post-title portfolio-title Pazopanib Hydrochloride Tablets IP 400mg Taj Pharma 2020-03-16 12:03:44 no no

Pazopanib Hydrochloride Tablets IP 400mg Taj Pharma

Pazopanib Hydrochloride Tablets IP 400mg Taj Pharma

Overview

INTRODUCTION

Pazopanib 400mg Tablet is a protein kinase inhibitor used in the treatment of kidney cancer and soft tissue sarcoma.

Pazopanib 400mg Tablet should be taken on an empty stomach, but try to have it at the same time every day to get the most benefits. Your doctor will decide what dose is necessary and how often you need to take it. This will depend on what you are being treated for and may change from time to time. You should take it exactly as your doctor has advised. Taking it in the wrong way or taking too much can cause very serious side effects. It may take several weeks or months for you to see or feel the benefits but do not stop taking it unless your doctor tells you to.

Diarrhea and high blood pressure are the most common side effects of this medicine. Doctor may advise for regular monitoring of your blood pressure while on treatment. Drink plenty of fluids to overcome diarrhea or consult with your doctor if it bothers you. This medicine may reduce the number of blood cells in your blood, thereby, increasing the susceptibility to infections. Hence, inform your doctor if you experience fever, flu-like symptoms and shortness of breath.

Before taking it, tell your doctor if you have heart disease, liver, or kidney problems or are taking any medicines to treat infections. Many other medicines can affect, or be affected by, this medicine so let your healthcare team know all medications you are using. This medicine is not recommended during pregnancy or while breastfeeding. The use of effective contraception by both males and females during treatment is important to avoid pregnancy.

USES OF PAZOPANIB TABLET

  • Kidney cancer
  • Soft tissue sarcoma

SIDE EFFECTS OF PAZOPANIB TABLET

Common

  • Headache
  • Nausea
  • Vomiting
  • Musculoskeletal (bone, muscle or joint) pain
  • Fatigue
  • Change in color of hair
  • Diarrhea
  • High blood pressure
  • Decreased appetite
  • Weight loss
  • Taste change
  • Abnormal skin pigmentation
  • Hair discoloration
  • Tumor pain
  • Breathlessness

HOW TO USE PAZOPANIB TABLET

Take this medicine in the dose and duration as advised by your doctor. Swallow it as a whole. Do not chew, crush or break it. Pazopanib 400mg Tablet is to be taken empty stomach.

HOW PAZOPANIB TABLET WORKS

Pazopanib 400mg Tablet is an anti-cancer medication. It works by binding and inhibiting the enzyme receptors (tyrosine kinase) that are responsible for the proliferation of the cancerous cells. It also restricts the growth of new blood vessels within the tumor. This is how it works against cancer.

SAFETY ADVICE

warningsAlcohol

CONSULT YOUR DOCTOR

It is not known whether it is safe to consume alcohol with Pazopanib 400mg Tablet. Please consult your doctor.

warningsPregnancy

CONSULT YOUR DOCTOR

Pazopanib 400mg Tablet is unsafe to use during pregnancy as there is definite evidence of risk to the developing baby. However, the doctor may rarely prescribe it in some life-threatening situations if the benefits are more than the potential risks. Please consult your doctor.

warningsBreastfeeding

UNSAFE

Pazopanib 400mg Tablet is unsafe to use during breastfeeding. Data suggests that the drug may cause toxicity to the baby.

warningsDriving

UNSAFE

Pazopanib 400mg Tablet may decrease alertness, affect your vision or make you feel sleepy and dizzy. Do not drive if these symptoms occur.

warningsKidney

SAFE IF PRESCRIBED

Pazopanib 400mg Tablet is safe to use in patients with kidney disease. No dose adjustment of Pazopanib 400mg Tablet is recommended.

warningsLiver

CAUTION

Pazopanib 400mg Tablet should be used with caution in patients with liver disease. Dose adjustment of Pazopanib 400mg Tablet may be needed. Please consult your doctor.
Use of Pazopanib 400mg Tablet is not advised in patients with moderate to severe liver disease.

Pazopanib Hydrochloride Tablets IP 400mg Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT

a) Pazopanib Hydrochloride Tablets IP 200mg Taj Pharma
b) Pazopanib Hydrochloride Tablets IP 400mg Taj Pharma

2.QUALITATIVE AND QUANTITATIVE COMPOSITION??????????????????????????????

a) Each film-coated tablet contains:
Pazopanib (as hydrochloride) IP? 200mg
Excipients????? q.s

b) Each film-coated tablet contains:
Pazopanib (as hydrochloride) IP? 400mg
Excipients????? q.s.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM????

Film-coated tablet.

Pazopanib Hydrochloride 200 mg film-coated tablets
Capsule-shaped, pink, film-coated tablet.

Pazopanib Hydrochloride 400 mg film-coated tablets
Capsule-shaped, white, film-coated tablet.

4.CLINICAL PARTICULARS

4.1 Therapeutic indications

Renal cell carcinoma (RCC)
Pazopanib Hydrochloride is indicated in adults for the first-line treatment of advanced renal cell carcinoma (RCC) and for patients who have received prior cytokine therapy for advanced disease.

Soft-tissue sarcoma (STS)
Pazopanib Hydrochloride is indicated for the treatment of adult patients with selective subtypes of advanced soft-tissue sarcoma (STS) who have received prior chemotherapy for metastatic disease or who have progressed within 12 months after (neo) adjuvant therapy.

Efficacy and safety has only been established in certain STS histological tumour subtypes (see section 5.1).

?4.2 Posology and method of administration

Pazopanib Hydrochloride treatment should only be initiated by a physician experienced in the administration of anti-cancer medicinal products.

Posology

Adults

The recommended dose of pazopanib for the treatment of RCC or STS is 800 mg once daily.

Dose modifications

Dose modification (decrease or increase) should be in 200 mg decrements or increments in a stepwise fashion based on individual tolerability in order to manage adverse reactions. The dose of pazopanib should not exceed 800 mg.

Paediatric population

Pazopanib should not be used in children younger than 2 years of age because of safety concerns with regard to organ growth and maturation (see sections 4.4 and 5.3).

The safety and efficacy of pazopanib in children aged 2 to 18 years of age have not yet been established. No data are available (see section 5.1).

Elderly

There are limited data on the use of pazopanib in patients aged 65 years and older. In the RCC studies of pazopanib, overall no clinically significant differences in safety of pazopanib were observed between subjects aged at least 65 years and younger subjects. Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some elderly patients cannot be ruled out.

Renal impairment

Renal impairment is unlikely to have a clinically relevant effect on pazopanib pharmacokinetics given the low renal excretion of pazopanib and metabolites (see section 5.2). Therefore, no dose adjustment is required in patients with creatinine clearance above 30 ml/min. Caution is advised in patients with creatinine clearance below 30 ml/min as there is no experience of pazopanib in this patient population.

Hepatic impairment

Dosing recommendations in hepatically impaired patients are based on pharmacokinetic studies of pazopanib in patients with varying degrees of hepatic dysfunction (see section 5.2). All patients should have liver function tests to determine whether they have hepatic impairment before starting and during pazopanib therapy (see section 4.4). Administration of pazopanib to patients with mild or moderate hepatic impairment should be undertaken with caution and close monitoring of tolerability. 800 mg pazopanib once daily is the recommended dose in patients with mild abnormalities in serum liver tests (defined either as normal bilirubin and any degree of alanine aminotransferase (ALT) elevation or as an elevation of bilirubin (>35% direct) up to 1.5 x upper limit of normal (ULN) regardless of the ALT value). A reduced pazopanib dose of 200 mg once daily is recommended in patients with moderate hepatic impairment (defined as an elevation of bilirubin >1.5 to 3 x ULN regardless of the ALT value) (see section 5.2).

Pazopanib is not recommended in patients with severe hepatic impairment (defined as total bilirubin >3 x ULN regardless of the ALT value).

See section 4.4 for liver monitoring and dose modification for patients with drug-induced hepatotoxicity.

Method of administration

Pazopanib is for oral use. It should be taken without food, at least one hour before or two hours after a meal (see section 5.2). The film-coated tablets should be taken whole with water and not broken or crushed (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Hepatic effects

Cases of hepatic failure (including fatalities) have been reported during use of pazopanib. Administration of pazopanib to patients with mild or moderate hepatic impairment should be undertaken with caution and close monitoring. 800 mg pazopanib once daily is the recommended dose in patients with mild abnormalities in serum liver tests (either normal bilirubin and any degree of ALT elevation or elevation of bilirubin up to 1.5 x ULN regardless of the ALT value). A reduced pazopanib dose of 200 mg once daily is recommended in patients with moderate hepatic impairment (elevation of bilirubin >1.5 to 3 x ULN regardless of the ALT value) (see sections 4.2 and 5.2). Pazopanib is not recommended in patients with severe hepatic impairment (total bilirubin >3 x ULN regardless of the ALT value) (see sections 4.2 and 5.2). Exposure at a 200 mg dose is markedly reduced, though highly variable, in these patients, with values considered insufficient to obtain a clinically relevant effect.

In clinical studies with pazopanib, increase in serum transaminases (ALT, aspartate aminotransferase [AST]) and bilirubin were observed (see section 4.8). 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 mild (>3 x ULN) to severe (>8 x ULN) elevation of ALT. Patients who carry the HLA-B*57:01 allele 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 section 5.1).

