natco Sorafenib Sorafenat

Product Name: Sorafenib Tosylate Tablets (Nexavar)

[Storage] Store in a tightly closed container at a temperature below 25°C.

[Packaging] 0.2 g × 120 tablets per box.

Full Pinyin Code: JiaBenHuangSuanSuoLaFeiNiPian (DuoJiMei)

[Active Ingredient] Chemical Name: 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide 4-methylbenzenesulfonate. Molecular Formula: C21H16ClF3N4O3 • C7H8O3S. Molecular Weight: 637.0.

[Indications/Therapeutic Uses] 1. Treatment of unresectable advanced renal cell carcinoma. 2. Treatment of unresectable or metastatic primary hepatocellular carcinoma. Currently, there is a lack of data from randomized controlled clinical trials comparing Sorafenib with interventional therapies—such as Transarterial Chemoembolization (TACE)—in patients with advanced hepatocellular carcinoma. Therefore, the relative merits of this product compared to interventional therapies have not yet been established, nor is it clear whether the use of Sorafenib is beneficial for patients who have previously undergone interventional therapy.

[Dosage and Administration] Oral administration; swallow whole with a glass of warm water. Recommended Dosage: The recommended dose 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. [Adverse Reactions] The following data are primarily derived from safety data obtained during clinical trials of this product in patients with advanced hepatocellular carcinoma and advanced renal cell carcinoma, including data from Western and Asian countries (see

[Contraindications] This product is contraindicated in patients with severe hypersensitivity to sorafenib or to any of the excipients (inactive ingredients) of the drug.

[Precautions] This product must be administered under the supervision of a physician experienced in its use. Currently, there is a lack of data from randomized controlled clinical trials comparing sorafenib with interventional therapies—such as TACE—in patients with advanced hepatocellular carcinoma; therefore, the relative benefit of this product compared to interventional therapies has not yet been established, nor is it clear whether the use of sorafenib is beneficial in patients who have previously undergone interventional therapy (see [section]). Please read the package insert carefully and use as directed by a physician.

[Pediatric Use] Data regarding the safety and efficacy of sorafenib in pediatric patients are not yet available.

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

[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 use 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 (teratogenicity), developmental abnormalities, and fetal death (embryotoxicity). The use of sorafenib during pregnancy should be avoided. It should be used in pregnant women only if the potential benefit of treatment outweighs the potential risk to the fetus (see

[Drug Interactions] Docetaxel: Results from previous studies indicate that when docetaxel (75 mg/m² or 100 mg/m²) is administered in combination with sorafenib (0.2 g or 0.4 g administered twice daily)—with sorafenib being withheld for three days during docetaxel administration—the AUC of docetaxel may increase by 36% to 80%. Therefore, caution is advised when administering this product in combination with docetaxel (see

[Overdosage] There are no specific therapeutic measures for sorafenib overdose. The maximum dose of sorafenib administered to date is 0.8 g twice daily; the primary adverse reactions observed at this dose were diarrhea and dermatologic toxicities. In the event of a suspected overdose, the drug should be discontinued, and appropriate supportive care should be administered to the patient.

[Pharmacology and Toxicology] Pharmacological Action: Sorafenib is a multi-kinase inhibitor that inhibits tumor cell proliferation *in vitro*. Sorafenib inhibits tumor cell proliferation—including in the murine renal cell carcinoma (RENCA) model and various human tumor xenograft models in athymic mice—and inhibits tumor angiogenesis. Toxicology Studies: The preclinical safety of sorafenib was evaluated in mice, rats, dogs, and rabbits. Repeated-dose toxicity studies revealed mild to moderate changes (degeneration and regeneration) in various organs. In juvenile and growing dogs, effects on bone and teeth were observed following repeated dosing; these effects included irregular thickening of the femoral epiphyseal plate (at sorafenib doses of 600 mg/m² body surface area—equivalent to 1.2 times the clinically recommended dose of 500 mg/m² body surface area), hypocellularity of the bone marrow adjacent to the growth plate (at 200 mg/m²/day), and alterations in dentin composition (at 600 mg/m²/day). Similar findings were not observed in adult dogs. Mutagenicity: *In vitro* chromosomal aberration assays were conducted using mammalian cells (Chinese Hamster Ovary); sorafenib demonstrated genotoxicity in the presence of metabolic activation. *In vitro* cytogenetic assays (Ames tests) performed on a specific intermediate generated during the manufacturing process yielded positive results; consequently, the limit for this intermediate in the final drug product is controlled to be below 0.15%. However, Ames tests and *in vivo* mouse micronucleus assays indicated that sorafenib itself is not genotoxic (at a concentration of 0.34% for this intermediate in the test article). Carcinogenicity: Carcinogenicity studies for sorafenib have not been conducted. Reproductive Toxicity: Specific animal fertility studies have not been conducted. However, changes in reproductive organs were observed in animals during repeated-dose toxicity studies; therefore, impairment of both male and female fertility is anticipated. Typical changes included degeneration and arrested development of the testes, epididymides, prostate, and seminal vesicles in rats. These effects were pronounced at a daily sorafenib dose of 150 mg/m² body surface area (equivalent to 0.3 times the clinically recommended dose of 500 mg/m²). At a dose of 30 mg/m²/day, central necrosis of the corpora lutea and arrested follicular development were observed in the ovaries of female rats. In test dogs, degeneration of the seminiferous tubules occurred at a dose of 600 mg/m²/day, and decreased sperm count was observed at a dose of 1200 mg/m²/day. Sorafenib administration in rats and rabbits resulted in embryotoxicity and teratogenicity, including reduced maternal and fetal body weights, increased incidence of abortions, and an increased frequency of external and visceral malformations. Adverse fetal effects were observed in rats and rabbits at oral doses of 6 mg/m²/day and 36 mg/m²/day, respectively.

