Composition, form of production and packaging
The tablets covered with a film cover of red color, round, biconcave, on one side of the tablet the company logo is squeezed out, on the other - the figure "200".
1 tab.
sorafenib tosylate 274 mg,
which corresponds to the content of sorafenib 200 mg
Excipients: microcrystalline cellulose - 16 mg, croscarmellose sodium - 36.4 mg, hypromellose 5 cp - 10.2 mg, magnesium stearate - 2.55 mg, sodium lauryl sulfate - 1.7 mg.
The composition of the membrane: hypromellose 15 cP - 6 mg, macrogol 3350 - 2 mg, titanium dioxide - 1.73 mg, iron oxide red - 0.27 mg.
28 pcs. - blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Antitumor drug. Sorafenib is a multi-kinase inhibitor. Reduces the proliferation of tumor cells in vitro.
It was shown that sorafenib inhibits numerous intracellular kinases (c-CRAF, BRAF and mutant BRAF) and kinases located on the cell surface (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3 and PDGFR-?) . It is believed that some of these kinases are involved in the signaling systems of the tumor cell, in the processes of angiogenesis and apoptosis. Sorafenib inhibits tumor growth in hepatocellular carcinoma and renal cell carcinoma, differentiated thyroid cancer in humans.
PHARMACOKINETICS
Suction
After taking the drug inside, the average relative bioavailability is 38-49%. C max sorafenib in plasma is achieved approximately 3 hours after ingestion. When taken with a meal with a moderate fat content, bioavailability of sorafenib approximately corresponds to bioavailability when taken on an empty stomach. When taken with a high-fat diet, bioavailability is reduced by approximately 29% compared with fasting.
When the drug is administered orally at doses exceeding 400 mg 2 times / day, mean C max and AUC increase in proportion.
Distribution
Taking repeated doses of sorafenib for 7 days resulted in a 2.5-7-fold increase in the accumulation compared to a single dose.
C ss of sorafenib in blood plasma are reached within 7 days, the ratio of C max to C min is less than 2.
The pharmacokinetics of sorafenib in the equilibrium state at a dose of 400 mg 2 times / day when ingested were studied in patients with thyroid cancer, hepatocellular carcinoma and renal cell carcinoma. The highest exposure was noted in patients with thyroid cancer, although the exposure variability was high for all types of tumors. The clinical significance of greater AUC in patients with thyroid cancer is not established.
Binding to blood plasma proteins - 99.5%.
Metabolism and excretion
Sorafenib metabolism is mainly carried out in the liver by oxidation mediated by the CYP3A4 isoenzyme, as well as by UGT1A9 mediated glucuronation.
Sorafenib conjugates can be cleaved in the gastrointestinal tract due to the activity of bacterial glucuronidase, which allows reabsorption of the unconjugated active substance. Simultaneous use of neomycin affects this process, reducing the average bioavailability of sorafenib up to 54%.
When the equilibrium state is reached, sorafenib accounts for approximately 70-85%. Identified 8 metabolites of sorafenib, 5 of them found in plasma. The main circulating in the plasma sorafenib metabolite, pyridine N-oxide, has an in vitro activity similar to that of sorafenib, and is approximately 9-16%.
After ingestion of sorafenib in a dose of 100 mg for 14 days, 96% of the administered dose is withdrawn, 77% is excreted through the intestine, 19% - with urine in the form of glucuronides. Unchanged sorafenib, in an amount of 51% of the prescribed dose, is determined in the stool.
T 1/2 of sorafenib is about 25-48 hours.
Pharmacokinetics in special clinical cases
An analysis of demographic data suggests that dose adjustment of the drug, depending on age or sex, is not required.
Data on the pharmacokinetics of the drug in children are absent.
The pharmacokinetics of sorafenib were studied after administration of the drug in a single dose of 400 mg in patients with normal renal function and in patients with mild renal insufficiency (CK 50-80 mL / min), medium (QC 30 to <50 mL / min) and severe <30 ml / min) of a degree not requiring dialysis. The effect of renal dysfunction on the pharmacokinetics of sorafenib was not detected. For patients with mild, moderate and severe renal failure not requiring hemodialysis, there is no need to reduce the dose.