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.

See Table 1 for dose modification guidance for patients with baseline values of total bilirubin ?1.5 x ULN and AST and ALT ?2 x ULN:

Table 1 Dose modifications for drug-induced hepatotoxicity

Liver test valuesDose modification
Transaminase elevation between 3 and 8 x ULNContinue on pazopanib with weekly monitoring of liver function until transaminases return to Grade 1 or baseline.
Transaminase elevation of >8 x ULNInterrupt pazopanib until transaminases return to Grade 1 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 daily and perform serum liver tests weekly for 8 weeks. Following reintroduction of pazopanib, if transaminase elevations >3 x ULN recur, then pazopanib should be permanently discontinued.

Transaminase elevations >3 x ULN concurrently with bilirubin elevations >2 x ULNPermanently discontinue pazopanib.

Patients should be monitored until return to Grade 1 or baseline. Pazopanib is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinaemia 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 section 4.5) and should be undertaken with caution and close monitoring.

Hypertension

In clinical studies with pazopanib, events of hypertension including newly diagnosed symptomatic episodes of elevated blood pressure (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. Elevated blood pressure levels (systolic blood pressure ?150 mm Hg or diastolic blood pressure ?100 mm Hg) occurred early in the course of treatment (approximately 40% of cases occurred by day 9 and approximately 90% of cases occurred in the first 18 weeks). 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 judgement) (see sections 4.2 and 4.8). 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. Patients developing PRES/RPLS should permanently discontinue treatment with pazopanib.

Interstitial lung disease (ILD)/Pneumonitis

ILD, which can be fatal, has been reported in association with pazopanib (see section 4.8). Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and discontinue pazopanib in patients developing ILD or pneumonitis.

Cardiac dysfunction/Heart failure

The risks and benefits of pazopanib should be considered before beginning therapy in patients who have pre-existing cardiac dysfunction. The safety and pharmacokinetics of pazopanib in patients with moderate to severe heart failure or those with a below normal left ventricular ejection fraction (LVEF) have not been studied.

In clinical studies with pazopanib, events of cardiac dysfunction such as congestive heart failure and decreased LVEF have occurred (see section 4.8). In a randomised study comparing pazopanib and sunitinib in RCC (VEG108844), subjects had baseline and follow up LVEF measurements. Myocardial dysfunction occurred 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. Congestive heart failure was reported in 3 out of 240 subjects (1%) in the Phase III VEG110727 STS study. Decreases in LVEF in subjects who had post-baseline and follow-up LVEF measurement were detected in 11% (15/140) in the pazopanib arm, compared with 3% (1/39) in the placebo arm.

Risk factors

Thirteen of the 15 subjects in the pazopanib arm of the STS Phase III study had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk by increasing cardiac after-load. 99% of patients (243/246) enrolled in the STS Phase III study, including the 15 subjects, received anthracycline. Prior anthracycline therapy may be a risk factor for cardiac dysfunction.

Outcome

Four of the 15 subjects had full recovery (within 5% of baseline) and 5 had partial recovery (within the normal range, but >5% below baseline). One subject did not recover and follow-up data were not available for the other 5 subjects.

Management

Interruption of pazopanib and/or dose reduction should be combined with treatment of hypertension (if present, refer to hypertension warning section above) in patients with significant reductions in LVEF, as clinically indicated.

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 and torsade de pointes have occurred (see section 4.8). Pazopanib should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medicinal products that may prolong QT interval and in patients with relevant pre-existing cardiac disease. When using pazopanib, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g. calcium, magnesium, potassium) within normal range is recommended.

Arterial thrombotic events

In clinical studies with pazopanib, myocardial infarction, myocardial ischaemia, ischaemic stroke and transient ischaemic attack were observed (see section 4.8). 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 on 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. While observed in both RCC and STS studies, the incidence was higher in the STS population (5%) than in the RCC population (2%).

Thrombotic microangiopathy (TMA)

TMA has been reported in clinical studies of pazopanib as monotherapy, in combination with bevacizumab, and in combination with topotecan (see section 4.8). Patients developing TMA should permanently discontinue treatment with pazopanib. Reversal of effects of TMA has been observed after treatment was discontinued. Pazopanib is not indicated for use in combination with other agents.

Haemorrhagic events

In clinical studies with pazopanib haemorrhagic events have been reported (see section 4.8). Fatal haemorragic events have occurred. Pazopanib has not been studied in patients who had a history of haemoptysis, cerebral haemorrhage or clinically significant gastrointestinal (GI) haemorrhage in the past 6 months. Pazopanib should be used with caution in patients with significant risk of haemorrhage.

Aneurysms and artery dissections

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysm and/or artery dissections. Before initiating pazopanib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Gastrointestinal (GI) perforations and fistula

In clinical studies with pazopanib, events of GI perforation or fistula have occurred (see section 4.8). 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 section 4.8). Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism should be treated as per standard medical practice prior to the start of pazopanib treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction on pazopanib treatment. Laboratory monitoring of thyroid function should be performed periodically and managed as per standard medical practice.

Proteinuria

In clinical studies with pazopanib, proteinuria has been reported. Baseline and periodic urinanalysis during treatment is recommended and patients should be monitored for worsening proteinuria. Pazopanib should be discontinued if the patient develops nephrotic syndrome.

Pneumothorax

In clinical studies with pazopanib in advanced soft tissue sarcoma, events of pneumothorax have occurred (see section 4.8). Patients on pazopanib treatment should be observed closely for signs and symptoms of pneumothorax.

Paediatric population

Because the mechanism of action of pazopanib can severely affect organ growth and maturation during early post-natal development in rodents (see section 5.3), pazopanib should not be given to paediatric patients younger than 2 years of age.

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 studies 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.

Pregnancy

Pre-clinical studies in animals have shown reproductive toxicity (see section 5.3). If pazopanib is used during pregnancy, or if the patient becomes pregnant whilst receiving pazopanib, the potential hazard to the foetus should be explained to the patient. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with pazopanib (see section 4.6).

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 section 4.5). Selection of alternative concomitant medicinal products with no or minimal potential to inhibit CYP3A4, P-gp or BCRP should be considered.

Concomitant treatment with inducers of CYP3A4 should be avoided due to risk of decreased exposure to pazopanib (see section 4.5).

Cases of hyperglycaemia have been observed during concomitant treatment with ketoconazole.

Concomitant administration of pazopanib with uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) substrates (e.g. irinotecan) should be undertaken with caution since pazopanib is an inhibitor of UGT1A1 (see section 4.5).

Grapefruit juice should be avoided during treatment with pazopanib (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on pazopanib

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). Pharmacokinetic parameter comparisons of pazopanib Cmax?(range of means 27.5 to 58.1 ?g/ml) and AUC(0-24)?(range of means 48.7 to 1040 ?g*h/ml) after administration of pazopanib 800 mg alone and after administration of pazopanib 400 mg plus ketoconazole 400 mg (mean Cmax?59.2 ?g/ml, mean AUC(0-24)1300 ?g*h/ml) indicated that, in the presence of a strong CYP3A4 and P-gp inhibitor a dose reduction to pazopanib 400 mg once daily 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 contains an inhibitor of CYP3A4 and may also increase plasma concentrations of pazopanib.

Administration of 1500 mg lapatinib (a substrate for and weak inhibitor of CYP3A4 and P-gp and a potent inhibitor of 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. Inhibition of P-gp and/or BCRP by lapatinib likely contributed to the increased exposure to pazopanib.

Co-administration of pazopanib with a CYP3A4, P-gp, and BCRP inhibitor, such as lapatinib, will result in an increase in plasma pazopanib concentrations. Co-administration with potent P-gp or BCRP inhibitors may also alter the exposure and distribution of pazopanib, including distribution into the central nervous systems (CNS).

Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided (see section 4.4). 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. In such cases there should be close attention to adverse drug reaction, and 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 medicinal product with no or minimal potential to inhibit P-gp or BCRP is recommended.

CYP3A4, P-gp, BCRP inducers

CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. Co-administration of pazopanib with potent P-gp or BCRP inducers may alter the exposure and distribution of pazopanib, including distribution into the CNS. Selection of an alternative concomitant medication with no or minimal enzyme or transporter induction potential is recommended.

Effects of pazopanib on other medicinal products

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 dextrometrophan to dextrophan 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.

Based on?in vitro?IC50?and?in vivo?plasma Cmax?values, pazopanib metabolites GSK1268992 and GSK1268997 may contribute to the net inhibitory effect of pazopanib towards BCRP. Furthermore, inhibition of BCRP and P-gp by pazopanib in the gastrointestinal tract cannot be excluded. Care should be taken when pazopanib is co-administered with other oral BCRP and P-gp substrates.

In vitro, pazopanib inhibited human organic anion transporting polypeptide (OATP1B1). It cannot be excluded that pazopanib will affect the pharmacokinetics of substrates of OATP1B1 (e.g. statins, see ?Effect of concomitant use of pazopanib and simvastatin? below).

Pazopanib is an inhibitor of the uridine diphosphoglucuronosyl-transferase 1A1 (UGT1A1) enzyme?in vitro. The active metabolite of irinotecan, SN-38, is a substrate for OATP1B1 and UGT1A1. Co-administration of pazopanib 400 mg once daily with cetuximab 250 mg/m2?and irinotecan 150 mg/m2?resulted in an approximately 20% increase in systemic exposure to SN-38. Pazopanib may have a greater impact on SN-38 disposition in subjects with the UGT1A1*28 polymorphism relative to subjects with the wild-type allele. However, the UGT1A1 genotype was not always predictive of the effect of pazopanib on SN-38 disposition. Care should be taken when pazopanib is co-administered with substrates of UGT1A1.

Effect of concomitant use of pazopanib and simvastatin

Concomitant use of pazopanib and simvastatin increases the incidence of ALT elevations. Results from a meta-analysis using pooled data from clinical studies with pazopanib show that ALT >3x ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (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 section 4.4). In addition, concomitant use of pazopanib and other statins should be undertaken with caution as there are insufficient data available to assess their impact on ALT levels. It cannot be excluded that pazopanib will affect the pharmacokinetics of other statins (e.g. atorvastatin, fluvastatin, pravastatin, rosuvastatin).

Effect of food on pazopanib

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.

Medicinal products 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. If the concomitant use of a proton-pump inhibitor (PPI) is medically necessary, it is recommended that the dose of pazopanib be taken without food once daily in the evening concomitantly with the PPI. If the concomitant administration of an H2-receptor antagonist is medically necessary, pazopanib should be taken without food at least 2 hours before or at least 10 hours after a dose of an H2-receptor antagonist. Pazopanib should be administered at least 1 hour before or 2 hours after administration of short-acting antacids. The recommendations for how PPIs and H2-receptor antagonists are co-administered are based on physiological considerations.

?4.6 Fertility, pregnancy and lactation

Pregnancy/ Contraception in males and females

There are no adequate data from the use of pazopanib in pregnant women. Studies in animals have?shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Pazopanib should not be used during pregnancy unless the clinical condition of the woman requires treatment with pazopanib. If pazopanib is used during pregnancy, or if the patient becomes pregnant while receiving pazopanib, the potential hazard to the foetus should be explained to the patient.

Women of childbearing potential should be advised to use adequate contraception during treatment and for at least 2 weeks after the last dose of pazopanib and to avoid becoming pregnant while receiving treatment with pazopanib.

Male patients (including those who have had vasectomies) should use condoms during sexual intercourse while taking pazopanib and for at least 2 weeks after the last dose of pazopanib to avoid potential exposure to the medicinal product for pregnant partners and female partners of reproductive potential.

Breast-feeding

The safe use of pazopanib during breast-feeding has not been established. It is not known whether pazopanib or its metabolites are excreted in human milk. There are no animal data on the excretion of pazopanib in animal milk. A risk to the breast-fed child cannot be excluded. Breast-feeding should be discontinued during treatment with pazopanib.

Fertility

Animal studies indicate that male and female fertility may be affected by treatment with pazopanib (see section 5.3).

4.7 Effects on ability to drive and use machines

Pazopanib Hydrochloride has no or negligible influence on the ability to drive and use machines. A detrimental effect on such activities cannot be predicted 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 tasks that require judgement, motor or cognitive skills. Patients should avoid driving or using machines if they feel dizzy, tired or weak.

4.8 Undesirable effects

Summary of the safety profile

Pooled data from the pivotal RCC study (VEG105192, n=290), the extension study (VEG107769, n=71), the supportive Phase II study (VEG102616, n=225) and the randomised, open-label, parallel group Phase III non-inferiority study (VEG108844, n=557) were evaluated in the overall evaluation of safety and tolerability of pazopanib (total n=1149) in subjects with RCC (see section 5.1).

Pooled data from the pivotal STS study (VEG110727, n=369) and the supportive Phase II study (VEG20002, n=142) was evaluated in the overall evaluation of safety and tolerability of pazopanib (total safety population n=382) in subjects with STS (see section 5.1).

The most important serious adverse reactions identified in the RCC or STS studies were transient ischaemic attack, ischaemic stroke, myocardial ischaemia, myocardial and cerebral infarction, cardiac dysfunction, gastrointestinal perforation and fistula, QT prolongation, Torsade de Pointes and pulmonary, gastrointestinal and cerebral haemorrhage, all adverse reactions being reported in <1% of treated patients. Other important serious adverse reactions identified in STS studies included venous thromboembolic events, left ventricular dysfunction and pneumothorax.

Fatal events that were considered possibly related to pazopanib included gastrointestinal haemorrhage, pulmonary haemorrhage/haemoptysis, abnormal hepatic function, intestinal perforation and ischaemic stroke.

The most common adverse reactions (experienced by at least 10% of the patients) of any grade in the RCC and STS trials included: diarrhoea, hair colour change, skin hypopigmentation, exfoliative rash, hypertension, nausea, headache, fatigue, anorexia, vomiting, dysgeusia, stomatitis, weight decreased, pain, elevated alanine aminotransferase and elevated aspartate aminotransferase.

Adverse drug reactions, all grades, which were reported in RCC and STS subjects or during the post-marketing period are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been utilised for the classification of frequency: 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); and not known (cannot be estimated from the available data).

Categories have been assigned based on absolute frequencies in the clinical trial data. Post-marketing data on safety and tolerability across all pazopanib clinical studies and from spontaneous reports have also been evaluated. Within each system organ class, adverse reactions with the same frequency are presented in order of decreasing seriousness.

Tabulated list of adverse reactions

Table 2 Treatment-related adverse reactions reported in RCC studies (n = 1149) or during post-marketing period

System Organ ClassFrequency

(all grades)

Adverse reactionsAll grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Infections and InfestationsCommonInfections (with or without neutropenia)?not knownnot knownnot known
UncommonGingival infection1 (<1%)00
Infectious peritonitis1 (<1%)00
Neoplasms benign, malignant and unspecified (incl cysts and polyps)UncommonTumour pain1 (<1%)1 (<1%)0
Blood and lymphatic system disordersCommonThrombocytopenia80 (7%)10 (<1%)5 (<1%)
Neutropenia79 (7%)20 (2%)4 (<1%)
Leukopenia63 (5%)5 (<1%)0
UncommonPolycythaemia6 (0.03%)10
RareThrombotic microangiopathy (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome)?not knownnot knownnot known
Endocrine disordersCommonHypothyroidism83 (7%)1 (<1%)0
Metabolism and nutrition disordersVery commonDecreased appetitee317 (28%)14 (1%)0
CommonHypophosphataemia21 (2%)7 (<1%)0
Dehydration16 (1%)5 (<1%)0
UncommonHypomagnesaemia10 (<1%)00
Psychiatric disordersCommonInsomnia30 (3%)00
Nervous system disordersVery commonDysgeusiac254 (22%)1 (<1%)0
Headache122 (11%)11 (<1%)0
CommonDizziness55 (5%)3 (<1%)1 (<1%)
Lethargy30 (3%)3 (<1%)0
Paraesthesia20 (2%)2 (<1%)0
Peripheral sensory neuropathy17 (1%)00
UncommonHypoaesthesia8 (<1%)00
Transient ischaemic attack7 (<1%)4 (<1%)0
Somnolence3 (<1%)1 (<1%)0
Cerebrovascular accident2 (<1%)1 (<1%)1 (<1%)
Ischaemic stroke2 (<1%)01 (<1%)
RarePosterior reversible encephalopathy / reversible posterior leukoencephalopathy syndrome?not knownnot knownnot known
Eye disordersCommonVision blurred19 (2%)1 (<1%)0
UncommonRetinal detachment?1 (<1%)1 (<1%)0
Retinal tear?1 (<1%)1 (<1%)0
Eyelash discolouration4 (<1%)00
Cardiac disordersUncommonBradycardia6 (<1%)00
Myocardial infarction5 (<1%)1 (<1%)4 (<1%)
Cardiac dysfunctionf4 (<1%)1 (<1%)0
Myocardial ischaemia3 (<1%)1 (<1%)0
Vascular disordersVery commonHypertension473 (41%)115 (10%)1 (<1%)
CommonHot flush16 (1%)00
Venous thromboembolic event?g13 (1%)6 (<1%)7 (<1%)
Flushing12 (1%)00
UncommonHypertensive crisis6 (<1%)02 (<1%)
Haemorrhage1 (<1%)00
Not knownAneurysms and artery dissectionsNot knownNot knownNot known
Respiratory, thoracic and mediastinal disordersCommonEpistaxis50 (4%)1 (<1%)0
Dysphonia48 (4%)00
Dyspnoea42 (4%)8 (<1%)1 (<1%)
Haemoptysis15 (1%)1 (<1%)0
UncommonRhinorrhoea8 (<1%)00
Pulmonary haemorrhage2 (<1%)00
Pneumothorax1 (<1%)00
RareInterstitial lung disease/pneumonitis?not knownnot knownnot known
Gastrointestinal disordersVery commonDiarrhoea614 (53%_)65 (6%)2 (<1%)
Nausea386 (34%)14 (1%)0
Vomiting225 (20%)18 (2%)1 (<1%)
Abdominal paina139 (12%)15 (1%)0
CommonStomatitis96 (8%)4 (<1%)0
Dyspepsia83 (7%)2 (<1%)0
Flatulence43 (4%)00
Abdominal distension36 (3%)2 (<1%)0
Mouth ulceration28 (2%)3 (<1%)0
Dry mouth27 (2%)00
UncommonPancreatitis8 (<1%)4 (<1%)0
Rectal haemorrhage8 (<1%)2 (<1%)0
Haematochezia6 (<1%)00
Gastrointestinal haemorrhage4 (<1%)2 (<1%)0
Melaena4 (<1%)1(<1%)0
Frequent bowel movements3 (<1%)00
Anal haemorrhage2 (<1%)00
Large intestine perforation2 (<1%)1 (<1%)0
Mouth haemorrhage2 (<1%)00
Upper gastrointestinal haemorrhage2 (<1%)1 (<1%)0
Enterocutaneous fistula1 (<1%)00
Haematemesis1 (<1%)00
Haemorrhoidal haemorrhage1 (<1%)00
Ileal perforation1 (<1%)01 (<1%)
Oesophageal haemorrhage1 (<1%)00
Retroperitoneal haemorrhage1 (<1%)00
Hepatobiliary disordersCommonHyperbilirubinaemia38 (3%)2 (<1%)1 (<1%)
Hepatic function abnormal29 (3%)13 (1%)2 (<1%)
Hepatotoxicity18 (2%)11(<1%)2 (<1%)
UncommonJaundice3 (<1%)1 (<1%)0
Drug induced liver injury2 (<1%)2 (<1%)0
Hepatic failure1 (<1%)01 (<1%)
Skin and subcutaneous disordersVery commonHair colour change404 (35%)1 (<1%)0
Palmar-plantar erythrodysaesthesia syndrome206 (18%)39 (3%)0
Alopecia130 (11%)00
Rash129 (11%)7 (<1%)0
CommonSkin hypopigmentation52 (5%)00
Dry skin50 (4%)00
Pruritus29 (3%)00
Erythema25 (2%)00
Skin depigmentation20 (2%)00
Hyperhidrosis17 (1%)00
UncommonNail disorders11 (<1%)00
Skin exfoliation10 (<1%)00
Photosensitivity reaction7 (<1%)00
Rash erythematous6 (<1%)00
Skin disorder5 (<1%)00
Rash macular4 (<1%)00
Rash pruritic3 (<1%)00
Rash vesicular3 (<1%)00
Pruritus generalised2 (<1%)1 (<1%)0
Rash generalised2 (<1%)00
Rash papular2 (<1%)00
Plantar erythema1 (<1%)00
Musculoskeletal and connective tissue disordersCommonArthralgia48 (4%)8 (<1%)0
Myalgia35 (3%)2 (<1%)0
Muscle spasms25 (2%)00
UncommonMusculoskeletal pain9 (<1%)1 (<1%)0
Renal and urinary disordersVery CommonProteinuria135 (12%)32 (3%)0
UncommonHaemorrhage urinary tract1 (<1%)00
Reproductive system and breast disordersUncommonMenorrhagia3 (<1%)00
Vaginal haemorrhage3 (<1%)00
Metrorrhagia1 (<1%)00
General disorders and administration site conditionsVery commonFatigue415 (36%)65 (6%)1 (<1%)
CommonMucosal inflammation86 (7%)5 (<1%)0
Asthenia82 (7%)20 (2%)1 (<1%)
Oedemab72 (6%)1 (<1%)0
Chest pain18 (2%)2 (<1%)0
UncommonChills4 (<1%)00
Mucous membrane disorder1 (<1%)00
InvestigationsVery commonAlanine aminotransferase increased246 (21%)84 (7%)14 (1%)
Aspartate aminotransferase increased211 (18%)51 (4%)10 (<1%)
CommonWeight decreased96 (8%)7 (<1%)0
Blood bilirubin increased61 (5%)6 (<1%)1 (<1%)
Blood creatinine increased55 (5%)3 (<1%)0
Lipase increased51 (4%)21 (2%)7 (<1%)
White blood cell count decreasedd51 (4%)3 (<1%)0
Blood thyroid stimulating hormone increased36 (3%)00
Amylase increased35 (3%)7 (<1%)0
Gamma-glutamyltransferase increased31 (3%)9 (<1%)4 (<1%)
Blood pressure increased15 (1%)2 (<1%)0
Blood urea increased12 (1%)1 (<1%)0
Liver function test abnormal12 (1%)6 (<1%)1 (<1%)
UncommonHepatic enzyme increased11 (<1%)4 (<1%)3 (<1%)
Blood glucose decreased7 (<1%)01 (<1%)
Electrocardiogram QT prolonged7 (<1%)2 (<1%)0
Transaminase increased7 (<1%)1 (<1%)0
Thyroid function test abnormal3 (<1%)00
Blood pressure diastolic increased2 (<1%)00
Blood pressure systolic increased1 (<1%)00
?Treatment-related adverse reaction reported during post-marketing period (spontaneous case reports and serious adverse reactions from all pazopanib clinical studies).

The following terms have been combined:

a?Abdominal pain, abdominal pain upper and abdominal pain lower

b?Oedema, oedema peripheral, eye oedema, localised oedema and face oedema

c?Dysgeusia, ageusia and hypogeusia

d?White cell count decreased, neutrophil count decreased and leukocyte count decreased

e?Decreased appetite and anorexia

f?Cardiac dysfunction, left ventricular dysfunction, cardiac failure and restrictive cardiomyopathy

g?Venous thromboembolic event, deep vein thrombosis, pulmonary embolism and thrombosis

Neutropenia, thrombocytopenia and palmar-plantar erythrodysaethesia syndrome were observed more frequently in patients of East Asian descent.

Table 3 Treatment-related adverse reactions reported in STS studies (n=382)

System Organ ClassFrequency

(all grades)

Adverse reactionsAll grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Infections and infestationsCommonGingival infection4 (1%)00
Neoplasms benign, malignant and unspecified (incl cysts and polyps)Very commonTumour pain121 (32%)32 (8%)0
Blood and lymphatic system disordersfVery commonLeukopenia106 (44%)3 (1%)0
Thrombocytopenia86 (36%7 (3%)2 (<1%)
Neutropenia79 (33%)10 (4%)0
UncommonThrombotic microangiopathy (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome)1 (<1%)1 (<1%)0
Endocrine disordersCommonHypothyroidism18 (5%)00
Metabolism and nutrition disordersVery commonDecreased appetite108 (28%)12 (3%)0
Hypoalbuminemiaf81 (34%)2 (<1%)0
CommonDehydration4 (1%)2 (1%)0
UncommonHypomagnesaemia1 (<1%)00
Psychiatric disordersCommonInsomnia5 (1%)1 (<1%)0
Nervous system disordersVery commonDysgeusiac79 (21%)00
Headache54 (14%)2 (<1%)0
CommonPeripheral sensory neuropathy30 (8%)1 (<1%)0
Dizziness15 (4%)00
UncommonSomnolence3 (<1%)00
Paresthesia1 (<1%)00
Cerebral infarction1 (<1%)01 (<1%)
Eye disordersCommonVision blurred15 (4%)00
Cardiac disordersCardiac dysfunctiong21 (5%)3 (<1%)1 (<1%)
Left ventricular dysfunction13 (3%)3 (<1%)0
Bradycardia4 (1%)00
UncommonMyocardial infarction1 (<1%)00
Vascular disordersVery commonHypertension152 (40%)26 (7%)0
CommonVenous thromboembolic eventd13 (3%)4 (1%)5 (1%)
Hot flush12 (3%)00
Flushing4 (1%)00
UncommonHaemorrhage2 (<1%)1 (<1%)0
Not knownAneurysms and artery dissectionsNot knownNot knownNot known
Respiratory, thoracic and mediastinal disordersCommonEpistaxis22 (6%)00
Dysphonia20 (5%)00
Dyspnoea14 (4%)3 (<1%)0
Cough12 (3%)00
Pneumothorax7 (2%)2 (<1%)1 (<1%)
Hiccups4 (1%)00
Pulmonary haemorrhage4 (1%)1 (<1%)0
UncommonOropharyngeal pain3 (<1%)00
Bronchial haemorrhage2 (<1%)00
Rhinorrhoea1 (<1%)00
Haemoptysis1 (<1%)00
RareInterstitial lung disease/pneumonitis?not knownnot knownnot known
Gastrointestinal disordersVery commonDiarrhoea174 (46%)17 (4%)0
Nausea167 (44%)8 (2%)0
Vomiting96 (25%)7 (2%)0
Abdominal paina55 (14%)4 (1%)0
Stomatitis41 (11%)1 (<1%)0
CommonAbdominal distension16 (4%)2 (1%)0
Dry mouth14 (4%)00
Dyspepsia12 (3%)00
Mouth haemorrhage5 (1%)00
Flatulence5 (1%)00
Anal haemorrhage4 (1%)00
UncommonGastrointestinal haemorrhage2 (<1%)00
Rectal haemorrhage2 (<1%)00
Enterocutaneous fistula1 (<1%)1 (<1%)0
Gastric haemorrhage1 (<1%)00
Melaena2 (<1%)00
Oesophageal haemorrhage1 (<1%)01 (<1%)
Peritonitis1 (<1%)00
Retroperitoneal haemorrhage1 (<1%)00
Upper gastrointestinal haemorrhage1 (<1%)1 (<1%)0
Ileal perforation1 (<1%)01 (<1%)
Hepatobiliary disordersUncommonHepatic function abnormal2 (<1%)01 (<1%)
Skin and subcutaneous disordersVery commonHair colour change93 (24%)00
Skin hypopigmentation80 (21%)00
Exfoliative rash52 (14%)2 (<1%)0
CommonAlopecia30 (8%)00
Skin disorderc26 (7%)4 (1%)0
Dry skin21 (5%)00
Hyperhydrosis18 (5%)00
Nail disorder13 (3%)00
Pruritus11 (3%)00
Erythema4 (1%)00
UncommonSkin ulcer3 (<1%)1 (<1%)0
Rash1 (<1%)00
Rash papular1 (<1%)00
Photosensitivity reaction1 (<1%)00
Palmar-plantar erythrodysaesthesia syndrome2 (<1%)00
Musculoskeletal and connective tissue disordersCommonMusculoskeletal pain35 (9%)2 (<1%)0
Myalgia28 (7%)2 (<1%)0
Muscle spasms8 (2%)00
UncommonArthralgia2 (<1%)00
Renal and urinary disordersUncommonProteinuria2 (<1%)00
Reproductive system and breast disorderUncommonVaginal haemorrhage3 (<1%)00
Menorrhagia1 (<1%)00
General disorders and administration site conditionsVery commonFatigue178 (47%)34 (9%)1 (<1%)
CommonOedemab18 (5%)1 (<1%)0
Chest pain12 (3%)4 (1%)0
Chills10 (3%)00
UncommonMucosal inflammatione1 (<1%)00
Asthenia1 (<1%00
InvestigationshVery commonWeight decreased86 (23%)5 (1%)0
CommonEar, nose and throat examination abnormale29 (8%)4 (1%)0
Alanine aminotransferase increased8 (2%)4 (1%)2 (<1%)
Blood cholesterol abnormal6 (2%)00
Aspartate aminotransferase increased5 (1%)2 (<1%)2 (<1%)
Gamma glutamyltransferase increased4 (1%)03 (<1%)
UncommonBlood bilirubin increased2 (<1%)00
Aspartate aminotransferase2 (<1%)02 (<1%)
Alanine aminotransferase1 (<1%)01 (<1%)
Platelet count decreased1 (<1%)01 (<1%)
Electrocardiogram QT prolonged2 (<1%)1 (<1%)0
?Treatment-related adverse reaction reported during post-marketing period (spontaneous case reports and serious adverse reactions from all pazopanib clinical studies).

The following terms have been combined:

a?Abdominal pain, abdominal pain upper and gastrointestinal pain

b?Oedema, oedema peripheral and eyelid oedema

c?The majority of these cases were Palmar-plantar erythrodysaesthesia syndrome

d?Venous thromboembolic events ? includes Deep vein thrombosis, Pulmonary embolism and Thrombosis terms

e?The majority of these cases describe mucositis

f?Frequency is based on laboratory value tables from VEG110727 (N=240). These were reported as adverse events less frequently by investigators than as indicated by laboratory value tables.

g?Cardiac dysfunction events ? includes Left ventricular dysfunction, Cardiac failure and Restrictive cardiomyopathy

h?Frequency is based on adverse events reported by investigators. Laboratory abnormalities were reported as adverse events less frequently by investigators than as indicated by laboratory value tables.

Neutropenia, thrombocytopenia and palmar-plantar erythrodysaethesia syndrome were observed more frequently in patients of East Asian descent.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

Pazopanib doses up to 2000 mg have been evaluated in clinical studies. Grade 3 fatigue (dose-limiting toxicity) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2000 mg and 1000 mg daily, respectively.

There is no specific antidote for overdose with pazopanib and treatment of overdose should consist of general supportive measures.

?5.PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, protein kinase inhibitors, ATC code: L01XE11

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) -? and ??, 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-? 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.

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 section 4.4).

Clinical studies

Renal cell carcinoma (RCC)

The safety and efficacy of pazopanib in RCC were evaluated in a randomised, double-blind, placebo-controlled multicentre study. Patients (N = 435) with locally advanced and/or metastatic RCC were randomised 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 was 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-na?ve and 202 were second-line patients who had received one prior IL-2 or INF?-based therapy. The performance status (ECOG) was similar between the pazopanib and placebo groups (ECOG 0: 42% vs. 41%, ECOG 1: 58% vs. 59%). The majority of patients had either favourable (39%) or intermediate (54%), MSKCC (Memorial Sloan Kettering Cancer Centre) / Motzer prognostic factors. 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-na?ve 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 (treatment-na?ve and cytokine pre-treated).

Table 4 Overall efficacy results in RCC by independent assessment

Endpoints/Study populationPazopanibPlaceboHR (95% CI)P value

(one-sided)

PFS
Overall* ITTN = 290N = 145
Median (months)9.24.20.46 (0.34, 0.62)<0.0000001
Response rateN = 290N = 145
% (95% CI)30 (25.1,35.6)3 (0.5, 6.4)?<0.001
HR = hazard ratio; ITT = intent to treat; PFS = progression-free survival. * – treatment-na?ve and cytokine pre-treated populations

Figure 1 Kaplan-Meier curve for progression-free survival by independent assessment for the overall population (treatment-na?ve and cytokine pre-treated populations) (VEG105192)

x axis; Months, y axis; Proportion Progression Free, Pazopanib ??? (N = 290) Median 9.2 months; Placebo ——– (N = 145) Median 4.2 months; Hazard Ratio = 0.46, 95% CI (0.34, 0.62), P <0.0000001

Figure 2 Kaplan-Meier curve for progression-free survival by independent assessment for the treatment-na?ve population (VEG105192)

x axis; Months, y axis; Proportion Progression Free, Pazopanib ??? (N = 155) Median 11.1 months; Placebo ——– (N = 78) Median 2.8 months; Hazard Ratio = 0.40, 95% CI (0.27, 0.60), P <0.0000001

Figure 3 Kaplan-Meier Curve for progression-free survival by independent assessment for the cytokine pre-treated population (VEG105192)

x axis; Months, y axis; Proportion Progression Free, Pazopanib ??? (N = 135) Median 7.4 months; Placebo ——– (N = 67) Median 4.2 months; Hazard Ratio = 0.54, 95% CI (0.35, 0.84), P <0.001

For patients who responded to treatment, the median time to response was 11.9 weeks and the median duration of response was 58.7 weeks as per independent review (VEG105192).

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 randomised 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 per cent of placebo patients received post-study therapy compared to 30% of pazopanib patients.

No statistical differences were observed between treatment groups for Global Quality of Life using EORTC QLQ-C30 and EuroQoL EQ-5D.

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. Median PFS was 11.9 months.

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 = 1110) with locally advanced and/or metastatic RCC who had not received prior systemic therapy, were randomised 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 summarised in Table 5.

Table 5 Overall efficacy results

EndpointPazopanib

N = 557

Sunitinib

N = 553

HR

(95% CI)

PFS
Overall
Median (months)

(95% CI)

8.4

(8.3, 10.9)

9.5

(8.3, 11.0)

1.047

(0.898, 1.220)

Overall Survival

Median (months)

(95% CI)

 

28.3

(26.0, 35.5)

 

29.1

(25.4, 33.1)

 

0.915a

(0.786, 1.065)

HR = hazard ratio; PFS = progression-free survival;?a?P?value = 0.245 (2-sided)

Figure 4 Kaplan-Meier Curve for progression-free survival by independent assessment for the overall population (VEG108844)

Subgroup analyses of PFS were performed for 20 demographic and prognostic factors. The 95% confidence intervals for all subgroups include a hazard ratio of 1. In the three smallest of these 20 subgroups, the point estimate of the hazard ratio exceeded 1.25; i.e. in subjects with no prior nephrectomy (n=186, HR=1.403, 95% CI (0.955, 2.061)), baseline LDH >1.5 x ULN (n=68, HR=1.72, 95% CI (0.943, 3.139)), and MSKCC: poor risk (n=119, HR=1.472, 95% CI (0.937, 2.313)).

Soft-tissue sarcoma (STS)

The efficacy and safety of pazopanib in STS were evaluated in a pivotal Phase III randomised, double-blind, placebo-controlled multicentre study (VEG110727). A total of 369 patients with advanced STS were randomised to receive pazopanib 800 mg once daily or placebo. Importantly, only patients with selective histological subtypes of STS were allowed to participate to the study, therefore efficacy and safety of pazopanib can only be considered established for those subgroups of STS and treatment with pazopanib should be restricted to such STS subtypes.

The following tumour types were eligible:

Fibroblastic (adult fibrosarcoma, myxofibrosarcoma, sclerosing epithelioid fibrosarcoma, malignant solitary fibrous tumours), so-called fibrohistiocytic (pleomorphic malignant fibrous histiocytoma [MFH], giant cell MFH, inflammatory MFH), leiomyosarcoma, malignant glomus tumours, skeletal muscles (pleomorphic and alveolar rhabdomyosarcoma), vascular (epithelioid hemangioendothelioma, angiosarcoma), uncertain differentiation (synovial, epithelioid, alveolar soft part, clear cell, desmoplastic small round cell, extra-renal rhabdoid, malignant mesenchymoma, PEComa, intimal sarcoma), malignant peripheral nerve sheath tumours, undifferentiated soft tissue sarcomas not otherwise specified (NOS) and other types of sarcoma (not listed as ineligible).

The following tumour types were not eligible:

Adipocytic sarcoma (all subtypes), all rhabdomyosarcoma that were not alveolar or pleomorphic, chondrosarcoma, osteosarcoma, Ewing tumours/primitive neuroectodermal tumours (PNET), GIST, dermofibromatosis sarcoma protuberans, inflammatory myofibroblastic sarcoma, malignant mesothelioma and mixed mesodermal tumours of the uterus.

Of note, patients with adipocytic sarcoma were excluded from the pivotal Phase III study as in a preliminary Phase II study (VEG20002) activity (PFS at week 12) observed with pazopanib in adipocytic did not meet the prerequisite rate to allow further clinical testing.

Other key eligibility criteria of the VEG110727 study were: histological evidence of high or intermediate grade malignant STS and disease progression within 6 months of therapy for metastatic disease, or recurrence within 12 months of (neo) -/adjuvant therapy.

Ninety-eight percent (98%) of subjects received prior doxorubicin, 70% prior ifosfamide, and 65% of subjects had received at least three or more chemotherapeutic agents prior to study enrolment.

Patients 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 was 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). The median duration of follow-up of subjects (defined as date of randomisation 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 progression-free survival (PFS assessed by independent radiological review); the secondary endpoints included overall survival (OS), overall response rate and duration of response.

Table 6 Overall efficacy results in STS by independent assessment (VEG110727)

Endpoints / study populationPazopanibPlaceboHR (95% CI)P value

(two-sided)

PFS
Overall ITTN = 246N = 123
Median (weeks)20.07.00.35 (0.26, 0.48)<0.001
LeiomyosarcomaN = 109N = 49
Median (weeks)20.18.10.37 (0.23, 0.60)<0.001
Synovial sarcoma subgroupsN = 25N = 13
Median (weeks)17.94.10.43 (0.19, 0.98)0.005
‘Other STS’ subgroupsN = 112N = 61
Median (weeks)20.14.30.39 (0.25, 0.60)<0.001
OS
Overall ITTN = 246N = 123
Median (months)12.610.70.87 (0.67, 1.12)0.256
Leiomyosarcoma*N = 109N = 49
Median (months)16.714.10.84 (0.56, 1.26)0.363
Synovial sarcoma subgroups*N = 25N = 13
Median (months)8.721.61.62 (0.79, 3.33)0.115
?Other STS? subgroups*N = 112N = 61
Median (months)10.39.50.84 (0.59, 1.21)0.325
Response rate (CR+PR)
% (95% CI)4 (2.3, 7.9)0 (0.0, 3.0)
Duration of response
Median (weeks) (95% CI)38.9 (16.7, 40.0)
HR = hazard ratio; ITT = intent to treat; PFS = progression-free survival; CR = complete response; PR = partial response. OS = overall survival

* Overall survival for the respective STS histological subgroups (leiomyosarcoma, synovial sarcoma and ?Other? STS) should be interpreted with caution due to the small number of subjects and wide confidence intervals

A similar improvement in PFS based on investigator assessments was observed in the pazopanib arm compared with the placebo arm (in the overall ITT population HR: 0.39; 95% CI, 0.30 to 0.52, p <0.001).

Figure 5 Kaplan-Meier Curve for Progression-Free Survival in STS by Independent Assessment for the Overall Population

No significant difference in OS was observed between the two treatment arms at the final OS analysis performed after 76% (280/369) of the events had occurred (HR 0.87, 95% CI 0.67, 1.12 p=0.256).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Pazopanib Hydrochloride in all subsets of the paediatric population in treatment of kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney) (see section 4.2 for information on paediatric use).

The European Medicines Agency has deferred the obligation to submit the results of studies with Pazopanib Hydrochloride in one or more subsets of the paediatric population in the treatment of rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma and Ewing sarcoma family of tumours (see section 4.2 for information on paediatric use).

?5.2 Pharmacokinetic properties

Absorption

Upon oral administration of a single pazopanib 800 mg dose to patients with solid tumours, maximum plasma concentration (Cmax) of approximately 19 ? 13 ?g/ml was obtained after median 3.5 hours (range 1.0-11.9 hours) and an AUC0-??of approximately 650 ? 500 ?g.h/ml was obtained. Daily dosing results in 1.23- to 4-fold increase in AUC0-T.

There was no consistent increase in AUC or Cmax?at pazopanib doses above 800 mg.

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 two hours after food or at least one hour before food (see section 4.2).

Administration of a pazopanib 400 mg crushed tablet increased AUC(0-72)?by 46% and Cmax?by approximately 2 fold and decreased tmax?by approximately 2 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 (see section 4.2).

Distribution

Binding of pazopanib to human plasma protein in vivo was greater than 99% with no concentration dependence over the range of 10-100 ?g/ml. In vitro studies suggest that pazopanib is a substrate for P-gp and BCRP.

Biotransformation

Results from?in vitro?studies demonstrated that metabolism of pazopanib is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. The four principle pazopanib metabolites account for only 6% of the exposure in plasma. One of these metabolites inhibits the proliferation of VEGF-stimulated human umbilical vein endothelial cells with a similar potency to that of pazopanib, the others are 10- to 20-fold less active. Therefore, activity of pazopanib is mainly dependent on parent pazopanib exposure.

Elimination

Pazopanib is eliminated slowly with a mean half-life of 30.9 hours after administration of the recommended dose of 800 mg. Elimination is primarily via faeces with renal elimination accounting for <4% of the administered dose.

Special populations

Renal impairment

Results indicate that less than 4% of an orally administered pazopanib dose is excreted in the urine as pazopanib and metabolites. Results from population pharmacokinetic modelling (data from subjects with baseline CLCR values ranging from 30.8 ml/min to 150 ml/min) indicated that renal impairment is unlikely to have clinically relevant effect on pazopanib pharmacokinetics. No dose adjustment is required in patients with creatinine clearance above 30 ml/min. Caution is advised in patients with creatinine clearance below 30 ml/min as there is no experience of pazopanib in this patient population (see section 4.2).

Hepatic impairment

Mild

The median steady-state pazopanib Cmax?and AUC(0-24)?in patients with mild abnormalities in hepatic parameters (defined as either normal bilirubin and any degree of ALT elevation or as an elevation of bilirubin up to 1.5 x ULN regardless of the ALT value) after administration of 800 mg once daily are similar to the median in patients with normal hepatic function (see Table 7). 800 mg pazopanib once daily is the recommended dose in patients with mild abnormalities of serum liver tests (see section 4.2).

Moderate

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 Cmax?and AUC(0-24)?values after administration of 200 mg pazopanib once daily in patients with moderate hepatic impairment were approximately 44% and 39%, of the corresponding median values after administration of 800 mg once daily in patients with normal hepatic function, respectively (see Table 7).

Based on safety and tolerability data, the dose of pazopanib should be reduced to 200 mg once daily in subjects with moderate hepatic impairment (see section 4.2).

Severe

The median steady-state Cmax?and AUC(0-24)?values after administration of 200 mg pazopanib once daily in patients with severe hepatic impairment were approximately 18% and 15%, of the corresponding median values after administration of 800 mg once daily in patients with normal hepatic function. Based on the diminished exposure and limited hepatic reserve pazopanib is not recommended in patients with severe hepatic impairment (defined as total bilirubin >3 X ULN regardless of any level of ALT) (see section 4.2).

Table 7 Median steady-state pazopanib pharmacokinetics measured in subjects with hepatic impairment.

GroupInvestigated doseCmax?(?g/ml)AUC (0-24) (?g x hr/ml)Recommended dose
Normal hepatic function800 mg OD52.0

(17.1-85.7)

888.2

(345.5-1482)

800 mg OD
Mild HI800 mg OD33.5

(11.3-104.2)

774.2

(214.7-2034.4)

800 mg OD
Moderate HI200 mg OD22.2

(4.2-32.9)

256.8

(65.7-487.7)

200 mg OD
Severe HI200 mg OD9.4

(2.4-24.3)

130.6

(46.9-473.2)

Not recommended
OD ? once daily

?5.3 Preclinical safety data

The preclinical safety profile of pazopanib was assessed in mice, rats, rabbits and monkeys. In repeat dose studies in rodents, effects in a variety of tissues (bone, teeth, nail beds, reproductive organs, haematological tissues, kidney and pancreas) appear related to the pharmacology of VEGFR inhibition and/or disruption of VEGF signalling pathways, with most effects occurring at plasma exposure levels below those observed in the clinic. Other observed effects include body weight loss, diarrhoea and/or morbidity that were either secondary to local gastrointestinal effects caused by high local mucosal medicinal product exposure (monkeys) or pharmacological effects (rodents). Proliferative hepatic lesions (eosinophilic foci and adenoma) were seen in female mice at exposures 2.5 times human exposure based on AUC.

In juvenile toxicity studies, when pre-weaning rats were dosed from day 9 post partum through to day 14 post partum, pazopanib caused mortalities and abnormal organ growth/maturation in kidney, lung, liver and heart, at a dose approximately 0.1 times the clinical exposure based on AUC in adult humans. 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. Human paediatric patients are at increased risk for bone and teeth effects as compared to adults, as these changes, including inhibition of growth (shortened limbs), fragile bones and remodelling of teeth, were present in juvenile rats at ?10 mg/kg/day (equal to approximately 0.1-0.2 times the clinical exposure based on AUC in adult humans) (see section 4.4).

Reproductive, fertility and teratogenic effects

Pazopanib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits at exposures more than 300-fold lower than the human exposure (based on AUC). Effects included reduced female fertility, increased pre- and post-implantation loss, early resorptions, embryo lethality, decreased foetal body weight and cardiovascular malformation. Decreased corpora lutea, increased cysts and ovarian atrophy have also been noted in rodents. In a rat male fertility study, there was no effect on mating or fertility, but decreased testicular and epididymal weights were noted with reductions in sperm production rates, sperm motility, and epididymal and testicular sperm concentrations observed at exposures 0.3 times human exposure based on AUC.

Genotoxicity

Pazopanib did not cause genetic damage when tested in genotoxicity assays (Ames assay, human peripheral lymphocyte chromosome aberration assay and rat in vivo micronucleus). A synthetic intermediate in manufacture of pazopanib, which is also present in the final drug substance in low amounts, was not mutagenic in the Ames assay but genotoxic in the mouse lymphoma assay and?in vivo?mouse micronucleus assay.

Carcinogenicity

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.

6.PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Pazopanib Hydrochloride 200 mg film-coated tablets

Tablet core
Magnesium stearate
Microcrystalline cellulose
Povidone
Sodium starch glycolate

Tablet coating
Hypromellose
Iron oxide red
Macrogol 400
Polysorbate 80
Titanium dioxide

Pazopanib Hydrochloride 400 mg film-coated tablets

Tablet core
Magnesium stearate
Microcrystalline cellulose
Povidone
Sodium starch glycolate

Tablet coating
Hypromellose
Macrogol 400
Polysorbate 80
Titanium dioxide

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

?6.5 Nature and contents of container

Pazopanib Hydrochloride 200 mg film-coated tablets

HDPE bottles with polypropylene child resistant closures containing either 30 or 90 tablets.

Pazopanib Hydrochloride 400 mg film-coated tablets

HDPE bottles with polypropylene child resistant closures containing either 30 or 60 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

?7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA)

Pazopanib Hydrochloride Tablets IP 400mg Taj Pharma

Package leaflet: Information for the patient

Pazopanib

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read itagain.
  • If you have any further questions, ask your doctor orpharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harmthem, even if their signs of illness are the same asyours.
  • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section4.

What is in this leaflet:

  1. What Pazopanib Taj Pharma is and what it is used for
  2. What you need to know before you take Pazopanib Taj Pharma
  3. How to take Pazopanib Taj Pharma
  4. Possible side effects
  5. How to store Pazopanib Taj Pharma
  6. Contents of the pack and other information
1 WHAT PAZOPANIB TAJ PHARMA IS AND WHAT IT IS USED FOR

Pazopanib Taj Pharma is a type of medicine called a protein kinase inhibitor. It works by preventing the activity of proteins that are involved in the growth and spread of cancer cells.

Pazopanib Taj Pharma is used in adults to treat:
– kidney cancer that is advanced or has spread to other organs.
– certain forms of soft-tissue sarcoma, which is a type of cancer that affects the supportive tissues of the body. It can occur in muscles, blood vessels, fat tissue or other tissues that support, surround and protect the organs.

2 WHAT YOU NEED TO KNOW BEFORE YOU TAKE PAZOPANIB TAJ PHARMA

Do not take Pazopanib Taj Pharma
if you are allergic to pazopanib or any of the other ingredients of this medicine (listed in section 6).

Check with your doctor if you think this applies to you.

Warnings and precautions
Talk to your doctor before taking Pazopanib Taj Pharma:
– if you have heart disease.
– if you have liver disease.
– if you have had heart failure or a heart attack.
– if you have had prior collapse of a lung.
– if you have had problems with bleeding, blood clots or narrowing of the arteries
– if you have had stomach or bowel problems such as perforation (hole) or fistula (abnormal passages forming between parts of the intestine).
– if you have thyroid problems.
– if you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a blood vessel wall.

Tell your doctor if any of these apply to you. Your doctor will decide whether Pazopanib Taj Pharma is suitable for you. You may need extra tests to check that your heart and liver are working properly.

High blood pressure and Pazopanib Taj Pharma
Pazopanib Taj Pharma can raise your blood pressure. Your blood pressure will be checked before you take Pazopanib Taj Pharma and while you are taking it. If you have high blood pressure you will be treated with medicines to reduce it.

– Tell your doctor if you have high blood pressure.

If you are going to have an operation Your doctor will stop Pazopanib Taj Pharma at least 7 days before your operation as it may affect wound healing. Your treatment will be restarted when the wound has adequately healed.

Conditions you need to look out for
Pazopanib Taj Pharma can make some conditions worse or cause serious side effects. You must look out for certain symptoms while you are taking Pazopanib Taj Pharma to reduce the risk of any problems. See section 4.

Children and adolescents
Pazopanib Taj Pharma is not recommended for people aged under 18. It is not yet known how well it works in this age group. Moreover it should not be used in children younger than 2 years of age because of safety concerns.

Other medicines and Pazopanib Taj Pharma
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This includes herbal medicines and other medicines you?ve bought without a prescription.

Some medicines may affect how Pazopanib Taj Pharma works or make it more likely that you?ll have side effects. Pazopanib Taj Pharma can also affect how some other medicines work. These include:
– clarithromycin, ketoconazole, itraconazole, rifamicin, telithromycin, voriconazzole (used to treat infection).
– atazanavir, indinavir, nelfinavir, ritonavir, saquinavir (used to treat HIV).
– nefazodone (used to treat depression).
– simvastatin and possibly other statins (used to treat high cholesterol levels).
– medicines that reduce stomach acid. The type of medicine that you are taking to reduce your stomach acid (e.g. proton pump inhibitor, H2 antagonists or antacids) may affect how Pazopanib Taj Pharma is taken. Please consult your doctor or nurse for advice.

Tell your doctor or pharmacist if you take any of these.

Pazopanib Taj Pharma with food and drink
Don?t take Pazopanib Taj Pharma with food, as it affects the way the medicine is absorbed. Take it at least two hours after a meal or one hour before a meal (see section 3).
Do not drink grapefruit juice while you are being treated with Pazopanib Taj Pharma as this may increase the chance of side effects.

Pregnancy, breast-feeding and fertility
Pazopanib Taj Pharma is not recommended if you are pregnant. The effect of Pazopanib Taj Pharma during pregnancy is not known.

Tell your doctor if you are pregnant or planning to get pregnant.
Use a reliable method of contraception while you?re taking Pazopanib Taj Pharma, and at least for 2 weeks after, to prevent pregnancy.
If you do become pregnant during treatment with Pazopanib Taj Pharma, tell your doctor.

Don?t breast-feed while taking Pazopanib Taj Pharma. It is not known whether the ingredients in Pazopanib Taj Pharma pass into breast milk. Talk to your doctor about this.

Male patients (including those who have had vasectomies) who have partners who are either pregnant or who could become pregnant (including those who use other methods of contraception) should use condoms during sexual intercourse while taking Pazopanib Taj Pharma and for at least 2 weeks after the last dose.

Fertility may be affected by treatment with Pazopanib Taj Pharma. Talk to your doctor about this.

Driving and using machines
Pazopanib Taj Pharma can have side effects that may affect your ability to drive or use machines. – Avoid driving or using machines if you feel dizzy, tired or weak, or if your energy levels are low.

3 HOW TO TAKE PAZOPANIB TAJ PHARMA

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

How much to take
The usual dose is two Pazopanib Taj Pharma 400 mg tablets (800 mg pazopanib) taken once a day. This is the maximum dose per day. Your doctor may need to reduce your dose if you get side effects.

When to take
Don?t take Pazopanib Taj Pharma with food. Take it at least two hours after a meal, or one hour before a meal. For example, you could take it two hours after breakfast or one hour before lunch. Take Pazopanib Taj Pharma at about the same time each day.

Swallow the tablets whole with water, one after the other. Do not break or crush the tablets as this affects the way the medicine is absorbed and may increase the chance of side effects.

If you take more Pazopanib Taj Pharma than you should
If you take too many tablets, contact a doctor or pharmacist for advice. If possible show them the pack, or this leaflet.

If you forget to take Pazopanib Taj Pharma
Do not take a double dose to make up for a forgotten dose. Just take your next dose at the usual time.

Don?t stop Pazopanib Taj Pharma without advice
Take Pazopanib Taj Pharma for as long as your doctor recommends. Don?t stop unless your doctor advises you to.

4 POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them.

?Possible serious side effects

Swelling of the brain (reversible posterior leukoencephalopathy syndrome) Pazopanib Taj Pharma can, on rare occasions, cause swelling of the brain, which may be life threatening. Symptoms include:
– loss of speech
– change of vision
– seizure (fits)
– confusion
– high blood pressure

Stop taking Pazopanib Taj Pharma and seek medical help immediately if you get any of these symptoms, or if you get headache accompanied with any of these symptoms.

Hypertensive crisis (sudden and severe rise in blood pressure)
Pazopanib Taj Pharma can on occasion cause a sudden and severe rise in blood pressure. This is known as a hypertensive crisis. Your doctor will monitor your blood pressure while you are taking Pazopanib Taj Pharma. Signs and symptoms of a hypertensive crisis may include:
– severe chest pain
– severe headache
– blurred vision
– confusion
– nausea
– vomiting
– severe anxiety
– shortness of breath
– seizures (fits)
– fainting

Stop taking Pazopanib Taj Pharma and seek medical help immediately if you develop hypertensive crisis.

Heart conditions
The risks of these problems may be higher for people with an existing heart problem, or who are taking other medicines. You will be checked for any heart problems while you are taking Pazopanib Taj Pharma.

