pazopanib (Votrient)

Dosing and uses of Votrient (pazopanib)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet

• 200mg
• 400mg

 

Advanced Renal Cell Carcinoma

800 mg PO qDay on empty stomach (at least 1 hr ac or 2 hr pc)

 

Soft Tissue Sarcomas

800 mg PO qDay on empty stomach (at least 1 hr ac or 2 hr pc)

Indication: Treatment of advanced soft tissue sarcoma in patients who have received prior chemotherapy

Limitations of use: Efficacy not demonstrated in adipocytic soft tissue sarcoma or gastrointestinal stromal tumors

 

Ovarian Cancer (Orphan)

Orphan designation for treatment of ovarian cancer

Orphan sponsor

• GlaxoSmithKline

 

Dosage modification

In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability

Coadministration with strong CYP3A4 inhibitors: Avoid if possible, but if coadministration is warranted, decrease pazopanib dose to 400 mg/day; further dose reduction may be needed if adverse effects occur

Coadministration with strong CYP3A4 inducers: Should not use pazopanib in patients unable to avoid use of strong CYP3A4 inducers (eg, rifampin)

 

Renal Impairment

Renal impairment: No dosage adjustment required

 

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

 

Administration

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

Food also increases bioavailability, possibly resulting in increased toxicity

 

Pediatric dosage forms and strengths

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

Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early postnatal development, particularly in children younger than 2 years

 

Votrient (pazopanib) adverse (side) effects

>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

 

Warnings

Black box warnings

Severe hepatotoxicity including fatalities reported in postmarketing survaillance

 

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

 

Pregnancy and lactation

Pregnancy category: d

Lactation: Unknown whether distributed in breast milk, do not nurse

 

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.

 

Pharmacology of Votrient (pazopanib)

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%)