Votrient Prescribing Information
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)].
Renal Cell Carcinoma
VOTRIENT® is indicated for the treatment of adults with advanced renal cell carcinoma (RCC).
Soft Tissue Sarcoma
VOTRIENT is indicated for the treatment of adults with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.
Limitations of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.
Recommended Dosage
The recommended dosage of VOTRIENT is 800 mg (four 200 mg tablets) orally once daily without food (at least 1 hour before or 2 hours after a meal) until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3)]. The dosage should be modified for hepatic impairment and in patients taking certain concomitant drugs [see Dosage and Administration (2.3, 2.4)].
Swallow tablets whole. Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure [see Clinical Pharmacology (12.3)].
If a dose is missed, it should not be taken if it is < 12 hours until the next dose.
Dosage Modifications for Adverse Reactions
Table 1 summarizes the recommended dose reductions.
| 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 |
Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.
Table 2 summarizes the recommended dosage modifications for adverse reactions.
| 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. | |
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 (8.7)].
Dosage Modifications for Drug Interactions
Strong CYP3A4 Inhibitors
Avoid concomitant use of strong CYP3A4 inhibitors by use of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg [see Drug Interactions (7.1)].
Strong CYP3A4 Inducers
Avoid concomitant use of strong CYP3A4 inducers by use of an alternate concomitant medication with no or minimal enzyme induction potential. VOTRIENT is not recommended in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].
Gastric Acid-Reducing Agents
Avoid concomitant use of gastric acid-reducing agents. If concomitant use of a gastric acid-reducing agent cannot be avoided, consider short-acting antacid in place of proton pump inhibitors (PPIs) and H2-receptor antagonists. Separate short-acting antacid and VOTRIENT dosing by several hours [see Drug Interactions (7.4), Clinical Pharmacology (12.3)].
Tablets: 200 mg, modified capsule-shaped, gray or pink, film-coated with ‘GS JT’ debossed on one side.
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 AUC at the MRHD of 800 mg/day), while fetal weight was reduced at doses greater than or equal to 3 mg/kg/day (AUC not calculated).
Lactation
Risk Summary
There is no data on the presence of pazopanib or its metabolites in human milk or their effects on the breastfed infant or milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with VOTRIENT and for 2 weeks after the final dose.
Females and Males of Reproductive Potential
VOTRIENT can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to starting treatment with VOTRIENT.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with VOTRIENT and for at least 2 weeks after the last dose.
Males
Advise males (including those who have had vasectomies) with female partners of reproductive potential to use condoms during treatment with VOTRIENT and for at least 2 weeks after the last dose.
Infertility
Based on findings from animal studies, VOTRIENT may impair fertility in females and males of reproductive potential while receiving treatment [see Nonclinical Toxicology (13.1)].
Pediatric Use
The safety and effectiveness of VOTRIENT in pediatric patients have not been established.
VOTRIENT is not indicated for use in pediatric patients [see Warnings and Precautions (5.18)]. Based on its mechanism of action, pazopanib may have severe effects on organ growth and maturation during early postnatal development. Administration of pazopanib to juvenile rats < 21 days old resulted in toxicity to the lungs, liver, heart, and kidney and in death at doses significantly lower than the clinically recommended dose or doses tolerated in older animals (see Juvenile Animal Toxicity Data).
The safety and efficacy of VOTRIENT or an unapproved pazopanib formulation were investigated but not established in two open-label studies: a study in 37 pediatric patients 2 to < 17 years with recurrent or refractory solid tumors [NCT00929903] and a study in 46 pediatric patients 1 year to < 17 years with refractory solid tumors, including sarcoma [NCT01956669]. Meaningful anti-tumor activity was not observed in these studies.
Juvenile Animal Toxicity Data
In rats, weaning occurs at Day 21 postpartum which approximately equates to a human pediatric age of 2 years. In a juvenile animal toxicology study performed in rats, when animals were dosed from Day 9 through Day 14 postpartum (pre-weaning), pazopanib caused abnormal organ growth/maturation in the kidney, lung, liver, and heart at approximately 0.1-fold the AUC in adults at the MRHD of 800 mg/day of VOTRIENT. At approximately 0.4-fold the AUC in adults at the MRHD of 800 mg/day, pazopanib administration resulted in mortality.
In repeat-dose toxicology studies in rats, including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses greater than or equal to 3 mg/kg/day (approximately 0.07-fold the AUC at the MRHD of 800 mg/day). Doses of 300 mg/kg/day (approximately 0.8-fold the AUC at the MRHD of 800 mg/day) were not tolerated in 13- and 26-week studies and animals required dose reductions due to body weight loss and morbidity. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken, and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at doses greater than or equal to 30 mg/kg/day (approximately 0.35-fold the AUC at the MRHD of 800 mg/day) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. Similar findings were noted in repeat-dose studies in juvenile rats dosed with pazopanib beginning Day 21 postpartum (post-weaning). In the post-weaning animals, the occurrence of changes in teeth and bones occurred earlier and with greater severity than in older animals. There was evidence of tooth degeneration and decreased bone growth at doses greater than or equal to 30 mg/kg (approximately 0.1- to 0.2-fold the AUC at the MRHD of 800 mg/day). Pazopanib exposure in juvenile rats was lower than that seen at the same dose levels in adult animals, based on comparative AUC values. At pazopanib doses approximately 0.5- to 0.7-fold the AUC at the MRHD of 800 mg/day, decreased bone growth in juvenile rats persisted even after the end of the dosing period. Finally, despite lower pazopanib exposures than those reported in adult animals or adult humans, juvenile animals administered 300 mg/kg/dose pazopanib required dose reduction within 4 weeks of dosing initiation due to significant toxicity, although adult animals could tolerate this same dose for at least 3 times as long [see Warnings and Precautions (5.18)].
Geriatric Use
In pooled clinical trials with VOTRIENT, 30% of 2080 patients were aged ≥ 65 years. More patients ≥ 65 years had ALT elevations > 3 × ULN compared to patients < 65 years (23% versus 18%) [see Warnings and Precautions (5.1)].
In the RCC trials, 33% of 586 patients were aged ≥ 65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients.
In the STS trials, 24% of 382 patients were aged ≥ 65 years. Patients aged ≥ 65 years had a higher incidence of Grade 3 or 4 fatigue (19% versus 12% for patients aged < 65 years), hypertension (10% versus 6%), decreased appetite (11% versus 2%), ALT elevations (3% versus 2%) and AST elevations (4% versus 1%). In the randomized STS trial (VEG110727), no overall differences in effectiveness of VOTRIENT were observed between patients aged ≥ 65 years and younger patients.
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.
Hepatic Impairment
No dose adjustment is required in patients with mild hepatic impairment (either total bilirubin ≤ ULN and ALT > ULN or bilirubin > 1 to 1.5 × ULN and any ALT value). VOTRIENT is not recommended in patients with moderate (total bilirubin > 1.5 to 3 × ULN and any ALT value) and severe (total bilirubin > 3 × ULN and any ALT value) hepatic impairment [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].
None.