Cardiac dysfunction/heart failure, heart attack
Pazopanib Taj Pharma can affect how well your heart pumps or can increase the likelihood of having a heart attack. Signs and symptoms include:
– irregular or fast heartbeat
– rapid fluttering of your heart
– fainting
– chest pain or pressure
– pain in your arms, back, neck or jaw
– shortness of breath
– leg swelling

Seek medical help immediately if you get any of these symptoms.

Changes in heart rhythm (QT prolongation)
Pazopanib Taj Pharma can affect heart rhythm which in some people can develop into a potentially serious heart condition known as torsade de pointes. This can result in a very fast heartbeat causing a sudden loss of consciousness.

Tell your doctor if you notice any unusual changes in your heart beat, such as beating too fast or too slow.

Stroke
Pazopanib Taj Pharma can increase your likelihood of having a stroke. Signs and symptoms of stroke may include:
– numbness or weakness on one side of your body
– difficulty talking
– headache
– dizziness

Seek medical help immediately if you get any of these symptoms.

Bleeding
Pazopanib Taj Pharma can cause severe bleeding in the digestive system (such as stomach, oesophagus, rectum or intestine), or the lungs, kidneys, mouth, vagina and brain, although this is uncommon. Symptoms include:
– passing blood in the stools or passing black stools
– passing blood in the urine
– stomach pain
– coughing or vomiting up blood

Seek medical help immediately if you get any of these symptoms.

Perforation and fistula
Pazopanib Taj Pharma can cause a tear (perforation) in your stomach or intestinal wall or the development of an abnormal connection between two parts of your digestive tract (a fistula). Signs and symptoms may include:
– severe stomach pain
– nausea and/or vomiting
– fever
– development of a hole (perforation) in the stomach, intestine or bowel from which bloody or foul smelling pus is released
Seek medical help immediately if you get any of these symptoms.

Liver problems
Pazopanib Taj Pharma can cause problems with your liver which may develop into serious conditions such as liver dysfunction and liver failure, which may be fatal. Your doctor will be checking your liver enzymes while you are taking Pazopanib Taj Pharma. Signs that your liver may not be working properly may include:
– yellowing of your skin or the whites of your eyes (jaundice)
– dark urine
– tiredness
– nausea
– vomiting
– loss of appetite
– pain on the right side of your stomach area (abdomen)
– bruising easily

Seek medical help immediately if you get any of these symptoms.

Blood clots
Deep vein thrombosis (DVT) and pulmonary embolism
Pazopanib Taj Pharma may cause blood clots in your veins, especially in your legs (deep vein thrombosis or DVT), which may also travel to your lungs (pulmonary embolism). Signs and symptoms may include:
– sharp chest pain
– shortness of breath
– rapid breathing
– leg pain
– swelling of your arms and hands or legs and feet

Thrombotic microangiopathy (TMA)
Pazopanib Taj Pharma may cause blood clots in the small blood vessels in the kidneys and brain accompanied by a decrease in red blood cells and cells involved in clotting (thrombotic microangiopathy, TMA). Signs and symptoms may include:
– bruising easily
– high blood pressure
– fever
– confusion
– drowsiness
– seizures (fits)
– decrease in urine output

Seek medical help immediately if you get any of these symptoms.

Infections
Infections occurring while you take Pazopanib Taj Pharma may possibly become serious. Symptoms of infections may include:
– fever
– flu-like symptoms such as cough, tiredness and body aches that do not go away
– shortness of breath and/or wheezing
– pain while urinating
– cuts, scrapes or wounds that are red, warm, swollen or painful

Seek medical help immediately if you get any of these symptoms.

Lung inflammation
Pazopanib Taj Pharma can, on rare occasions, cause lung inflammation (interstitial lung disease, pneumonitis), which in some people can be fatal. Symptoms include shortness of breath or cough that will not go away. You will be checked for any lung problems while you are taking Pazopanib Taj Pharma.
Seek medical help immediately if you get any of these symptoms.

Thyroid problems
Pazopanib Taj Pharma can lower the amount of thyroid hormone produced in your body. This can result in weight increase and tiredness. You will be checked for thyroid hormone levels while you are taking Pazopanib Taj Pharma.
Tell your doctor if you notice significant weight gain or tiredness.

Blurry or impaired vision
Pazopanib Taj Pharma can cause separation or tear of the lining of the back part of the eye (retinal detachment or tear). This can result in blurry or impaired vision.
Tell your doctor if you notice any change in your vision.

Possible side effects (including possible serious side effects under the relevant frequency category).

Very common side effects (may affect more than 1 in 10 people):
– high blood pressure
– diarrhoea
– feeling or being sick (nausea or vomiting)
– stomach pain
– loss of appetite
– weight loss
– taste disturbance or loss of taste
– sore mouth
– headache
– tumour pain
– lack of energy, feeling weak or tired
– changes in hair colour
– unusual hair loss or thinning
– loss of skin pigment
– skin rash, possibly involving peeling of the skin
– redness and swelling of the palms of the hands or soles of the feet

Tell your doctor or pharmacist if any of these side effects becomes troublesome.

Very common side effects that may show up in your blood or urine tests:
– increase in liver enzymes
– decrease in albumin in the blood
– protein in the urine
– decrease in the number of blood platelets (cells that help blood to clot)
– decrease in the number of white blood cells

Common side effects (may affect up to 1 in 10 people):
– indigestion, bloating, flatulence
– nose bleed
– dry mouth or mouth ulcers
– infections
– abnormal drowsiness
– difficulty sleeping
– chest pain, shortness of breath, leg pain, and swelling of the legs/feet. These could be signs of a blood clot in your body (thromboembolism). If the clot breaks off, it may travel to your lungs and this may be life threatening or even fatal.
– heart becomes less effective at pumping blood around the body (cardiac dysfunction)
– slow heart beat
– bleeding in the mouth, rectum or lung
– dizziness
– blurred vision
– hot flushes
– swelling caused by fluid of face, hands, ankles, feet or eyelids
– tingling, weakness or numbness of the hands, arms, legs or feet
– skin disorders, redness, itching, dry skin – nail disorders
– burning, prickling, itching or tingling skin sensation
– sensation of coldness, with shivering
– excessive sweating
– dehydration
– muscle, joint, tendon or chest pain, muscle spasms
– hoarseness
– shortness of breath
– cough
– coughing up blood
– hiccups
– collapsed lung with air trapped in the space between the lung and chest, often causing shortness of breath (pneumothorax)

Tell your doctor or pharmacist if any of these effects become troublesome.

Common side effects that may show up in your blood or urine tests:
– underactive thyroid gland
– abnormal liver function
– increase in bilirubin (a substance produced by the liver)
– increase in lipase (an enzyme involved in digestion
– increase in creatinine (a substance produced in muscles)
– changes in the levels of other different chemicals / enzymes in the blood. Your doctor will inform you of the results of the blood tests

Uncommon side effects (may affect up to 1 in 100 people):
– stroke
– temporary fall in blood supply to the brain (transient ischaemic attack)
– interruption of blood supply to part of the heart or heart attack (myocardial infarction)
– partial interruption of blood supply to part of the heart (myocardial ischaemia)
– blood clots accompanied by a decrease in red blood cells and cells involved in clotting (thrombotic microangiopathy, TMA). These may harm organs such as the brain and kidneys.
– increase in the number of red blood cells
– sudden shortness of breath, especially when accompanied with sharp pain in the chest and /or rapid breathing (pulmonary embolism)
– severe bleeding in the digestive system (such as stomach, oesophagus or intestine), or the kidneys, vagina and brain
– heart rhythm disturbance (QT prolongation)
– hole (perforation) in stomach or intestine
– abnormal passages forming between parts of the intestine (fistula)
– heavy or irregular menstrual periods
– sudden sharp increase in blood pressure (hypertensive crisis)
– inflammation of the pancreas (pancreatitis)
– liver inflamed, not working well or damaged
– yellowing of the skin or whites of the eyes (jaundice)
– inflammation of the lining of the abdominal cavity (peritonitis)

– runny nose
– rashes which may be itchy or inflamed (flat or raised spots or blisters)
– frequent bowel movements
– increased sensitivity of the skin to sunlight

– decreased feeling or sensitivity, especially in the skin

Rare side effects (may affect up to 1 in 1,000 people):
– inflammation of the lung (pneumonitis)

Not known (frequency cannot be estimated from the available data):
– an enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections)

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5 HOW TO STORE PAZOPANIB TAJ PHARMA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date (EXP) which is stated on the bottle and the carton. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

?6 CONTENTS OF THE PACK AND OTHER INFORMATION

What Pazopanib Taj Pharma contains

– The active substance is pazopanib (as hydrochloride).

a) Each film-coated tablet contains:
Pazopanib (as hydrochloride) IP? 200mg
Excipients????? q.s

b) Each film-coated tablet contains:
Pazopanib (as hydrochloride) IP? 400mg
Excipients????? q.s.

– The other ingredients in the 200 mg and 400 mg tablets are: hypromellose, macrogol 400, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, sodium starch glycolate, titanium dioxide. The 200 mg tablets also contain iron oxide red.

Contents of the pack

Pazopanib Taj Pharma 200 mg film-coated tablets are capsule-shaped, pink. They are supplied in bottles of 30 or 90 tablets.

Pazopanib Taj Pharma 400 mg film-coated tablets are capsule-shaped, white. They are supplied in bottles of 30 or 60 tablets.

Not all pack sizes or tablet strengths may be available.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

 

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