Sorafenat(甲苯磺酸索拉非尼片)

【Function and indication】Treatment of inoperable advanced renal cell carcinoma.
Treatment of inoperable or distantly metastatic hepatocellular carcinoma.
There is currently a lack of randomized controlled clinical research data comparing sorafenib with interventional treatments such as transcatheter arterial chemoembolization (TACE) in patients with advanced hepatocellular carcinoma. Therefore, it is not clear whether Nexavar is superior to interventional treatment, nor is it clear whether Sorafenib is beneficial for patients who have previously received interventional treatment. It is recommended that doctors consider the specific situation of the patient and choose the appropriate treatment method.

【Model and specification】200mg*120 tablets/box

【Usage and dosage】Nexavar (sorafenib) is a red, film-coated tablet with a specification of 200mg per tablet. The recommended dose of sorafenib for the treatment of renal cell carcinoma is 400mg, twice a day, and it should not be taken with food (it is advisable to take the medicine 1 hour before or 2 hours after eating). Pharmaceutical manufacturers recommend that the drug can be used for a long time unless the efficacy of sorafenib is reduced or the patient cannot tolerate its toxicity. If the patient has adverse drug reactions, the dose of sorafenib can be reduced to 400 mg, once a day or once every other day.

[Clinical Research] Trial 100391 is a randomized, discontinuous Phase II clinical study of patients with metastatic malignant tumors, including patients with renal cell carcinoma (RCC). The primary endpoint of the trial is the proportion of patients without tumor progression at 24 weeks after randomization (N=65).
The results of the trial showed that the pFS (163 days) of the sorafenib group was significantly higher than that of the placebo group (41 days), and the difference was statistically significant (p=0.0001, HR=0.29), and the proportion of no tumor progression in the sorafenib group (50%) was significantly higher than that in the placebo group (18%).
Trial 11515 is a non-randomized, non-controlled, open Phase II clinical study of sorafenib for the treatment of advanced renal cancer conducted in Japan. The main purpose is to observe the safety, efficacy and pharmacokinetic characteristics of sorafenib 0.4g, twice daily.
Results: 16 patients in the trial were “partially responded” (pR) with a response rate of 12.4%; the researchers evaluated 19 patients as “partially responded” (pR), with a response rate of 14.7%. Based on the researchers’ evaluation, the median progression-free survival (pFS) was 224 days.

[Precautions] Nexavar must be taken under the guidance of a physician with experience in its use.
There is currently a lack of randomized controlled clinical research data comparing sorafenib with interventional treatments such as TACE in patients with advanced hepatocellular carcinoma. Therefore, it is not clear whether Nexavar has advantages over interventional treatments, nor is it clear whether sorafenib is beneficial for patients who have previously received interventional treatments. It is recommended that doctors consider the specific circumstances of the patient and choose appropriate treatment methods.
Pregnancy: Women of childbearing age should pay attention to contraception during treatment. Women of childbearing age should be informed of the possible harm of drugs to the fetus, including severe malformations (teratogenicity), developmental disorders and fetal death (embryotoxicity). Sorafenib should be avoided during pregnancy. It can only be used in pregnant women when the benefits of treatment outweigh the possible harm to the fetus.
In animal experiments, sorafenib has been found to be teratogenic and embryo-fetal toxic (including increased risk of miscarriage and developmental disorders), and these harmful effects occur at doses significantly lower than clinical doses. Based on the mechanism of sorafenib’s inhibition of multiple kinases and the results of animal experiments, it is speculated that pregnant women taking sorafenib will harm the fetus.
Lactating women should stop breastfeeding during sorafenib treatment.
Skin toxicity: Hand-foot skin reaction and rash are common adverse reactions to sorafenib. Rash and hand-foot skin reaction are usually NCI CTCAE 1-2 grades, and most of them occur within 6 weeks after starting sorafenib. Treatment of skin toxicity includes topical medication to relieve symptoms, temporary discontinuation of medication, and/or dose adjustment of sorafenib. For patients with severe skin toxicity or persistent reactions, sorafenib needs to be permanently discontinued.
Hypertension: The incidence of hypertension in patients taking sorafenib increases. Drug-related hypertension is mostly mild to moderate, and often occurs in the early stages after starting medication, and can be controlled with conventional antihypertensive drugs. Blood pressure should be monitored routinely, and treatment should be carried out according to standard treatment plans if necessary. Patients with severe or persistent hypertension or hypertensive crisis after taking antihypertensive drugs should consider permanent discontinuation of sorafenib.
Bleeding: Sorafenib treatment may increase the chance of bleeding. Severe bleeding is uncommon. Once bleeding requires treatment, it is recommended to consider permanent discontinuation of sorafenib.
Warfarin: Some patients who take sorafenib and warfarin at the same time occasionally bleed or have elevated INR. Patients who take warfarin should regularly monitor changes in prothrombin time, INR values, and pay attention to clinical signs of bleeding.
Wound healing complications: There is no special study on the effect of sorafenib on wound healing. Patients who need major surgery are advised to suspend sorafenib. There is limited clinical experience on when patients should use sorafenib again after surgery, so clinical considerations should be made before deciding whether to take it again to ensure wound healing.
Myocardial ischemia and/or myocardial infarction: In trial 11213, the incidence of treatment-related myocardial ischemia/myocardial infarction was higher in the sorafenib group (2.9%) than 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 and recent myocardial infarction were not included in either trial. Temporary or permanent discontinuation of sorafenib treatment should be considered in patients who develop myocardial ischemia and/or myocardial infarction.
Gastrointestinal perforation: Gastrointestinal perforation is uncommon. Gastrointestinal perforation has been reported in less than 1% of patients taking sorafenib. In some cases, gastrointestinal perforation was not associated with intra-abdominal tumors. Nexavar treatment should be discontinued.
Hepatic impairment: There are no data on the use of sorafenib in patients with severe hepatic impairment (Child-Pugh class C). Since sorafenib is mainly eliminated by the liver, its exposure will be increased in patients with severe liver impairment.
Drug-drug interactions:
UGT1A1 pathway: It is recommended to be cautious when sorafenib is used in combination with drugs that are metabolized/eliminated through the UGT1A1 pathway (such as irinotecan).
Docetaxel: Previous study results showed that the co-administration of docetaxel (75 mg/m2 or 100 mg/m2) and sorafenib (0.2 g or 0.4 g, twice daily) (sorafenib was stopped for 3 days during docetaxel administration) can lead to a 36-80% increase in the AUC of docetaxel. It is recommended to be cautious when Nexavar is used in combination with docetaxel.
Effects on driving and machine operation: There are currently no studies on the effects of sorafenib on driving and machine operation. There is no evidence that sorafenib affects the ability to drive and operate machines.

