Votrient

Votrient

pazopanib

Manufacturer:

Novartis Healthcare

Distributor:

Zuellig
Full Prescribing Info
Contents
Pazopanib HCl.
Description
Each 200 mg tablet contains 216.7 mg of pazopanib hydrochloride, which is equivalent to 200 mg of pazopanib as free base.
Each 400 mg tablet contains 433.4 mg of pazopanib hydrochloride, which is equivalent to 400 mg of pazopanib as free base.
Excipients/Inactive Ingredients: Tablet Core: Magnesium stearate, Microcrystalline cellulose, Povidone (K30), Sodium starch glycollate.
Tablet coating: 200 mg (Opadry Pink): Hypromellose, Iron Oxide Red (E172), Macrogol/PEG 400, Polysorbate 80, Titanium dioxide (E171).
400 mg (Opadry White): Hypromellose, Macrogol/PEG 400, Polysorbate 80, Titanium dioxide (E171).
Action
Pharmacotherapeutic group: Antineoplastic agents - Protein kinase inhibitor. ATC Code: L01XE11.
Pharmacology: Pharmacodynamics: Mechanism of action: Pazopanib is an orally administered, potent multi-target tyrosine kinase inhibitor (TKI) of Vascular Endothelial Growth Factor Receptors (VEGFR)-1, -2, and -3, platelet-derived growth factor (PDGFR)-alpha and -beta, and stem cell factor receptor (c-KIT), with IC50 values of 10, 30, 47, 71, 84 and 74 nM, respectively. In preclinical experiments, pazopanib dose-dependently inhibited ligand-induced auto-phosphorylation of VEGFR-2, c-Kit and PDGFR-beta receptors in cells. In vivo, pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in various animal models, and the growth of multiple human tumour xenografts in mice.
Clinical Studies: Renal Cell Carcinoma (RCC): The safety and efficacy of pazopanib in renal cell carcinoma (RCC) were evaluated in a randomized, double-blind, placebo-controlled multi-centre study. Patients (N= 435) with locally advanced and/or metastatic RCC were randomized to receive pazopanib 800 mg once daily or placebo. The primary objective of the study was to evaluate and compare the two treatment arms for progression-free survival (PFS) and the principle secondary endpoint is overall survival (OS). The other objectives were to evaluate the overall response rate and duration of response.
From the total of 435 patients in this study, 233 patients were treatment naïve and 202 were second line patients who had received one prior IL-2 or INF alpha-based therapy. The performance status (ECOG) was similar between the pazopanib and placebo groups (ECOG 0: 42% vs. 41%, ECOG 1: 58% vs. 59%). All patients had clear cell histology or predominantly clear cell histology. Approximately half of all patients had 3 or more organs involved in their disease and most patients had the lung (74%), and/or lymph nodes (54%) as a metastatic location for disease at baseline.
A similar proportion of patients in each arm were treatment-naive and cytokine-pre-treated (53% and 47% in pazopanib arm, 54% and 46% in placebo arm). In the cytokine-pre-treated subgroup, the majority (75%) had received interferon based treatment.
Similar proportions of patients in each arm had prior nephrectomy (89% and 88% in the pazopanib and placebo arms, respectively) and/or prior radiotherapy (22% and 15% in the pazopanib and placebo arms, respectively.
The primary analysis of the primary endpoint PFS is based on disease assessment by independent radiological review in the entire study population (first line and second line). (See Table 1.)

