Sunitinib

514.55

398.47

V99T50803M

750690

DTXSID1041134

C71622

Orange solid

L01EX01|L01XE04|L - Antineoplastic and immunomodulating agents

29337900

77.2

2.6

Solid

1.2±0.1 g/cm3

189-191°C

572.1°C at 760 mmHg

299.8℃

1.611

H2O: >25 mg/mL over pH of 1.2 to 6.8

1.26X10-14 mm Hg at 25 deg C (est)

8.95None

8.95 |pKa: 8.5

MW: 532.56 /Maleate/|Yellow to orange powder; pKa = 8.95; solubility in aqueous media over the range of pH 1.2 to pH 6.8 is in excess of 25 mg/mL; log Kow = 5.2 at pH 7 /Sunitinib malate/|Hydroxyl radical reaction rate constant = 3.35X10-10 cu cm/molec-sec at 25 °C (est)|Ozone radical reaction rate constant = 2.51X10-16 cu cm/molec-sec at 25 °C (est)

24/25

P201, P202, P260, P261, P264, P270, P271, P280, P281, P301+P312, P302+P352, P304+P312, P304+P340, P308+P313, P312, P314, P322, P330, P363, P405, P501

H302

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.|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/|For more Disposal Methods (Complete) data for Sunitinib (8 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including sunitinib malate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sunitinib malate/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/|For more Preventive Measures (Complete) data for Sunitinib (19 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/

The maximally tolerated dose for rat, mouse, and dog when given orally is greater than 500 mg/kg. The maximally tolerated dose of a non-human primate is greater 1200 mg/kg.

In large clinical trials of sunitinib, elevations in serum aminotransferase levels were common, occurring in 39% of sunitinib vs 23% of placebo recipients. Values greater than 5 times the upper limit of normal (ULN) occurred in only 2% to 3% of sunitinib recipients (and 1% of controls). These abnormalities were usually asymptomatic. Dose adjustment or temporary discontinuation and restarting at a lower dose is recommended if enzyme levels are markedly elevated (ALT or AST persistently greater than 5 times ULN or bilirubin more than 3 times ULN). Sunitinib therapy is also associated with a high rate of serum bilirubin elevations, generally in the mild-to-moderate range and not in association with ALT or AST elevations. These changes are probably due to interaction with hepatic UDP-glucuronyltransferase, the enzyme that is also responsible for bilirubin excretion.

... A 57-year-old woman who started sunitinib treatment for relapsed metastatic gastrointestinal stromal tumor after imatinib failure had disease stabilization and normal liver function through 8 cycles of sunitinib 50 mg/day for 4 weeks, followed by 2 weeks off treatment. Her continuing medications included acetaminophen approximately 4.5 g/wk, as well as standard medications for asthma. In cycle 8, she received oral levothyroxine 50-150 microg/day for approximately 30 days to control hypothyroidism before beginning cycle 9 of sunitinib. On day 4 of cycle 9, she was hospitalized with progressively rising circulating liver enzyme levels. She died 4 days postadmission despite discontinuation of sunitinib and initiation of intensive supportive treatment. At autopsy, her liver showed severe centrilobular necrosis with moderate-to-severe steatosis and minimal parenchymal invasion by the neoplasm. Viral stains were negative. Hepatic failure has been reported rarely in patients receiving sunitinib. Autopsy results excluded neoplastic disease progression and viral infection in the etiology of the event, and the patient may have died of the combined interaction of sunitinib, acetaminophen, and levothyroxine. Although sunitinib was not more than a possible hepatotoxin (Roussel Uclaf Causality Assessment Method) and may even have been hepatoprotective over a 48-week period against chronic intake of acetaminophen (probable hepatotoxin) by producing regional hypothyroidism within the liver, it is hypothesized that correction of the putative hepatic hypothyroidism with oral levothyroxine (possible hepatotoxin) and reinitiation of sunitinib treatment may have triggered hepatic necrosis. ...|Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. Concurrent administration of SUTENT with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary active metabolite) Cmax and AUC0-infinity values, respectively, after a single dose of Sunitinib in healthy volunteers. Co-administration of sunitinib with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of sunitinib.|CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. Concurrent administration of sunitinib with the strong CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active metabolite) Cmax and AUC0-infinity values, respectively, after a single dose of sunitinib in healthy volunteers. Co-administration of sunitinib with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital) may decrease sunitinib concentrations.|St. John's wort may cause unpredictable decreases in plasma sunitinib concentrations and should be avoided during sunitinib therapy.

Sunitinib should be used with caution in patients at increased risk for cardiac arrhythmias, including those with a history of prolongation of the QT interval, those receiving antiarrhythmic agents, and those with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Periodic monitoring with on-treatment ECGs and serum magnesium and potassium concentrations should be considered. Caution and reduction of sunitinib dosage should be considered in patients receiving strong CYP3A4 inhibitors concomitantly.

Binding of sunitinib and its primary metabolite to human plasma protein in vitro was 95% and 90%, respectively.

