Votrient Drug Information

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.

Dosage Modifications for Adverse Reactions Table 1 summarizes the recommended dose reductions. Table 1. Recommended Dose Reductions of VOTRIENT for Adverse Reactions Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.

Table 2. Recommended Dosage Modifications of VOTRIENT for Adverse Reactions Interstitial Lung Disease / Pneumonitis Any grade Permanently discontinue. Posterior Reversible Encephalopathy Syndrome

Dosage Modifications for Hepatic Impairment Moderate and Severe Hepatic Impairment In patients with moderate hepatic impairment, 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).

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. 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. 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS section reflect exposure of 977 patients who received VOTRIENT as a single agent, including 586 VOTRIENT-treated patients with RCC. The data described in the WARNINGS AND PRECAUTIONS also reflects exposure of 382 patients with advanced soft tissue sarcoma who received VOTRIENT as a single agent, with a median duration of treatment of 3.6 months (range, 0 to 53).

The most common adverse reactions (≥ 20%) in these 382 patients were fatigue, diarrhea, nausea, decreased weight, hypertension, decreased appetite, vomiting, tumor pain, hair color changes, musculoskeletal pain, headache, dysgeusia, dyspnea, and skin hypopigmentation. Renal Cell Carcinoma The safety of VOTRIENT was evaluated in 290 patients with RCC who participated in VEG105192, a randomized, double-blind, placebo-controlled trial. The median duration of treatment was 7.4 months (range, 0 to 23) for patients who received VOTRIENT.

Forty-two percent of patients on VOTRIENT required a dose interruption and 36% required a dose reduction. Table 3 presents adverse reactions in VEG105192. Table 3.

Table 4 presents the laboratory abnormalities in VEG105192. Table 4. Select Laboratory Abnormalities (> 10%) in Patients with RCC Who Received VOTRIENT with a Difference Between Arms of ≥ 5% Compared to Placebo in VEG 1 0 Additional adverse reactions from other clinical trials in patients with RCC who received VOTRIENT include arthralgia and muscle spasms.

Soft Tissue Sarcoma The safety of VOTRIENT was evaluated in 240 patients who participated in VEG110727, a randomized, double-blind, placebo-controlled trial. The median duration of treatment was 4.5 months (range, 0 to 24) for patients who received VOTRIENT. Fifty-eight percent of patients on VOTRIENT required a dose interruption and 38% required a dose reduction.

Seventeen percent of patients who received VOTRIENT discontinued therapy due to adverse reactions. Table 5 presents the adverse reactions in VEG110727. Table 5.

Table 6 presents the laboratory abnormalities in VEG110727. Table 6. Select Laboratory Abnormalities (> 10%) in Patients with STS Who Received VOTRIENT with a Difference Between Arms of ≥ 5% Compared to Placebo in VEG Other Clinically Relevant Adverse Reactions Lipase Elevations In a single-arm RCC trial (VEG102616), elevated lipase was observed for 27% of 181 patients with available laboratory data.

In the RCC trials, clinical pancreatitis was observed in < 1% of 586 patients. Bradycardia In the randomized RCC trial (VEG105192), bradycardia based on vital signs (< 60 beats per minute) was observed in 19% of 280 patients treated with VOTRIENT. Bradycardia was reported as an adverse reaction in 2% of 290 patients.

In the randomized STS trial (VEG110727), bradycardia based on vital signs (< 60 beats per minute) was observed in 19% of 238 patients treated with VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Polycythemia Eye Disorders: Retinal detachment/tear Gastrointestinal Disorders: Pancreatitis Metabolic and Nutrition Disorder: Tumor lysis syndrome (including fatal cases) Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture (including fatal cases)

Effect of Other Drugs on VOTRIENT Strong CYP3A4 Inhibitors Coadministration of pazopanib with strong inhibitors of CYP3A4 increases pazopanib concentrations. 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.

Strong CYP3A4 Inducers Coadministration of strong CYP3A4 inducers may decrease plasma pazopanib concentrations. VOTRIENT is not recommended if chronic use of strong CYP3A4 inducers cannot be avoided. 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.

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.

Concomitant Use With Simvastatin

Concomitant use of VOTRIENT with simvastatin increases the incidence of ALT elevations. 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.

Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

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.

Drugs That Prolong the QT Interval VOTRIENT is associated with QTc interval prolongation. Avoid coadministration of VOTRIENT with drugs known to prolong the QT/QTc interval.

Pregnancy Risk Summary Based on animal reproduction studies and its mechanism of action, 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 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).

Pediatric Use The safety and effectiveness of VOTRIENT in pediatric patients have not been established. VOTRIENT is 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.

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 and a study in 46 pediatric patients 1 year to < 17 years with refractory solid tumors, including sarcoma. 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.

Provide general supportive measures to manage an overdose. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.