular (C-CRAF, BRAF and mutant BRAF) and kinase located on the cell surface (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3 and PDGFR-β). I believe that some of these kinases involved in signaling systems of tumor cells, angiogenesis and apoptosis. Sorafenib inhibits tumor growth in hepatocellular, renal cell carcinoma, differentiated thyroid cancer in humans.

Pharmacokinetics 
After administration of sorafenib tablets, its average relative bioavailability of 38-49%. The half-life of sorafenib is approximately 25-48 hours. Receiving repeated doses of sorafenib for 7 days resulted in a 2.5-7-fold increase in accumulation compared to single dose. Equilibrium concentrations of sorafenib in plasma achieved within 7 days, the ratio of the maximum/minimum concentration is less than 2. The pharmacokinetics of sorafenib at steady state at a dose of 400 mg 2 times per day at intake were studied in patients with thyroid cancer, hepatocellular cancer and renal cell carcinoma. The highest exposure was observed in patients with thyroid cancer, although variability in exposure was high for all tumor types. The clinical significance of the greater area under the curve "concentration-time" (AUC) in patients with thyroid cancer is not established. 
Absorption and distribution 
The maximum concentration (C_max) of sorafenib in plasma achieved after approximately 3 hours after ingestion. When taken along with food with moderate fat content the bioavailability of sorafenib is approximately equivalent to bioavailability when fasting. When taken with foods high in fat, the bioavailability is reduced by approximately 29% compared to drug intake on an empty stomach. 
When assigning oral doses exceeding 400 mg 2 times per day, With average_max and area under the curve "concentration-time" (AUC) increase disproportionately. The link with proteins is 99.5%. 
Metabolism and excretion 
Metabolism of sorafenib is primarily in the liver by oxidation, mediated by CYP3A4, but also by glukuronirovania. mediated by UGT1A9. Sorafenib conjugates may be cleaved in the gastrointestinal tract through the activity of bacterial glucuronidase, which allows you to reabsorbiruetsa conjugarea drug. The simultaneous use of neomycin affects this process, reducing the average bioavailability of sorafenib to 54%. When equilibrium had been reached in the sorafenib accounted for approximately 70-85%. Identified 8 metabolites of sorafenib. 5 of them are found in plasma. The main circulating plasma metabolite of sorafenib – pyridine N-oxide has in vitro activity similar to the activity of sorafenib, and is approximately 9-16%. 
After oral doses of 100 mg of sorafenib in the form of solution for 14 days displayed 96% of the administered dose, 77% excreted via the gut, 19% – by the kidneys in the form of glucuronides. Unchanged sorafenib, in the amount of 51% of the administered dose, determined in the stool.

Pharmacokinetics in special populations 
Analysis of demographic data indicates that the correction of the dose depending on the age or sex is not required. 
Children 
Data on the pharmacokinetics of the drug in children are missing. 
Renal failure 
The pharmacokinetics of sorafenib were studied after a single dose of 400 mg in patients with normal renal function and patients who do not require dialysis, with light (creatinine clearance (CC) 50-80 ml/min), moderate (CC between 30 to <50 ml/min) and severe (CC <30 ml/min) reduced renal function. The impact of reduced renal function on the pharmacokinetics of sorafenib has not been detected. For patients with mild, moderate or severe renal insufficiency not requiring hemodialysis, need to reduce the dosage is missing. 
Liver failure 
Sorafenib appears, mainly, liver. In patients with hepatocellular cancer with light (class a according to the classification of child-Pugh) or medium (class according To the classification of child-Pugh) degrees of hepatic insufficiency, the pharmacokinetic parameters of sorafenib was the same as in patients with normal hepatic function. The pharmacokinetics of sorafenib in patients without hepatocellular carcinoma with mild (class a according to the classification of child-Pugh) or medium (class according To the classification of child-Pugh) degrees of hepatic failure was similar to the pharmacokinetics of sorafenib in healthy people. У больных с тяжелой степенью печеночной недостаточности (класс С по классификации Чайлд-Пью) фармакокинетика сорафениба не изучена.

