Sorafenib

464.825

464.82

608-209-4

9ZOQ3TZI87

747971

DTXSID7041128

C61948

White solid

L01EX02|L01XE05|L - Antineoplastic and immunomodulating agents

29350090

92.35000

4.1

White to off-white solid

1.5±0.1 g/cm3

215 °C

523.3±50.0 °C at 760 mmHg

270.3±30.1 °C

1.626

1.71e-03 g/L

Store at 25 deg C (77 deg F); excursions permitted to 15-30 deg C (59-86 deg F)

4.76E-11mmHg at 25°C

4.11X10-14 mm Hg at 25 deg C (est)

Henry's Law constant = 1.85X10-20 atm-cu m/mol at 25 °C (est)

White to yellowish or brownish solid. Practically insoluble in aqueous media, slightly soluble in ethanol and soluble in PEG 400 /Sorafenib tosylate/

2

R36/37/38:Irritating to eyes, respiratory system and skin .

S26-S37/39

HM1650000

Xi

Stable if stored as directed; avoid strong oxidizing agents. /Sorafenib tosylate/

P201, P202, P260, P263, P264, P270, P273, P281, P308+P313, P314, P391, P405, P501

H351

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including sorafenib tosylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sorafenib tosylate/|Drug Name: Nexavar; FDA Application No.: (NDA) 021923; Active Ingredient: Sorafenib tosylate; Company: Bayer Healthcare; Original Approval or Tentative Approval Date: December 20, 2005; Chemical Type: 1 New molecular entity (NME); Review Classification: Priority review drug, orphan drug. /Sorafenib tosylate/

|Danger|H351 (50%): Suspected of causing cancer [Warning Carcinogenicity]|P201, P202, P260, P263, P264, P270, P273, P281, P308+P313, P314, P391, P405, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Breathing equipment: NIOSH/MSHA-approved respirator. Protection of hands: chemical-resistant rubber gloves. Eye protection: chemical safety goggles. /Sorafenib tosylate/

Suitable extinguishing agents: water spray, carbon dioxide, dry chemical powder or foam Protective equipment: wear self-contained breathing apparatus and protective clothing to prevent contact with skin and eyes. /Sorafenib tosylate/

Accidental release measures: After Inhalation: cordon off area of spill; wear self-contained breathing apparatus, protective clothing and heavy rubber gloves. Measures for cleaning/collecting: absorb solutions with finely- powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces and equipment by scrubbing with alcohol; dispose of contaminated material /in accordance with prevailing country, federal, state and local regulations/. /Sorafenib tosylate/

Information for safe handling: avoid inhalation and contact with skin, eyes and clothing; material may be an irritant. /Sorafenib tosylate/

The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea and dermatologic events. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals.

In large clinical trials of sorafenib, elevations in serum aminotransferase levels were common, occurring in up to half of patients, but values greater than 5 times the upper limit of normal (ULN) occurred in only 1% to 3% of treated subjects. In addition, there have been several single case reports of clinically apparent liver injury arising during sorafenib therapy which was often severe and occasionally fatal. The onset of acute liver injury ranged from a few days to 8 weeks of starting sorafenib, and the pattern of injury was typically hepatocellular with marked elevations in serum aminotransferase levels. Immunoallergic and autoimmune features were absent. Recovery was usually rapid once sorafenib was stopped, but some cases were associated with progressive liver injury and hepatic failure. Most of the reports of severe liver injury occurred in patients being treated for hepatocellular carcinoma who also had cirrhosis or in patients receiving other potentially hepatotoxic drugs31.

