pazopanib (Rx)

>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

Postmarketing Reports

Gastrointestinal disorders: Pancreatitis

Musculoskeletal and connective tissue disorders: Arthralgia, muscle spasms

Eye disorders: Retinal detachment/tear

Interstitial lung disease

Polycythemia

Tumor lysis syndrome

Vascular disorders: Arterial (including aortic) aneurysms, dissections, and rupture

Contraindications

Hypersensitivity

Cautions

Severe hepatotoxicity, including fatalities, has been reported

Increases in serum transaminase levels and bilirubin observed; severe and fatal hepatotoxicity has occurred; measure liver chemistries before initiation of treatment and regularly during treatment

Patients >65 years are at greater risk for hepatotoxicity

Hypertension, including hypertensive crisis have occurred; blood pressure should be well controlled prior to initiating therapy; monitor blood pressure within one week after starting therapy and frequently thereafter

Rare occurrences of QT prolongation and torsades de pointes reported during clinical trials; consider monitoring electrocardiograms and electrolytes

Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) observed; permanently discontinue therapy if TMA occurs

Hematologic parameter alterations (ie, leukopenia, neutropenia, thrombocytopenia, lymphocytopenia) reported in 31-37%

Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin, grapefruit juice) may increase pazopanib serum levels

CYP3A4 inducers (eg, rifampin, carbamazepine) decrease pazopanib serum levels

Gastrointestinal perforation or fistula reported; fatal perforation events have occurred; use with caution in patients at risk for gastrointestinal perforation or fistula

Events of cardiac dysfunction (decreased LVEF and congestive heart failure) have been observed; baseline and periodic evaluation of LVEF recommended in patients at risk of cardiac dysfunction

Avoid concomitant use with drugs that raise gastric pH; consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2 receptor antagonists; separate antacid and pazopanib dosing by several hr

Reversible posterior leukoencephalopathy syndrome (RPLS) has been observed and can be fatal; permanently discontinue therapy in patients developing RPLS

Interruption of therapy recommended in patients undergoing surgical procedures

Hypothyroidism may occur; monitoring of thyroid function tests recommended

Monitor urine protein. interrupt treatment for 24-hr urine protein ≥3 g and discontinue for repeat episodes despite dose reductions

Serious infections (with or without neutropenia), some with fatal outcome, reported; monitor for signs and symptoms and treat active infection promptly; interrupt or discontinue therapy

Interstitial lung disease/pneumonitis reported; monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and discontinue therapy in patients developing ILD or pneumonitis

Fatal hemorrhagic events reported; therapy has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients

Arterial thromboembolic events that can be fatal reported; use with caution in patients who are at increased risk for these events

Venous thromboembolic events (VTE) reported, including fatal pulmonary emboli (PE); monitor for signs and symptoms of VTE and PE; monitor for signs and symptoms of VTE and PE

Animal studies have shown therapy can severely affect organ growth and maturation during early post-natal development; safety and effectiveness in pediatric patients not established

Can cause fetal harm when administered to a pregnant woman; advise females of reproductive potential of the potential hazard to fetus and to use effective contraception during treatment and for at least 2 weeks after last dose

Cases of tumor lysis syndrome (TLS), including fatal cases, reported in RCC and STS patients; patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration; closely monitor patients at risk, consider appropriate prophylaxis, and treat as clinically indicated

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

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

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

Absorption

Peak Plasma Time: 2-4 hr

Peak Plasma Concentration: 58.1 mcg/mL

AUC: 1,037 hr•mcg/mL

Cmax and AUC increased 2-fold with food; also increased if table crushed

Distribution

Protein Bound: >99%

Pgp substrate

Metabolism

Metabolized by CYP3A4 (major), CYP1A2 and CYP2C8 (minor)

Elimination

Half-Life: 30.9 hr

Excretion: Feces (Primarily); urine (<4%)

Oral Administration

Take without food at least 1 hr ac or 2 hr pc

Do not crush or chew (increases bioavailability and absorption rate, with possible increased toxicity)

Food also increases bioavailability, possibly resulting in increased toxicity

Storage

Store at room temperature between 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)