Pazopanib Hydrochloride

Indications

Pazopanib Hydrochloride is used for: Renal cell carcinoma, soft tissue sarcoma

Adult Dose

Advanced Renal Cell Carcinoma 800 mg PO qDay on empty stomach Soft Tissue Sarcomas 800 mg PO qDay on empty stomach Hepatic Impairment Billirubin <1.5 x ULN or ALT >ULN: No dosage adjustment required Billirubin >1.5-3 x ULN: Decreased dose to 200 mg PO qDay Billirubin >3 x ULN: Not recommended

Child Dose

Safety and efficacy not established; not indicated for use in pediatric patients

Renal Dose

Renal impairment: No dosage adjustment required

Administration

Should be taken on an empty stomach: Take at least 1 hr before or 2 hr after meals. Swallow whole, do not break/crush.

Contra Indications

Hypersensitivity.

Precautions

Hepatic Toxicity and Hepatic Impairment, QT Prolongation, Cardiac Dysfunction, Hemorrhagic Events, Thromboembolic Events, Gastrointestinal Perforation and Fistula, Hypertension, Hypothyroidism, Pregnancy. Lactation: Unknown whether distributed in breast milk, do not nurse

Pregnancy-Lactation

Pregnancy Based on animal reproduction studies and mechanism of action, it can cause fetal harm when administered to pregnant woman; there are no available data in pregnant women to inform drug-associated risk; in animal developmental and reproductive toxicology studies, oral administration of pazopanib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity, and abortion at systemic exposures lower than that observed at maximum recommended human dose of 800 mg (based on AUC); advise pregnant women or women of childbearing potential of potential risk to fetus Lactation There is no information regarding presence of drug or its metabolites in human milk, or effects on breastfed infant, or on milk production; because of potential for serious adverse reactions in breast- fed infants, advise a lactating woman not to breastfeed during treatment and for 2 weeks after final dose

Interactions

Co-administration w/ CYP3A4 (eg, itraconazole, clarithromycin, atazanavir, idinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice), P-gp & BCRP inhibitors, high-/low-fat food increases exposure & conc of pazopanib. Co-administration w/ CYP3A4 (eg, rifampicin) inducers may decrease plasma pazopanib conc. P-gp & BCRP inducers may alter exposure & distribution of pazopanib. Pazopanib may alter exposure &/or distribution of CYP3A4 substrates (eg, midazolam), CYP2C8 substrates (eg, paclitaxel) & UGT1A1 substrates (eg, irinotecan & its active metabolite SN-38). Pazopanib may increase the ratio of dextrometrophan to dextrophan conc after administration of dextrometrophan. Proton-pump inhibitors (eg, esomeprazole) & other agents that increase gastric pH may decrease bioavailability of pazopanib. Concomitant use w/ simvastatin & other statins may lead to ALT elevations.

Adverse Effects

Side effects of Pazopanib Hydrochloride : >10% ALT (SGPT) level raised (all grades, 53%; grade 3, 10%; grade 4, 2% ) AST/SGOT level raised (all grades, 53%; grade 3, 7%; grade 4, less than 1% ) Diarrhea (52%), Increased glucose (41%), Hypertension (40%), Hair depigmentation (38%) Leukopenia (all grades, 37%; grade 3, 0%; grade 4, 0% ) Increased bilirubin level (all grades, 36%; grade 3, 3%; grade 4, less than 1% ) Neutropenia (all grades, 34%; grade 3, 1%; grade 4, less than 1% ) Phosphorous decreased (34%) Thrombocytopenia (all grades, 32%; grade 3, less than 1%; grade 4, less than 1% ) Lymphocytopenia (all grades, 31%; grade 3, 4%; grade 4, less than 1% ) Sodium decreased (31%), Magnesemium decreased (26%), Nausea (26%), Weakness (22%), Vomiting (21%), Anorexia (22%), Fatigue (19%), Bradycardia (19%) Hemorrhage (all grades, 13% to 16%; grade 3 to 5, 2%) Myocardial dysfunction (ie, >15% decline in LVEF from baseline or ≥10% with baseline below normal) (11-13%) Abdominal pain (11%) 1-10% (select) Headache (10%), Proteinuria (9%), Weight loss (9%), Alopecia (8%), Dysgeusia (8%), Rash (8%), Hypothyroidism (4% to 7% ), Palmar-plantar erythrodysesthesia (6%), Chest pain (5%), Dyspepsia (5%), Skin depigmentation (3%), Prolonged QT interval (<2%), Hepatotoxicity (1%-2%), Facial edema (1%), Rectal hemorrhage (1%), Transient ischemic attack (1%), Hemorrhagic death (0.9%-1%) <1% Cardiac dysfunction (eg, decreased LVEF, CHF) (0.6%) Congestive heart failure (0.5%), Torsades de pointes, Cerebrovascular accident, Pancreatitis Frequency Not Defined Myocardial infarction, Gastrointestinal fistula, Gastrointestinal perforation

Mechanism of Action

Multikinase inhibitor (including VEGF & PDGF receptor tyrosine kinases) some of which are implicated in tumor growth, angiogenesis, & metastasis