PORENZA

Pazopanib is a kinase inhibitor.

Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-Dimethyl-2 H -indazol-6-yl)methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide monohydrochloride.

It has the molecular formula

C 21 H 23 N 7 O 2 S·HCl and a molecular weight of 473.98 g/mol.

Pazopanib hydrochloride has the following chemical structure: Pazopanib hydrochloride is a white to slightly yellow solid.

It is very slightly soluble in aqueous solutions, being practically insoluble above pH 4.

Pazopanib tablets are for oral use.

Each 200-mg tablet of pazopanib tablets contains 200 mg of pazopanib equivalent to 216.7 mg of pazopanib hydrochloride.

The inactive ingredients of pazopanib tablets are: Tablet Core: magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.

Gray film-coat: hydroxypropyl cellulose, hydroxypropyl methylcellulose, iron oxide black, polyethylene glycol 8000, and titanium dioxide. structuure.jpg.

Pazopanib tablets are a kinase inhibitor indicated for the treatment of adults with: advanced renal cell carcinoma (RCC). advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

The efficacy of pazopanib tablets for the treatment of patients with adipocytic soft tissue sarcoma or gastrointestinal stromal tumors has not been demonstrated. 1.1 Renal Cell Carcinoma Pazopanib tablets are indicated for the treatment of adults with advanced renal cell carcinoma (RCC). 1.2 Soft Tissue Sarcoma Pazopanib tablets are indicated for the treatment of adults with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

The efficacy of pazopanib tablets for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.

QT space extension, history (of) Aneurysm, history (d) History of thromboembolic accident History of treatment with anthracycline Cardiopathies Large tumour load Dehydration Female likely to be pregnant Left ventricular ejection fraction (decrease) Pregnancy Hemoptysis, history (d) Brain haemorrhage, history (d) Gastrointestinal haemorrhage, recent history (d) Male of childbearing age Hypertension Heart failure Hepatic impairment Renal impairment Surgical intervention Pregnant or likely partner Patient carrying the allele HLA-B*5701 Subject at risk of heart Subject at risk of thromboembolic accident Subject at risk of QT space prolongation Subject at risk of digestive fistula Subject at risk of gastrointestinal perforation Subject at risk for tumour lysis syndrome Subject at risk of bleeding Subject under 18 Subject over 60 years Thrombosis, recent history (de) Vectomy.

Pazopanib is a multi-tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-ɑ and -β, fibroblast growth factor receptor (FGFR)-1 and -3, cytokine receptor (Kit), interleukin-2 receptor-inducible T-cell kinase (Itk), lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c­-Fms).

In vitro, pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit, and PDGFR-β receptors.

In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in a mouse model, and the growth of some human tumor xenografts in mice. 12.2 Pharmacodynamics Increases in blood pressure have been observed and are related to steady-state trough plasma pazopanib concentrations.

QT prolongation potential of pazopanib was assessed in a randomized, blinded, parallel trial (N = 96) using moxifloxacin as a positive control. pazopanib tablets 800 mg orally under fasting conditions was administered on Days to 8 and 1,600 mg was administered on Day 9 after a meal in order to increase exposure to pazopanib and its metabolites.

No large changes (i.e.,> 20 msec) in QTc interval following exposure to pazopanib were detected in this QT trial.

The trial was not able to exclude small changes (< 10 msec) in QTc interval, because assay sensitivity below this threshold (< 10 msec) was not established in this trial. 12.3 Pharmacokinetics The recommended dosage of 800 mg once daily results in mean AUC of 1,037 mcg•h/mL and C max of 58.1 mcg/mL.

There was no consistent increase in AUC or C max at pazopanib doses above 800 mg. Administration of a single 400-mg crushed tablet increased AUC 0-72h by 46% and C max by approximately 2-fold and decreased T max by approximately 2 hours compared with administration of the whole tablet.

The median time to achieve peak concentrations was to 4 hours after a dose.

Systemic exposure to pazopanib is increased when administered with food.

Administration of pazopanib with a high-fat (approximately 50% fat) or low-fat (approximately 5% fat) meal results in an approximately 2-fold increase in AUC and C max.