Показания к применению

• Метастатический почечно-клеточный рак.
• Hepatocellular carcinoma.
• Locally common or metastatic differentiated thyroid cancer resistant to radioactive iodine.

Contraindications

• Hypersensitivity to sorafenib or any other component of the drug.
• Pregnancy.
• The period of breastfeeding.
• Children's age (the efficacy and safety not established).

With caution

The drug should be used with caution in the following conditions:

• skin diseases;
• arterial hypertension;
• increased bleeding or bleeding in anamnesis;
• unstable angina;
• myocardial infarction;
• combined therapy with docetaxel and irinotecan.

Use during pregnancy and breastfeeding

Pregnancy 
Women should avoid pregnancy during treatment with sorafenib. 
Women with preserved reproductive capacity must be informed about the potential dangers of the drug Safeness to the fetus, including teratogenicity problems with the survival of the fetus and embryo toxicity. During and for at least 2 weeks after treatment with sorafenib, you must use reliable methods of contraception. 
Studies of the drug Xopenex in pregnant women have not been conducted. In studies in animals have shown reproductive toxicity of sorafenib, including the ability of the substance to cause malformations. In experiments on rats it was shown that sorafenib and its metabolites cross the placenta. It is assumed that sorafenib inhibits angiogenesis in the fetus. 
Breastfeeding 
Unknown, selects whether sorafenib with women's milk. Animals are observed a selection of milk of sorafenib and/or its metabolites. Because many medicines are excreted in breast milk and the effect of sorafenib on infants have not been studied, women should abandon breastfeeding during treatment with the drug Xopenex.

Method of application and doses

The recommended daily dose Xopenex is 800 mg (4 tablets of 200 mg). The daily dose administered in two doses (2 tablets 2 times a day) or in between meals, either with food, containing low or moderate amount of fat. Tablets are swallowed with a glass of water. 
Treatment continues for as long as clinical efficacy of the drug, or until its unacceptable toxic effects. The development of possible adverse drug reactions may require temporary interruption and/or dose reduction of the drug Xopenex. 
Dose reduction in patients with metastatic renal cell carcinoma and hepatic cell carcinoma 
If necessary, the dose of the drug Xopenex can be reduced to 400 mg 1 time per day or up to 400 mg a day. Buy Sorafenib Price Sorafenib India cost from the manufacturer

Table 1.
Recommendations to reduce dose Xopenex in the development of skin toxicity:

Dose reduction in patients with differentiated thyroid cancer 
If necessary, reduce the dose Xopenex to 600 mg per day the drug is taken 2 times a day (2 tablets and 1 tablet every 12 hours). 
If necessary, the dose of the drug Safeness can be further reduced to 400 mg daily (1 tablet 2 times a day) or up to 200 mg 1 time per day. After reducing the severity of adverse reactions, with the exception of hematologic, dose Xopenex can be increased.

Table 2.
The recommended dose Xopenex for patients with differentiated thyroid carcinoma requiring dose reduction:

Table 3.
Recommendations but lower the dose Xopenex in the development of skin toxicity:

* If within 28 days of drug therapy Xopenex in a reduced dose dermal toxicity will not exceed the 1-St degree, it is possible to increase the dose Xopenex one dose level compared to the reduced dose.

A separate group of patients 
Children 
The safety and efficacy of the drug Xopenex in children is not established. Correction of the dose depending on the age of the patient (older 65 years), sex or body mass is not required. 
Reduced liver function 
Patients with reduced liver function class A and b according to the classification of child-Pugh dose adjustment is not required. Drug treatment Xopenex patients with reduced hepatic function the class C classification child-Pugh not been studied. Buy Sorafenib Price Sorafenib India
The decline in renal function 
Patients with mild, moderate and severe renal failure (without dialysis) does not require dose reduction of the drug Xopenex. The use of the drug Xopenex in the treatment of patients undergoing hemodialysis, have not been studied. In patients with risk for impaired renal function should be monitored fluid and electrolyte balance.

Side effects

Listed below are adverse events that are marked when using the drug Xopenex in clinical studies or based on data from post-marketing use, are distributed by frequency of occurrence in accordance with the following gradation: very often (≥1/10), often (≥1/100 to <1/10), infrequently (≥1/1000 to <1/100), rare (≥1/10, 000 to <1/1 000). 
For adverse effects identified during post-marketing observations, and which cannot reliably estimate frequency or establish a causal relationship with the drug, stated "frequency unknown". 
In each frequency group, undesirable effects are presented in decreasing order of importance. 
With the hematopoietic system: very often – lymphopenia; often – leukopenia, neutropenia, anemia, thrombocytopenia. 
From the side of cardiovascular system: very often – bleeding (including bleeding from the gastrointestinal*, respiratory tract* and cerebral hemorrhaging*), increase in blood pressure; often – congestive heart failure*, myocardial ischemia and/or infarction*, the tides; infrequently – hypertensive crisis*; rarely – prolonged QT interval. 
The respiratory system: often – rhinorrhea, dysphonia; infrequently phenomena similar to interstitial lung diseases* (including pneumonitis, radiation pneumonitis, acute respiratory distress syndrome, interstitial pneumonia, pneumonitis, which inflammation of the lungs). 
The skin and skin appendages: very often – dry skin, skin rash, alopecia, Palmar-plantar erythrodysaesthesia, erythema, skin itching; often – keratoacanthoma/squamous cell carcinoma of the skin, exfoliative dermatitis, acne, skin peeling, hyperkeratosis, folliculitis; infrequently – eczema, erythema multiforme; frequency unknown return radiation dermatitis, Stevens-Johnson syndrome, leukocytoclastic vasculitis, toxic epidermal necrolysis*. 
On the part of the digestive system: very often – diarrhea, nausea, vomiting, constipation, anorexia; often – stomatitis (including dry mucous membranes of the mouth and glossodynia), dyspepsia, dysphagia, gastroesophageal reflux; infrequently – gastritis, pancreatitis, perforation of the gastrointestinal tract, increase the concentration of bilirubin (including jaundice), cholecystitis, cholangitis; rarely – drug-induced hepatitis*. 
From the nervous system: often – peripheral sensory neuropathy, dysgeusia; infrequentlysyndrome rear reversible encephalopathy*.  Buy Sorafenib Price Sorafenib India
Mental disorders: often – depression. 
On the part of the organ of hearing: often – ringing in the ears. 
From the side of musculoskeletal system: very often – arthralgia; often – myalgia, muscle spasms; frequency is unknown – rhabdomyolysis, necrosis of the jaw. 
From the urogenital system: often – renal insufficiency, proteinuria; rarely – nephrotic syndrome.  
From the reproductive function: often – erectile dysfunction; infrequently – gynecomastia. 
From the endocrine system: often – hypothyroidism; infrequently – hyperthyroidism. 
The immune system: infrequently – anaphylactic reaction, hypersensitivity reactions (including skin reactions and urticaria); frequency unknown – angioedema. 
Violations of laboratory parameters: very often – hypophosphatemia, increased activity of lipase and amylase; often transient increase of transaminases (aspartate aminotransferase, alanine aminotransferase), hypocalcemia, hypokalemia, hyponatremia; infrequently – dehydration, transient increase of alkaline phosphatase activity, a deviation from a normal value of international normalized ratio (INR) and prothrombin. 
Other: very often – fatigue, pain syndrome of different localization (including pain in the mouth, abdominal pain, bone pain, pain in the region of the tumour, headache), weight loss, infection, increased body temperature; often – asthenia, flu-like symptoms, inflammation of mucous membranes.

* – adverse reactions can have life-threatening consequences or death. Such phenomena occurred either rarely or at least infrequently.