[Pharmacokinetics] Compared to an oral solution, the mean relative bioavailability of sorafenib tablets is approximately 38% to 49%. The elimination half-life of sorafenib is approximately 25 to 48 hours. Compared to a single dose, repeated administration over 7 days results in an accumulation factor of 2.5 to 7 times. After 7 days of administration, sorafenib plasma concentrations reached steady state, with an average peak-to-trough ratio of less than 2. Absorption and Distribution: Peak plasma concentrations of sorafenib are reached approximately 3 hours after oral administration. Bioavailability is similar under conditions of a moderate-fat diet versus a fasted state. When administered with a high-fat diet, the bioavailability of sorafenib is reduced by 29% compared to the fasted state. When oral doses exceed 0.4 g administered twice daily, the increases in mean Cmax and AUC are not proportional to the dose. *In vitro*, sorafenib is 99.5% bound to human plasma proteins. Metabolism and Elimination: Sorafenib is primarily metabolized in the liver via CYP3A4-mediated oxidation, as well as via UGT1A9-mediated glucuronidation. At steady state, sorafenib accounts for approximately 70% to 85% of the total circulating analytes in plasma. There are 8 known metabolites of sorafenib, 5 of which have been detected in plasma. The major circulating metabolite of sorafenib in plasma is the pyridine N-oxide. *In vitro* studies indicate that this metabolite possesses potency similar to that of sorafenib and accounts for approximately 9% to 16% of the circulating analytes in steady-state plasma. Following a single oral dose of 100 mg sorafenib (solution formulation), 96% of the administered dose was eliminated within 14 days; of this, 77% was excreted via feces, and 19% was excreted via urine, primarily in the form of glucuronidated metabolites. Fifty-one percent of the administered dose was excreted in feces as unchanged drug, while no unchanged drug was detected in urine. *In vitro* Enzyme Inhibition Studies: Studies using human liver microsomes demonstrated that sorafenib competitively inhibits CYP2C19, CYP2D6, and CYP3A4. Sorafenib may increase the plasma concentrations of certain co-administered drugs that are substrates of these enzymes. Sorafenib inhibits glucuronidation via the UGT1A1 and UGT1A9 pathways. When these drugs are co-administered with sorafenib, the exposure concentrations of substrates metabolized by UGT1A1 and UGT1A9 may increase. *In vitro* studies demonstrate that sorafenib inhibits CYP2B6 and CYP2C8, with Ki values of 6 µM and 1–2 µM, respectively. When co-administered with sorafenib, the systemic exposure to CYP2B6 and CYP2C8 substrates increases. CYP2C9 Substrates: Studies using human liver microsomes indicate that sorafenib competitively inhibits CYP2C9, with a Ki value of 7–8 µM. The potential effect of sorafenib on CYP2C9 substrates was evaluated in patients (sorafenib group vs. placebo group) receiving concomitant warfarin; the mean change in PT-INR from baseline in the sorafenib group was not greater than that in the placebo group. These results suggest that sorafenib is not an *in vivo* inhibitor of CYP2C9. CYP3A4 Inhibitors Ketoconazole is a strong inhibitor of CYP3A4 (in studies involving healthy male volunteers

[See section: Clinical Trials]). Physicians are advised to consider the patient's specific circumstances comprehensively when selecting appropriate treatment modalities.