[Adverse Reactions and Contraindications] Safety data from key clinical studies in Europe and the United States that support the marketing of Nexavar: Common adverse reactions include diarrhea, rash, alopecia and hand-foot skin reactions (corresponding to hand-foot dysesthesia syndrome in the International Medical Terminology Dictionary (MedDRA)).
The following lists drug-related adverse events reported in multiple clinical trials according to different system organs (MedDRA) and frequency of occurrence (in accordance with the guidelines of the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMp) on drug instructions). The incidence is defined as: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100).
In each incidence group, adverse reactions are arranged in descending order of severity.
Infection and infection: uncommon folliculitis and infection.
Abnormalities of the blood and lymphatic system: very common lymphocytopenia, common leukopenia, neutropenia, anemia, thrombocytopenia.
Immune system abnormalities: uncommon hypersensitivity reactions (including skin reactions and urticaria). Endocrine abnormalities: Hypothyroidism is uncommon.
Nutritional metabolic abnormalities: Hypophosphatemia is uncommon, anorexia is common, hyponatremia and dehydration are uncommon.
Psychiatric symptoms: Depression is common.
Nervous system abnormalities: Peripheral sensory neuropathy is common, reversible posterior leukoencephalopathy is uncommon*.
Ears and labyrinth: Tinnitus is common.
Heart: Myocardial ischemia and myocardial infarction*, congestive heart failure* are uncommon.
Vascular abnormalities: Bleeding (including gastrointestinal bleeding*, respiratory bleeding* and cerebral hemorrhage*), hypertension are very common, and hypertensive crisis* is uncommon.
Respiratory, thoracic and mediastinal: Hoarseness is common, and rhinorrhea is uncommon.
Gastrointestinal system abnormalities: Diarrhea, nausea, and vomiting are very common, constipation, stomatitis (including dry mouth and glossal pain), dyspepsia, and dysphagia are common, and gastroesophageal reflux, pancreatitis, gastritis, and gastrointestinal perforation* are uncommon.
Hepatobiliary system abnormalities: Elevated bilirubin and jaundice are uncommon.
Skin and subcutaneous tissue disorders: very common rash, alopecia, hand-foot skin reaction (included in MedDRA as “hand-foot dysesthesia syndrome”), pruritus, erythema, common dry skin, exfoliative dermatitis, acne, desquamation, uncommon eczema, multiforme erythema, keratoacanthoma/squamous cell carcinoma of the skin.
Skeletal muscles, connective tissue and bone: common arthralgia and myalgia.
Reproductive system and breast: common erectile dysfunction, uncommon male breast development.
General condition: very common fatigue, pain (including mouth pain, abdominal pain, bone pain, headache and cancer pain), common weakness, fever, influenza symptoms.
Laboratory tests: very common elevated amylase and lipase, common weight loss, transient transient elevation of transaminases, uncommon transient elevation of alkaline phosphatase, abnormal international normalized ratio (INR) of clotting time, abnormal prothrombin.
* Events that may endanger the patient’s life or cause the patient’s death. Such events are uncommon.
In a phase II clinical study involving 638 patients treated with sorafenib (including 202 patients with renal cell carcinoma, 137 patients with hepatocellular carcinoma, and 299 patients with other cancers), common drug-related adverse events were rash (38%), diarrhea (37%), hand-foot skin reaction (35%), and fatigue (33%). In patients treated with sorafenib, the incidence of CTCAE (version 2.0) grade 3 and 4 drug-related adverse events was 37% and 3%, respectively.

