VOTRIENT
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VOTRIENT (VOTRIENT).
Pazopanib is a tyrosine kinase inhibitor that inhibits VEGFR-1, -2, -3, PDGFR-α/β, FGFR-1, -3, and c-Kit.
| Metabolism | Primarily metabolized by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. |
| Excretion | Primarily hepatic metabolism via CYP3A4, with 57% excreted in feces (as metabolites) and 26% in urine (as metabolites). Less than 1% excreted unchanged in urine. |
| Half-life | Terminal half-life is 30-35 hours, supporting once-daily dosing. Steady state reached in approximately 2 weeks. |
| Protein binding | >99.5% bound to plasma proteins (primarily albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Apparent Vd is approximately 6.3 L/kg (range 4.1-12.8 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is 20-30% (fasting state), which can be increased by food (especially high-fat meals). |
| Onset of Action | Oral: Therapeutic effect (tumor response) typically observed within 8-12 weeks, though onset varies by indication. |
| Duration of Action | Continuous daily dosing required for sustained effect. Duration of action is related to plasma concentration; drug levels decline slowly over 4-5 days after discontinuation. |
| Molecular Weight | 437.52 |
| Action Class | Tyrosine kinase inhibitors |
| Brand Substitutes | Pazocam 400mg Tablet, Pazoci 400 Tablet, Pazliz 400 Tablet, Pazocam 200mg Tablet, Pazolit 200mg Tablet, Pazoci 200 Tablet, Pazliz 200 Tablet, Pazolong 200mg Tablet |
800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not studied in severe renal impairment (CrCl <30 mL/min). |
| Liver impairment | Child-Pugh Class A: 200 mg once daily; Child-Pugh Class B: 200 mg once daily; Child-Pugh Class C: not recommended. |
| Pediatric use | Safety and efficacy not established; no standard dosing recommendations. |
| Geriatric use | No specific dose adjustment based on age; monitor renal and hepatic function closely. |
| 1st trimester | Contraindicated. Based on mechanism of action, there is potential for teratogenicity. Animal studies show embryofetal toxicity at maternal exposures below human exposure. |
| 2nd trimester | Contraindicated. Can cause fetal harm; no adequate human studies. |
| 3rd trimester | Contraindicated. Risk of fetal harm, including oligohydramnios and neonatal renal dysfunction. |
Clinical note
Comprehensive clinical and safety monograph for VOTRIENT (VOTRIENT).
| Placental transfer | Pazopanib crosses the placenta in animal studies. Data in humans are limited, but based on molecular weight and lipophilicity, placental transfer is expected. |
| Breastfeeding | It is not known whether pazopanib is excreted in human milk. Because many drugs are excreted in milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug. |
■ FDA Black Box Warning
Hepatotoxicity: Severe and fatal hepatotoxicity has been observed. Monitor liver function before and during treatment. Do not use in patients with severe hepatic impairment.
| Serious Effects |
Hypersensitivity to pazopanib or any component of the formulation
| Precautions | Hepatotoxicity: Monitor LFTs; interrupt or discontinue if severe elevation occurs., Cardiovascular effects: QT prolongation, hypertension, left ventricular dysfunction, and arterial thrombotic events., Hemorrhage: Serious and fatal hemorrhage; use with caution in patients at high risk., Gastrointestinal perforation or fistula: Discontinue if occurs., Thyroid dysfunction: Monitor thyroid function prior to and during treatment., Proteinuria: Monitor urine protein; discontinue for nephrotic syndrome., Wound healing complications: Withhold for at least 7 days prior to elective surgery., Posterior reversible encephalopathy syndrome (PRES): Discontinue if suspected., Fetal harm: Can cause fetal harm; advise women of reproductive potential of potential risk. |
| Food/Dietary | Take at least 1 hour before or 2 hours after a meal; avoid high-fat meals as they increase absorption and risk of toxicity. Do not consume grapefruit or grapefruit juice. Avoid St. John's wort. Maintain consistent timing of dosing with respect to food. |
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| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Pregnancy Category D. Pazopanib is teratogenic in animal studies. First trimester exposure carries risk of major congenital malformations, including skeletal, cardiovascular, and neural tube defects. Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and spontaneous abortion due to anti-angiogenic effects. Use is contraindicated in pregnancy. |
| Fetal Monitoring | Monitor maternal blood pressure every 2 weeks, liver function tests (ALT, AST, bilirubin) every 4 weeks, thyroid function tests monthly, and urinalysis for proteinuria. Perform fetal ultrasound for growth and amniotic fluid volume every 4 weeks if exposed during pregnancy. |
| Fertility Effects | Pazopanib may impair female fertility by reducing ovarian function and inducing amenorrhea. In males, animal studies show reduced spermatogenesis and testicular degeneration. Reversibility unknown. |
| Clinical Pearls | Monitor liver function tests prior to initiation and monthly; dose reduce or hold for ALT >3x ULN. Assess blood pressure weekly for first 2 months, then monthly; manage hypertension aggressively. Contraindicated with strong CYP3A4 inducers/inhibitors; avoid concurrent use. Check thyroid function periodically; hypothyroidism is common. Do not crush tablets due to absorption variability. |
| Patient Advice | Take VOTRIENT exactly as prescribed, once daily without food (at least 1 hour before or 2 hours after a meal). · Do not crush, chew, or split tablets; swallow whole. · You will need regular blood tests to monitor liver function and blood pressure. · Report any signs of liver problems: yellowing skin/eyes, dark urine, nausea, vomiting, abdominal pain. · Avoid grapefruit, grapefruit juice, and St. John's wort while taking this medication. · Use effective contraception during treatment and for at least 2 weeks after the last dose. · Notify your doctor if you experience severe diarrhea, bleeding, or symptoms of heart failure (shortness of breath, swelling). |