Sorafenib does not appear to affect the metabolism of warfarin (a CYP2C9 substrate) in vivo; mean changes from baseline in prothrombin time (PT)/international normalized ratio (INR) did not appear to be greater in patients receiving sorafenib as compared with placebo. However, infrequent bleeding events or elevations in INR have been reported in some patients receiving concomitant therapy with warfarin and sorafenib.|Potential pharmacokinetic interaction with doxorubicin and irinotecan (increased area under the serum concentration-time curve (AUC) of doxorubicin and of irinotecan and its active metabolite SN-38). The clinical importance of these findings is not known. Caution is advised.|In vitro studies indicate that sorafenib inhibits glucuronidation by the uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and 1A9 pathways; potential pharmacokinetic interaction (increased systemic exposure to UGT 1A1 or 1A9 substrates). Caution is advised when sorafenib is used concomitantly with drugs predominantly metabolized by the UGT 1A1 pathway (e.g., irinotecan, whose active metabolite SN-38 is metabolized by UGT 1A1).|In vitro studies using human hepatic microsomes indicate that sorafenib inhibits CYP isoenzymes 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4; however, sorafenib does not appear to alter exposure to dextromethorphan (a CYP2D6 substrate), midazolam (a CYP3A4 substrate), or omeprazole (a CYP2C19 substrate). The manufacturer states that it is unlikely that sorafenib will alter the metabolism of substrates of CYP isoenzymes 2C19, 2D6, or 3A4 in vivo or induce CYP isoenzymes 1A2 or 3A4. However, sorafenib may increase systemic exposure to CYP2B6 or CYP2C8 substrates; caution is advised when substrates of CYP2B6 or CYP2C8 are used concomitantly with sorafenib.|For more Interactions (Complete) data for Sorafenib (6 total), please visit the HSDB record page.

99.5% bound to plasma proteins.

Sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma.|FDA Label|Hepatocellular carcinomaNexavar is indicated for the treatment of hepatocellular carcinoma.Renal cell carcinomaNexavar is indicated for the treatment of patients with advanced renal cell carcinoma who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy.Differentiated thyroid carcinomaNexavar is indicated for the treatment of patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine.|Drug: Sorafenibtosylate

Sorafenib is an oral multi-kinase inhibitor that is used in the therapy of advanced renal cell, liver and thyroid cancer. Sorafenib has been associated with a low rate of transient elevations in serum aminotransferase levels during therapy that are generally mild and asymptomatic. Sorafenib has also been linked to rare instances of clinically apparent liver injury which can be severe and even fatal.

Antineoplastic Agents

Antineoplastic Agents; Protein Kinase Inhibitors|Nexavar is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC). /Included in US product label/|Nexavar is indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment. /Included in US product label/|Nexavar is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). /Included in US product label/

Palmar-plantar erythrodysesthesia (commonly referred to as hand-foot syndrome) and rash are common adverse effects of sorafenib, occurring in 30 and 40%, respectively, of patients receiving the drug in clinical studies, compared with 7 and 16%, respectively, of patients receiving placebo. Analysis of cumulative event rates suggests that rash and hand-foot syndrome usually are grade 1 or 2 and generally appear during the first 6 weeks of treatment with sorafenib. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary interruption of therapy, and/or dosage modification of sorafenib; in severe or persistent cases, permanent discontinuance of sorafenib therapy may be necessary.|Possible increased risk of bleeding. In clinical studies, bleeding (regardless of causality) was reported in 15.3 or 8.2% of patients receiving sorafenib or placebo, respectively. The incidences of grade 3 and 4 bleeding were 2 and 0%, respectively, in patients receiving sorafenib compared with 1.3 and 0.2%, respectively, in patients receiving placebo. Fatal hemorrhage occurred in one patient in each treatment group. Permanent discontinuance of sorafenib should be considered if any bleeding episode requires medical intervention.|GI perforation, sometimes associated with apparent intra-abdominal tumor, has been reported rarely in patients receiving sorafenib. Sorafenib therapy should be discontinued if GI perforation occurs.|Based on its mechanism of action and findings in animals, Nexavar may cause fetal harm when administered to a pregnant woman. Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. Advise women of childbearing potential to avoid becoming pregnant while on Nexavar because of the potential hazard to the fetus.|For more Drug Warnings (Complete) data for Sorafenib (16 total), please visit the HSDB record page.

No large changes in QTc interval were observed. After one 28-day treatment cycle, the largest mean QTc interval change of 8.5 ms (upper bound of two-sided 90% confidence interval, 13.3 ms) was observed at 6 hours post-dose on day 1 of cycle 2.