[See section: Clinical Trials].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial cannot be directly compared to rates in other clinical trials, nor do they reflect the rates observed in actual clinical practice.

Safety data from pivotal clinical studies conducted in Western regions that supported the approval of this product:

The most common adverse reactions include diarrhea, rash, alopecia, and hand-foot skin reactions (corresponding to "Hand-foot syndrome" in the Medical Dictionary for Regulatory Activities [MedDRA]).

[See section: Clinical Trials]. Physicians are advised to consider the patient's specific circumstances comprehensively when selecting appropriate treatment modalities.

Pregnancy: Women of childbearing potential should practice effective contraception during treatment. Women of childbearing potential should be informed of the potential hazards of the drug to the fetus, including severe malformations (teratogenicity), developmental abnormalities, and fetal death (embryotoxicity). The use of sorafenib should be avoided during pregnancy. Sorafenib should be used in pregnant women only if the potential benefit to the mother outweighs the potential risk to the fetus.

Animal studies have demonstrated that sorafenib is teratogenic and embryofetotoxic (including an increased risk of miscarriage and developmental abnormalities), and these adverse effects occurred at doses significantly lower than the clinical dose. Based on the mechanism of action of sorafenib—which involves the inhibition of multiple kinases—and the results of animal studies, it is presumed that the use of sorafenib by pregnant women would cause harm to the fetus.

Women who are breastfeeding should discontinue nursing during treatment with sorafenib.

Cutaneous Toxicity: Hand-foot skin reactions and rash are the most common adverse reactions associated with sorafenib use. Rash and hand-foot skin reactions are typically classified according to the NCI CTCAE Grade 1 to 2, and typically occurring within 6 weeks of initiating sorafenib therapy. Management of dermatologic toxicities involves topical medications to alleviate symptoms, temporary interruption of treatment, and/or dose adjustment of sorafenib. For patients experiencing severe or persistent dermatologic toxicities, discontinuation of sorafenib may be required.

Hypertension: An increased incidence of hypertension has been observed in patients treated with sorafenib. Hypertension is typically mild to moderate in severity and generally manifests during the early stages of treatment; it can be controlled with standard antihypertensive medications. Blood pressure should be monitored regularly and treated according to standard medical practice as needed. For patients with severe or persistent hypertension despite antihypertensive therapy, or those experiencing a hypertensive crisis, discontinuation of sorafenib should be considered.

Hemorrhage: Treatment with sorafenib may increase the risk of bleeding. Severe bleeding events are uncommon. If bleeding occurs and requires medical intervention, discontinuation of sorafenib should be considered.

Warfarin: In some patients receiving concomitant therapy with sorafenib and warfarin, occasional bleeding events or elevations in INR have been reported. Patients receiving concomitant warfarin therapy should undergo regular monitoring of prothrombin time and INR values, and be observed for clinical signs of bleeding.

Wound Healing Complications: Formal studies evaluating the effect of sorafenib on wound healing have not been conducted. It is recommended that sorafenib be temporarily discontinued in patients undergoing major surgical procedures. Clinical experience regarding the timing of sorafenib re-initiation following surgery is limited; therefore, the decision to resume therapy should be based on clinical judgment, ensuring that adequate wound healing has occurred.

Myocardial Ischemia and/or Myocardial Infarction: In Study 11213, treatment-related myocardial ischemia/infarction occurred in the sorafenib group... ...the incidence rate (2.9%) was higher than that in the placebo group (0.4%). In Trial 100554, the incidence of treatment-related myocardial ischemia/myocardial infarction was 2.7% in the sorafenib group and 1.7% in the placebo group. Patients with unstable coronary artery disease or recent myocardial infarction were not enrolled in these two trials. For patients who develop myocardial ischemia and/or myocardial infarction, temporary interruption or permanent discontinuation of sorafenib therapy should be considered.

Gastrointestinal Perforation: Gastrointestinal perforation is uncommon. Gastrointestinal perforation was reported in less than 1% of patients receiving sorafenib. In some cases, the gastrointestinal perforation was unrelated to intra-abdominal tumors. Treatment with this product should be discontinued (see [Clinical Trials]).

Renal Cell Carcinoma:

The safety and efficacy of sorafenib for the treatment of advanced renal cell carcinoma were investigated in the following four clinical trials:

Trial 11213 was a Phase III, international, multicenter, randomized, double-blind, placebo-controlled study involving 903 patients with unresectable or metastatic renal cell carcinoma who had received at least one prior systemic therapy (chemotherapy or immunotherapy). The primary endpoints were Overall Survival (OS) and Progression-Free Survival (PFS); the secondary endpoint was the Tumor Response Rate (RR). Patients were randomized into two groups: an investigational group receiving sorafenib 0.4 g twice daily (N=451), and a control group receiving placebo (N=452). Baseline demographic characteristics were balanced between the two groups. Approximately half of the patients had an ECOG* performance status of 0, while the other half belonged to the MSKCC** favorable-risk group (* ECOG: Eastern Cooperative Oncology Group; ** MSKCC: Memorial Sloan Kettering Cancer Center).

