Cipla Soranib Sorafenib 200mg

[Drug Name] Nexavar

[Generic Name] Sorafenib Tosylate Tablets

[Composition] The active ingredient is sorafenib tosylate.

[Indications] 1. Treatment of unresectable advanced renal cell carcinoma. 2. Treatment of unresectable or metastatic hepatocellular carcinoma.

[Specification] 200 mg × 120 tablets

[Dosage and Administration] Recommended Dose: The recommended dose of sorafenib is 0.4 g (2 × 0.2 g) taken orally twice daily, either on an empty stomach or with a low-to-moderate fat meal. Method of Administration: Oral administration; swallow the tablets with a glass of warm water. Duration of Treatment: Treatment should be continued until the patient no longer derives clinical benefit or until intolerable toxicity occurs. Dose Adjustment and Special Instructions: Management of suspected adverse reactions may require temporary interruption or dose reduction of sorafenib. If necessary, the dose of sorafenib may be reduced to 0.4 g (2 × 0.2 g) once daily or once every other day. Adjustments for Cutaneous Toxicity: Grade 1 Cutaneous Adverse Reactions: Numbness, dysesthesia, paresthesia, tingling sensation, painless swelling, or erythema/discomfort of the hands and/or feet that does not interfere with daily activities. If these symptoms occur at any time, it is recommended to continue treatment with the product while providing topical therapy to alleviate symptoms. Grade 2 Cutaneous Adverse Reactions: Erythema and swelling of the hands and/or feet accompanied by pain, and/or discomfort that interferes with daily activities. Upon the first occurrence, continue treatment with the product while providing topical therapy to alleviate symptoms. If symptoms do not improve within 7 days, or upon the second or third occurrence, interrupt treatment with the product until toxicity resolves to Grade 0–1. When resuming treatment, reduce the dose to a single dose (0.4 g daily or 0.4 g every other day). Upon the fourth occurrence, treatment with the product should be permanently discontinued. Grade 3 Cutaneous Adverse Reactions: Moist desquamation, ulceration, blistering, severe pain, or severe discomfort of the hands and/or feet that renders the patient unable to work or perform normal daily activities. Upon the first or second occurrence, interrupt treatment with the product until toxicity resolves to Grade 0–1. When resuming treatment with this product, the dosage should be reduced to a single dose (0.4 g daily or 0.4 g every other day). If the adverse event recurs a third time, treatment with this product should be permanently discontinued. Pediatric Patients: Safety and efficacy data regarding the use of sorafenib in pediatric patients are not yet available. Elderly Patients (≥ 65 years): No dosage adjustment is required based on the patient's age (≥ 65 years), gender, or body weight. Patients with Hepatic Impairment: No dosage adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh A and B). Studies regarding the use of sorafenib in patients with severe hepatic impairment (Child-Pugh C) have not been conducted. Patients with Renal Impairment: No dosage adjustment is required for patients with mild to moderate renal impairment. Studies regarding the use of sorafenib in patients with severe renal impairment or those undergoing dialysis have not been conducted.

[Adverse Reactions] Safety Data from Pivotal Clinical Studies (Western Populations) Supporting Product Approval: Data were derived from 1,286 patients treated with sorafenib as monotherapy (predominantly Caucasian, including a minority of African, Asian, Hispanic, and other ethnic groups). The most common drug-related adverse events were diarrhea, rash, alopecia, and hand-foot syndrome. Laboratory Abnormalities: Elevations in lipase and amylase levels are commonly observed following the administration of sorafenib. In the studies, 12% of patients in the sorafenib group experienced Grade 3 or 4 lipase elevations (CTCAE criteria), compared to 7% in the placebo group. Grade 3 or 4 amylase elevations (CTCAE criteria) occurred in 1% of patients in the sorafenib group, compared to 3% in the placebo group. Among 451 patients treated with sorafenib, 2 cases of pancreatitis occurred (Grade 4 CTCAE); in the placebo group, 1 case occurred among 451 patients (Grade 2 CTCAE). Safety Data Results in Asian Populations: Study 11515 was a non-randomized, uncontrolled, open-label Phase II clinical study conducted in Japan evaluating sorafenib for the treatment of advanced renal cell carcinoma. Compared to the pivotal clinical studies conducted in Western populations, the drug-related adverse events reported in this study were similar; the most common events included lipase elevation, hand-foot syndrome, alopecia, amylase elevation, rash/desquamation, and diarrhea. Trial 11559 is an ongoing, multicenter, non-randomized Phase III clinical study conducted in Asia—including mainland China and Taiwan—evaluating sorafenib for the treatment of advanced renal cell carcinoma. To date, among the 29 patients who have received at least one dose of sorafenib, 21 patients (72.4%) experienced drug-related adverse events. Common adverse events included hand-foot skin reaction (27.6%), rash (20.7%), hypertension (6.9%), diarrhea (6.9%), and fatigue (6.9%). Throughout the trial, sorafenib demonstrated a favorable safety profile; the observed adverse events were predominantly mild and well-tolerated.

