Nexavar^® (Tablets) Instructions for Use

Marketing Authorization Holder

Bayer, AG (Germany)

ATC Code

L01EX02 (Sorafenib)

Active Substance

Sorafenib (Rec.INN registered by WHO)

Dosage Form

Nexavar®

Film-coated tablets, 200 mg: 28, 56, or 112 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets red in color, round, biconvex, with the company logo embossed on one side of the tablet and “200” on the other side.

Excipients: tablet core: croscarmellose sodium, microcrystalline cellulose, hypromellose (5 cP), magnesium stearate, sodium lauryl sulfate; film coating: hypromellose (15 cP), macrogol 3350, titanium dioxide, iron oxide red (E172).

28 pcs. – blisters (1) – cardboard packs with first-opening control.
28 pcs. – blisters (2) – cardboard packs with first-opening control.
28 pcs. – blisters (4) – cardboard packs with first-opening control.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent, protein kinase inhibitor

Pharmacological Action

Antitumor agent. Sorafenib is a multikinase inhibitor. It reduces the proliferation of tumor cells in vitro.

Sorafenib has been shown to inhibit numerous intracellular kinases (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3 and PDGFR-β). It is believed that some of these kinases are involved in tumor cell signaling, angiogenesis, and apoptosis processes. Sorafenib inhibits tumor growth in human hepatocellular carcinoma and renal cell carcinoma.

Pharmacokinetics

After oral administration, the C_max of sorafenib in plasma is reached in approximately 3 hours. The relative bioavailability averages 38-49%. When taken with a moderate-fat meal, the bioavailability of sorafenib is approximately equivalent to that when taken on an empty stomach. When taken with a high-fat meal, bioavailability is reduced by approximately 29% compared to taking on an empty stomach. When administered orally at doses exceeding 400 mg twice daily, the mean C_max and AUC increase disproportionately.

When sorafenib is administered in repeated doses for 7 days, accumulation increases by 2.5-7 times compared to a single dose.

Steady-state plasma concentrations of sorafenib are reached within 7 days, and the C_max to C_min ratio is less than 2.

It is metabolized mainly in the liver by oxidation mediated by the CYP3A4 isoenzyme, as well as by glucuronidation mediated by UGT1A9.

Sorafenib conjugates are cleaved in the gastrointestinal tract due to bacterial glucuronidase activity, allowing for reabsorption of the unconjugated active substance. Concurrent use of neomycin affects this process, reducing the mean bioavailability of sorafenib to 54%.

At steady state, Sorafenib accounts for approximately 70-85%. Eight metabolites of sorafenib have been identified, five of which have been found in plasma. The main circulating plasma metabolite of sorafenib, pyridine N-oxide, has in vitro activity similar to that of sorafenib and accounts for approximately 9-16%.

After oral administration of sorafenib at a dose of 100 mg for 14 days, 96% of the administered dose is excreted, 77% is excreted in feces, and 19% in urine as glucuronides. 51% of unchanged sorafenib is found in feces.

The T_1/2 of sorafenib is approximately 25-48 hours.

Indications

Metastatic renal cell carcinoma.

Hepatocellular carcinoma.

ICD codes

Dosage Regimen

The recommended daily dose of sorafenib is 800 mg in 2 doses, either between meals or with food containing low or moderate amounts of fat.

Treatment is continued as long as clinical efficacy is maintained or until unacceptable toxicity occurs.

The development of adverse reactions may require temporary discontinuation and/or dose reduction of sorafenib. If necessary, the dose of sorafenib can be reduced to 400 mg once daily.

If skin toxicity develops, a dose reduction of sorafenib is required.

Adverse Reactions

From the hematopoietic system very common – lymphopenia; common – leukopenia, neutropenia, anemia, thrombocytopenia.

From the cardiovascular system very common – bleeding (including gastrointestinal bleeding, respiratory tract bleeding and cerebral hemorrhage), increased blood pressure; common – congestive heart failure, myocardial ischemia and/or myocardial infarction; uncommon – hypertensive crisis; rare – QT interval prolongation.

From the respiratory system common – hoarseness; uncommon – rhinorrhea, phenomena similar to interstitial lung diseases (pneumonitis, radiation pneumonitis, acute respiratory distress syndrome, interstitial pneumonia, pulmonitis, lung inflammation).

From the skin and skin appendages very common – skin rash, alopecia, palmar-plantar erythrodysesthesia, erythema, skin itching; common – exfoliative dermatitis, acne, dry skin, skin peeling; uncommon – folliculitis, eczema, erythema multiforme, keratoacanthoma/squamous cell carcinoma of the skin; frequency unknown – recurrent radiation dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the digestive system very common – diarrhea, nausea, vomiting; common – stomatitis, dry oral mucosa, glossodynia, dyspepsia, dysphagia, anorexia, constipation; uncommon – gastroesophageal reflux, gastritis, pancreatitis, gastrointestinal perforation, increased bilirubin levels (including jaundice), cholecystitis, cholangitis; frequency unknown – drug-induced hepatitis.

From the nervous system common – peripheral sensory neuropathy, depression; uncommon – reversible encephalopathic syndrome.

From the hearing organ common – ringing in the ears.

From the musculoskeletal system common – arthralgia, myalgia; frequency unknown – rhabdomyolysis.

From the urinary system common – renal failure.

From reproductive function common – erectile dysfunction; uncommon – gynecomastia.

From the endocrine system uncommon – hypothyroidism, hyperthyroidism.

From the immune system uncommon – hypersensitivity reactions (including skin reactions and urticaria); frequency unknown – angioedema, anaphylactic reactions.

Laboratory parameters very common – hypophosphatemia, increased levels of lipase and amylase; common – transient increase in transaminase activity (ALT, AST), hypocalcemia; uncommon – dehydration, hyponatremia, transient increase in alkaline phosphatase level, deviation from normal values of INR and prothrombin.

Other: very common – increased fatigue, pain syndrome of various localization (including mouth pain, abdominal pain, tumor pain, headache, limb pain); common – asthenia, flu-like syndrome, increased body temperature, weight loss; uncommon – infections.

Contraindications

Pregnancy, lactation (breastfeeding), childhood, hypersensitivity to sorafenib.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Pregnancy should be avoided during treatment with sorafenib. During and for at least 2 weeks after sorafenib therapy, reliable methods of contraception must be used.

Special Precautions

Treatment with sorafenib should be carried out under the supervision of a specialist experienced in the use of antitumor drugs.

Use with caution in skin diseases, arterial hypertension, increased bleeding tendency or history of bleeding, unstable angina, previous myocardial infarction, concurrently with irinotecan and docetaxel.

During sorafenib therapy, peripheral blood counts (including leukocyte count and platelets) should be monitored periodically.

The most common adverse reactions with sorafenib were skin reactions in the extremities (palmar-plantar erythrodysesthesia) and rash. In most cases, they were grade 1 and 2 and occurred mainly during the first 6 weeks of treatment. Topical agents with symptomatic action can be used to treat skin toxic reactions. If necessary, treatment is temporarily discontinued and/or sorafenib doses are modified or, in severe or recurrent cases of skin reactions, sorafenib therapy is discontinued.

An increased incidence of arterial hypertension was recorded in patients treated with sorafenib. Arterial hypertension was usually mild to moderate, observed at the beginning of treatment, and was manageable with standard antihypertensive drugs. During treatment with sorafenib, blood pressure should be regularly monitored and, if necessary, its increase should be corrected with antihypertensive therapy. In cases of severe or persistent arterial hypertension or the occurrence of hypertensive crises despite adequate antihypertensive therapy, discontinuation of sorafenib treatment should be considered.

Sorafenib may lead to an increased risk of bleeding. Severe bleeding occurs rarely. If any bleeding requiring medical intervention occurs, it is recommended to consider discontinuing sorafenib treatment. When warfarin and sorafenib were co-administered, rare episodes of bleeding or increased INR were observed in some patients. When warfarin and sorafenib are co-administered, regular determination of prothrombin time, INR, and clinical signs of bleeding is necessary.

In case of surgical interventions, temporary discontinuation of sorafenib therapy is recommended as a precaution. Clinical observations regarding resumption of sorafenib after surgical interventions are very limited. Therefore, the decision to resume sorafenib therapy after surgical interventions should be based on a clinical assessment of the adequacy of wound healing.