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)|Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)

The mean relative bioavailability is 38-49% for the tablet form, when compared to an oral solution. Sorafenib reached peak plasma levels in 3 hours following oral administration. With a high-fat meal, bioavailability is reduced by 29% compared to administration in the fasted state.|Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites.|Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces and 19% of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in feces but not in urine.|After administration of Nexavar tablets, the mean relative bioavailability was 38-49% when compared to an oral solution. Following oral administration, sorafenib reached peak plasma levels in approximately 3 hours. With a moderate-fat meal (30% fat; 700 calories), bioavailability was similar to that in the fasted state. With a high-fat meal (50% fat; 900 calories), bioavailability was reduced by 29% compared to that in the fasted state. It is recommended that Nexavar be administered without food. Mean Cmax and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. In vitro binding of sorafenib to human plasma proteins was 99.5%.|The absorption and the basic pharmacokinetics following a single dose of sorafenib tosylate were evaluated in female CD-1 mice, male Wistar rats, and female Beagle dogs. For the determination of the absorption of sorafenib in rats, bile duct-cannulated rats (n=5/group) were used. Twenty-four hours after surgery (14)C-sorafenib tosylate was administered orally or intravenously to the rats at a dose of 5 mg/kg sorafenib. The absorption of sorafenib was almost complete in female CD-1 mice (78.6%) and male Wistar rats (79.2%). In Beagle dogs the absorption (67.6 %, calculated from AUC norm values after intravenous and oral administration) and the absolute bioavailability (59.9 %) were lower than in rodents. Maximum plasma concentrations of radioactivity between 1.5 hr and 2 hr after oral administration were observed in all species. After intravenous administration of (14)C-sorafenib tosylate to mice, rats, and dogs the elimination of the radioactivity from plasma occurred with similar terminal half-lives of 6.8, 8.8, and 7.3 hours, respectively. The terminal half-lives of radioactivity after oral administration were 6.1 hours in mice and 5.8 hours in dogs. In rats, terminal half-live after oral administration was longer (11.2 hr) than after intravenous administration. In rats, the elimination of the unchanged compound was slower (half life: 9.3 hr) than in the mice (half life: 6.5 hr) and dogs (half life:4.3 hr). The total plasma clearance in rats was 0.044 L/(hr/kg) corresponding to a blood clearance of 0.049 L/(hr/kg). In mice and dogs the total plasma clearance was 0.13 and 0.15 lL/(hr/kg) respectively. The volume of distribution at steady state ranged from 0.65 l/kg to 0.74 l/kg, depending on the species.

Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady- state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady-state.|Sorafenib undergoes oxidative metabolism by hepatic CYP3A4, as well as glucuronidation by UGT1A9. Inducers of CYP3A4 activity can decrease the systemic exposure of sorafenib. Sorafenib accounted for approximately 70-85% of the circulating analytes in plasma at steady-state. Eight metabolites of sorafenib have been identified, of which 5 have been detected in plasma. The main circulating metabolite of sorafenib, the pyridine N-oxide that comprises approximately 9-16% of circulating analytes at steady-state, showed in vitro potency similar to that of sorafenib.|Sorafenib has known human metabolites that include A-D-GlucuronideDISCONTINUED and Sorafenib .

25-48 hours|After intravenous administration of (14)C-sorafenib tosylate to mice, rats, and dogs the elimination of the radioactivity from plasma occurred with similar terminal half-lives of 6.8, 8.8, and 7.3 hours, respectively. The terminal half-lives of radioactivity after oral administration were 6.1 hours in mice and 5.8 hours in dogs. In rats, terminal half-live after oral administration was longer (11.2 hr) than after intravenous administration. In rats, the elimination of the unchanged compound was slower (half life: 9.3 hr) than in the mice (half life: 6.5 hr) and dogs (half life:4.3 hr).|The mean elimination half-life of sorafenib was approximately 25 to 48 hours.