[Precautions] Adequate clinical study data specifically regarding the Chinese population are currently lacking; therefore, this product should be administered under the supervision of a physician experienced in its use. Skin Toxicity: Hand-foot skin reactions and rash are the most common adverse reactions associated with sorafenib administration. These skin reactions and rashes are typically Grade 1 or 2 according to the NCI-CTC (National Cancer Institute Common Toxicity Criteria) and generally manifest within the first 6 weeks of initiating sorafenib therapy. Management of skin toxicity reactions may involve topical medications to alleviate symptoms, temporary interruption of treatment, and/or dose adjustment of sorafenib. Patients experiencing severe or persistent skin toxicity may require permanent discontinuation of sorafenib. In severe cases, permanent discontinuation is required. Hypertension: The incidence of hypertension is increased in patients receiving sorafenib therapy. Drug-related hypertension is typically mild to moderate in severity, often manifesting during the early stages of treatment, and can be controlled with standard antihypertensive medications. Blood pressure should be monitored routinely, and treatment should be administered according to standard clinical guidelines as needed. For patients with severe or persistent hypertension despite antihypertensive therapy, or those who develop a hypertensive crisis, permanent discontinuation of sorafenib should be considered. Hemorrhage: Sorafenib therapy may increase the risk of bleeding. Severe bleeding events are uncommon. Should a bleeding event occur that requires medical intervention, permanent discontinuation of sorafenib is recommended. Warfarin: In some patients receiving concomitant therapy with sorafenib and warfarin, occasional bleeding events or an elevation in the International Normalized Ratio (INR) have been observed. For patients concomitantly receiving warfarin, prothrombin time and INR values should be monitored routinely, and patients should be observed for clinical signs of bleeding. Wound Healing Complications: Specific studies regarding the effect of sorafenib on wound healing have not been conducted. Temporary discontinuation of sorafenib is recommended in patients undergoing major surgical procedures. Clinical experience regarding the timing of re-initiation of sorafenib after surgery is limited; therefore, the decision to resume treatment should be based on clinical judgment, ensuring that adequate wound healing has occurred. Myocardial Ischemia and/or Myocardial Infarction: In Study 11213, the incidence of treatment-related myocardial ischemia/infarction was higher in the sorafenib group (2.9%) than in the placebo group (0.4%). Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. In patients who develop myocardial ischemia and/or myocardial infarction, temporary or permanent discontinuation of sorafenib therapy should be considered. Gastrointestinal Perforation: Gastrointestinal perforation is an uncommon event. Gastrointestinal perforation has been reported in less than 1% of patients receiving sorafenib. In some cases, these events were not associated with apparent intra-abdominal tumor involvement; treatment with this product should be discontinued. Hepatic Impairment: No data are available for patients with Child-Pugh Class C hepatic impairment. Since sorafenib is primarily eliminated via the liver, exposure to the drug may be increased in patients with severe hepatic impairment. Drug-Drug Interactions: UGT1A1 Pathway: Caution is advised when co-administering sorafenib with drugs metabolized via the UGT1A1 pathway (e.g., irinotecan). Docetaxel: When docetaxel (75 mg/m² or 100 mg/m²) was co-administered with this product (0.2 g or 0.4 g twice daily), with a 3-day interval between the administration of this product and docetaxel, the AUC of docetaxel increased by 36% to 80%. Caution is advised when co-administering this product with docetaxel (see