Click on icon to see table/diagram/image

For patients who responded to treatment, the median duration of response was 58.7 weeks as per independent review. The median overall survival (OS) data at the protocol specified final survival analysis were 22.9 months and 20.5 months [HR = 0.91 (95% CI: 0.71, 1.16; p = 0.224)] for patients randomized to the pazopanib and placebo arms, respectively. The OS results are subject to potential bias as 54% of patients in the placebo arm also received pazopanib in the extension part of this study following disease progression. Sixty-six percent of placebo patients received post-study therapy compared to 30% of pazopanib patients.
In the pivotal study, the QoL assessments were based on blinded self-reported global scores from two protocol-specified questionnaires, EORTC QLQ-C30 and EuroQoL EQ-5D. Analysis was based on patients who continued on therapy in both arms, prior to progression. The assessments showed no difference between treatment with pazopanib or placebo (p > 0.05), indicating no negative impact of pazopanib on global quality of life.
In a Phase II study of 225 patients with locally recurrent or metastatic clear cell renal cell carcinoma, objective response rate was 35% and median duration of response was 68 weeks, as per independent review.
The safety, efficacy and quality of life of pazopanib versus sunitinib was evaluated in a randomised, open-label, parallel group Phase III non-inferiority study (VEG108844). In VEG108844, patients (N = 1,110) with locally advanced and/or metastatic RCC who had not received prior systemic therapy, were randomized to receive either pazopanib 800 mg once daily continuously or sunitinib 50 mg once daily in 6-week cycles of dosing with 4 weeks on treatment followed by 2 weeks without treatment.
The primary objective of this study was to evaluate and compare PFS in patients treated with pazopanib to those treated with sunitinib. Demographic characteristics were similar between the treatment arms. Disease characteristics at initial diagnosis and at screening were balanced between the treatment arms with the majority of patients having clear cell histology and Stage IV disease.
VEG108844 achieved its primary endpoint of PFS and demonstrated that pazopanib was non-inferior to sunitinib, as the upper bound of the 95% CI for the hazard ratio was less than the protocol-specified non-inferiority margin of 1.25. Overall efficacy results are summarized in Table 2. (See Table 2.)

Click on icon to see table/diagram/image

Soft tissue sarcoma (STS): The safety and efficacy of pazopanib in STS were evaluated in a randomized, double-blind, placebo-controlled multi-centre study. Patients (N=369) with advanced STS who had received prior chemotherapy, including anthracycline treatment, or were unsuited for such therapy, were randomized to receive pazopanib 800 mg once daily or placebo.
Prior to randomization, eligible subjects were stratified by the factors of WHO performance status (WHO PS) (0 or 1) at baseline and the number of lines of prior systemic therapy for advanced disease (0 or 1 vs. 2+). In each treatment group, there were a slightly greater percentage of subjects in the 2+ lines of prior systemic therapy for advanced disease (58% and 55% respectively for placebo and pazopanib treatment arms) compared with 0 or 1 lines of prior systemic therapy (42% and 45% respectively for placebo and pazopanib treatment arms). There were slightly more subjects with a WHO PS of 1 at baseline. The median duration of follow-up of subjects (defined as date of randomization to date of last contact or death) was similar for both treatment arms (9.36 months for placebo [range 0.69 to 23.0 months] and 10.04 months for pazopanib [range 0.2 to 24.3 months].
The primary objective of the study was to evaluate and compare the two treatment arms for progression-free survival (PFS), based on the ITT population, and the principle secondary endpoint is overall survival (OS).
The initial analysis of the primary endpoint PFS was based on disease assessment by independent radiological review in the entire ITT study population. (See Table 3.)

Click on icon to see table/diagram/image

Similar to the assessments by independent radiology review, a clinically meaningful and statistically significant improvement in PFS based on investigator assessments was observed in the pazopanib arm compared with the placebo arm (HR: 0.39; 95% CI, 0.30 to 0.52, p <0.001).
The hazard ratio at the pre-specified interim analysis for overall survival in favour of pazopanib was not statistically significant; the median overall survival in the placebo arm was 10.4 months (95% CI 8.7 to 12.7) and was 11.9 months (95% CI 10.7 to 15.1) in the pazopanib arm; HR = 0.82 (97.87% CI: 0.59 to 1.14, p = 0.156).
Pharmacogenomics: In a pharmacogenetic meta-analysis of data from 31 clinical studies of pazopanib administered either as monotherapy or in combination with other agents, ALT > 5 X ULN (NCI CTC Grade 3) occurred in 19% of HLA-B*57:01 allele carriers and in 10% of non-carriers. In this dataset, 133/2235 (6%) of the patients carried the HLA-B*57:01 allele (see Precautions).
Pharmacokinetics: Absorption: Pazopanib is absorbed orally with median time to achieve peak concentrations of 2.0 to 4.0 hours after the dose. Daily dosing results in 1.23- to 4-fold increase in AUC. There was no consistent increase in AUC and Cmax when the pazopanib dose increased above 800 mg once daily.
Systemic exposure to pazopanib is increased when administered with food. Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in AUC and Cmax. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal (see Dosage & Administration and Interactions).
Administration of a single pazopanib 400 mg crushed tablet increased AUC(0-72) by 46% and Cmax by approximately 2 fold and decreased tmax by approximately 1.5 hours compared to administration of the whole tablet. These results indicate that the bioavailability and the rate of pazopanib oral absorption are increased after administration of the crushed tablet relative to administration of the whole tablet. Therefore, due to this potential for increased exposure, tablets should not be crushed (see Dosage & Administration).
Distribution: Binding of pazopanib to human plasma protein in vivo was greater than 99% with no concentration dependence over the range of 10 to 100 microgram/mL. In vitro studies suggest that pazopanib is a substrate for P-glycoprotein (Pgp) and breast cancer resistant protein (BCRP).
Biotransformation/metabolism: Results from in vitro studies demonstrated that the metabolism of pazopanib is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8.
Elimination: Pazopanib is eliminated slowly with mean half-life of 30.9 hours after administration of the recommended dose of 800 mg. Elimination is primarily via feces with renal elimination accounting for <4% of the administered dose.
Special Populations: Renal Impairment: In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30 to 150 mL/min) did not influence clearance of pazopanib. Renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary in patients with creatine clearance ≥ 30 mL/min (see Dosage & Administration).
Hepatic Impairment: The median steady-state pazopanib Cmax and AUC(0-24) in patients with mild hepatic impairment (defined as either normal bilirubin and any degree of ALT elevations or as an elevation of bilirubin up to 1.5 X ULN regardless of the ALT value) after a once daily dose of 800 mg/day (30.9 microgram/mL, range 12.5 to 47.3 and 841.8 microgram.hr/mL, range 600.4 to 1,078) are similar to the median in patients with no hepatic impairment (49.4 microgram/mL, range 17.1 to 85.7 and 888.2microgram.hr/mL, range 345.5 to 1,482) (see Dosage & Administration).
The maximally tolerated pazopanib dose (MTD) in patients with moderate hepatic impairment (defined as an elevation of bilirubin > 1.5 X to 3 X ULN regardless of the ALT values) was 200 mg once daily. The median steady-state values of Cmax (22.4 microgram/mL, range 6.4 to 32.9) and AUC(0-24) (350.0 microgram.hr/mL, range 131.8 to 487.7) after administration of 200 mg pazopanib once daily in subjects with moderate hepatic impairment were approximately 45% and 39%, respectively, that of the corresponding median values after administration of 800 mg once daily in subjects with normal hepatic function (see Dosage & Administration).
There are insufficient data in patients with severe hepatic impairment (total bilirubin > 3 X ULN regardless of the ALT value); therefore, use of pazopanib is not recommended in these patients.
Toxicology: Non-Clinical Safety Data: Safety pharmacology and repeat dose toxicity: In toxicology studies in rats, there were effects in a variety of tissues (bone, teeth, bone marrow, nail beds, reproductive organs, hematological tissues, kidney, adrenal glands, lymph node, pituitary, and pancreas) consistent with VEGFR inhibition and/or disruption of VEGF signalling pathways with some effects occurring at doses of 3 mg/kg/day (approximately 0.1-fold the AUC at the MRHD of 800 mg/day).
Hepatic effects included mild elevations of liver transaminases in rodents and bilirubin elevations in monkeys without associated histopathology at doses that produced systemic exposures approximately 0.1 and 0.6 times the human clinical exposure, respectively.
Carcinogenicity and mutagenicity: In two year carcinogenicity studies with pazopanib, there were increased numbers of liver adenomas noted in mice and duodenal adenocarcinomas noted in rats. Based on the rodent-specific pathogenesis and mechanism for these findings, they are not considered to represent an increased carcinogenic risk for patients taking pazopanib. Pazopanib did not cause genetic damage when tested in genotoxicity assays (Ames assay, human peripheral lymphocyte chromosome aberration assay, and rat in vivo micronucleus assay).
Fertility: In female rats, reduced fertility (including increased pre- and post-implantation loss, and early resorptions) was noted at dosages ≥ 10 mg/kg/day (approximately 0.2-fold the AUC at the MRHD of 800 mg/day). Decreased corpora lutea were noted in monkeys given 500 mg/kg/day for up to 34 weeks, in mice given ≥ 100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given 300 mg/kg/day for 26 weeks (approximately equal to, 0.6, 1.4 and 0.9-fold the AUC at the MRHD of 800 mg/day, respectively).
Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates, sperm motility, and epididymal and testicular sperm concentrations observed at ≥ 100 mg/kg/day (approximately 0.5-fold the AUC at the MRHD of 800 mg/day) following 15 weeks of dosing. Following 26 weeks of dosing, there were decreased testicular and epididymal weights, atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis of male rats given doses ≥ 30 mg/kg/day (approximately 0.4-fold the AUC at the MRHD of 800 mg/day).
Reproductive toxicity: For information on reproductive toxicity, see Use in Pregnancy & Lactation.
Juvenile animal studies: In juvenile toxicity studies, when pre-weaning rats were dosed from day 9 post partum through day 14 postpartum, pazopanib caused mortalities and abnormal organ growth/maturation in kidney, lung, liver and heart, at a dose approximately 0.1-fold the AUC at the MRHD of 800 mg/day. When post weaning rats were dosed from day 21 post partum to day 62 post partum, toxicological findings were similar to adult rats at comparable exposures with changes in bone, trachea, teeth, adrenal, pancreas, stomach, duodenum, lymph node, male mammary gland and reproductive organs. In rats, weaning occurs at day 21 postpartum which approximately equates to a human pediatric age of 2 years. Human pediatric patients are at increased risk for bone and teeth effects as compared to adults, as these changes, including shortened limbs, were present in juvenile rats at ≥ 10 mg/kg/day (equal to approximately 0.1-0.2-fold the AUC at the MRHD of 800 mg/day) (see PRECAUTIONS).
Indications/Uses
Renal cell carcinoma (RCC): Pazopanib is indicated for the treatment of advanced and/or metastatic renal cell carcinoma (RCC).
Soft tissue sarcoma (STS): Pazopanib is indicated for the treatment of patients with advanced Soft Tissue Sarcoma (STS) who have received prior chemotherapy.
The Phase III trial population excluded patients with gastrointestinal stromal tumour (GIST) or adipocytic STS.
Dosage/Direction for Use
General target population: The recommended dose of pazopanib is 800 mg orally once daily (see Method of Administration as follows).
If a dose is missed, it should not be taken if it is less than 12 hours until the next dose.
Dose Modifications: Dose modification, either an increase or decrease in dose, should be in 200 mg increments in a stepwise fashion based on individual tolerability in order to manage adverse reactions. The dose of pazopanib should not exceed 800 mg.
Special populations: Renal Impairment: Renal impairment is not expected to have a clinically relevant effect on pazopanib pharmacokinetics given the low renal excretion of pazopanib and metabolites (see Pharmacology: Pharmacokinetics: Elimination under Actions). Renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary in patients with creatinine clearance ≥ 30 mL/min. There is no experience of pazopanib in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis; therefore, use of pazopanib is not recommended in these patients.
Hepatic Impairment: The safety and pharmacokinetics of pazopanib in patients with pre-existing hepatic impairment have not been fully established (see Precautions).
No dose adjustment is required in patients with mild hepatic impairment as defined by alanine aminotransferase (ALT) and bilirubin (see Pharmacology under Actions).
The dose of pazopanib should be reduced to 200 mg per day in patients with moderate hepatic impairment (see Pharmacology under Actions).
There are insufficient data in patients with severe hepatic impairment (total bilirubin > 3 times the upper limit of normal [X ULN] regardless of the ALT value); therefore, use of pazopanib is not recommended in these patients.
Pediatric patients (below 18 years): The safety and efficacy of pazopanib in children have not been established. (See Precautions and Pharmacology: Toxicology: Non-Clinical Safety Data under Actions.)
Geriatric patients: No alteration of dosage, dosing frequency or route of administration is required in patients over 65 years.
Method of administration: Pazopanib should be taken without food (at least one hour before or two hours after a meal) (see Interactions and Pharmacology under Actions). Pazopanib should be taken whole with water and must not be broken or crushed (see Pharmacology: Pharmacokinetics under Actions). If a dose is missed, it should not be taken if it is less than 12 hours until the next dose.
Overdosage
Pazopanib doses up to 2,000 mg daily have been evaluated in clinical trials. Grade 3 fatigue (dose limiting toxicity) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg and 1,000 mg daily, respectively.
Symptoms and Signs: There is currently limited experience with overdosage in pazopanib.
Treatment: Further management should be as clinically indicated or as recommended by the national poisons centre, where available. Haemodialysis is not expected to enhance the elimination of pazopanib because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.
Contraindications
Pazopanib is contraindicated in patients with hypersensitivity to any of the ingredients.
Special Precautions
Hepatic Effects: Cases of hepatic failure (including fatalities) have been reported during use of pazopanib. In clinical trials with pazopanib, increase in serum transaminases (ALT, aspartate aminotransferase [AST]) and bilirubin were observed (see Adverse Reactions). In the majority of the cases, isolated increases in ALT and AST have been reported, without concomitant elevations of alkaline phosphatase or bilirubin. Patients over 60 years of age may be at greater risk for ALT >3 X ULN. Patients who carry the HLA-B*57:01 allele also have an increased risk of pazopanib-associated ALT elevations. Liver function should be monitored in all subjects receiving pazopanib, regardless of genotype or age (see Pharmacology under Actions). The vast majority (over 90%) of all transaminase elevations of any grade occurred in the first 18 weeks. Grades are based on the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3 (NCI CTCAE).
Serum liver tests should be performed before initiation of treatment with pazopanib, at weeks 3, 5, 7 and 9, then at Months 3 and 4, with additional tests as clinically indicated. Periodic testing should then continue after Month 4.
The following guidelines are provided for patients with baseline values of total bilirubin ≤ 1.5 X ULN and AST and ALT ≤ 2 X ULN.
Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on pazopanib with weekly monitoring of liver function until ALT return to Grade 1 (NCI CTCAE) or baseline.
Patients with ALT of > 8 X ULN should have pazopanib interrupted until they return to Grade 1 (NCI CTCAE) or baseline. If the potential benefit of reinitiating pazopanib treatment is considered to outweigh the risk for hepatotoxicity, then reintroduce pazopanib at a reduced dose of 400 mg once daily and perform serum liver tests weekly for 8 weeks (see Dosage & Administration). Following reintroduction of pazopanib, if ALT elevations > 3 X ULN recur, then pazopanib should be permanently discontinued.
If ALT elevations > 3 X ULN occur concurrently with bilirubin elevations > 2 X ULN pazopanib should be permanently discontinued. Patients should be monitored until return to Grade 1 (NCI CTCAE) or baseline. Pazopanib is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert's syndrome. Patients with only a mild indirect hyperbilirubinaemia, known or suspected Gilbert's syndrome, and elevation in ALT > 3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations.
Concomitant use of pazopanib and simvastatin increases the risk of ALT elevations (see Interactions) and should be undertaken with caution and close monitoring.
Beyond recommending that patients with mild hepatic impairment are treated with 800 mg pazopanib once daily and reducing the initial starting dose to 200 mg per day for patients with moderate impairment, no further dose modification guidelines based on results of serum liver tests during therapy have been established for patients with pre-existing hepatic impairment.
Hypertension: In clinical studies with pazopanib, events of hypertension including hypertensive crisis have occurred. Blood pressure should be well controlled prior to initiating pazopanib. Patients should be monitored for hypertension early after starting treatment (no longer than one week after starting pazopanib) and frequently thereafter to ensure blood pressure control, and treated promptly with a combination of standard anti-hypertensive therapy and pazopanib dose reduction or interruption as clinically warranted (see Dosage & Administration and Adverse Reactions). Hypertension (systolic blood pressure ≥ 150 or diastolic blood pressure ≥ 100 mm Hg) occurs early in the course of pazopanib treatment (approximately 40% of cases occurred by Day 9 and approximately 90% of cases occurred in the first 18 weeks). Pazopanib should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persists despite anti-hypertensive therapy and pazopanib dose reduction.
Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leukoencephalopathy syndrome (RPLS): PRES/RPLS has been reported in association with pazopanib. PRES/RPLS can present with headache, hypertension, seizure, lethargy, confusion, blindness and other visual and neurological disturbances, and can be fatal. Pazopanib should be permanently discontinued in patients developing PRES/RPLS.
Interstitial Lung Disease (ILD)/Pneumonitis: ILD, which can be fatal, has been reported in association with pazopanib (see Adverse Reactions). Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and discontinue pazopanib in patients developing ILD or pneumonitis.
Cardiac Dysfunction: In clinical trials with pazopanib, events of cardiac dysfunction such as congestive heart failure and decreased left ventricular ejection fraction (LVEF) have occurred. In a randomised RCC trial of pazopanib compared with sunitinib, in subjects who had baseline and follow-up LVEF measurements, myocardial dysfunction was observed in 13% (47/362) of subjects in the pazopanib arm compared to 11% (42/369) of subjects in the sunitinib arm. Congestive heart failure was observed in 0.5% of subjects in each treatment arm. In the phase III STS clinical trial, congestive heart failure was reported in 3 out of 240 subjects (1%). In this trial decreases in LVEF in subjects who had post-baseline measurement were detected in 11% (16/142) in the pazopanib arm compared with 5% (2/40) in the placebo arm. Fourteen of the 16 subjects in the pazopanib arm had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) by increasing cardiac after-load. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of pazopanib (interruption and re-initiation at a reduced dose based on clinical judgment). Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction.
QT Prolongation and Torsade de Pointes: In clinical studies with pazopanib, events of QT prolongation or Torsade de Pointes have occurred (see Adverse Reactions). Pazopanib should be used with caution in patients with a history of QT interval prolongation in patients taking antiarrythmics or other medications that may potentially prolong QT interval, or in patients with relevant pre-existing cardiac disease. When using pazopanib, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (calcium, magnesium, potassium) within normal range is recommended.
Arterial Thrombotic Events: In clinical studies with pazopanib, myocardial infarctions, angina, ischemic stroke and transient ischemic attack were observed (see Adverse Reactions). Fatal events have been observed. Pazopanib should be used with caution in patients who are at increased risk of thrombotic events or who have had a history of thrombotic events. Pazopanib has not been studied in patients who have had an event within the previous 6 months. A treatment decision should be made based upon the assessment of individual patient's benefit/risk.
Venous Thromboembolic Events: In clinical studies with pazopanib, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. The incidence was higher in the STS population (5%) than in the RCC population (2%).
Thrombotic Microangiopathy (TMA): Thrombotic microangiopathy (TMA) has been reported in clinical trials of pazopanib as monotherapy, in combination with bevacizumab, and in combination with topotecan (see Adverse Reactions). Pazopanib should be permanently discontinued in patients developing TMA. Reversal of effects of TMA has been observed after treatment was discontinued. Pazopanib is not indicated for use in combination with other agents.
Hemorrhagic Events: In clinical studies with pazopanib hemorrhagic events have been reported (see Adverse Reactions). Fatal haemorrhagic events have occurred. Pazopanib has not been studied in patients who had a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. Pazopanib should be used with caution in patients with significant risk of hemorrhage.
Gastrointestinal Perforations and Fistula: In clinical studies with pazopanib, events of gastrointestinal (GI) perforation or fistula have occurred (see Adverse Reactions). Fatal perforation events have occurred. Pazopanib should be used with caution in patients at risk for GI perforation or fistula.
Wound Healing: No formal studies of the effect of pazopanib on wound healing have been conducted. Since Vascular Endothelial Growth Factor (VEGF) inhibitors may impair wound healing, treatment with pazopanib should be stopped at least 7 days prior to scheduled surgery. The decision to resume pazopanib after surgery should be based on clinical judgement of adequate wound healing. Pazopanib should be discontinued in patients with wound dehiscence.
Hypothyroidism: In clinical studies with pazopanib, events of hypothyroidism have occurred (see Adverse Reactions). Proactive monitoring of thyroid function tests is recommended.
Proteinuria: In clinical studies with pazopanib, proteinuria has been reported (see Adverse Reactions). Baseline and periodic urinalyses during treatment are recommended and patients should be monitored for worsening proteinuria. Pazopanib should be discontinued if the patient develops nephrotic syndrome.
Tumor lysis syndrome (TLS): Cases of TLS, including fatal cases, have been reported in patients treated with pazopanib (see Adverse Reactions). Patients generally at risk of TLS are those with rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Preventative measures such as treatment of high uric acid levels and intravenous hydration should be considered prior to initiation of pazopanib. Patients at risk should be closely monitored and treated as clinically indicated.
Infections: Cases of serious infections (with or without neutropenia), in some cases with fatal outcome, have been reported.
Combination with other systemic anti-cancer therapies: Clinical trials of pazopanib in combination with pemetrexed (non-small cell lung cancer (NSCLC)) and lapatinib (cervical cancer) were terminated early due to concerns over increased toxicity and/or mortality, and a safe and effective combination dose has not been established with these regimens. Pazopanib is not indicated for use in combination with other anti-cancer agents.
Juvenile animal toxicity: Because the mechanism of action of pazopanib can severely affect organ growth and maturation during early post-natal development (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions), pazopanib should not be given to human pediatric patients younger than 2 years of age.
Interactions: Concomitant treatment with strong inhibitors of CYP3A4, P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) should be avoided due to risk of increased exposure to pazopanib (see Interactions). Selection of alternative concomitant medicinal products with no or minimal potential to inhibit CYP3A4, P-gp or BCRP should be considered.
Driving and using machines: There have been no studies to investigate the effect of pazopanib on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology of pazopanib. The clinical status of the patient and the adverse event profile of pazopanib should be borne in mind when considering the patient's ability to perform task that require judgment, motor and cognitive skills.
Use in Pregnancy: Pre-clinical studies in animals have shown reproductive toxicity (see Use in Pregnancy & Lactation). Based on animal reproduction studies and its mechanism of action, pazopanib can cause fetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to a fetus. Females of reproductive potential should be advised to avoid becoming pregnant while receiving treatment with pazopanib (see Use in Pregnancy & Lactation).
Use In Pregnancy & Lactation
Pregnancy: Risk summary: Based on animal reproduction studies and its mechanism of action, pazopanib can cause fetal harm when administered to a pregnant woman (see Pharmacology under Actions). There are no adequate data from the use of pazopanib in pregnant women. In animal developmental toxicity 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 maximum recommended human dose of 800 mg (based on AUC). Pazopanib should be not be used during pregnancy unless the clinical condition of the woman requires treatment with pazopanib. Pregnant women or females of reproductive potential should be advised of the potential risk to the fetus.
Animal data: In a female fertility and early embryonic development study in rats, post-implantation loss, embryo lethality and decreased fetal body weights were noted at dosages ≥10 mg/kg/day (approximately 0.2-fold the AUC at the MRHD of 800 mg/day) and increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4-fold the AUC at the MRHD of 800 mg/day).
In embryo-fetal development toxicity studies, pazopanib produced teratogenic effects (including cardiovascular malformations), delayed ossification, increased post-implantation loss, reduced fetal body weight and embryo lethality in rats at a dose level of ≥3 mg/kg/day (approximately 0.1-fold the AUC at the MRHD of 800 mg/day). In rabbits, maternal toxicity (body weight loss, reduced food consumption), increased post-implantation loss and abortion were observed at doses ≥30 mg/kg/day (approximately 0.007-fold the AUC at the MRHD of 800 mg/day), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated).
Lactation: Risk summary: There is no information regarding the presence of pazopanib or its metabolites in human milk, or their effects on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions in breastfed infants from pazopanib, a lactating woman should be advised not to breastfeed during treatment with pazopanib.
Females and Males of Reproductive Potential: Females of reproductive potential should be advised to use effective contraception during treatment with pazopanib and for at least 2 weeks after the last dose.
Male patients (including those who have had vasectomies) with female partners who are pregnant, possibly pregnant, or who could become pregnant should use condoms while taking pazopanib and for at least 2 weeks after the last dose.
Infertility: Based on findings from animal studies, pazopanib may impair fertility in males and females of reproductive potential while receiving treatment. (See Pharmacology: Toxicology: Non-Clinical Safety Data under Actions.)
Adverse Reactions
Summary of the safety profile: The safety and efficacy of pazopanib in renal cell carcinoma (RCC) were evaluated in a randomized, double-blind, placebo-controlled multi-center study. Patients with locally advanced and/or metastatic RCC were randomized to receive pazopanib 800 mg once daily (N=290) or placebo (N=145). The median duration of treatment was 7.4 months for the pazopanib arm and 3.8 months for the placebo arm.
The safety and efficacy of pazopanib in soft tissue sarcoma (STS) were evaluated in a randomized, double-blind, placebo-controlled multi-center study. Patients (N = 369) with advanced STS who had received prior anthracycline treatment, or were unsuited for such therapy, were randomized to receive pazopanib 800 mg once daily (N = 246) or placebo (N = 123). The median duration of treatment was 4.5 months for the pazopanib arm and 1.9 months for the placebo arm. Adverse reactions are listed as follows by MedDRA body system organ class.
Tabulated summary of adverse drug reactions from clinical trials: Adverse drug reactions from clinical trials (Table 4) are listed by MedDRA system organ class. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 4.)

Click on icon to see table/diagram/image

Neutropenia, thrombocytopenia and palmar-plantar erythrodysaesthesia syndrome were observed more frequently in patients of East Asian descent.
Table 5 presents laboratory abnormalities occurring in ≥ 15% of patients who received pazopanib in the pivotal RCC study. Grades are based on the NCI CTCAE. (See Table 5.)

Click on icon to see table/diagram/image

Table 6 presents laboratory abnormalities occurring in ≥ 15% of patients who received pazopanib in the pivotal STS study. Grades are based on the NCI CTCAE. (See Table 6.)

Click on icon to see table/diagram/image

The following adverse drug reactions have been identified during post-approval use of pazopanib. This includes spontaneous case reports as well as serious adverse events from ongoing studies, clinical pharmacology studies and exploratory studies in unapproved indications. (See Table 7.)

Click on icon to see table/diagram/image
Drug Interactions
Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib.
CYP3A4, P-gp, BCRP Inhibitors: Pazopanib is a substrate for CYP3A4, P-gp and BCRP. Concurrent administration of pazopanib (400 mg once daily) with the strong CYP3A4 and P-gp inhibitor, ketoconazole (400 mg once daily) for 5 consecutive days, resulted in a 66% and 45% increase in mean pazopanib AUC(0-24) and Cmax, respectively, relative to administration of pazopanib alone (400 mg once daily for 7 days). Pazopanib Cmax and AUC increase in a less than dose proportional fashion with increasing dose over the range of 50 mg to 2000 mg. Therefore, a dose reduction to 400 mg pazopanib once daily in the presence of strong CYP3A4 inhibitors will, in the majority of patients, result in systemic exposure similar to that observed after administration of 800 mg pazopanib once daily alone. Some patients however may have systemic pazopanib exposure greater than what has been observed after administration of 800 mg pazopanib alone.
Co-administration of pazopanib with other strong inhibitors of the CYP3A4 family (e.g., itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase pazopanib concentrations. Grapefruit juice may also increase plasma concentrations of pazopanib.
Administration of 1500 mg lapatinib a substrate and weak inhibitor of CYP3A4, Pgp and BCRP with 800 mg pazopanib resulted in an approximately 50% to 60% increase in mean pazopanib AUC(0-24) and Cmax compared to administration of 800 mg pazopanib alone. Co-administration of pazopanib with a CYP3A4, Pgp, and BCRP inhibitor, such as lapatinib, will result in an increase in plasma pazopanib concentrations.
Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If no medically acceptable alternative to a strong CYP34A inhibitor is available, the dose of pazopanib should be reduced to 400 mg daily during concomitant administration (see Precautions). Further dose reduction may be considered if possible drug-related adverse events are observed.
Combination with strong P-gp or BCRP inhibitors should be avoided, or selection of an alternate concomitant medication with no or minimal potential to inhibit P-gp or BCRP is recommended.
CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended.
Effects of Pazopanib on CYP Substrates: In vitro studies with human liver microsomes showed that pazopanib inhibited CYP enzymes 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, and 2E1. Potential induction of human CYP3A4 was demonstrated in an in vitro human PXR assay. Clinical pharmacology studies, using pazopanib 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 cancer patients. Pazopanib resulted in an increase of approximately 30% in the mean AUC and Cmax 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). Co-administration of pazopanib 800 mg once daily and paclitaxel 80 mg/m2 (CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of 26% and 31% in paclitaxel AUC and Cmax, respectively.
Effects of Pazopanib on Other Enzymes and Transporters: In vitro studies also showed that pazopanib is a potent inhibitor of UGT1A1 and OATP1B1 with IC50 of 1.2 and 0.79 μM, respectively. Pazopanib may increase concentrations of drugs primarily eliminated through UGT1A1 and OATP1B1.
Effect of concomitant use of Pazopanib and Simvastatin: Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with pazopanib, ALT > 3xULN was reported in 126/895 (14%) of patients who did not use statins, compared with11/41 (27%) of patients who had concomitant use of simvastatin (p = 0.038). If a patient receiving concomitant simvastatin develops ALT elevations, follow guidelines for pazopanib posology and discontinue simvastatin (see Precautions). Insufficient data are available to assess the risk of concomitant administration of alternative statins and pazopanib.
Drug-food/drink interactions: Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in AUC and Cmax. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a meal (see Dosage & Administration and Pharmacology under Actions).
Medicines that raise gastric pH: Concomitant administration of pazopanib with esomeprazole decreases the bioavailability of pazopanib by approximately 40% (AUC and Cmax), and co-administration of pazopanib with medicines that increase gastric pH should be avoided.
Storage
Store at temperatures not exceeding 30°C.
ATC Classification
L01EX03 - pazopanib ; Belongs to the class of other protein kinase inhibitors. Used in the treatment of cancer.
Presentation/Packing
FC tab 200 mg x 30's. 400 mg x 30's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in