Sorafenib is excreted mainly by the liver. In patients with hepatocellular carcinoma with mild (class A on the Child-Pugh scale) or moderate (class B on the Child-Pugh scale) degree of renal failure, the pharmacokinetic parameters of sorafenib were the same as in patients with normal liver function. The pharmacokinetics of sorafenib in patients without hepatic cell carcinoma with a lung (class A Child-Pugh classification) or moderate (class B Child-Pugh classification) degree of hepatic insufficiency was similar to the pharmacokinetics of sorafenib in healthy individuals. In patients with severe hepatic insufficiency (class C on the Child-Pugh scale), the pharmacokinetics of sorafenib have not been studied.
INDICATIONS
- metastatic renal cell carcinoma;
- hepatocellular carcinoma;
- Locally distributed or metastatic differentiated thyroid cancer, resistant to radioactive iodine.
DOSING MODE
The recommended daily dose of Nexavar is 800 mg (4 tablets of 200 mg). The daily dose is prescribed in 2 divided doses (2 tablets 2 times / day), or in the intervals between meals, or together with food containing a low or moderate amount of fat. The tablets are swallowed with a glass of water.
Treatment continues as long as the clinical efficacy of the drug persists or until the appearance of its unacceptable toxic effect.
The development of possible unwanted drug reactions may require the temporary cessation and / or reduction of the Nexavar dose.
Dose reduction in patients with metastatic renal cell carcinoma and hepatocellular carcinoma
If necessary, the dose of Nexavar can be reduced to 400 mg 1 time / day or up to 400 mg every other day.
Table 1. Recommendations for reducing the dose of Nexavar with the development of skin toxicity
Episodes of skin toxicity Recommendations for correction of doses of Nexavar
1 degree of skin toxicity: numbness, dysesthesia, paresthesia, painless swelling, erythema, or discomfort in the palms or soles of the feet, which do not interfere with normal patient activity
Anyone on the account Treatment with Nexavar continues with a combination of local symptomatic therapy.
2 degree of skin toxicity: erythema and swelling of the palms or soles of the feet, accompanied by pain and / or discomfort, which limit the patient's normal activity
1 st episode The treatment with Nexavar is continued against a background of local symptomatic therapy. If there is no improvement within 7 days - see below.
Absence of decrease in intensity of skin symptoms within 7 days or 2 nd or 3 rd episode Suspend therapy with Nexavar until skin toxicity is stopped or its severity decreases to the 1 st degree of toxicity. When you resume therapy, reduce the dose of Nexavar to 400 mg / day 1 time / day or to 400 mg every other day.
4-th episode Therapy with Nexavar should be stopped.
3 degree of skin toxicity: wet desquamation, ulceration, blisters, severe pain in the palms or soles of the feet, severe discomfort, not allowing the patient to perform their professional duties or serve themselves
1 st or 2 nd episodes Suspend therapy with Nexavar until skin toxicity is stopped or its severity is reduced to the 1 st degree of toxicity. When you resume therapy, reduce the dose of Nexavar to 400 mg 1 time / day or to 400 mg every other day.
The third episode Therapy with Nexavar should be discontinued.
Dose reduction in patients with differentiated thyroid cancer
If it is necessary to reduce the dose of Nexavar to 600 mg / day, the drug is prescribed 2 times / day (2 tablets and 1 tablet with an interval of 12 hours).
If necessary, the dose of Nexavar can be further reduced to 400 mg / day (1 tablet 2 times / day) or up to 200 mg 1 time / day. After reducing the severity of adverse reactions, with the exception of hematologic, the dose of Nexavar may be increased.
Table 2. Recommended doses of Nexavar for patients with differentiated thyroid cancer who require a dose reduction
Daily dose of Nexavar
First dose reduction
600 mg 2 tablets. and 1 tab. with an interval of reception of 12 hours (on the first reception any of these doses can occur)
Second dose reduction
400 mg of 1 tab. 2 times / day
Third dose reduction
200 mg of 1 tab. 1 time / day
Table 3. Recommendations for reducing the dose of Nexavar in the development of skin toxicity
Episodes of skin toxicity Recommendations for correction of doses of the drug Nexavar *
1 degree of skin toxicity: numbness, dysesthesia, paresthesia, painless swelling, erythema, or discomfort in the palms or soles of the feet, which do not interfere with normal patient activity
Anyone on the account Treatment with Nexavar continues with a combination of local symptomatic therapy.
2 degree of skin toxicity: erythema and swelling of the palms or soles of the legs, accompanied by pain and / or discomfort, which limit the patient's normal activity
1 st episode Treatment is continued using a reduced dose of Nexavar 600 mg / day (400 mg and 200 mg at 12 h intervals) and with local symptomatic therapy. If there is no improvement within 7 days, see below.
