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Pazopanib is a small molecule inhibitor of multiple protein tyrosine kinases with potential antineoplastic activity.

It is developed by GlaxoSmithKline and was FDA approved on October 19, 2009.

Treatment of advanced renal cell cancer and advanced soft tissue sarcoma (in patients previously treated with chemotherapy)

Pazopanib is a synthetic indazolylpyrimidine and reaches steady state concentrations of >15 μg/ml. This concentration is high enough to observe maximal inhibition of VEGFR2 phosphorylation and some anti-tumour activity (concentration required to inhibit receptors is 0.01-0.084 μmol/L).

A reduction in tumour blood flow, increased tumour apoptosis, inhibition of tumour growth, reduction in tumour interstitial fluid pressure, and hypoxia in cancer cells can be observed in patients receiving treatment.

Vascular endothelial growth factor receptor 1 Inhibitor Vascular endothelial growth factor receptor 2 Inhibitor Vascular endothelial growth factor receptor 3 Inhibitor + 3 more targets.

of pazopanib in cancer patients is slow and incomplete.

In patients with solid tumour, over a dose range of 50-2000 mg, absorption is nonlinear.

Significant accumulation of pazopanib can also be observed in patients receiving 800 mg once daily for 22 days.

Crushing tablets may increase exposure (increase in Cmax and AUC, while Tmax decreases by 2 hours).

Bioavailability, oral tablet 800 mg, cancer patient = 21% Bioavailability may be low due to incomplete absorption from the gastrointestinal tract.

The major circulating component of the drug in the systemic is pazopanib, and not its metabolites.

Mean maximum plasma concentration= 58.1 µg/mL Mean AUC= 1037 µg.

Vd steady state, Intravenous administration 5 mg, cancer patient = 11.1 L (range of 9.15-13.4).

Metabolized by

CYP3A4 and to a lesser extent by CYP1A2 and CYP2C8.

Metabolites are less active than pazopanib (10-20-fold less active).

Three of its metabolites can be observed in the systemic and account for <10% of plasma radioactivity.

Primarily excreted via feces (82.2%) and to a negligible extent via urine (<4%) in cancer patients.

Most of the administered dose is excreted unchanged.

Approximately 10% of dose are oxidative metabolites and are mostly eliminated via the feces.

Oral absorption is not the rate limiting step of elimination from the plasma.

cancer patient, Intravenous administration 5 mg = 4 mL/min Half of the absorbed dose is cleared via oxidative metabolism.

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Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in of 3 patients dosed at 2,000 mg daily (2.5 times the recommended dose) and 1,000 mg daily (1.25 times the recommended dose), respectively.

Provide general supportive measures to manage an overdose.

Hemodialysis is not expected to enhance the elimination of pazopanib tablets because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal).

Impairment: 200 mg orally once daily. 2.1 Recommended Dosage The recommended dosage of pazopanib tablets 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.

The dosage should be modified for hepatic impairment and in patients taking certain concomitant drugs.

Swallow tablets whole.

Do not crush tablets due to the potential for increased rate of absorption, which may affect systemic exposure.

If a dose is missed, it should not be taken if it is <12 hours until the next dose. 2.2 Dosage Modifications for Adverse Reactions Table 1 summarizes the recommended dose reductions.

Table 1.

Recommended Dose Reductions of Pazopanib tablets for Adverse Reactions 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 pazopanib tablets in patients unable to tolerate the second dose reduction.

Table 2 summarizes the recommended dosage modifications for adverse reactions.

Table 2.

Recommended Dosage Modifications of Pazopanib Tablets for Adverse Reactions Adverse Reaction Severity a Dosage Modification Hepatic Toxicity Isolated ALT elevations between 3 x ULN and 8 x ULN Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.

ALT elevations of > 8 x ULN Withhold until improvement to Grade 1 or baseline.

If the potential benefit for resuming treatment with pazopanib tablets 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 x ULN recur despite dose reduction(s).

ALT elevations > 3 x ULN occur concurrently with bilirubin elevations > 2 x 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 x ULN should be managed per the recommendations outlined for isolated ALT elevations.

Left Ventricular Systolic Dysfunction Symptomatic or Grade 3 Withhold until improvement to Grade < 3.

Resume treatment based on medical judgement.

Grade 4 Permanently discontinue.

Grade 2 Withhold until improvement to Grade ≤ 1.

Resume at reduced dose.

Grade 2 recurs after dose interruption and reduction.

Grade 3 or 4 Permanently discontinue.

Arterial Thromboembolic Events Any grade

Permanently discontinue.

Grade 3 Withhold pazopanib tablets and resume at same dose if managed with appropriate therapy for at least one week.

Thrombotic Microangiopathy Any grade

Gastrointestinal Perforation Any grade

Grade 2 or 3 Withhold and resume based on medical judgement.

Disease / Pneumonitis Any grade Permanently discontinue.

Posterior Reversible Encephalopathy Syndrome Any grade Permanently discontinue.

Grade 2 or 3 Reduce dose 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 24-hour urine protein ≥ 3 grams Confirmed nephrotic syndrome Withhold until improvement to Grade ≤ 1.

Resume at a reduced dose.

Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.

ALT, alanine aminotransferase; ULN, upper limit of normal. a National Cancer Institute Common Terminology Criteria for Adverse Events, version 5. 2.3 Dosage Modifications for Hepatic Impairment Moderate and Severe Hepatic Impairment In patients with moderate hepatic impairment [total bilirubin > 1.5 to 3 x upper limit of normal (ULN) and any alanine aminotransferase (ALT) value], consider alternatives to pazopanib tablets.

If pazopanib tablets are used in patients with moderate hepatic impairment, reduce the pazopanib tablets dose to 200 mg orally once daily.

Pazopanib tablets are not recommended in patients with severe hepatic impairment (total bilirubin > 3 x ULN and any ALT value) .

CYP3A4 Inducers Avoid concomitant use of strong CYP3A4 inducers by use of an alternate concomitant medication with no or minimal enzyme induction potential.

Pazopanib tablets are not recommended in patients who cannot avoid chronic use of strong CYP3A4 inducers.

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 H 2 -receptor antagonists.

Separate short-acting antacid and pazopanib tablets dosing by several hours.

Pazopanib tablets 200 mg tablets are supplied as gray, capsule shape, biconvex film-coated tablet.

Engraved “P200” on one side, “APO” on the other side: Bottles of 120 tablets: NDC 51407-872-12 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Based on animal reproduction studies and its mechanism of action, pazopanib tablets can cause fetal harm when administered to a pregnant woman.

There are no available data on pazopanib tablets 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) .

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.

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).

The safety and effectiveness of pazopanib tablets in pediatric patients have not been established.

Pazopanib tablets are 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.

The safety and efficacy of pazopanib tablets or an unapproved pazopanib formulation were investigated but not established in two open-label studies: a study in 37 pediatric patients 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.

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 pazopanib.

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 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.

In pooled clinical trials with pazopanib tablets, 30% of 2,080 patients were aged ≥ 65 years.

More patients ≥ 65 years had ALT elevations > 3 x ULN compared to patients < 65 years (23% versus 18%) .

In the

RCC trials, 33% of 586 patients were aged ≥ 65 years.

No overall differences in safety or effectiveness of pazopanib tablets were observed between these patients and younger patients.

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 pazopanib tablets were observed between patients aged ≥ 65 years and younger patients.