Sorafenib interacts with multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-ß). Several of these kinases are thought to be involved in angiogenesis, thus sorafenib reduces blood flow to the tumor. Sorafenib is unique in targeting the Raf/Mek/Erk pathway. By inhibiting these kinases, genetic transcription involving cell proliferation and angiogenesis is inhibited.|Sorafenib is U.S. Food and Drug Administration-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal-regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor-induced cSCC. Here, /the researchers/ report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun-NH2-kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif-containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis.|Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration. Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype. Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC(50) = 18 umol/L; K(i) = 11.7 umol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R(2) = 0.38 and R(2) = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure. This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib.|Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib was shown to inhibit multiple intracellular (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT- 3, RET, RET/PTC, VEGFR-1, VEGFR- 2, VEGFR- 3, and PDGFR-beta). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis and apoptosis. Sorafenib inhibited tumor growth of hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and differentiated thyroid carcinoma (DTC) human tumor xenografts in immunocompromised mice. Reductions in tumor angiogenesis were seen in models of HCC and RCC upon sorafenib treatment, and increases in tumor apoptosis were observed in models of HCC, RCC, and DTC.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ Fatal adverse events (FAEs) have been reported with sorafenib, a vascular endothelial growth factor receptor kinase inhibitor (VEGFR TKI). /The authors/ performed an up-to-date and detailed meta-analysis to determine the overall risk of FAEs associated with sorafenib. Databases, including PubMed, Embase and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies. Eligible studies included randomized controlled trials evaluating sorafenib effects in patients with all malignancies. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated for FAEs. In addition, subgroup analyses were performed according to tumor type and therapy regimen. 13 trials recruiting 5,546 patients were included in our analysis. The overall incidence of FAEs with sorafenib was 1.99% (95%CI, 0.98-4.02%). Patients treated with sorafenib had a significantly increased risk of FAEs compared with patients treated with control medication, with an RR of 1.77 (95%CI 1.25-2.52, P=0.001). Risk varied with tumor type, but appeared independent of therapy regimen. A significantly increased risk of FAEs was observed in patients with lung cancer (RR 2.26; 95% CI 1.03-4.99; P= 0.043) and renal cancer (RR 1.84; 95% CI 1.15-2.94; P= 0.011). The most common causes of FAEs were hemorrhage (8.6%) and thrombus or embolism (4.9%). It is important for health care practitioners to be aware of the risks of FAEs associated with sorafenib, especially in patients with renal and lung cancer.|/CASE REPORTS/ Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFbeta and VEGF receptors that is licensed for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Current evidence-based post-nephrectomy management of individuals with localized RCC consists of surveillance-based follow up. The SORCE trial is designed to investigate whether treatment with adjuvant sorafenib can reduce recurrence rates in this cohort. ... /The authors/ report an idiosyncratic reaction to sorafenib resulting in fatal hepatotoxicity and associated renal failure in a 62 year-old man treated with sorafenib within the SORCE trial.|/CASE REPORTS/ Hepatocellular carcinoma (HCC) is a critical global health issue and the third most common cause of cancer-related deaths worldwide. The majority of patients who present HCC are already at an advanced stage and their tumors are unresectable. Sorafenib is a multi-kinase inhibitor of the vascular endothelial growth factor pathway and was recently introduced as a therapy for advanced HCC. Furthermore, studies have shown that oral sorafenib has beneficial effects on survival. However, many patients experience diverse side effects, and some of these are severe. ... /The authors/ report the case of a HCC patient that developed a liver abscess while being treated with sorafenib.|/OTHER TOXICITY INFORMATION/ Possible increased risk of bleeding. In clinical studies, bleeding (regardless of causality) was reported in 15.3 or 8.2% of patients receiving sorafenib or placebo, respectively. The incidences of grade 3 and 4 bleeding were 2 and 0%, respectively, in patients receiving sorafenib compared with 1.3 and 0.2%, respectively, in patients receiving placebo. Fatal hemorrhage occurred in one patient in each treatment group. Permanent discontinuance of sorafenib should be considered if any bleeding episode requires medical intervention.|/OTHER TOXICITY INFORMATION/ Sorafenib-induced hepatitis is characterized by a hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and International Normalized Ratio (INR) may also occur. The incidence of severe drug-induced liver injury, defined as elevated transaminase levels above 20 times the upper limit of normal or transaminase elevations with significant clinical sequelae (for example, elevated INR, ascites, fatal, or transplantation), was two of 3,357 patients (0.06%) in a global monotherapy database. Monitor liver function tests regularly. In case of significantly increased transaminases without alternative explanation, such as viral hepatitis or progressing underlying malignancy, discontinue Nexavar.

4-(4-(3-(4-Chloro-3-trifluoromethylphenyl)ureido)phenoxy)pyridine-2-carboxylic acid methyamide-4-methylbenzenesulfonate

Oral: Tablets, film-coated: 200 mg (of sorafenib) Nexavar (Bayer, comarketed by Onyx). /Sorafenib tosylate/

LC/MS/MS determination in serum.

Human drugs -> Orphan -> Nexavar -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients