Sunitinib

... 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.

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.；More importantly, there have been several case reports of clinically apparent liver injury attributed to sunitinib therapy. The time to onset was after several cycles of therapy. The pattern of serum enzyme elevations was typically hepatocellular and the clinical presentation resembled acute hepatic necrosis. In some instances, the injury may have been due to hypotension, shock or ischemia rather than direct hepatotoxicity (Case 1). Regardless, the injury can be severe and several instances of acute liver failure and death have been reported. Immunoallergic features (rash, fever and eosinophilia) are not common.；Finally, sunitinib has also been reported to cause hyperammonemia and encephalopathy in rare patients with cancer treated with conventional or even low oral doses (Case 2). The time to onset was within 1 to 3 weeks, presenting with confusion and irritability with minimal elevations in serum enzymes and bilirubin and marked increases (4-10 times the ULN) in serum ammonia. Recovery is rapid once sunitinib is stopped and the syndrome can recur with re-exposure. Interesting, there appears to be little cross-reactivity to this complication with other tyrosine kinase inhibitors.；Likelihood score: B (highly likely cause of clinically apparent liver injury, including hyperammonemic syndrome).

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/

/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.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

sunitinib

Sutent®

Antineoplastic agents

8

most-DILI-concern

/LABORATORY ANIMALS: Acute Exposure/ In non-clinical studies mortality was observed following as few as 5 daily doses of 500 mg/kg (3000 mg/sq m) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ ... This paper characterizes the organ toxicity of sunitinib in Sprague-Dawley rats and cynomolgus monkeys, and the reversibility of any treatment-induced effects. Rats and monkeys received sunitinib (0-15 and 0-20 mg/kg/day, respectively) orally on a consecutive daily dosing schedule for thirteen weeks or on an intermittent daily dosing schedule for up to nine months. Clinical observations and laboratory parameters were recorded. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed. In rats, sunitinib was generally tolerated at 0.3 and 1.5 mg/kg/day, and findings were reversible. In monkeys, the level at which there were no observed adverse effects was 1.5 mg/kg/day, and findings were similarly reversible (except for uterine/ovarian weight changes and skin pallor). Data suggest that inhibition of multiple RTK pathways may induce pharmacologic effects on organ systems in nonclinical species. Key pharmacologic effects of sunitinib included reversible inhibition of neovascularization into the epiphyseal growth plate, and impaired corpora lutea formation and uterine development during estrus. Similar observations have been noted with this class of RTK signaling inhibitors and are consistent with pharmacologic perturbations of physiologic/angiogenic processes associated with the intended molecular targets.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Physeal dysplasia was observed in cynomolgus monkeys with open growth plates treated for >/= 3 months (3 month dosing 2, 6, 12 mg/kg/day; 8 cycles of dosing 0.3, 1.5, 6.0 mg/kg/day) with sunitinib at doses that were > 0.4 times the RDD based on systemic exposure (AUC). ... The incidence and severity of physeal dysplasia were dose-related and were reversible upon cessation of treatment ... A no effect level was not observed in monkeys treated continuously for 3 months, but was 1.5 mg/kg/day when treated intermittently for 8 cycles.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In developing rats treated continuously for 3 months (1.5, 5.0 and 15.0 mg/kg) or 5 cycles (0.3, 1.5, and 6.0 mg/kg/day), bone abnormalities consisted of thickening of the epiphyseal cartilage of the femur and an increase of fracture of the tibia at doses >/= 5 mg/kg (approximately 10 times the RDD based on AUC). Additionally, caries of the teeth were observed in rats at >5 mg/kg. Findings in the teeth were not reversible. ... In rats the no effect level in bones was </= 2 mg/kg/day.

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.

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/

◉ Summary of Use during Lactation；No information is available on the clinical use of sunitinib during breastfeeding. Because sunitinib and its metabolite are over 90% bound to plasma proteins, the amount in milk is likely to be low. However, one of its metabolites has a half-life of up to 110 hours, and might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during sunitinib therapy and for at least 4 weeks after the last dose.；◉ Effects in Breastfed Infants；Relevant published information was not found as of the revision date.；◉ Effects on Lactation and Breastmilk；Relevant published information was not found as of the revision date.

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/

MEDICATION

Use (kg; approx.) in Germany (2009): >25；Consumption (g per capita; approx.) in Germany (2009): 0.000305；Calculated removal (%): 7.2

The formation of the pyrrole was performed according to the classical Knorr synthesis, and hydrolysis of the tert-butylester with a subsequent decarboxylation reaction occurred smoothly with sulfuric acid in aqueous methanol at 65 °C. Thereafter, reaction with the Vilsmeier reagent (chloromethylenedimethylammonium chloride) in acetonitrile afforded the corresponding complex, which upon addition of 5-fluorooxindole and pulverized potassium hydroxide yielded the desired product.