Pazopanib
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From MedlinePlus, U.S. National Library of Medicine
Boxed warning
WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [see Warnings and Precautions (5.1)]. WARNING: HEPATOTOXICITY See full prescribing information for complete boxed warning. Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. ( 5.1 )
Handling and access
NIOSH hazardous drug
Table 2NIOSH lists pazopanib as a hazardous drug. AHFS class: 10:00 antineoplastic agents.
- Meets the NIOSH definition of a hazardous drug (carcinogenicity, developmental or reproductive toxicity, organ toxicity at low doses, or genotoxicity) without MSHI or a Group 1 or 2A carcinogen classification.
- Only a developmental and/or reproductive hazard: precautions matter most for workers who are pregnant, breastfeeding, or trying to conceive.
Handle with the precautions your facility uses for hazardous drugs (USP <800>). NIOSH's Managing Hazardous Drug Exposures lists controls by drug form and activity.
Dosing in kidney impairment
Renal Impairment No dose adjustment is recommended for patients with renal impairment. VOTRIENT has not been studied in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis.
| Dose reduction | For renal cell carcinoma | For soft tissue sarcoma |
| First | 400 mg orally once daily | 600 mg orally once daily |
| Second | 200 mg orally once daily | 400 mg orally once daily |
Dosing in liver impairment
Dosage Modifications for Hepatic Impairment Moderate and Severe Hepatic Impairment In patients with moderate hepatic impairment [total bilirubin > 1.5 to 3 × upper limit of normal (ULN) and any alanine aminotransferase (ALT) value], consider alternatives to VOTRIENT. If VOTRIENT is used in patients with moderate hepatic impairment, reduce the VOTRIENT dose to 200 mg orally once daily.
VOTRIENT is not recommended in patients with severe hepatic impairment (total bilirubin > 3 × ULN and any ALT value) [see Use in Specific Populations] .
| Abbreviations: ALT, alanine aminotransferase; ULN, upper limit of normal. aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 5. | ||
| Adverse reaction | Severitya | Dosage modification |
| Hepatic Toxicity [see Warnings and Precautions (5.1)] | Isolated ALT elevations between 3 × ULN and 8 × ULN | Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline. |
| Isolated ALT elevations of > 8 × ULN | Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks. Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s). | |
| ALT elevations > 3 × ULN occur concurrently with bilirubin elevations > 2 × ULN | Permanently discontinue and continue to monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations. | |
| Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)] | Symptomatic or Grade 3 | Withhold until improvement to Grade < 3. Resume treatment based on medical judgement. |
| Grade 4 | Permanently discontinue. | |
| Hemorrhagic Events [see Warnings and Precautions (5.4)] | Grade 2 | Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1). Permanently discontinue if Grade 2 recurs after dose interruption and reduction. |
| Grade 3 or 4 | Permanently discontinue. | |
| Arterial Thromboembolic Events [see Warnings and Precautions (5.5)] | Any grade | Permanently discontinue. |
| Venous Thromboembolic Events [see Warnings and Precautions (5.6)] | Grade 3 | Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week. |
| Grade 4 | Permanently discontinue. | |
| Thrombotic Microangiopathy [see Warnings and Precautions (5.7)] | Any grade | Permanently discontinue. |
| Gastrointestinal Perforation [see Warnings and Precautions (5.8)] | Any grade | Permanently discontinue. |
| Gastrointestinal Fistula [see Warnings and Precautions (5.8)] | Grade 2 or 3 | Withhold and resume based on medical judgement. |
| Grade 4 | Permanently discontinue. | |
| Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions (5.9)] | Any grade | Permanently discontinue. |
| Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)] | Any grade | Permanently discontinue. |
| Hypertension [see Warnings and Precautions (5.11)] | Grade 2 or 3 | Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy. |
| Grade 4 or hypertensive crisis | Permanently discontinue. | |
| Proteinuria [see Warnings and Precautions (5.14)] | 24-hour urine protein ≥ 3 grams | Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1). Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions. |
| Confirmed nephrotic syndrome | Permanently discontinue. | |
Drug interactions
Check pazopanib against a medication listLabel text (9 paragraphs)
Strong CYP3A4 Inhibitors : Avoid coadministration of VOTRIENT with strong CYP3A4 inhibitors. If coadministration cannot be avoided, reduce the dose of VOTRIENT. ( 2.4 , 7.1 ) Strong CYP3A4 Inducers : Consider an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT is not recommended if chronic use of strong CYP3A4 inducers cannot be avoided. ( 2.4 , 7.1 ) CYP Substrates : Coadministration of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.
( 7.2 ) Concomitant Use With Simvastatin : Concomitant use of VOTRIENT with simvastatin increases the risk of alanine aminotransferase (ALT) elevations. Increase to weekly monitoring of liver function as recommended. Withhold VOTRIENT and resume at reduced dose, or permanently discontinue based on severity of hepatotoxicity. ( 7.3 ) Concomitant Use With Gastric Acid-Reducing Agents : Avoid concomitant use of VOTRIENT with gastric acid-reducing agents. Consider short-acting antacids in place of proton pump inhibitors (PPIs) and H2-receptor antagonists. Separate antacid and pazopanib dosing by several hours. ( 2.4 , 7.4 )
7.1 Effect of Other Drugs on VOTRIENT Strong CYP3A4 Inhibitors Coadministration of pazopanib with strong inhibitors of CYP3A4 increases pazopanib concentrations [see Clinical Pharmacology (12.3)] . Avoid coadministration of VOTRIENT with strong CYP3A4 inhibitors and consider an alternate concomitant medication with no or minimal enzyme inhibition potential. If coadministration of a strong CYP3A4 inhibitor cannot be avoided, reduce the dose of VOTRIENT [see Dosage and Administration (2.4)] . Strong CYP3A4 Inducers Coadministration of strong CYP3A4 inducers may decrease plasma pazopanib concentrations. Consider an alternate concomitant medication with no or minimal enzyme induction potential.
VOTRIENT is not recommended if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.4)] . Transporters Coadministration of strong inhibitors of P-gp or BCRP may increase pazopanib concentrations. Avoid concomitant use of VOTRIENT with strong inhibitors of P-gp or BCRP. Consider selection of alternative concomitant medicinal products with no or minimal potential to inhibit P-gp or BCRP.
7.2 Effects of VOTRIENT on Other Drugs CYP Substrates Coadministration of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 may result in inhibition of the metabolism of these products and create the potential for serious adverse reactions. The concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended [see Clinical Pharmacology (12.3)] .
7.3 Concomitant Use With Simvastatin Concomitant use of VOTRIENT with simvastatin increases the incidence of ALT elevations. Across clinical trials of VOTRIENT as a single agent, ALT > 3 × ULN was reported in 126/895 (14%) of patients who did not use statins compared with 11/41 (27%) of patients who had concomitant use of simvastatin. If a patient receiving concomitant simvastatin develops ALT elevations, increase to weekly monitoring of liver function as recommended. Withhold VOTRIENT and resume at reduced dose, or permanently discontinue based on severity of hepatotoxicity [see Dosage and Administration (2.2), Warnings and Precautions (5.1)] .
Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.
7.4 Concomitant Use With Gastric Acid-Reducing Agents Concomitant use of VOTRIENT with esomeprazole, a PPI, decreased the exposure of pazopanib. Avoid concomitant use of VOTRIENT with gastric acid-reducing agents. If concomitant administration with a gastric acid-reducing agent cannot be avoided, consider short-acting antacids in place of PPIs and H2-receptor antagonists. Separate short-acting antacid and pazopanib dosing by several hours to avoid a reduction in pazopanib exposure [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)] .
7.5 Drugs That Prolong the QT Interval VOTRIENT is associated with QTc interval prolongation [see Warnings and Precautions (5.2), Clinical Pharmacology (12.2)] . Avoid coadministration of VOTRIENT with drugs known to prolong the QT/QTc interval.
Contraindications
None. None. ( 4 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
CLikelihood score C: Probable cause of clinically apparent liver injury.
Pazopanib is a multi-kinase inhibitor active against vascular endothelial growth factor receptors-1, -2 and -3 that is used in the therapy of advanced renal cell carcinoma and soft tissue sarcomas. Pazopanib therapy is commonly associated with transient elevations in serum aminotransferase during therapy and has been linked to rare, but occasionally severe and even fatal cases of clinically apparent acute liver injury.
ABCDEA: well known cause; E: unlikely cause. [HD]: high doses only.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Based on animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)] , VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no available data on VOTRIENT use in pregnant women to evaluate for a 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 the MRHD of 800 mg/day (based on AUC) ( see Data ). Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies and miscarriage is 2% to 4% and 15% to 20%, respectively.
Data Animal Data In a female fertility and early embryonic development study, female rats were administered oral pazopanib at least 15 days prior to mating and for 6 days after mating, which resulted in increased pre-implantation loss and early resorptions at dosages greater than or equal to 30 mg/kg/day (approximately 0.4-fold the AUC at the MRHD of 800 mg/day). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8-fold the AUC at the MRHD of 800 mg/day). Postimplantation loss, embryolethality, and decreased fetal body weights were noted in females administered doses greater than or equal to 10 mg/kg/day (approximately 0.3-fold the AUC at the MRHD of 800 mg/day).
In embryo-fetal developmental toxicity studies in rats and rabbits, oral pazopanib was administered to pregnant animals during organogenesis. In rats, dose levels of greater than or equal to 3 mg/kg/day (approximately 0.1-fold the AUC at the MRHD of 800 mg/day) resulted in teratogenic effects, including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch), incomplete or absent ossification, increases in postimplantation loss, embryolethality and reduced fetal body weight.
In rabbits, maternal toxicity, increased postimplantation loss and abortion were observed at doses greater than or equal to 30 mg/kg/day (approximately 0.007-fold the AUC at the MRHD of 800 mg/day). In addition, severe maternal body weight loss and 100% litter loss were observed at doses greater than or equal to 100 mg/kg/day (0.02-fold the…
Breastfeeding (LactMed)
No information is available on the clinical use of pazopanib during breastfeeding. Because pazopanib is more than 99% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 31 hours and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during pazopanib therapy and for 2 weeks after the final dose.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
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