Votrient 200 and 400 mg FC tablets

VOTRIENT is indicated for the treatment of advanced and/or metastatic renal cell carcinoma (RCC) in adults.

VOTRIENT 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 have only been established in certain STS histological tumour subtypes (see section 5.1).

Posology: VOTRIENT is for the use as a single chemotherapeutic medicine and is not for concurrent administration with other chemotherapeutic medicines. The recommended dose of VOTRIENT for the treatment of RCC or STS is 800 mg orally once daily. VOTRIENT should be taken whole with water and must not be broken or crushed (see section 5.2). If a dose is missed, it should not be taken if it is less than 12 hours until the next dose.

Dose Modifications: Dose modification, either an increase or decrease in dose, should be in 200 mg increments in a stepwise fashion based on individual tolerability in order to manage adverse reactions. The daily dose of VOTRIENT should not exceed 800 mg.

Special Populations

Paediatric population (below 18 years): The safety and efficacy of VOTRIENT in children have not been established (see section 4.4).

Elderly: No alteration of dosage, dosing frequency or route of administration is required in patients over 65 years.

Renal Impairment: Renal impairment is not expected to have a clinically relevant effect on pazopanib pharmacokinetics given the low renal excretion of pazopanib and metabolites (see section 5.2). Renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary in patients with creatinine clearance u2265 30 ml/min. There is no experience of VOTRIENT in patients with severe renal impairment or in patients undergoing peritoneal dialysis or haemodialysis, therefore, use of VOTRIENT is not recommended in these patients.

Hepatic Impairment: The safety and pharmacokinetics of VOTRIENT in patients with pre-existing hepatic impairment have not been fully established (see section 4.4). No dose adjustment is required in patients with mild hepatic impairment as defined by alanine aminotransferase (ALT) and bilirubin (see Pharmacological Properties- Pharmacokinetic properties: special populations). The dose of VOTRIENT should be reduced to 200 mg per day in patients with moderate hepatic impairment (see Pharmacological Properties). Pazopanib is not recommended in patients with severe hepatic impairment (defined as total bilirubin >3 x ULN regardless of the ALT value). Cases of hepatic failure including fatal outcome have occurred in patients treated with VOTRIENT (see section 4.8).

Method of administration: VOTRIENT should be taken without food (at least one hour before or two hours after a meal) (see section 5.2).

Hypersensitivity to the active component and other ingredients contained in the product.

Hepatic Effects: Cases of hepatic failure (including fatalities) have been reported during use of VOTRIENT. In clinical trials with VOTRIENT, increase in serum transaminases (ALT, aspartate aminotransferase (AST)) and bilirubin were observed (see Undesirable effects). 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 may be at greater risk for ALT > 3 X ULN. Patients who carry the HLA-B*57:01 allele also have an increased risk of VOTRIENT-associated ALT elevations. Liver function should be monitored in all subjects receiving VOTRIENT, regardless of genotype or age (see section 5.1). The vast majority (over 90 %) of all transaminase elevations of any grade occurred in the first 18 weeks. Grades are based on the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3 (NCI CTCAE).

Serum liver tests should be performed before initiation of treatment with VOTRIENT, 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.

• Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 (NCI CTCAE) or baseline.
• Patients with ALT of > 8 X ULN should have VOTRIENT interrupted until they return to Grade 1 (NCI CTCAE) or baseline. If the potential benefit of re-initiating VOTRIENT treatment is considered to outweigh the risk for hepatotoxicity, then re-introduce VOTRIENT at a reduced dose of 400 mg once daily and perform serum liver tests weekly for 8 weeks (see section 4.2). Following re-introduction of VOTRIENT, if ALT elevations > 3 X ULN recur, then VOTRIENT should be permanently discontinued.
• If ALT elevations > 3 X ULN occur concurrently with bilirubin elevations > 2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until return to Grade 1 (NCI CTCAE) or baseline. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbertu2019s syndrome. Patients with only a mild indirect hyperbilirubinaemia, known or suspected Gilbertu2019s syndrome, and elevation in ALT > 3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations.

Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations (see section 4.5) and should be undertaken with caution and close monitoring. Beyond recommending that patients with mild hepatic impairment are treated with 800 mg VOTRIENT once daily and reducing the initial starting dose to 200 mg per day for patients with moderate impairment, no further dose modification guidelines based on results of serum liver tests during therapy have been established for patients with pre-existing hepatic impairment.

Hypertension: In clinical studies with VOTRIENT, events of hypertension including hypertensive crisis have occurred. Blood pressure should be well controlled prior to initiating VOTRIENT Patients should be monitored for hypertension early after starting treatment (no longer than one week after starting VOTRIENT) and frequently thereafter to ensure blood pressure control, and treated promptly with a combination of standard anti-hypertensive therapy and VOTRIENT dose reduction or interruption as clinically warranted (see Posology and method of administration and Undesirable effects). Hypertension (systolic blood pressure u2265 150 mm Hg or diastolic blood pressure u2265 100 mm Hg) occurs early in the course of VOTRIENT treatment (approximately 40 % of cases occurred by Day 9 and approximately 90 % of cases occurred in the first 18 weeks). In the case of persistent hypertension despite antihypertensive therapy, VOTRIENT dose may be reduced (see section 4.2). VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persists despite anti-hypertensive therapy and VOTRIENT dose reduction.

Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leukoencephalopathy syndrome (RPLS): PRES/RPLS has been reported in association with VOTRIENT. PRES/RPLS can present with headache, hypertension, seizure, lethargy, confusion, blindness and other visual and neurological disturbances, and can be fatal. Permanently discontinue VOTRIENT in patients developing PRES/RPLS.

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

Cardiac dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as congestive heart failure and decreased left ventricular ejection fraction (LVEF) have occurred. In a randomized RCC trial of VOTRIENT myocardial dysfunction was observed in 13 % (47/362) of subjects in the VOTRIENT Congestive heart failure was observed in 0.5 % of subjects. In the Phase III STS clinical trial, congestive heart failure was reported in 3 out of 240 subjects (1%). In this trial decreases in LVEF in subjects who had post-baseline measurement were detected in 11 % (16/142) in the VOTRIENT arm compared with 5 % (2/40) in the placebo arm. Fourteen of the 16 subjects in the VOTRIENT arm had concurrent hypertension which may have exacerbated cardiac dysfunction in patients at risk (e.g., those with prior anthracycline therapy) by increasing cardiac after-load. Blood pressure should be monitored and managed promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment). Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction.

QT Prolongation and Torsade de Pointes: In clinical studies with VOTRIENT, events of QT prolongation or Torsade de Pointes have occurred (see section 4.8). VOTRIENT should be used with caution in patients with a history of QT interval prolongation, patients taking anti-dysrhythmics or other medications that may potentially prolong QT interval, or in patients with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (calcium, magnesium, potassium) within normal range is recommended.

Arterial Thrombotic Events: In clinical studies with VOTRIENT, myocardial infarctions, angina, ischemic stroke and transient ischemic attack were observed (see section 4.8). Fatal events have been observed. VOTRIENT should be used with caution in patients who are at increased risk of thrombotic events or who have had a history of thrombotic events. VOTRIENT has not been studied in patients who have had an event within the previous 6 months. A treatment decision should be made based upon the assessment of individual patientu2019s benefit/risk.

Venous thromboembolic events: In clinical studies with VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. The incidence was higher in the STS population (5 %) than in the RCC population (2 %).

Thrombotic microangiopathy (TMA): Thrombotic microangiopathy (TMA) has been reported in clinical trials of VOTRIENT as monotherapy, in combination with bevacizumab, and in combination with topotecan (see section 4.8). VOTRIENT should be permanently discontinued in patients developing TMA. Reversal of effects of TMA has been observed after treatment was discontinued. VOTRIENT is not indicated for use in combination with other agents.

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

Gastrointestinal Perforations and Fistula: In clinical studies with VOTRIENT, events of gastrointestinal (GI) perforation or fistula have occurred (see section 4.8). Fatal perforation events have occurred. VOTRIENT should be used with caution in patients at risk for GI perforation or fistula.

Wound Healing: No formal studies of the effect of VOTRIENT on wound healing have been conducted. Since Vascular Endothelial Growth Factor (VEGF) inhibitors may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgement of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence.

Hypothyroidism: In clinical studies with VOTRIENT, events of hypothyroidism have occurred (see section 4.8). Proactive monitoring of thyroid function tests is recommended.

Proteinuria: In clinical studies with VOTRIENT, proteinuria has been reported (see section 4.8). Baseline and periodic urinalyses during treatment are recommended and patients should be monitored for worsening proteinuria. VOTRIENT should be discontinued if the patient develops nephrotic syndrome.

Tumour lysis syndrome (TLS): Cases of TLS, including fatal cases, have been reported in patients treated with VOTRIENT (see section 4.8). Patients generally at risk of TLS are those with rapidly growing tumours, a high tumour burden, renal dysfunction, or dehydration. Preventative measures such as treatment of high uric acid levels and intravenous hydration should be considered prior to initiation of VOTRIENT. Patients at risk should be closely monitored and treated as clinically indicated.

Infections: Cases of serious infections (with or without neutropenia), in some cases with fatal outcome, have been reported.

Combination with other systemic anti-cancer therapies: Clinical trials of VOTRIENT 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. VOTRIENT is not indicated for use in combination with other anti-cancer agents.

Juvenile animal toxicity: Because the mechanism of action of VOTRIENT can severely affect organ growth and maturation during early post-natal development, VOTRIENT should not be given to human paediatric patients younger than 2 years of age.

Women of childbearing potential / Contraception in males and females

Females of reproductive potential should be advised to use effective contraception during treatment with VOTRIENT and for at least 2 weeks after the last dose.

Male patients (including those who have had vasectomies) with female partners who are pregnant, possibly pregnant, or who could become pregnant should use condoms while taking VOTRIENT and for at least 2 weeks after the last dose.

Pregnancy

VOTRIENT should not be used during pregnancy (See section 4.3) There are no adequate data from the use of VOTRIENT in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Women of childbearing potential should use adequate contraception and should not become pregnant while receiving treatment with VOTRIENT.

Breastfeeding

Because of the potential for serious adverse reactions in breastfed infants from VOTRIENT, breastfeeding should be discontinued during treatment with VOTRIENT. (see section 4.6)

Fertility

Based on findings from animal studies, VOTRIENT may impair fertility in males and females of reproductive potential while receiving treatment.

The clinical status of the patient and the adverse event profile especially fatigue and possible blurred vision of VOTRIENT should be borne in mind when considering the patientu2019s ability to perform task that require judgment, motor and cognitive skills.

The safety and efficacy of VOTRIENT in renal cell carcinoma (RCC) were evaluated in a randomised, double-blind, placebo-controlled multi-centre study. Patients with locally advanced and/or metastatic RCC were randomised to receive VOTRIENT 800 mg once daily (N=290) or placebo (N=145). The median duration of treatment was 7,4 months for the VOTRIENT arm and 3,8 months for the placebo arm.

The safety and efficacy of VOTRIENT in soft tissue sarcoma (STS) were evaluated in a randomized, double-blind, placebo-controlled multi-center study. Patients (N=369) with advanced STS who had received prior anthracycline treatment, or were unsuited for such therapy, were randomized to receive VOTRIENT 800 mg once daily (N=246) or placebo (N=123). The median duration of treatment was 4,5 months for the VOTRIENT arm and 1,9 months for the placebo arm.

Adverse medicine reactions from clinical trials (Table 1) are listed by MedDRA system organ class. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (u22651/10); common (u22651/100 to <1/10); uncommon (u22651/1,000 to <1/100); rare (u22651/10,000 to <1/1,000); very rare (<1/10,000).

Table 1 Adverse medicine reactions, by organ class and frequency, reported in RCC (VEG105192) and STS (VEG110727) studies

Adverse drug reactions Frequency classification RCC N=290 STS N=240 Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Tumour pain u2666 Very common Blood and lymphatic system disorders Neutropenia Common u2666 Thrombocytopenia Common u2666 Endocrine disorders Hypothyroidism* Common Common Metabolism and nutrition disorders Anorexia Very common Very common Weight decreased Common Very common Nervous system disorders Dizziness u2666 Very common Dysgeusia Common Very common Headache Very common Very common Insomnia u2666 Common Ischaemic stroke* Uncommon Uncommon Transient ischaemic attack* Common u2666 Cardiac disorders Cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure)* Uncommon Common Bradycardia (asymptomatic) Very common u2020 Very common u2020 Myocardial infarction* Uncommon Common Myocardial ischaemia* Common u2666 QT prolongation* Common Common Torsade de Pointes* Uncommon u2666 Vascular disorders Cerebral haemorrhage* Uncommon Uncommon Epistaxis Common Common Gastrointestinal haemorrhage* Common Common Haematuria Common Uncommon Hypertension* Very common Very common Pulmonary haemorrhage* Uncommon Common Venous thromboembolic events* Common Common Respiratory, thoracic and mediastinal disorders Cough u2666 Very common Dysphonia Common Common Dyspnoea u2666 Very common Pneumothorax u2666 Common Gastrointestinal disorders Abdominal pain Very common Very common Diarrhoea Very common Very common Dyspepsia Common Common Gastrointestinal perforation* Uncommon u2666 Gastrointestinal fistula* Uncommon Uncommon Lipase elevations Common u2021 u2666 Nausea Very common Very common Stomatitis u2666 Very common Vomiting Very common Very common Hepatobiliary disorders Alanine aminotransferase increased* Very common Common Aspartate aminotransferase increased* Very common Common Hepatic function abnormal* Common u2666 Hyperbilirubinaemia* Common Uncommon Skin and subcutaneous tissue disorders Alopecia Common Very common Dry skin u2666 Common Exfoliative rash u2666 Very common Hair depigmentation Very common Very common Nail disorder u2666 Common Palmar-plantar erythrodysaesthesia syndrome (Foot-hand syndrome) Common Very common Rash Common Uncommon Skin depigmentation Common Very common Musculoskeletal and connective tissue disorders Musculoskeletal pain u2666 Very common Myalgia u2666 Very common Renal and urinary disorders Proteinuria* Common Uncommon General disorders and administration site conditions Asthenia Very common Uncommon Chest pain* Common Very common Chills u2666 Common Fatigue Very common Very common Oedema peripheral u2666 Very common Vision blurred u2666 Common * - See WARNINGS AND SPECIAL PRECAUTIONS for additional information. u2666 - Adverse event was not considered causally related to VOTRIENT in the pivotal clinical trial for this indication. Note: Laboratory findings which met the CTC-AE criteria were recorded as adverse events at the discretion of the Investigator u2020 - Frequency based on heart rate measurement (< 60 beats per minute) rather than adverse event reports. Symptomatic bradycardia has been identified rarely based on a review of the VOTRIENT safety database . u2021 - For RCC, the frequency category is based on data from the supportive single-arm study VEG102616.

Grade 3 fatigue (dose limiting toxicity) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2 000 mg and 1 000 mg daily, respectively.

Symptoms and Signs: There is currently limited experience with overdosage in VOTRIENT.

Treatment: Further management should be as clinically indicated or as recommended by the national poisons centre, where available. Haemodialysis is not expected to enhance the elimination of pazopanib because pazopanib is not significantly renally excreted and is highly bound to plasma proteins Treatment should be supportive and symptomatic. Cardiovascular monitoring for dysrhythmias and hypertension is required. Hepatic function should be assessed.