For the treatment of advanced renal cell carcinoma as well as the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.|FDA Label|Gastrointestinal stromal tumour (GIST)Sutent is indicated for the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumour (GIST) in adults after failure of imatinib mesilate treatment due to resistance or intolerance.Metastatic renal cell carcinoma (MRCC)Sutent is indicated for the treatment of advanced/metastatic renal cell carcinoma (MRCC) in adults.Pancreatic neuroendocrine tumours (pNET)Sutent is indicated for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumours with disease progression in adults.Experience with Sutent as first-line treatment is limited (see section 5.1).|Treatment of gastro-intestinal stromal tumours|Gastrointestinal stromal tumour (GIST)Sunitinib Accord is indicated for the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumour (GIST) in adults after failure of imatinib treatment due to resistance or intolerance.Metastatic renal cell carcinoma (MRCC)Sunitinib Accord is indicated for the treatment of advanced/metastatic renal cell carcinoma (MRCC) in adults.Pancreatic neuroendocrine tumours (pNET)Sunitinib Accord is indicated for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumours (pNET) with disease progression in adults.|Drug: Sunitinibmalate

Sunitinib is multi-specific tyrosine kinase receptor inhibitor that is used in the therapy of gastrointestinal stromal tumors and advanced renal cell carcinoma. Sunitinib therapy is associated with transient elevations in serum aminotransferase and bilirubin levels and rare instances of clinically apparent acute liver injury.

Antineoplastic Agents

Angiogenesis Inhibitors; Antineoplastic Agents|Sunitinib malate is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate. /Included in US product label/|Sunitinib malate is indicated for the treatment of advanced renal cell carcinoma. /Included in US product label/|Sunitinib malate is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease. /Included in US product label/

/BOXED WARNING/ HEPATOTOXICITY-Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported.|Sunitinib has been associated with hepatotoxicity, which may result in liver failure or death. Liver failure has been observed in clinical trials (7/2281 [0.3%]) and post-marketing experience. Liver failure signs include jaundice, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor liver function tests (ALT, AST, bilirubin) before initiation of treatment, during each cycle of treatment, and as clinically indicated. Sunitinib should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart Sunitinib if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure. Safety in patients with ALT or AST >2.5 x ULN or, if due to liver metastases, >5.0 x ULN has not been established.|Cardiovascular events, including heart failure, myocardial disorders and cardiomyopathy, some of which were fatal, have been reported through post-marketing experience.|Among patients receiving sunitinib for metastatic renal cell cancer in the randomized trial, 21% had a left ventricular ejection fraction (LVEF) below the lower limit of normal, and 4% experienced a decline in LVEF (to a value below 50% or as a reduction greater than 20% from the baseline value). Left ventricular dysfunction was reported in 1% and congestive heart failure in less than 1% of patients receiving sunitinib.|For more Drug Warnings (Complete) data for Sunitinib (33 total), please visit the HSDB record page.

Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA on January 26, 2006.

Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)|Agents and endogenous substances that antagonize or inhibit the development of new blood vessels. (See all compounds classified as Angiogenesis Inhibitors.)|Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12 hours (Tmax) following oral administration. Food has no effect on the bioavailability of sunitinib. Sunitinib may be taken with or without food. The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and RCC.|Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. Elimination is primarily via feces. In a human mass balance study of [14C]sunitinib, 61% of the dose was eliminated in feces, with renal elimination accounting for 16% of the administered dose.|2230 L (apparent volume of distribution, Vd/F)|34 - 62 L/h [Total oral clearance]|Following oral administration, peak plasma concentrations of sunitinib generally occur within 6-12 hours. Food has no effect on bioavailability of sunitinib.|Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 62.9 - 101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles in the dosing regimens tested.|Sunitinib and its primary active metabolite are 95 and 90% bound to human plasma proteins in vitro, respectively.|The apparent volume of distribution (Vd/F) for sunitinib was 2230 L. In the dosing range of 25 - 100 mg, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionately with dose.|For more Absorption, Distribution and Excretion (Complete) data for Sunitinib (11 total), please visit the HSDB record page.

Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4.|Sunitinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 to several metabolites. The main circulating metabolite, an N-desethyl derivative, has been shown to be equipotent to sunitinib in biochemical and cellular assays; this metabolite accounts for approximately 23-37% of total plasma concentrations of the drug and also is metabolized by CYP3A4.|Sunitinib and its primary active metabolite were the major drug-related compounds identified in plasma, urine, and feces, representing 91.5%, 86.4% and 73.8% of radioactivity in pooled samples, respectively.

Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively.|Following oral administration of a single dose in healthy volunteers, the terminal half-life of sunitinib or its primary active metabolite is approximately 40-60 or 80-110 hours, respectively.