[Drug Interactions]). Effects on Ability to Drive and Use Machines: No studies on the effects of sorafenib on the ability to drive and use machines have been conducted to date. [Use in Pregnant and Lactating Women] Pregnancy: There are currently no adequate clinical data regarding the use of sorafenib in pregnant women. Animal studies have demonstrated reproductive toxicity, including teratogenicity. Sorafenib and its metabolites cross the placental barrier in rats; it is hypothesized that sorafenib may inhibit fetal angiogenesis. Women of childbearing potential should practice effective contraception during treatment. If sorafenib is used during pregnancy, the patient should be informed of the potential hazards to the fetus, including severe malformations, developmental impairment, and fetal death (embryotoxicity). Sorafenib should be avoided during pregnancy. It should be used in pregnant women only if the potential benefit of treatment outweighs the potential risk to the fetus. Based on the known multi-kinase inhibitory mechanism of sorafenib and the results of animal studies—in which various adverse effects occurred at exposure levels significantly lower than clinical doses—it is hypothesized that the use of sorafenib in pregnant women would be harmful to the fetus. Animal studies in women of childbearing potential have demonstrated that sorafenib possesses teratogenic and embryotoxic properties. Adequate contraceptive measures should be employed during treatment and for at least 2 weeks following the cessation of treatment. Lactation: It is currently unknown whether sorafenib is excreted in human milk. Animal studies have shown that sorafenib and/or its metabolites are excreted into milk. Since many drugs are excreted in milk, and the effects of sorafenib on nursing infants have not been studied, women should discontinue breastfeeding during treatment with this drug. Fertility: Results from animal studies indicate that sorafenib may impair male and female fertility.

[Pediatric Use] There are currently no data regarding the safety and efficacy of sorafenib in pediatric patients.

[Geriatric Use] No dose adjustment is required based on the patient's age (over 65 years).

[Drug Interactions] CYP3A4 Inducers: There are currently no clinical data regarding the effect of CYP3A4 inducers on the metabolism of sorafenib. CYP3A4 inducers (such as rifampin, *Hypericum perforatum* [commonly known as St. John's wort], phenytoin, carbamazepine, phenobarbital, and dexamethasone) may accelerate the metabolism of sorafenib, thereby reducing sorafenib concentrations. CYP3A4 Inhibitors: Ketoconazole is a potent inhibitor of CYP3A4. When healthy male volunteers received ketoconazole once daily for 7 consecutive days in combination with a single 50 mg dose of sorafenib, the mean plasma concentration of sorafenib remained unchanged. Therefore, a metabolic drug interaction between sorafenib and CYP3A4 inhibitors is unlikely. CYP2C9 Substrates: Warfarin is a substrate of CYP2C9; the effect of sorafenib on warfarin metabolism was evaluated by comparing patients receiving sorafenib with those receiving a placebo. Compared to the placebo group, the mean PT-INR values in patients receiving sorafenib in combination with warfarin remained unchanged. However, INR values should be monitored regularly when patients are co-administered warfarin. Selective Substrates of CYP Isoforms: With respect to these cytochrome P450 isoenzymes, sorafenib acts as neither an inhibitor nor an inducer. Interactions with Other Antineoplastic Agents: In clinical trials, sorafenib was administered in combination with other antineoplastic agents at standard doses, including gemcitabine, oxaliplatin, doxorubicin, and irinotecan. Sorafenib does not affect the metabolism of gemcitabine or oxaliplatin. When paclitaxel (225 mg/m²) and carboplatin (AUC = 6) are administered in combination with this product (0.1 g, 0.2 g, or 0.4 g twice daily), withholding this product for 3 days before and after the administration of paclitaxel/carboplatin does not result in a significant effect on the pharmacokinetics of paclitaxel or carboplatin. The co-administration of sorafenib and doxorubicin may result in a 21% increase in the mean AUC of doxorubicin in patients with hepatocellular carcinoma. When sorafenib is co-administered with irinotecan, the AUC of SN-38—the active metabolite of irinotecan (metabolized via the UGT1A1 enzyme)—increases by 67% to 120%, while the AUC of irinotecan increases by 26% to 42%. The clinical significance associated with this is currently unknown (see

[Precautions] When administered in combination with Docetaxel (75 mg/m² or 100 mg/m²; administered twice daily at a dose of 0.2 g or 0.4 g from Day 2 to Day 19 of a 21-day treatment cycle), and with a 3-day interval between the administration of this product and Docetaxel, the AUC of Docetaxel increased by 36–80%, and the Cmax increased by 16–32%. Caution is advised when administering this product in combination with Docetaxel.

[Overdosage] There are currently no specific treatment measures for Sorafenib overdose. The highest dose of Sorafenib administered was 0.8 g twice daily; the primary adverse reactions observed at this dose were diarrhea and dermatological toxicities. In the event of a suspected overdose, the drug should be discontinued, and the patient should be closely monitored and provided with appropriate supportive care.

[Pharmacology and Toxicology] Pharmacological Action: Sorafenib is a multi-kinase inhibitor that inhibits tumor cell proliferation *in vitro*. Sorafenib inhibits the proliferation of tumor cells, including murine renal cell carcinoma cells.

Product Specifications

Product Name: Nexavar (Sorafenib Tosylate Tablets) — 200 mg × 120 Tablets — Cipla Soranib (Sorafenib 200 mg)

Common Name: Nexavar

Composition: The active ingredient is Sorafenib Tosylate.

Dosage Form: Tablets

Specification: 200 mg × 120 tablets

Manufacturer: Cipla Ltd. (India)

Indications: 1. Treatment of advanced renal cell carcinoma that is not amenable to surgery. 2. Treatment of primary hepatocellular carcinoma that is not amenable to surgery or has metastasized distantly.

Dosage and Administration: Recommended Dosage: The recommended dosage of Sorafenib is 0.4 g (two 0.2 g tablets) taken twice daily, either on an empty stomach or with a low-to-moderate fat meal. Administration: For oral use; swallow the tablets with a glass of warm water. Duration of Treatment: Treatment should be continued until the patient no longer derives clinical benefit or until intolerable toxicity occurs. Dosage Adjustment and Special Instructions for Use: Management of suspected adverse reactions involves temporarily withholding or reducing the dosage of Sorafenib. If necessary, the dosage may be reduced to 0.4 g (two 0.2 g tablets) once daily or once every other day. Dosage adjustments should be made based on skin toxicity as follows: Grade 1 Skin Adverse Reactions: Symptoms such as dysesthesia, paresthesia, numbness, painless swelling, or erythema/discomfort of the hands and feet that does not interfere with daily activities—should these occur at any time—warrant a dosage adjustment consisting of continuing the use of this product while administering topical treatment to alleviate symptoms. Grade 2 Skin Adverse Reactions: Erythema and swelling of the hands and feet accompanied by pain, and/or discomfort of the hands and feet that interferes with daily living activities. Upon the first occurrence of such reactions, the dosage adjustment involves continuing the use of this product while administering topical treatment to alleviate symptoms. If symptoms do not improve within 7 days, or upon the second or third occurrence of such reactions, treatment with this product should be interrupted until the toxicity resolves. ...to Grade 0–1. When resuming treatment with this product, reduce the dosage to a single dose (0.4 g daily or 0.4 g every other day). If this reaction occurs a fourth time, treatment with this product should be permanently discontinued. Grade 3 Cutaneous Adverse Reactions: Moist desquamation, ulceration, blistering of the hands and feet, pain, or severe discomfort in the hands and feet that renders the patient unable to work or perform normal daily activities. Upon the first or second occurrence, treatment with this product should be interrupted until the toxicity resolves to Grade 0–1. When resuming treatment with this product, reduce the dosage to a single dose (0.4 g daily or 0.4 g every other day). If this reaction occurs a third time, treatment with this product should be permanently discontinued. Pediatric Patients: There are currently no data available regarding the safety and efficacy of sorafenib use in pediatric patients. Elderly Patients (Aged >65 years): No dosage adjustment is required based on the patient's age (over 65 years), gender, or body weight. Patients with Hepatic Impairment: No dosage adjustment is required for patients with mild to moderate hepatic impairment (Child-Pugh A and B). No studies have been conducted on the use of sorafenib in patients with severe hepatic impairment (Child-Pugh C). Patients with Renal Impairment: No dosage adjustment is required for patients with mild to moderate renal impairment. No studies have been conducted on the use of sorafenib in patients with severe renal impairment or those undergoing dialysis.