In clinical studies in patients with differentiated thyroid cancer were observed more often Palmar-plantar erythrodysesthesia, diarrhea, alopecia, weight loss, fever, hypocalcemia, caraguatatuba/squamous cell skin cancer than in patients with renal cell carcinoma and hepatic cell carcinoma. cost from the manufacturer

Overdose

Symptoms: may increase side effects, especially diarrhea and skin reactions. 
Treatment: symptomatic. The antidote of sorafenib is not known.

Interaction with other medicinal products and other forms of interaction

Inducers of CYP3A4 
Drugs that induce CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, dexamethasone and preparations, containing extract of the herb St. John's wort) may increase metabolism of sorafenib and thus decrease its concentration in the body. 
Long simultaneous reception of sorafenib in conjunction with rifampicin resulted in a decrease in AUC (area under the curve "concentration-time") of sorafenib on average by 37%. 
Inhibitors of CYP3A4 
Clinical pharmacokinetic interactions of sorafenib with inhibitors of cytochrome CYP3A4 is unlikely. 
Substrates of CYP2C9 
Simultaneous reception of sorafenib and warfarin did not lead to changes of mean values of prothrombin time and international normalized ratio (INR) compared with placebo. However, it is recommended regular determination of INR in all patients, receiving mixed therapy with warfarin and sorafenib. 
Substrates of specific isoenzymes of the cytochrome P450 group 
Co-administration of midazolam, dextromethorphan, and omeprazole, which are substrates of cytochromes CYP3A4, CYP2D6 and CYP2C19 respectively, and a 4-week course of sorafenib did not lead to changes in the level of exposure of the medications listed above. These observations indicate that sorafenib neither inhibits nor induces isoenzymes of the cytochrome P450 group. As a result of simultaneous application of sorafenib and paclitaxel had an increase, and not decrease exposure to 6-HE-paclitaxel, the active metabolite of paclitaxel that is formed by CYP2C8. These data indicate that sorafenib in vivo might not be inhibitor of CYP2C8. Concurrent use of sorafenib and cyclophosphamide resulted in a slight decrease in cyclophosphamide exposure, but was not observed to reduce the systemic exposure of 4-Oh-cyclophosphamide, an active metabolite of cyclophosphamide. which is formed mainly by CYP2B6. These data indicate that sorafenib in vivo cannot be an inhibitor of CYP2B6. 
Combination with other anticancer drugs 
Sorafenib has no clinically meaningful effect on the pharmacokinetics of gemcitabine, cisplatin, carboplatin, oxaliplatin and cyclophosphamide. 
Paclitaxel / carboplatin 
Concomitant use of paclitaxel (225 mg/m2) and carboplatin (AUC = 6) together with sorafenib (<400 mg 2 times a day), with 3-day intervals in the sorafenib before and after the appointment of paclitaxel and carboplatin, had no significant effect on the pharmacokinetics of paclitaxel. Concomitant use of paclitaxel (225 mg/m2 1 once in 3 weeks) and carboplatin (AUC = 6) with sorafenib (400 mg 2 times a day without any interruption in the application of sorafenib) led to increased exposure of sorafenib in 47%, paclitaxel – 29% 6-IT is a derivative of paclitaxel by 50%. Pharmacokinetics of carboplatin remained unchanged. 
These data show that there is no need to adjust dosing in the application of paclitaxel and carboplatin with sorafenib with a 3-day interval in taking sorafenib. Remain unknown clinical significance of increased exposure of sorafenib and paclitaxel together with the use of sorafenib without a break in its application. 
Capecitabine 
Concurrent use of capecitabine (750-1050 mg/m2 2 times per day from 1st to 14th day every 21 days) and sorafenib (200 or 400 mg 2 times a day with no breaks in reception) do not lead to significant changes in the exposure of sorafenib, however, the exposure of capecitabine increased by 15-50%. and exposure of fluorouracil (metabolite of capecitabine) increased to 0-52%. Remains unknown the clinical significance of this small or moderate increase in exposure of capecitabine and fluorouracil while taking sorafenib. 
Doxorubicin / irinotecan 
The simultaneous appointment of sorafenib and doxorubicin leads to an increase in doxorubicin AUC of 21%. Together with the appointment of sorafenib and irinotecan, whose active metabolite SN-38 further metabolized by UGT1A1 participation, it was observed increase in AUC of SN-38 on a 67-120% increase in AUC of irinotecan to 26-42%. Остается неизвестным клиническое значение данных наблюдений. 
Docetaxel 
Concomitant use of docetaxel (75 or 100 mg/m2 once every 21 days) and sorafenib (200 or 400 mg 2 times a day with 2 th to 19-th day during the 21-day cycle) with 3-day intervals before and after the appointment of is accompanied by the increase in docetaxel AUC and_max docetaxel respectively on 36-80% and 16-32%. Together with the appointment of sorafenib and docetaxel should be used with caution. 
Neomycin 
The simultaneous use of neomycin, a non-systemic antibacterial drug for eradication of gastrointestinal flora, leading to effects on the enterohepatic circulation of sorafenib with a further decrease in exposure of sorafenib. In healthy volunteers treated with neomycin for 5 days, the average bioavailability of sorafenib was reduced to 54%. The clinical significance of these data is not known. The influence of other antibiotics on the pharmacokinetics of sorafenib have not been studied, it is assumed that this impact will be determined by the ability of antibiotics to reduce the activity of glucuronidase. 
Combination with proton pump inhibitors 
Omeprazole 
Concomitant use of omeprazole has no effect on the pharmacokinetics of sorafenib. Dose adjustment of sorafenib is not required.

Special instructions

Drug treatment Xopenex should be under the supervision of a specialist with experience of therapy drugs. 
During drug therapy Xopenex should periodically monitor the peripheral blood parameters (including leukocyte formula and platelets). The most common adverse reactions while taking the drug Xopenex had a skin reaction in the limbs (Palmar-plantar erythrodysesthesia) and rash. In most cases, they were the 1st and 2nd degrees of severity and was manifested mainly during the first six weeks of treatment Xopenex. For treatment of dermal toxicity, it is possible to use local drugs with symptomatic effects. If you want to temporarily stop treatment or change the dose of the drug Xopenex or, in severe or recurring cases of skin reactions, the treatment with the drug Xopenex canceled. In patients receiving drug treatment Xopenex was registered increase in the incidence of hypertension. Hypertension usually wore light or moderate, was observed in the beginning of treatment and respond to treatment with standard antihypertensive drugs. During drug treatment Xopenex should regularly monitor blood pressure and, if necessary, to adjust it to increase the antihypertensive therapy. In cases of severe or persistent hypertension, or if the occurrence of hypertensive crises, despite adequate antihypertensive therapy, one should consider cessation of drug treatment Xopenex. The drug Xopenex may lead to an increased risk of bleeding. Heavy bleeding are rare. If you experience any bleeding requiring medical intervention, it is recommended to consider cessation of drug treatment Xopenex. 
Given the potential risk of bleeding in patients with differentiated thyroid cancer before the appointment of the drug Xopenex should conduct local treatment of tumor infiltration of the trachea, bronchi and esophagus. 
The joint appointment of warfarin and drug Safeness some patients have noted rare episodes of bleeding or increased International Normalized ratio (INR). The joint appointment of warfarin and drug Safeness needs regular determination of prothrombin time, INR, clinical signs of bleeding. 
In the case of surgical interventions recommended temporary cessation of drug therapy Xopenex the precautionary approach. Clinical observations concerning the resumption of drug Xopenex after surgery. very few. Therefore, the decision on the resumption of drug therapy Xopenex after surgery should be based on clinical assessment of adequacy of wound healing. 
In the event of ischemia and/or myocardial infarction should be temporarily or permanently discontinue therapy with Xopenex. The use of the drug Xopenex leads to prolongation of the interval QT/QTc, which may increase the risk of ventricular arrhythmias. The drug should be used Xopenex with caution in the following patients with a current lengthening of the QTc interval or with risk of developing this condition: congenital long QT syndrome; receiving therapy with anthracyclines at high total dose; taking certain antiarrhythmic agents or other drugs leading to prolonged QT interval; and patients with electrolyte disorders, including hypokalemia), hypocalcaemia or hypomagnesemia. In applying the drug Xopenex such patients should be periodic electrocardiographic monitoring to measure the concentration of electrolytes (magnesium, potassium, and calcium). 
Perforation of the gastrointestinal tract occurs infrequently and described less than 1% of patients receiving the drug Xopenex. In some cases, these events were not associated with tumors in the abdominal cavity. In the case of perforation of the gastrointestinal tract treatment with Xopenex should be abolished. 
There are no data on drug treatment Xopenex patients with severe hepatic impairment (class C classification for child-Pugh). Since sorafenib appears, mainly, liver, patients with severe liver dysfunction, may increase the action of the drug. 
In applying the drug Xopenex in patients with differentiated thyroid cancer is recommended to control the concentration of calcium in the blood. In clinical studies in patients with differentiated thyroid cancer, especially those with hypoparathyroidism in history, it was noted more frequent and severe manifestations of hypocalcemia than patients with renal cell and hepatocellular cancer. 
In some patients with differentiated thyroid cancer treated with the drug Xopenex in clinical studies, the concentration of thyroid-stimulating hormone exceeded 0.5 mu/L. When using the drug Xopenex these patients should monitor the concentration of thyroid-stimulating hormone. 
With caution assign product Safeness together with drugs that are metabolized/excreted mainly with the participation of UGT1A1 (e.g., irinotecan). 
Concomitant use of docetaxel (75 or 100 mg/m2), and drug Xopenex (200 or 400 mg 2 times a day) with 3-day intervals before and after the appointment of docetaxel accompanied by an increase in AUC of docetaxel on 36-80%. While the appointment of the drug Xopenex and docetaxel should be used with caution. 
The simultaneous use of neomycin may lead to decreased bioavailability of sorafenib. 
In two randomized, placebo-controlled trials comparing safety and efficacy of use as a first line of two-component chemotherapy based on platinum drugs (carboplatin/paclitaxel and separately gemcitabine/cisplatin) in combination with or without sorafenib in patients with advanced non-small cell lung cancer (NSCLC) failed to obtain data to improve overall survival. Safety data are generally consistent with previously described results. However, in both studies, in patients with squamous cell cancer treated with two-component chemotherapy based on platinum drugs in combination with sorafenib, there was a higher mortality compared with patients who received only a two-component chemotherapy based on platinum drugs (paclitaxel/carboplatin: a hazard ratio of 1.81, 95%; confidence interval of 1.19-to 2.74; gemcitabine/cisplatin: hazard ratio of 1.22, 95%; confidence interval of 0.82-1,80). Determining the causes of this phenomenon have been identified.

Effects on ability to drive vehicles and mechanisms

No data on the impact of sorafenib on the ability to drive vehicles and mechanisms. However, you should consider the side effect profile of the drug.

Release form

Tablets, film-coated 200 mg 
The primary packaging of the medicinal product. 
For 7 or 10 tablets, film-coated in a contour cell package made of polyvinylchloride film and aluminum foil printed patent. 
At 28, 30, 56, 60, 112, 120, 240 tablets, film-coated in a polymer jar with lid pulls with the first autopsy. The free space is filled with cotton wool medical. Banks label pasted paper label, or writing or of plastics, self-adhesive. 
Secondary packaging of a medicinal product. 
4 or 8 contour cell packs of 7 tablets along with an instruction for use is Packed into a pack made of cardboard for consumer packaging. 
For 3 or 6 contour cell packs of 10 pills together with the instruction for use is Packed into a pack made of cardboard for consumer packaging. 
1 Bank with instruction for use is Packed into a pack made of cardboard for consumer packaging. 
Bundles are placed in a group packaging.

Shelf life

3 years. Do not use after the expiry date printed on the package.

Storage conditions

In protected from light place at temperature not exceeding 25 °C. 
Keep out of reach of children.