Binding of pazopanib to human plasma protein in vivo was > 99% with no concentration dependence over the range of to 100 mcg/mL.

In vitro studies suggest that pazopanib is a substrate for P-gp and BCRP.

Pazopanib has a mean half-life of 31 hours after administration of the recommended dose of 800 mg. Metabolism In vitro studies demonstrated that pazopanib is metabolized by CYP3A4 with a minor contribution from CYP1A2 and CYP2C8.

Elimination is primarily via feces with renal elimination accounting for < 4% of the administered dose.

Specific Populations Patients with Hepatic Impairment

Table 7 presents a comparison of the median steady-state C max and the median AUC 0-24h values for patients with normal, mild, moderate and severe hepatic impairment.

The median steady-state of pazopanib C max and AUC 0-24h after a once-daily dose of 800 mg in patients with mild impairment were in a similar range as the median steady-state C max and median AUC 0-24h in patients with no hepatic impairment.

The maximum tolerated pazopanib dose in patients with moderate hepatic impairment was 200 mg once daily.

The median steady-state C max and the median AUC 0-24h were approximately 43% and 29%, respectively, of the corresponding median values after administration of 800 mg once daily in patients with no hepatic impairment.

The median steady-state C max and the median AUC 0-24h were approximately 18% and 15%, respectively, of the corresponding median values after administration of 800 mg once daily in patients with no hepatic impairment.

Table 7.

Pharmacokinetic Parameters of Pazopanib in Patients with Hepatic Impairment No Hepatic Impairment Mild Hepatic Impairment (total bilirubin ≤ ULN and ALT > ULN or total bilirubin > 1 to 1.5 x ULN and any ALT value) Moderate Hepatic Impairment (total bilirubin > 1.5 to 3 x ULN and any ALT value ) Severe Hepatic Impairment (total bilirubin > 3 x ULN and any ALT value) Dose 800 mg once daily 800 mg once daily 200 mg once daily 200 mg once daily Median steady.

• state C max (range) mcg/mL 52 (17 to 86) 34 (11 to 104) 22 (4.2 to 33) 9.4 (2.4 to 24) Median AUC 0-24h (range) mcg•h/mL 888 (346 to 1482) 774 (215 to 2034) 257 (66 to 488) 131 (47 to 473) Abbreviations: ALT, alanine aminotransferase; AUC, area under the curve; C max, maximum concentration; ULN, upper limit of normal.

Drug Interactions Studies Clinical Studies Strong

CYP3A4 Inhibitor: Coadministration of multiple doses of oral pazopanib tablets 400 mg with multiple doses of oral ketoconazole 400 mg (strong CYP3A4/P-gp inhibitor) resulted in a 1.7-fold increase in the AUC 0-24h and a 1.5-fold increase in the C max of pazopanib.

CYP3A4 Inhibitor: Coadministration of 1,500 mg lapatinib, a substrate and weak inhibitor of CYP3A4, P-gp, and BCRP, with pazopanib tablets 800 mg resulted in an approximately 50% to 60% increase in mean pazopanib AUC 0-24h and C max.

CYP1A2, CYP2C9 and CYP2C19 Substrates: Clinical studies, using pazopanib tablets 800 mg once daily, have demonstrated that pazopanib does not have a clinically relevant effect on the pharmacokinetics of caffeine (CYP1A2 probe substrate), warfarin (CYP2C9 probe substrate), or omeprazole (CYP2C19 probe substrate) in patients with cancer.

CYP3A4, CYP2D6, and CYP2C8 Substrates: Coadministration of pazopanib tablets resulted in an increase of approximately 30% in the mean AUC and C max of midazolam (CYP3A4 probe substrate) and increases of 33% to 64% in the ratio of dextromethorphan to dextrorphan concentrations in the urine after oral administration of dextromethorphan (CYP2D6 probe substrate).

Coadministration of pazopanib tablets 800 mg once daily and paclitaxel 80 mg/m 2 (CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of 26% and 31% in paclitaxel AUC and C max, respectively.

Coadministration of pazopanib tablets with esomeprazole, a PPI, decreased the exposure of pazopanib by approximately 40% (AUC and C max ) .

