PAZOPANIB HYDROCHLORIDE
Clinical safety rating: avoid
Contraindicated (not allowed)
Pazopanib is a multi-targeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptors (VEGFR-1, -2, -3), platelet-derived growth factor receptors (PDGFR-α, -β), and stem cell factor receptor (c-Kit). It also inhibits other kinases such as fibroblast growth factor receptors (FGFR-1, -3), cytokine receptor (Kit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor (c-Fms).
| Metabolism | Primarily metabolized by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Pazopanib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). |
| Excretion | Primarily fecal (83%), with renal elimination accounting for <4% of the administered dose. |
| Half-life | Terminal half-life is approximately 31 hours, supporting once-daily dosing. |
| Protein binding | >99% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is approximately 34.4 L (0.49 L/kg for a 70 kg individual), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 21–30% following a 800 mg dose; can be increased by food (high-fat meal) but is not recommended. |
| Onset of Action | Peak plasma concentrations attained 2–5 hours after oral administration; clinical effect (e.g., tumor response) typically observed within weeks. |
| Duration of Action | Duration of therapeutic effect is maintained with continuous daily dosing; steady-state reached within 2–3 weeks. |
800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal). Do not crush tablets.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Insufficient data for severe impairment (CrCl <30 mL/min). |
| Liver impairment | Mild impairment (Child-Pugh A): no dose adjustment. Moderate impairment (Child-Pugh B): reduce dose to 200 mg orally once daily, titrate as tolerated. Severe impairment (Child-Pugh C): contraindicated. |
| Pediatric use | Not approved for use in pediatric patients; safety and efficacy not established. |
| Geriatric use | No specific dose adjustment recommended. Monitor for greater sensitivity to adverse effects (e.g., hypertension, hepatotoxicity) due to potential age-related renal and hepatic function decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can cause hepatotoxicity and QT prolongation.
| Breastfeeding | No data on excretion in human milk. Pazopanib is highly protein bound (>99%) and has a large volume of distribution, suggesting minimal excretion into breast milk; however, due to potential for serious adverse reactions in breastfed infants (e.g., hypertension, impaired wound healing), breastfeeding is contraindicated during therapy and for at least 2 weeks after last dose. M/P ratio is unknown. |
| Teratogenic Risk | Based on animal studies and its mechanism of action (VEGF receptor inhibitor), pazopanib is associated with teratogenicity and embryofetal toxicity. In pregnant women, use is contraindicated. First trimester exposure carries risk of structural anomalies including cardiovascular and skeletal malformations. Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and potential fetal renal impairment due to anti-angiogenic effects. |
■ FDA Black Box Warning
Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function before and during treatment. Pazopanib should not be used in patients with severe hepatic impairment (Child-Pugh class C).
| Common Effects | soft tissue sarcoma |
| Serious Effects |
Severe hepatic impairment (Child-Pugh class C); history of hemoptysis or recent hemorrhage (within 2 weeks); prior serious adverse reaction to pazopanib; concomitant use with strong CYP3A4 inhibitors or inducers (if cannot be avoided).
| Precautions | Hepatotoxicity (monitor LFTs), hypertension (monitor blood pressure), QT prolongation (monitor ECG), cardiac dysfunction (including left ventricular ejection fraction decline), hemorrhage (especially in STS patients), thrombotic microangiopathy, gastrointestinal perforation or fistula, hypothyroidism, proteinuria, wound healing complications, increased risk of infection, and reversible posterior leukoencephalopathy syndrome (RPLS). |
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| Fetal Monitoring | Monitor blood pressure every 2 weeks during pregnancy (if inadvertent exposure). Perform fetal ultrasound for growth and anatomy at 18-22 weeks and serial growth scans every 4 weeks from 28 weeks. Monitor amniotic fluid index. Assess renal function (creatinine) in mother and fetus. Evaluate urine protein for proteinuria. |
| Fertility Effects | Pazopanib may impair fertility in females based on animal studies showing decreased ovarian weight, follicular atresia, and reduced corpora lutea. In males, testicular degeneration and reduced sperm count have been observed. Reversibility is unknown. Preclinical data suggest potential for ovarian failure and male infertility. |