Absence of a decrease in the intensity of skin symptoms within 7 days or 2nd episode Suspend therapy with Nexavar until skin toxicity is stopped or its severity is reduced to the 1 st degree of toxicity. When resuming therapy, reduce the dose of Nexavar (see Table 2).
3rd episode Suspend therapy with Nexavar until the skin toxicity is stopped or its severity is reduced to the 1 st degree of toxicity. When resuming therapy, reduce the dose of Nexavar (see Table 2).
4-th episode Therapy with Nexavar should be stopped.
3 degree of skin toxicity: wet desquamation, ulceration, blisters, severe pain in the palms or soles of the feet, severe discomfort, not allowing the patient to perform their professional duties or serve themselves
1 st episode Suspend therapy with Nexavar until skin toxicity is stopped or its severity is reduced to the 1 st degree of toxicity. When resuming therapy, reduce the dose of Nexavar (the first dose reduction see table 2).
2 nd episode Suspend therapy with Nexavar until the skin toxicity is stopped or its severity is reduced to the 1 st degree of toxicity. When resuming therapy, reduce the dose of Nexavar (the first dose reduction see table 2).
The third episode Therapy with Nexavar should be completely discontinued.
* If skin toxicity does not exceed 1 degree during a 28-day therapy with Nexavar, a dose increase of Nexavar may be increased by one dose level compared to a reduced dose.
Individual patient groups
Safety and effectiveness of Nexavar in children is not established.
Dose adjustments based on age (over 65 years), sex or body weight are not required.
Patients with a violation of liver function classes A and B on the Child-Pugh scale, dose adjustment is not required. Treatment with Nexavar for patients withimpaired liver function of class C on the Child-Pugh scale has not been studied.
Patients with mild, moderate and severe renal failure (without hemodialysis) do not need to reduce the dose of Nexavar. The use of Nexavar in patients onhemodialysis has not been studied.
Patients with a risk of renal dysfunction should monitor the water-electrolyte balance.
SIDE EFFECT
The following undesirable phenomena noted when applying Nexavar in clinical trials or based on post-marketing data are distributed according to the frequency of occurrence according to the following gradation: very often (? 1/10), often (from? 1/100 to <1 / 10), infrequently (from? 1/1000 to <1/100), rarely (from? 1/10 000 to <1/1 000).
For undesirable effects revealed during post-marketing observations and for which it is not possible to reliably estimate the frequency or establish a causal relationship with taking the drug, "frequency is unknown" is indicated.
In each frequency group, undesirable phenomena are presented in order of decreasing importance.
On the part of the hematopoiesis system: very often - lymphopenia; often - leukopenia, neutropenia, anemia, thrombocytopenia.
From the cardiovascular system: very often - bleeding (including bleeding from the gastrointestinal tract *, respiratory tract * and cerebral hemorrhage *), increasing blood pressure; often - chronic heart failure *, myocardial ischemia and / or myocardial infarction *, hot flashes; infrequently hypertensive crisis *; rarely - prolongation of the interval QT *.
From the respiratory system: often - rhinorrhea, dysphonia; infrequent rhinorrhea, phenomena similar to interstitial lung diseases * (including pneumonitis, radiation pneumonitis, acute respiratory distress syndrome, interstitial pneumonia, pulmonitis, pneumonia).
From the skin and skin appendages: very often - dry skin, skin rash, alopecia, palmar-plantar erythrodysesthesia, erythema, itchy skin; often - keratoacanthoma / squamous cell carcinoma of the skin, exfoliative dermatitis, acne, skin peeling, hyperkeratosis, folliculitis; infrequently - eczema, erythema multiforme; frequency unknown - recurrent radiation dermatitis, Stevens-Johnson syndrome, leukocytoclastic vasculitis, toxic epidermal necrolysis *.
From the digestive system: very often - diarrhea, nausea, vomiting, constipation, anorexia; often - stomatitis, dryness of the oral mucosa, glossodynia, dyspepsia, dysphagia, gastroesophageal reflux; infrequently - gastritis, pancreatitis, perforation of the gastrointestinal tract *, increased bilirubin concentration (including jaundice), cholecystitis, cholangitis; rarely - drug-induced hepatitis *.
From the side of the nervous system: often - peripheral sensory neuropathy, dysgeusia; infrequently - a syndrome of a back reversible encephalopathy *.