[Contraindications] Patients with severe allergic symptoms to sorafenib or the inactive ingredients of the drug are contraindicated.

[Pregnant women use] Pregnancy: There is no sufficient clinical data on the use of sorafenib by pregnant women. Animal experiments have shown that the drug has reproductive toxicity, including teratogenicity. Sorafenib and its metabolites can pass through the placental barrier of rats, and it is speculated that sorafenib can inhibit fetal angiogenesis.
Women of childbearing age should pay attention to contraception during treatment. If sorafenib is used during pregnancy, patients should be informed of the possible harm of the drug to the fetus, including severe malformations (teratogenicity), developmental disorders and fetal death (embryotoxicity). It should only be used in pregnant women when the benefits of treatment outweigh the possible harm to the fetus.
Women of childbearing age: Animal studies have shown that sorafenib is teratogenic and embryotoxic. Adequate contraceptive measures should be taken during treatment and for at least 2 weeks after the end of treatment.
Lactation: It is not yet known whether sorafenib is secreted through human breast milk. Animal studies have shown that sorafenib and/or its metabolites can be secreted into breast milk. Since many drugs are secreted from breast milk and the effects of sorafenib on infants are still under study, women should stop breastfeeding during treatment with this drug.
Reproductive capacity: Animal test results show that sorafenib impairs the reproductive capacity of men and women.

[Pediatric Use] There is no safety and efficacy data on the use of sorafenib in pediatric patients.

[Drug Interactions] CYp 3A4 Inducers:
Continuous co-administration of rifampicin and sorafenib can lead to an average 37% reduction in the AUC of sorafenib. Other CYp3A4 inducers such as Hypericum perforatum (or Hypericum perforatum, commonly known as St. John’s wort), phenytoin, carbamazepine, phenobarbital and dexamethasone may accelerate the metabolism of sorafenib, thereby reducing the drug concentration of sorafenib.
CYp 3A4 Inhibitors:
Ketoconazole is a strong inhibitor of CYp 3A4. Healthy male volunteers used ketoconazole once a day for 7 consecutive days and took a single dose of sorafenib 50 mg orally daily. The average AUC of sorafenib did not change. Therefore, it is unlikely that CYp 3A4 inhibitors affect the metabolism of sorafenib.
CYp 2C9 Substrates:
Warfarin is a substrate of CYp 2C9. The effect of sorafenib on warfarin metabolism was evaluated by comparing patients taking sorafenib and placebo. Compared with the placebo group, the mean pT-INR value of patients taking sorafenib in combination with warfarin did not change. However, INR values ​​should be monitored regularly when patients take warfarin in combination.
CYp isoenzyme selective substrates:
Midazolam, dextromethorphan and omeprazole are substrates of cytochrome CYp 3A4, CYp 2D6 and CYp 2C19, respectively. The combined use of sorafenib with the above three drugs does not change their exposure. This indicates that sorafenib is neither an inhibitor nor an inducer for these cytochrome p450 isoenzymes.
Interactions with other anti-tumor drugs:
In clinical trials, sorafenib was used in combination with other conventional doses of anti-tumor drugs, including gemcitabine, oxaliplatin, doxorubicin and irinotecan. Sorafenib does not affect the drug metabolism of gemcitabine and oxaliplatin.
When paclitaxel (225 mg/m2) and carboplatin (AUC=6) are used together with Nexavar (twice daily, 0.1 g, 0.2 g or 0.4 g each time) (Nexavar is discontinued for 3 days before and after the use of paclitaxel/carboplatin), there is no significant effect on the pharmacokinetics of paclitaxel.
The combination of sorafenib and doxorubicin can cause the AUC value of doxorubicin in patients to increase by 21%. When sorafenib and irinotecan are used in combination, the AUC of SN-38 increases by 67-120% and the AUC value of irinotecan increases by 26-42% due to the further metabolism of irinotecan’s active metabolite SN-38 through the UGT1A1 enzyme pathway. The clinical significance of this is unknown.
When docetaxel (75 mg/m2 or 100 mg/m2, once every 21 days) is used in combination with sorafenib (0.2 g or 0.4 g, twice daily, from day 2 to day 19 in a 21-day treatment cycle) (sorafenib is discontinued for 3 days when docetaxel is used), the AUC of docetaxel can be increased by 36-80% and the Cmax by 16-32%. It is recommended to be cautious when Nexavar is used in combination with docetaxel.

[Storage] Store in sealed containers below 25°C. Please keep the medicine out of the reach of children.

[Manufacturer] Natco, India