If myocardial ischemia and/or infarction occurs, sorafenib therapy should be temporarily or permanently discontinued.

Gastrointestinal perforation is uncommon and has been described in less than 1% of patients receiving Sorafenib. In some cases, these events were not associated with abdominal tumors. In case of gastrointestinal perforation, sorafenib treatment should be discontinued.

The use of sorafenib in patients with impaired liver function of Child-Pugh class C has not been studied. Since Sorafenib is mainly eliminated by the liver, an enhanced effect of the drug is possible in patients with severe liver dysfunction.

In patients at risk of renal impairment, water and electrolyte balance should be monitored. The use of sorafenib in patients on hemodialysis has not been studied.

Sorafenib should be used with caution concurrently with drugs that are metabolized/eliminated primarily via UGT1A1 (e.g., irinotecan).

Caution is required when sorafenib and docetaxel are used concomitantly.

Drug Interactions

Inducers of the CYP3A4 isoenzyme (including rifampicin, phenytoin, carbamazepine, phenobarbital, dexamethasone and preparations containing St. John’s wort extract) can enhance the metabolism of sorafenib and thus reduce its concentration in the body. Long-term concurrent administration of sorafenib with rifampicin led to an average decrease in the AUC of sorafenib by 37%.

Clinically significant pharmacokinetic interaction of sorafenib with CYP3A4 inhibitors is unlikely.

Concomitant administration of sorafenib and warfarin did not lead to changes in mean prothrombin time and INR values compared to placebo. However, regular determination of INR is recommended for all patients receiving combination therapy with warfarin and sorafenib.

As a result of the simultaneous use of sorafenib and paclitaxel, an increase, rather than a decrease, in the exposure of 6-OH-paclitaxel, an active metabolite of paclitaxel formed by CYP2C8, was observed. These data indicate that Sorafenib in vivo may not be an inhibitor of CYP2C8.

Concomitant use of sorafenib and cyclophosphamide led to a slight decrease in the exposure of cyclophosphamide, but no decrease in the systemic exposure of 4-OH-cyclophosphamide, which is an active metabolite of cyclophosphamide formed mainly by CYP2B6, was observed. These data indicate that Sorafenib in vivo may not be an inhibitor of CYP2B6.

Concomitant use of paclitaxel (225 mg/m² once every 3 weeks) and carboplatin (AUC=6) with sorafenib (400 mg twice daily without interruption of sorafenib use) led to an increase in sorafenib exposure by 35%, paclitaxel by 29% and 6-OH paclitaxel derivative by 50%. The pharmacokinetics of carboplatin remained unchanged. The clinical significance of these changes is unknown.

Concomitant use of capecitabine (750-1050 mg/m² from day 1 to 14 every 21 days) and sorafenib (200 or 400 mg twice daily without interruption) did not lead to significant changes in sorafenib exposure. However, capecitabine exposure increased by 15-50%, and 5-fluorouracil (a metabolite of capecitabine) exposure increased by 0-52%. The clinical significance of these changes is unknown.

Concomitant use of sorafenib and doxorubicin leads to a 21% increase in the AUC of doxorubicin. When sorafenib and irinotecan were co-administered, whose active metabolite SN-38 is further metabolized by UGT1A1, an increase in the AUC of SN-38 by 67-120% and an increase in the AUC of irinotecan by 26-42% were observed. The clinical significance of these observations is unknown.

Concomitant use of docetaxel (75 or 100 mg/m² once every 21 days) and sorafenib (200 or 400 mg twice daily from day 2 to day 19 during a 21-day cycle) with 3-day intervals before and after docetaxel administration is accompanied by an increase in the AUC and C_max of docetaxel by 36-80% and 16-32%, respectively. Caution is required with this combination.

Concomitant use of neomycin, a non-systemic antibacterial drug used for eradication of gastrointestinal flora, affects the enterohepatic circulation of sorafenib, leading to a decrease in sorafenib exposure. In healthy volunteers who received neomycin for 5 days, the mean bioavailability of sorafenib decreased to 54%. The clinical significance of these data is unknown. The effect of other antibiotics has not been studied but will likely depend on the ability to reduce glucuronidase activity.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.