In vitro studies with human liver microsomes showed that pazopanib inhibited the activities of CYP enzymes 1A2, 3A4, 2B6, 2C8, 2C9, 2Cl9, 2D6, and 2El.

Potential induction of human

CYP3A4 was demonstrated in an in vitro human pregnane X receptor (PXR) assay.

In vitro studies also showed that pazopanib inhibits UGT1A1 and organic anion-transporting polypeptide (OATP1B1) with IC 50 s of 1.2 and 0.79 mcM, respectively. 12.5 Pharmacogenomics Pazopanib can increase serum total bilirubin levels.

In vitro studies showed that pazopanib inhibits UGT1A1, which glucuronidates bilirubin for elimination.

A pooled pharmacogenetic analysis of 236 white patients who received pazopanib tablets showed that the (TA)7/(TA)7 genotype (UGT1A128/28) (underlying genetic susceptibility to Gilbert's syndrome) was associated with a statistically significant increase in the incidence of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes.

In a pooled pharmacogenetic analysis of data from 31 clinical studies of pazopanib administered as either monotherapy or in combination with other agents, ALT > 3 x ULN (Grade 2) occurred in 32% (42/133) of HLA-B57:01 allele carriers and in 19% (397/2,101) of non-carriers and ALT > 5 x ULN (Grade 3) occurred in 19% (25/133) of HLA-B57:01 allele carriers and in 10% (213/2,101) of non-carriers.

In this dataset, 6% (133/2,234) of the patients carried the HLA-B*57:01 allele.

Pazopanib is a potent inhibitor of tyrosine kinase of vascular endothelial growth factor receptors (VEGFR2, VEGFR1 and VEGFR3), platelet growth factor receptors (PDGFRα and PDGFRβ), stem cell factor receptor (c-KIT), and inhibits autophosphorylation of VEGFR2 induced by VEGF.

• (increase) (Very common)
• Hypomagnesaemia (Uncommon)
• Neutropenia (Common)
• Uremia (increase) (Common)
• ASAT (increase) (Very common)
• Blood cholesterol increased (Common)
• White Globules decreased (Common)
• Serum lipase (increase) (Common)
• Transaminases (increase) (Uncommon)
• Proteinuria (Very common)
• TSH (increase) (Common)
• Blood creatinine (increase) (Common)
• Liver enzymes (increase) (Uncommon)
• Hypoalbuminaemia (Very common)
• Amylasemia (increase) (Common)
• Liver status (abnormality) (Common)
• Hypophosphataemia (Common)
• Hyperbilirubinaemia (Common)
• Gamma GT (increase) (Common)
• Glycaemia decreased (Uncommon)
• Bilirubinaemia (increase) (Common)
• Platelet number decreased (Uncommon)
• Neutralophiles decreased Tumor lysis syndrome Tumor pain Alopecia (Common)
• Dry skin (Common)
• Dermatosis (Uncommon)
• Palmoplantary Erythema (Uncommon)
• Hypomelanosis (Common)
• Machinous eruption (Uncommon)
• Pruritus (Common)
• Papulous eruption (Uncommon)
• Mucite (Common)
• Hair colour (change) (Very common)
• Vesicular rash (Uncommon)
• Mucosal injury (Uncommon)
• Erythematous rash (Uncommon)
• Onychopathy (Uncommon)
• Skin exfoliation (Uncommon)
• Generalised pruritus (Uncommon)
• Palmoplantary Erythrodysaesthesia (Very common)
• Generalised rash (Uncommon)
• Hyperhidrosis (Common)
• Skin depigmentation (Common)
• Photosensitivity (Uncommon)
• Rash (Very common)
• Skin ulcer (Uncommon)
• Skin Erythema (Common)
• Pruriginous rash (Uncommon)
• Chest pain (Common)
• Enterocutaneous fistula (Uncommon)
• Edema (Common)
• Frisher (Uncommon)
• Fatigue (Very common)
• Asthenia (Common)
• Localized edema
• Face edema Peripheral edema Hypothyroidism (Common)
• Dysthyroidism (Uncommon)
• Metrorragie (Uncommon)
• Vaginal haemorrhage (Uncommon)
• Menorrhagia (Uncommon)
• Thrombocytopenia (Common)
• Leucopenia (Common)
• Anal haemorrhage (Uncommon)
• Haemorrhage (Uncommon)
• Polyglobulia (Uncommon)
• Oral haemorrhage (Uncommon)
• Thrombotic thrombocytopenic purpura Hepatic injury induced by a medicine (Uncommon)
• Hepatitistoxicity (Common)
• Ictery (Uncommon)
• Hepatic impairment Peritonitis (Uncommon)
• Infection (Common)
• Neutropenic infection (Common)
• Appetite decreased (Very common)
• Dehydration (Common)
• Weight (decrease) (Common)
• Anorexia Retina decollation (Uncommon)
• Retinal hair loss (Uncommon)
• Blurty vision (Common)
• Discoloration of eyelashes (Uncommon)
• Palpebral edema Eye edema Dysgueusia (Very common)
• Oropharyngeal pain (Uncommon)
• Feeling dizzy (Common)
• Rhinorrhea (Uncommon)
• Earache (Common)
• Oral ulceration (Common)
• Epistaxis (Common)
• Oral dryness (Common)
• Stomatitis (Common)
• Dysphony (Common)
• Augustusia
• Gingival infection Hypogueusia Lethargy (Common)
• Insomnia (Common)
• Hot flash (Common)
• Bradycardia (Uncommon)
• Cardiac dysfunction (Uncommon)
• Venous thromboembolic accident (Common)
• Hypertensive crisis (Uncommon)
• Increased systolic blood pressure (Uncommon)
• Congestive puff (Common)
• Blood pressure (increase) (Common)
• Diastolic hypertension (Uncommon)
• QT space extension (Uncommon)
• Hypertension (Very common)
• Cardiovascular disease (Uncommon)
• Myocardial infarction (Uncommon)
• Myocardial Ischemia (Uncommon)
• Dissection of the arterial system (Rare)
• Aneurysm (Rare)
• Thrombotic microangiopathy (Rare)
• Thrombosis Left ventricular dysfunction Deep thrombophlebitis
• Lung embolism Heart failure Abdominal distension (Common)
• Digestive haemorrhage (Uncommon)
• Dyspepsia (Common)
• Nausea (Very common)
• Diarrhoea (Very common)
• Rectorragie (Uncommon)
• Abdominal pain (Very common)
• Abnormal liver function (Common)
• Vomiting (Very common)
• Common stools (Uncommon)
• Hematemesis (Uncommon)
• Hematochesis (Uncommon)
• Colic perforation (Uncommon)
• Gastrointestinal haemorrhage (Uncommon)
• Melena (Uncommon)
• Hoquet (Common)
• Retroperitoneal haemorrhage (Uncommon)
• Esophagus haemorrhage (Uncommon)
• Haemorrhoidal haemorrhage (Uncommon)
• Gastric haemorrhage (Uncommon)
• Flatulence (Common)
• Pancreatitis (Uncommon)
• Intestinal perforation (Uncommon)
• Lower abdominal pain
• Upper abdominal pain Joint pain (Common)
• Musculoskeletal pain (Uncommon)
• Muscle spasm (Common)
• Muscle pain (Common)
• Somnolence (Uncommon)
• Peripheral sensory neuropathy (Common)
• Paraesthesia (Common)
• Headache (Very common)
• Stroke (Uncommon)
• Transient ischemic accident (Uncommon)
• Brain infarction (Uncommon)
• Ischemic stroke (Uncommon)
• Hypoesthesia (Uncommon)
• Reversible posterior encephalopathy syndrome (Rare)
• Bronchial haemorrhage (Uncommon)
• Cough (Common)
• Dyspnoea (Common)
• Hemoptysis (Common)
• Intrapulmonary haemorrhage (Uncommon)
• Pneumothorax (Uncommon)
• Lung injury (Rare)
• Interstitial pneumopathy (Rare)
• Urinary tract haemorrhage (Uncommon)
• Hemolytic and uremic syndrome.

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.