多吉美Sorafenib甲苯磺酸索拉非尼片

【Function and indications】
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 therapy such as transcatheter arterial chemoembolization (TACE) in patients with advanced hepatocellular carcinoma. Therefore, it is not clear whether Nexavar is superior to interventional therapy, nor is it clear whether sorafenib is beneficial for patients who have previously received interventional therapy. It is recommended that doctors consider the specific situation of the patient and choose appropriate treatment methods.

【Model and specification】
200mg*60 tablets/box

【Usage and dosage】
The medication is not affected by eating (take on an empty stomach or with a low-fat or medium-fat diet).
Recommended dose: The recommended dose of sorafenib is 0.4 g each time (2 x 0.2 g), twice a day, taken on an empty stomach or with a low-fat or medium-fat diet.
Treatment duration: Treatment should be continued until the patient is unable to benefit clinically or develops intolerable toxic reactions.
Dose Adjustment and Special Instructions for Use: Management of suspected adverse reactions includes interruption or reduction of sorafenib dose, if necessary, sorafenib dose reduced to 0.4 g once daily or every other day.
The following are recommendations for dose adjustments based on skin toxicity:
Grade 1 skin adverse reactions: numbness, hypoesthesia, paresthesia, tingling, painless swelling, erythema or discomfort in the hands and feet that does not affect daily activities (occurring at any time) – Continue to use Nexavar and give topical treatment to eliminate symptoms.
Grade 2 skin adverse reactions: painful erythema and swelling of the hands and feet, and/or discomfort in the hands and feet that affects daily life (first occurrence) – Continue to use Nexavar and give topical treatment to eliminate symptoms. If symptoms do not improve within 7 days, or occur for the second or third time: Interrupt Nexavar treatment until toxicity resolves to Grade 0-1. When restarting Nexavar treatment, reduce to a single dose (0.4 g daily or 0.4 g every other day). Fourth occurrence of grade 2 skin adverse reactions: Discontinue NEXAVAR.
Grade 3 skin adverse reactions: Moist desquamation, ulceration, blistering of the hands and feet, pain, or severe hand and foot discomfort that prevents the patient from working and normal life (first or second occurrence) – Interrupt NEXAVAR treatment until toxicity resolves to grade 0-1. When NEXAVAR treatment is restarted, reduce to a single dose (0.4 g daily or 0.4 g every other day). Third occurrence of grade 3 skin adverse reactions: Discontinue NEXAVAR treatment.
Patients with hepatic impairment: No dose adjustment is required for patients with mild to moderate hepatic impairment (Child-pugh A and B). Sorafenib has not been studied in patients with severe hepatic impairment (Child-pugh C).
Patients with renal impairment: No dose adjustment is required for patients with mild to moderate renal impairment. Sorafenib has not been studied in patients with severe renal impairment or those on dialysis. Monitoring of fluid and electrolyte balance is recommended for patients at risk for renal impairment.

【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 had a “partial response” (pR) with a response rate of 12.4%; the researchers evaluated 19 patients as “partial response” (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 an advantage over 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 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 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 disorders: Hypersensitivity reactions (including skin reactions and urticaria) are uncommon.
Endocrine disorders: Hypothyroidism is uncommon.
Nutritional metabolic disorders: Hypophosphatemia is uncommon, anorexia is common, hyponatremia and dehydration are uncommon.
Psychiatric symptoms: Depression is common.
Nervous system disorders: 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 disorders: Bleeding (including gastrointestinal bleeding*, respiratory bleeding* and cerebral hemorrhage*), hypertension are very common, hypertensive crisis* is uncommon.
Respiratory, thoracic and mediastinal: Hoarseness is common, rhinorrhea is uncommon.
Gastrointestinal system disorders: diarrhea, nausea, vomiting are very common; constipation, stomatitis (including dry mouth and tongue pain), dyspepsia, dysphagia are common; gastroesophageal reflux, pancreatitis, gastritis, gastrointestinal perforation* are uncommon.
Hepatobiliary system disorders: elevated bilirubin and jaundice are uncommon.
Skin and subcutaneous tissue disorders: rash, alopecia, hand-foot skin reaction (included in MedDRA as “hand-foot paresthesia syndrome”), pruritus, erythema are very common; dry skin, exfoliative dermatitis, acne, desquamation are common; eczema, erythema multiforme, keratoacanthoma/squamous cell carcinoma of the skin are uncommon.
Skeletal muscles, connective tissue and bones: joint pain and myalgia are common.
Reproductive system and breast: erectile dysfunction is common; male breast development is uncommon.
General condition: fatigue and pain (including mouth pain, abdominal pain, bone pain, headache and cancer pain) are very common; weakness, fever and influenza symptoms are common.
Laboratory examination: It is common to have elevated amylase and lipase, common weight loss, transient increase in transaminases, uncommon transient increase in alkaline phosphatase, abnormal international normalized ratio (INR) of coagulation time, and 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 drug-related adverse events of CTCAE (version 2.0) grade 3 and 4 were 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 pregnant women taking sorafenib. 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 experiments 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.
Breastfeeding: It is not yet known whether sorafenib is secreted through human milk. Animal experiments 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 have not yet been studied, 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:
The continuous co-administration of rifampicin and sorafenib can lead to an average reduction of sorafenib AUC by 37%. 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, the possibility of CYp 3A4 inhibitors affecting the metabolism of sorafenib is very small.
CYp 2C9 substrate: 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 and warfarin did not change. However, INR values ​​should be monitored regularly when patients take warfarin.
CYp isoenzyme selective substrate: 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 with Nexavar (twice a day, 0.1 g, 0.2 g or 0.4 g each time) (Nexavar was discontinued for 3 days before and after the use of paclitaxel/carboplatin), there will be no significant effect on the pharmacokinetics of paclitaxel.
When sorafenib and doxorubicin are used in combination, the AUC value of doxorubicin in patients can be increased by 21%. When sorafenib and irinotecan are used in combination, the active metabolite SN-38 of irinotecan is further metabolized through the UGT1A1 enzyme pathway. The combination of the two leads to an increase in the AUC of SN-38 by 67-120%, and an increase in the AUC value of irinotecan by 26-42%. 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. Keep the medicine out of reach of children.

[Manufacturer]
Bayer Schering Pharma, Germany