Pazopanib

Votrient is not indicated for use in combination with other /cancer therapy/ agents. Clinical trials of Votrient in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

In vitro studies suggested that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, absorption and subsequent elimination of pazopanib may be influenced by products that affect Pgp and BCRP. Concomitant treatment with strong inhibitors of Pgp or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib. Selection of alternative concomitant medicinal products with no or minimal potential to inhibit Pgp or BCRP should be considered.

Inhibitors of CYP3A4: Pharmacokinetic interaction (increased peak plasma concentrations and area under the plasma concentration-time curve (AUC) of pazopanib) observed during concomitant use of pazopanib ophthalmic solution with ketoconazole (a potent inhibitor of CYP3A4 and an inhibitor of Pgp) or during concomitant use of pazopanib oral tablets with lapatinib (a substrate and weak inhibitor of CYP3A4, Pgp, and BCRP). Concomitant use of pazopanib with a potent CYP3A4 inhibitor (e.g., clarithromycin, ketoconazole, ritonavir) should be avoided; if concomitant use cannot be avoided, pazopanib dosage should be reduced. The manufacturer states that concomitant use with grapefruit or grapefruit juice also should be avoided.

Concomitant use of Votrient and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with Votrient, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for Votrient or consider alternatives to Votrient. Alternatively, consider discontinuing simvastatin. Insufficient data are available to assess the risk of concomitant administration of alternative statins and Votrient.

For more Interactions (Complete) data for Pazopanib (13 total), please visit the HSDB record page.

In large clinical trials, abnormalities in routine liver tests were common in patients treated with pazopanib, with serum aminotransferase elevations occurring in up to half of patients and total serum bilirubin in approximately one-third. ALT and AST values greater than 5 times the upper limit of normal (ULN) occurred in 8% of patients and combinations of ALT and bilirubin elevations in 1% to 2%. In preliminary trials of pazopanib in various solid tumors, there were rare reports of hepatitis with jaundice in

IDENTIFICATION AND USE: Pazopanib is a white to slightly yellow solid formulated into film-coated tablets. Pazopanib, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent. It is used for the treatment of advanced renal cell carcinoma and for patients with advanced soft tissue sarcoma who have received prior chemotherapy. HUMAN EXPOSURE AND TOXICITY: Severe or fatal hepatotoxicity, manifested as increases in serum concentrations of aminotransferases and bilirubin, has been reported in patients receiving pazopanib. If hepatotoxicity occurs, pazopanib dosage should be reduced, or therapy should be interrupted or permanently discontinued. Woman should avoid the use of pazopanib during pregnancy. While there are no adequate and well-controlled studies in pregnant women, pazopanib has been shown to be teratogenic, embryotoxic, fetotoxic, and abortifacient in animal studies. If used during pregnancy or if the patient becomes pregnant while receiving pazopanib, the patient should be apprised of the potential fetal hazard. Prolongation of the QT interval and torsades de pointes and severe and sometimes fatal hemorrhage events have been reported in patients receiving pazopanib. Finally, GI perforation or fistula which can be fatal has also been associated with the use of pazopanib. ANIMAL STUDIES: While carcinogenicity studies with pazopanib have not been conducted, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci occurred in 2 females and a single case of adenoma in another female was observed at a dose of 1000 mg/kg/day. Pazopanib produced fetal teratogenic effects (including cardiovascular malformations and delayed ossification), reduced fetal body weight, and embryo lethality in rats at a dose level as low as 3 mg/kg/day. In rabbits, maternal toxicity (body weight loss, reduced food consumption, and abortion) was observed at doses as low as 30 mg/kg/day, while fetal weight was reduced at doses as low as 3 mg/kg/day. Pazopanib also reduced fertility in female rats at a dose of 300 mg/kg. Increased pre- and post-implantation loss and early resorptions were noted at doses as low as 10 mg/kg/day. Decreased corpora lutea were observed in monkeys and mice and ovarian atrophy was noted in rats. While pazopanib did not affect mating or fertility in male rats, reductions in sperm production rates, sperm motility, and epididymal and testicular sperm concentration was observed at doses as low as 100 mg/kg/day for 15 weeks. Following 26 weeks of dosing, male rats given doses of 30 mg/kg/day or greater exhibited decreased testicular and epididymal weights, atrophy and degeneration of the testes with aspermia, hypospermia and cribriform change in the epididymis. In toxicology studies in rats, there were effects in a variety of tissues (bone, teeth, bone marrow, nail beds, reproductive organs, hematological tissues, kidney, adrenal glands, lymph node, pituitary, and pancreas) consistent with vascular endothelial growth factor receptor (VEGFR) inhibition and/or disruption of VEGF signaling pathways with some effects occurring at doses of 3 mg/kg/day. Pazopanib was tested in a standard battery of genotoxicity studies. Pazopanib was found to be nonmutagenic and non-clastogenic when tested in a bacterial cell (Ames) assay, human peripheral lymphocyte chromosome aberration assay and rat micronucleus assay.

/SIGNS AND SYMPTOMS/ Severe or fatal hepatotoxicity, manifested as increases in serum concentrations of aminotransferases (ALT (SGPT), AST (SGOT)) and bilirubin, has been reported in patients receiving pazopanib.

/SIGNS AND SYMPTOMS/ Hemorrhage, sometimes severe or fatal, has been reported in patients receiving pazopanib.

/SIGNS AND SYMPTOMS/ Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively.

/SIGNS AND SYMPTOMS/ GI perforation or fistula, sometimes fatal, has been reported in patients receiving pazopanib.

For more Human Toxicity Excerpts (Complete) data for Pazopanib (16 total), please visit the HSDB record page.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

pazopanib

VotrientTM

Antineoplastic agents

8

most-DILI-concern

/LABORATORY ANIMALS: Acute Exposure/ A single intravenous dose of 3.75 mg/kg to conscious male cynomolgus monkeys produced a mild, reversible decrease in heart rate (11 to 45 beats/min or 7 to 26%), but had no effect on arterial pressures or body temperature, did not produce any abnormal changes in ECG intervals and there was no evidence of drug-related ECG waveform abnormalities or arrhythmias.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ A ... juvenile toxicity study was conducted to determine the potential effects of pazopanib on viability, growth and development when administered to juvenile rats from Day 21 to 62 post-partum (pp) at 10, 30 and 300 mg/kg/day (less than 1.0x human clinical exposure based on AUC in adults). Two female rats were terminated early due to excessive body weight loss and rats were administered 100 mg/kg for the remainder of the study. In contrast with juvenile animals dosed with pazopanib from Day 9 to Day 21 pp, administration of pazopanib from Day 21 to Day 62 pp was associated with toxicological findings that were similar to those noted in adult rats and include decreased body weight gain (> or = 10 mg/kg), broken and/or loose incisor teeth (> or = 30 mg/kg), alterations in the femur and tibia (growth plate hypertrophy, thinning of cortical bone, partial physeal closure and tibial fracture at > or = 30 mg/kg). Dose-dependent decreases in femoral length occurred at all dose levels and were proportional with body weight effects, suggesting an effect on overall growth of the juvenile animals. Other affected tissues include the trachea, adrenal, pancreas, stomach, duodenum, lymph node, male mammary gland and reproductive organs.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In repeat-dose toxicology studies in rats including 4-week, 13-week and 26-week administration, toxicities in bone, teeth and nail beds were observed at doses > or = 3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at > or = 30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC).

Pazopanib may cause fetal harm; the drug has been shown to be teratogenic, embryotoxic, fetotoxic, and abortifacient in animals. There are no adequate and well-controlled studies in pregnant women. Pregnancy should be avoided during therapy. If used during pregnancy or if the patient becomes pregnant while receiving pazopanib, the patient should be apprised of the potential fetal hazard.

Hemorrhage, sometimes severe or fatal, has been reported in patients receiving pazopanib. ... Pazopanib has not been evaluated in patients with a history of hemoptysis or patients with cerebral or clinically important GI hemorrhage within the past 6 months; therefore, the manufacturer recommends that pazopanib be avoided in such patients.

Pazopanib should be used with caution in patients who are at increased risk or who have a history of arterial thromboembolic events. Pazopanib has not been evaluated in patients who had experienced an arterial thromboembolic event within the past 6 months; therefore, the manufacturer recommends that pazopanib be avoided in such patients.

In patients with pre-existing moderate hepatic impairment, the starting dose of Votrient should be reduced or alternatives to Votrient should be considered. Treatment with Votrient is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT

Because pazopanib inhibits uridine diphosphate-glucuronosyltransferase (UGT) 1A1 (an enzyme that catalyzes the glucuronidation of bilirubin for elimination), mild elevations in indirect (unconjugated) bilirubin may occur in patients with deficient glucuronidation of bilirubin (i.e., Gilbert's syndrome).

/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 TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) 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/

Treatment of overdose with Votrient should consist of general supportive measures. There is no specific antidote for overdosage of Votrient. Hemodialysis is not expected to enhance the elimination of Votrient because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

For more Antidote and Emergency Treatment (Complete) data for Pazopanib (7 total), please visit the HSDB record page.

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

MEDICATION

THERAPEUTIC CATEGORY: Antineoplastic

Preparation: A. Boloor et al., World Intellectual Property Organization patent 02059110 (2002 to Glaxo); eidem, United States of America patent 7105530 (2006 to SKB).

The manufacturing process is a standard wet granulation process and consists of the following steps: granulation; milling; drying; blending and compression. The tablets are then film-coated.