Mental disorders: often - depression.
From the side of the organ of hearing: often - ringing in the ears.
From the musculoskeletal system: very often - arthralgia; often - myalgia, muscle spasms; frequency unknown - rhabdomyolysis, necrosis of the jaw.
From the urinary system: often - renal failure, proteinuria; rarely - nephrotic syndrome.
On the part of the reproductive function: often - erectile dysfunction; infrequently - gynecomastia.
From the endocrine system: often - hypothyroidism; infrequently hyperthyroidism.
From the side of the immune system: infrequently - anaphylactic reactions, hypersensitivity reactions (including skin reactions and urticaria); frequency unknown - angioedema.
Laboratory indicators: very often - hypophosphatemia, increased activity of lipase and amylase; often transient increase in the activity of transaminases (ALT, AST), hypocalcemia, hypokalemia, hyponatremia; infrequently - dehydration, hyponatremia, transient increase in activity of AP, deviation from the normal level of MHO and prothrombin.
Other: very often fatigue, pain syndrome of different localization (including pain in the oral cavity, abdominal pain, pain in the area of ​​the tumor, headache), weight loss, infections, increased body temperature; often - asthenia, flu-like syndrome, inflammation of the mucous membranes.
* - adverse reactions may have life-threatening consequences or death. Such phenomena occurred either infrequently, or less often than infrequently.
In clinical studies in patients with differentiated thyroid cancer, palmar-plantar erythrodysesthesia, diarrhea, alopecia, weight loss, fever, hypocalcemia, keratoacanthoma / squamous cell carcinoma of the skin were noticeably more frequent than in patients with renal cell carcinoma and hepatocellular cancer.
CONTRAINDICATIONS
- Pregnancy;
- the period of lactation (breastfeeding);
- Children's age (effectiveness and safety of use are not established);
- hypersensitivity to sorafenib or to any other component of the drug.
With caution should prescribe the drug for skin diseases, with arterial hypertension, with increased bleeding or bleeding history, with unstable angina, transferred myocardial infarction, concomitantly with irinotecan and docetaxel.
PREGNANCY AND LACTATION
Studies on the use of sorafenib in pregnant women have not been conducted.
Pregnancy should be avoided during treatment with sorafenib. During and for at least 2 weeks after sorafenib therapy, reliable contraceptive methods should be used.
Women of reproductive age should be informed of the potential risk of sorafenib for the fetus, which includes teratogenicity, problems with fetal survival and embryotoxicity.
It is not known whether sorafenib is excreted in breast milk. Because many drugs are excreted in breast milk and the effect of sorafenib on infants have not been studied, women should avoid breast-feeding during treatment with sorafenib.
In experimental studies in animals have shown reproductive toxicity sorafenib, including the ability of a substance to cause development defects. In experiments on rats that sorafenib and its metabolites cross the placental barrier. It is assumed that sorafenib inhibits angiogenesis in the fetus. Do animals have a selection of milk sorafenib and / or its metabolites.
APPLICATION FOR FUNCTIONS OF THE LIVER
When light or moderate renal impairment (creatinine clearance> 30ml / min) correction dose is not required sorafenib.
Information on the use of sorafenib in patients with severe renal insufficiency (creatinine clearance <30 mL / min) and in patients on hemodialysis not.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with impaired liver function classes A and B according to Child-Pugh classification correction dose is not required.
The use of sorafenib in patients with hepatitis and breach of the class of liver function by Child-Pugh classification has not been studied.
APPLICATION FOR CHILDREN
Contraindications: children's age (efficacy and safety have not been established).
APPLICATION IN ELDERLY PATIENTS
Dose adjustments depending on the patient's age (over 65 years), gender or body weight are required.
SPECIAL INSTRUCTIONS
Treatment with Nexavar should be under the supervision of a specialist who is experienced in the application of anticancer drugs.
During therapy with Nexavar must periodically monitor peripheral blood (including buffy formula and platelets).
The most common adverse drug reactions when receiving Nexavar were dermal reactions in the limb (hand-foot eritrodizesteziya) and rash. In most cases, they are the 1st and the 2nd degree and manifested mainly during the first 6 weeks of treatment with Nexavar. For the treatment of skin toxicity can be used local agents with symptomatic effect. If necessary, temporarily discontinue treatment and / or alter the dose of the drug Nexavar, or in severe or recurrent cases of cutaneous reactions therapy with Nexavar overturned.
Patients receiving treatment with Nexavar, an increased incidence of hypertension have been reported. Hypertension is usually carried light to moderate, it was observed at the beginning of treatment and resisted treatment with standard antihypertensive agents. During treatment with Nexavar should regularly monitor the blood pressure and adjust its increase antihypertensive treatment if necessary. In cases of severe or persistent hypertension, or the appearance of hypertensive crises, despite holding adequate antihypertensive therapy should consider discontinuing treatment with Nexavar.
Nexavar may lead to increased risk of bleeding. Severe bleeding occur rarely. If you experience any bleeding requiring medical intervention, it is recommended to consider the termination of treatment with Nexavar.
Given the potential risk of bleeding in patients with differentiated thyroid cancer patients before prescribing the drug Nexavar should conduct the topical treatment of tumor infiltration of the trachea, bronchus and esophagus.
The joint appointment of warfarin and drug Nexavar some patients had rare episodes of bleeding or increase MHO. The joint appointment of warfarin and drug Nexavar should be regularly determination of prothrombin time, MHO, clinical signs of bleeding.
In the case of surgical interventions recommended the suspension of therapy with Nexavar with positions precautions. Clinical observations on the resumption of the drug Nexavar after surgery, very few. Therefore, the decision to resume therapy with Nexavar after surgery should be based on the clinical evaluation of the adequacy of the wound healing.
In the event of ischemia and / or myocardial infarction should be temporarily or permanently discontinue therapy with Nexavar.
It is found that the use of the drug leads to Nexavar lengthening QT / QT interval cThat may increase the risk of ventricular arrhythmias. Nexavar drug should be used with caution in patients following the current interval lengthening QT c or at risk of developing such condition: congenital QT syndrome elongate slot; receiving anthracycline therapy in high total dose; taking certain antiarrhythmic drugs or other drugs, leading to QT interval prolongation; as well as in patients with electrolyte disturbances, including hypokalaemia, hypocalcaemia or hypomagnesemia. In applying the drug Nexavar such patients should be periodic monitoring ECG and measure the concentration of electrolytes (magnesium, potassium, calcium).
Gastrointestinal perforation occurs infrequently and is described in less than 1% of patients treated with Nexavar. In some cases, these events were not associated with tumors in the peritoneal cavity. In the case of perforation of the gastrointestinal tract treatment with Nexavar should be abolished.
There are no data on the treatment drug Nexavar in patients with severe hepatic impairment (class C by Child-Pugh classification). Since sorafenib derived mainly by the liver in patients with severe hepatic impairment may increase the drug.
In applying the drug Nexavar patients with differentiated thyroid cancer recommended to control blood calcium concentration. In clinical studies in patients with differentiated thyroid cancer, especially those with a history of hypoparathyroidism, observed more frequent and severe manifestations of hypocalcemia than patients with renal cell and hepatocellular carcinoma.
In some patients with differentiated thyroid cancer treated Nexavar drug in clinical trials, TSH concentration exceeded 0.5 mU / l. In applying the drug Nexavar in these patients should be monitored TSH concentration.
Precautions Nexavar administered with drugs that are metabolized / output predominantly involving UGT1A1 (e.g., irinotecan).
In two randomized, placebo-controlled studies, in comparing safety and efficacy of use as a first line of a two-component-based chemotherapy platinum drugs (carboplatin / paclitaxel and separately gemcitabine / cisplatin) in combination with sorafenib or without it with patients
of late stage lung (NSCLC non-small cell cancer ) it was not possible to obtain data to improve overall survival.
Safety data previously described results correspond in general. However, in both studies, in patients with squamous cell carcinoma of the lung treated with two-chemotherapy with platinum-based drugs in combination with sorafenib, it had a higher mortality compared with the group of patients who received only two-chemotherapy with platinum-based drugs (paclitaxel / carboplatin: hazard ratio 1.81, 95% confidence interval 1.19-2.74; gemcitabine / cisplatin: hazard ratio 1.22, 95% confidence interval 0.82-1.80). Defining the causes of this phenomenon have been identified.
OVERDOSE
In case of overdose may increase adverse effects, especially diarrhea and skin reactions.
Treatment: conduct symptomatic therapy. Antidote to sorafenib is not known.
DRUG INTERACTION
Inducers of CYP3A4: agents that induce the activity of CYP3A4 (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, dexamethasone and drugs containing St. John's wort herb extract), can increase the metabolism of sorafenib and thus reduce its concentration in the body. Continuous simultaneous reception sorafenib together with rifampicin resulted in a decrease in AUC of sorafenib on average 37%.
Inhibitors of CYP3A4: clinical pharmacokinetic interaction sorafenib with inhibitors of cytochrome CYP3A4 unlikely.
Substrates of CYP3A4:concomitant use of sorafenib and warfarin has not led to a change in the average values of prothrombin time and MHO versus placebo. However, we recommend regular determination MHO all patients receiving combination therapy with sorafenib and warfarin.
Substrates of particular isozymes of cytochrome P450 group:co-administration of midazolam, dextromethorphan and omeprazole are substrates isozymes CYP3A4, CYP2D6 and CYP2C19, respectively, and a 4-week course of sorafenib did not change the level of exposure of listed drugs. These observations testify that sorafenib not inhibit or induce isozymes of cytochrome P450 group. As a result of simultaneous application of sorafenib and paclitaxel there was an increase, rather than decrease the exposure of 6-OH paclitaxel, the active metabolite of paclitaxel, which is formed by CYP2C8. These data indicate that in vivo sorafenib can not be an inhibitor of CYP2C8.
The simultaneous use of cyclophosphamide and sorafenib resulted in a slight decrease in exposure cyclophosphamide, but it does not reduce systemic exposure observed 4-OH cyclophosphamide, which is an active metabolite of cyclophosphamide, which is formed mainly by CYP2B6. These data indicate that in vivo sorafenib can not be an inhibitor of CYP2B6.
Combination with other anticancer drugs: sorafenib no clinically significant effect on the pharmacokinetics of gemcitabine, cisplatin, oxaliplatin, and cyclophosphamide.
Paclitaxel / Carboplatin: simultaneous application of paclitaxel (225 mg / m 2) And carboplatin (AUC = 6) together with sorafenib (? 400 mg of 2 times / day), with 3-day intervals in receiving sorafenib before and after administration of paclitaxel and carboplatin, did not have any significant effect on the pharmacokinetics of paclitaxel.
The simultaneous use of paclitaxel (225 mg / m 2 1 every 3 weeks) and carboplatin (AUC = 6) with sorafenib (400 mg, 2 times / day without interruption in the use of Sorafenib) led to an increase in sorafenib exposure to 35% paclitaxel - 29% and 6-OH paclitaxel derivative - 50%. The pharmacokinetics of carboplatin remained unchanged.
These data show that there is no need to adjust the dosage when applying paclitaxel and carboplatin with sorafenib with a 3-day intervals in receiving sorafenib. Remains unknown clinical significance of a small increase in exposure sorafenib and paclitaxel, while the use sorafenib without interruption in its application.
Capecitabine: simultaneous application capecitabine (at 750-1050 mg / m 21 to 14 days after each 21 day) and sorafenib (200 or 400 mg of 2 times / day without interruption in reception) did not lead to significant changes in sorafenib exposure. However capecitabine exposure increased by 15-50%, and the exposure of 5-FU (a metabolite of capecitabine) increased by 0-52%. It remains unknown clinical significance of this small or moderate increase in exposure capecitabine and 5-FU while receiving sorafenib.
Doxorubicin / Irinotecan:co-administration of sorafenib and doxorubicin leads to an increase in AUC of doxorubicin by 21%. When concomitant administration of sorafenib and irinotecan active metabolite SN-38 which is further metabolized involving UGT1A1, showed an increase AUCSN-38 on 67-120% increase in AUC and irinotecan at 26-42%. It remains unknown clinical significance of these observations.
Docetaxel: simultaneous application of docetaxel (75 or 100 mg / m 2 once through each 21 day) and Nexavar preparation (200 mg or 400 mg of 2 times / day from the 2nd to 19-th day during the 21-day cycle) with 3 day intervals before and after administration of docetaxel is accompanied by an increase in AUC and Cmaxdocetaxel, respectively, 36-80% and 16-32%. When concomitant administration of sorafenib with docetaxel should be careful.
Neomycin: simultaneous application of neomycin, non-systemic antibiotic used for the eradication of gastrointestinal flora affects sorafenib enterohepatic circulation, leading to a decrease in sorafenib exposure. In healthy volunteers treated for 5 days neomycin the average bioavailability of sorafenib decreased to 54%. The clinical significance of these data is unknown. Effect of other antibiotics have not been studied, but will likely depend on the ability to reduce the activity of glucuronidase.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 25 В° C. Shelf life - 3 years.