Radiologically visible vascular invasion and/or extrahepatic spread

The final analysis demonstrated that sorafenib conferred a statistically significant advantage over placebo in terms of overall survival (OS) (HR = 0.69; P = 0.00058; see Table 18 and Figure 4). Across the prespecified stratification factors (ECOG performance status, presence or absence of radiologically visible vascular invasion and/or extrahepatic tumor spread, and geographic region), the hazard ratios favored sorafenib over placebo. The time to tumor progression (TTP) was longer in the sorafenib group compared to the placebo group (HR = 0.58; P = 0.000007; see Table 18 and Figure 5). Results from subgroup analyses regarding overall survival are presented as follows: for patients positive for Hepatitis B virus (based on laboratory results), see Table 19 and Figure 6; for patients positive for Hepatitis C virus (based on laboratory results), see Table 20; and for patients with a history of TACE treatment, see Table 21. Table 18: Efficacy Results for Study 100554

Efficacy Parameter | Sorafenib

(N=299) | Placebo

(N=303) | P-value | HR

(95% CI)

Overall Survival (OS) [Median, days

(95% CI)]

324

(286, 405) | 241

(206, 276) | 0.00058* | 0.69

(0.55, 0.87)

Time to Tumor Progression (TTP)** [Median, days

(95% CI)] | 168

(126, 210) | 86

(82, 120) | 0.000007 | 0.58

(0.45, 0.74)

CI: Confidence Interval; HR: Hazard Ratio

*For a comparison to be considered statistically significant, the p-value must be <0.0077 (O’Brien-Fleming stopping boundary).

**Radiological progression as determined by RECIST criteria.

Figure 4: Kaplan-Meier Curves for Overall Survival (OS) in Study 100554 (Intent-to-Treat Population)

Figure 5: Kaplan-Meier Curves for Time to Tumor Progression (TTP) in Study 100554 (Intent-to-Treat Population)

Table 19: Overall Survival* in Hepatitis B Virus-Positive Patients in Study 100554

Sorafenib Group (N=40) | Placebo Group (N=31)

Median Overall Survival (days) | 359 | 186

Hazard Ratio (HR)

(95% CI) | 0.67

(0.35, 1.31)

*Interpretation of subgroup analysis results should be undertaken with caution due to limited sample size. Figure 6: Survival Curves for Hepatitis B Virus-Positive Patients in Study 100554

Table 20: Overall Survival* for Hepatitis C Virus-Positive Patients in Study 100554

Sorafenib Group (N = 93) | Placebo Group (N = 84)

Median Overall Survival (days) | 426 | 241

Hazard Ratio (HR)

(95% C.I.) | 0.50

(0.33, 0.78)

*Interpretation of subgroup analysis results should be undertaken with caution due to limited sample size.

Table 21: Overall Survival for Patients with Prior TACE Treatment in Study 100554

Sorafenib Group (N = 86) | Placebo Group (N = 90)

Median Overall Survival (days) | 362 | 302

Hazard Ratio (HR)

(95% C.I.) | 0.75

(0.49, 1.14)

*Interpretation of subgroup analysis results should be undertaken with caution due to limited sample size and baseline imbalances.

Product Specifications

Product Name: Sorafenib Tosylate Tablets (Nexavar) 120 Tablets | Natco Sorafenib (Sorafenat)

Common Name: Nexavar

Composition: Sorafenib Tosylate Tablets 200 mg

Dosage Form: Tablets

Specification: 0.2 g × 120 tablets

Manufacturer: Natco Pharma Ltd

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. Currently, there is a lack of randomized controlled clinical study data comparing Sorafenib with interventional therapies—such as Transarterial Chemoembolization (TACE)—in patients with advanced hepatocellular carcinoma; therefore, the relative superiority or inferiority of this product compared to interventional therapies has not yet been established, nor has it been established whether the use of Sorafenib is beneficial for patients who have previously undergone interventional therapy.

Dosage and Administration:For oral administration; swallow with a glass of warm water. Recommended Dosage: The recommended dosage of Sorafenib is 0.4 g (2 × 0.2 g) taken twice daily, either on an empty stomach or with a low-to-moderate fat meal.