Sunitinib is a small molecule that inhibits multiple RTKs, some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRa and PDGFRb), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.|Sunitinib malate, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent. Receptor tyrosine kinases (RTKs) are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (eg, angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase. Although the exact mechanism of antineoplastic activity of sunitinib has not been fully elucidated, data from biochemical and cellular assays indicate that sunitinib may inhibit signal transduction pathways involving multiple receptor (ie, cell surface) tyrosine kinases, including platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR-1, VEGFR-2, VEGFR-3), stem cell factor receptor (ie, c-Kit), fms-like tyrosine kinase 3 (Flt-3), colony stimulating factor receptor type 1 (CSF-1R), and the glial cell line-derived neurotrophic factor receptor (RET). Sunitinib-induced inhibition of signal transduction pathways involving PDGFR-beta, VEGFR-2, and c-Kit has been confirmed in tumor xenografts expressing receptor tyrosine kinase targets in vivo. Sunitinib has been shown to inhibit growth of tumor cells expressing dysregulated target receptor tyrosine kinases (ie, PDGFR, RET, c-Kit) in vitro; the drug also has been shown to inhibit PDGFR-beta- and VEGFR-2-dependent tumor angiogenesis in vivo.|Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFR-beta, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFR-beta- and VEGFR2-dependent tumor angiogenesis in vivo.|... Sunitinib malate is an oral, multitargeted kinase inhibitor with antiangiogenic and antitumor activity due to inhibition of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor alpha (PDGFR-alpha), and the tyrosine kinases c-KIT and FLT3. Sunitinib has antitumor activity in various cancers, including imatinib-resistant gastrointestinal stromal tumors, metastatic breast cancer, neuroendocrine tumors, and renal-cell carcinoma. ...|Sunitinib, which is a multitargeted tyrosine-kinase inhibitor, exhibits antiangiogenic and antitumor activity, and extends survival of patients with metastatic renal-cell carcinoma (mRCC) and gastrointestinal stromal tumors (GIST). This molecule has also been reported to be associated with cardiotoxicity at a high frequency, but the mechanism is still unknown. In the present study, /investigators/ observed that Sunitinib showed high anti-proliferative effect on H9c2 cardiac muscle cells measured by PI staining and the MTT assay. But apoptotic markers (PARP cleavage, caspase 3 cleavage and chromatin condensation) were uniformly negative in H9c2 cells after Sunitinib treatment for 48 hr, indicating that another cell death pathway may be involved in Sunitinib-induced cardiotoxicity. /Investigators/ found Sunitinib dramatically increased autophagic flux in H9c2 cells. Acidic vesicle fluorescence and high expression of LC3-II in H9c2 cells identified autophagy as a Sunitinib-induced process that might be associated with cytotoxicity. Furthermore, knocking down Beclin 1 by RNA-interference to block autophagy in H9c2 cells revealed that the death rate was decreased when treated with Sunitinib in comparison to control cells. These results confirmed that autophagy plays an important role in Sunitinib-mediated H9c2 cells cytotoxicity. Taken together, the data presented here strongly suggest that autophagy is associated with Sunitinib-induced cardiotoxicity, and that inhibition of autophagy constitutes a viable strategy for reducing Sunitinib-induced cardiomyocyte death thereby alleviating Sunitinib cardiotoxicity.|For more Mechanism of Action (Complete) data for Sunitinib (9 total), please visit the HSDB record page.

Treatment of overdose with Sunitinib should consist of general supportive measures. There is no specific antidote for overdosage with Sunitinib.|/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/

/SIGNS AND SYMPTOMS/ HEPATOTOXICITY-Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported.|/SIGNS AND SYMPTOMS/ Cardiovascular events, including heart failure, myocardial disorders and cardiomyopathy, some of which were fatal, have been reported through post-marketing experience.|/CASE REPORTS/ A case of intentional overdose involving the ingestion of 1,500 mg of Sunitinib in an attempted suicide was reported without adverse reaction.|/CASE REPORTS/ ... A 69-year-old female patient with a history of metastatic renal cell carcinoma after left radical nephrectomy presented to our nephrology clinic after completing 2 courses of sunitinib therapy. The patient was noted to have progressive kidney dysfunction with proteinuria, together with peripheral eosinophilia and eosinophiluria, which developed during the first of 2 cycles of sunitinib therapy. Her concomitant medications included atenolol, triamterene/hydrochlorothiazide, amlodipine, and multivitamin tablets, all of which she had been receiving at stable doses over the previous 2 years. There were no other over-the-counter medications involved and other possible causes of interstitial nephritis were excluded. The proteinuria, eosinophilia, and eosinophiluria worsened with the second course and resolved after sunitinib discontinuation, which resulted in initial stabilization followed by slight improvement in kidney function. The Naranjo Adverse Drug Reaction Probability Scale score for this event was 7, indicating a probable association of the event with the drug. With clinical improvement after discontinuation of sunitinib and the presence of a solitary remaining kidney and thrombocytopenia, renal biopsy was not performed after discussion with the patient. When challenged with a related agent, sorafenib, the patient experienced worsening of serum creatinine and increasing eosinophilia, similar to that noted with sunitinib, suggesting that this event may be a class effect. ...|For more Human Toxicity Excerpts (Complete) data for Sunitinib (31 total), please visit the HSDB record page.

5-(5-fluoro-2-oxo-1,2-dihydroindolylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide

Table: Sunitinib Malate Preparations [Table#7781]

Human drugs -> Sutent -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human drugs -> Sunitinib Accord -> EMA Drug Category|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients