Votrient 200 mg film-coated tablets and 400mg film-coated tablets

Section 4.8 revised to change the frequency of infections ADR to common.
All other changes are editorial in nature.

Section 4.6 has been revised to include the following statement:

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 drug exposure to pregnant partners and female partners of reproductive potential.
Section 4.8 has been revised to include polycythaemia as an uncommon ADR. 

 

Section 4.6 updated to include the following text for women of child-bearing potential taking contraception: "during the treatment and at least 2 weeks after treatment".

The following text has been added to section 4.4:

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).
Section 5.1 has been updated to include the following:

 

Pharmacogenomics

In a pharmacogenetic meta-analysis of data from 31 clinical studies of pazopanib administered as either 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).

 

 

 

Section 5.3 has been revised to include carcinogenicity data.

7.       MARKETING AUTHORISATION HOLDER

Section 4.2 – Removal of ‘No data are available’ for the Paediatric population
Section 4.4 – Update Safety information (Hepatic function)
Section 4.8 - Update risk of retinal tears and retinal detachment
- Update adverse events in the Asian population
-Update the allocated frequency categories for existing ADRs

correction of typing errors.

Section 4.8 – To add HPRA contact details for ADR reporting

Section 5.1 – To update OS data for COMPARZ (VEG108844)

 

Change to Section 4.8

Votrient 200 mg and 400mg  film-coated tablets

VOTRIENT (II-23) - GDS 003 updates

 

Summary of changes for the SPC:

 

Updates to section 4.2 Posology and method of administration under the following heading:

 

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 as either normal bilirubin and any degree of alanine aminotransferase (ALT) elevation or as an elevation of bilirubin (> 35 % direct) up to 1.5 x upper limited 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 values) (see section 5.2).

 

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

 

 

Updates to section 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 as an 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 values) (see section 4.2 and 5.2). Pazopanib is not recommended in patients with severe hepatic impairment (total bilirubin > 3 x ULN regardless of any level of ALT) (see section 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, 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.

 

Serum liver tests should be monitored before initiation of treatment with pazopanib and at weeks 3, 5, 7 and 9. Thereafter, monitored at month 3 and at month 4, and as clinically indicated. Periodic monitoring 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 values	Dose modification
Transaminase elevation between 3 and 8 x ULN	Continue on pazopanib with weekly monitoring of liver function until transaminases return to Grade 1 or baseline.
Transaminase elevation of >8 x ULN	Interupt pazopanib until transaminases return to Grade 1 or baseline. If the potential benefit for reinitiating pazopanib treatment is considered to outweigh the risk for hepatotoxicity, then reintroduce pazopanib at a reduced dose of 400 mg daily and measure 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 ULN	Permanently 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.

 

 

·      Patients with isolated transaminase elevations ≤ 8 X upper limit of normal (ULN) may be continued on pazopanib with weekly monitoring of liver function until transaminases return to Grade 1 or baseline.

 

·      Patients with transaminases of > 8 X ULN should have pazopanib interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating pazopanib treatment is considered to outweigh the risk for hepatotoxicity, then reintroduce pazopanib at a reduced dose and measure serum liver tests weekly for 8 weeks (see section 4.2). Following reintroduction of pazopanib, if transaminase elevations > 3 X ULN recur, then pazopanib should be discontinued.

 

·      If transaminase elevations > 3 X ULN occur concurrently with bilirubin elevations > 2 X ULN, bilirubin fractionation should be performed. If direct (conjugated) bilirubin is > 35 % of total bilirubin, pazopanib should be discontinued.

 

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 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 judgment) (see section 4.2 and 4.8). Pazopanib should be discontinued if there is evidence of persistently elevated values of blood pressure (140/90 mm Hg) or if arterial hypertension is severe and persists despite anti-hypertensive therapy and pazopanib dose reduction.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.

 

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 LVEF has not been studied.

 

In clinical trials with pazopanib, events of cardiac dysfunction such as congestive heart failure and decreased left ventricular ejection fraction (LVEF) have occurred (see section 4.8). Congestive heart failure was reported in 2 out of 382 subjects (0.5 %) in the STS population. Decreases in LVEF in subjects who had post-baseline 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 antiarrythmics or other medicinal products that may prolong QT interval and those with relevant pre-existing cardiac disease. When using pazopanib, base line 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, ischemic stroke, and transient ischemic 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 for any of these thrombotic events or who have had a history of thrombotic events. Pazopanib has not been studied in patients who have had an event within the previous 6 months. A treatment decision should be made based upon the assessment of individual patient’s benefit/risk.

 

Venous Thromboembolic Events

 

In clinical studies with pazopanib, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. 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

 

Thrombotic microangiopathy (TMA) has been reported in clinical trials 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 is has not recommended been studied in patients who had a history of haemoptysis, cerebral, or clinically significant gastrointestinal (GI) haemorrhage in the past 6 months. Pazopanib should be used with caution in patients with significant risk of haemorrhage.

 

Gastrointestinal 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 on 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 Grade 4 proteinuria 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 trials of pazopanib in combination with pemetrexed (non-small cell lung cancer (NSCLC)) and lapatinib (cervical cancer) were terminated early due to concerns over increased toxicity and/or mortality, and a safe and effective combination dose has not been established with these regimens.

 

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).

 

 

Addition of the following side effects to section 4.8 Undesirable effects

 

System Organ Class	Frequency (all grades)		Adverse Reactions		All Grades n (%)		Grade 3 n (%)		Grade 4 n (%)
Rare		Thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome) †		not known		not known		not known
Rare		Posterior reversible encephalopathy / Reversible posterior leukoencephalopathy syndrome†		not known		not known		not known

 

 

Addition of the following information to section 4.9 Overdose:

 

Pazopanib doses up to 2,000 mg have been evaluated in clinical studies without dose-limiting toxicity. 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.

 

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

 

 

Addition of the following information to section 5.1 Pharmacodynamic properties:

 

Soft Tissue Sarcoma (STS)

 

The efficacy and safety of pazopanib in STS were evaluated in a pivotal phase III randomized, double-blind, placebo-controlled multi-centre trial (VEG110727). A total of 369 patients with advanced STS were randomized 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) excluding chondrosarcoma, Ewing tumours / Primitive neuroectodermal tumours (PNET), 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 week12) observed with pazopanib in adipocytic did not meet the prerequisite rate to allow further clinical testing.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Summary of changes for package leaflet:

 

 

Addition and deletion of the following information to section 4. Possible side effects

 

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

 

Conditions you need to look out for

 

Swelling of the brain (reversible posterior leukoencephalopathy syndrome which is a disorder of the brain)

Votrient can in rare occasions cause swelling of the brain, which may be life threatening. Symptoms include:

-    loss of speech

-    change of vision

-    seizure (fits)

-    confusion

 

-       Stop taking Votrient and seek medical advice immediately if you get any of these symptoms, or if you get headache accompanied with any of these symptoms.

 

Heart conditions

Votrient can affect heart rhythm (QT prolongation) 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. 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 Votrient.

 

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

 

Bleeding

Votrient can cause severe bleeding in the digestive system (such as stomach, gullet, 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 / vomiting up blood

 

-       Tell your doctor as soon as possible if you get any of these symptoms.

 

Thyroid problems

-Votrient can lower the amount of thyroid hormone produced in your body. You will be checked for this while you are taking Votrient.

 

Very common side effects

These 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 where the skin may peel

-        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 effect that may show up in your blood tests:

-        increase in liver enzymes

-        increase in albumin in the blood

-        decrease in the number of blood platelets (cells that help blood to clot)

-        decrease in the number of white blood cells

 

Common side effects

These may affect up to 1 in 10 people:

-        indigestion, bloating, flatulence

-        nose bleed

-        dry mouth or mouth ulcers, gum infection

-        infections

-          feeling weak or tired

-        abnormal drowsiness

-        difficulty in 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 attack, heart failure

-        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

-          tumour pain

-        hoarseness

-        shortness of breath

-        cough

-        coughing up blood

-        hiccups

-        lung collapses and air gets 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:

-        under-active thyroid gland

-        abnormal liver function

-        protein in the urine

-        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

These may affect up to 1 in 100 people:

-        stroke

-        temporary fall in blood supply to the brain (mini-stroke)

-        interruption of blood supply to part of the heart (myocardial infarction)

-        heart becomes less effective at pumping blood around the body (cardiac dysfunction)

-        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, gullet or intestine), or the kidneys, vagina and brain

-        heart rhythm disturbance (QT prolongation)

-          slow heart beat

-        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

-        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)

-          mouth ulcers

-        runny nose

-          black tar like stools

-          stools contain blood

-        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.

-          infections, with or without changes in white blood cells (cells that fight infection).

 

Uncommon side effects that may show up in your blood or urine tests:

-          low levels of calcium or magnesium in the blood

-          changes in the levels of different chemicals / enzymes in the blood. Your doctor will inform you of the results of the blood / urine tests

Rare side effects

These may affect up to 1 in 1,000 people

-          swelling of the brain that may be associated with high blood pressure, headache, loss of speech or vision, and/or seizure, which may be life threatening

-        blood clots accompanied by a decrease in red blood cells and cells involved in clotting. These may harm organs such as the brain and kidneys

 

 

 

An update to the first paragraph in Section 4.8 undesirable effects:

 

 Summary of the safety profile

Pooled data from the pivotal RCC trial (VEG105192, n=290), extension study (VEG107769, n=71), and the supportive Phase II trial (VEG102616, n=225) and the randomised, open-label, parallel group Phase III non-inferiority study (VEG108844, n=557) was evaluated in the overall evaluation of safety and tolerability of pazopanib (total n=1149586) in subjects with RCC (see section 5.1).

 

 

An update to the following table 1 of adverse reactions:

 

Tabulated list of adverse reactions

Table 1: Treatment-related adverse reactions reported in RCC studies (n = 1149) or during post marketing period

 

System Organ Class	Frequency (all grades)	Adverse Reactions	All Grades n (%)	Grade 3 n (%)	Grade 4 n (%)
Infections and Infestations	Uncommon	Infections (with or without neutropenia)†	not known	not known	not known
	Uncommon	Gingival infection	1 (< 1 %)	0	0
	Uncommon	Infectious peritonitis	1 (< 1 %)	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Common	Tumour pain	1 (< 1 %)	1 (< 1 %)	0
Blood and lymphatic system disorders	Common	Thrombocytopenia	80 (7 %)	10 (< 1 %)	5 (< 1 %)
	Common	Neutropenia	79 (7 %)	20 (2 %)	4 (< 1 %)
	Common	Leukopenia	63 (5 %)	5 (< 1 %)	0
Endocrine disorders	Common	Hypothyroidism	83 (7 %)	1 (< 1 %)	0
Metabolism and nutrition disorders	Very common	Decreased appetitee	317 (28 %)	14 (1 %)	0
	Common	Hypophosphataemia	21 (2 %)	7 (< 1 %)	0
	Common	Dehydration	16 (1 %)	5 (< 1 %)	0
	Uncommon	Hypomagnesaemia	10 (< 1 %)	0	0
Psychiatric disorders	Common	Insomnia	30 (3 %)	0	0
Nervous system disorders	Very common	Dysgeusiac	254 (22 %)	1 (< 1 %)	0
	Very common	Headache	122 (11 %)	11 (< 1 %)	0
	Common	Dizziness	55 (5 %)	3 (< 1 %)	1 (< 1 %)
	Common	Lethargy	30 (3 %)	3 (< 1 %)	0
	Common	Paraesthesia	20 (2 %)	2 (< 1 %)	0
	Common	Peripheral sensory neuropathy	17 (1 %)	0	0
	Uncommon	Hypoaesthesia	8 (< 1 %)	0	0
	Uncommon	Transient ischaemic attack	7 (< 1 %)	4 (< 1 %)	0
	Uncommon	Somnolence	3 (< 1 %)	1 (< 1 %)	0
	Uncommon	Cerebrovascular accident	2 (< 1 %)	1 (< 1 %)	1 (< 1 %)
	Uncommon	Ischaemic stroke	2 (< 1 %)	0	1 (< 1 %)
Eye disorders	Common	Vision blurred	19 (2 %)	1 (< 1 %)	0
	Uncommon	Eyelash discolouration	4 (< 1 %)	0	0
Cardiac disorders	Uncommon	Bradycardia	6 (< 1 %)	0	0
	Uncommon	Myocardial infarction	5 (< 1 %)	1 (< 1 %)	4 (< 1 %)
	Uncommon	Cardiac dysfunction f	4 (< 1 %)	1 (< 1 %)	0
	Uncommon	Myocardial ischaemia	3 (< 1 %)	1 (< 1 %)	0
Vascular disorders	Very common	Hypertension	473 (41 %)	115 (10 %)	1 (< 1 %)
	Common	Hot flush	16 (1 %)	0	0
	Common	Venous Thromboembolic event g	13 (1 %)	6 (< 1 %)	7 (< 1 %)
	Common	Flushing	12 (1 %)	0	0
	Uncommon	Hypertensive crisis	6 (< 1 %)	0	2 (< 1 %)
	Uncommon	Haemorrhage	1 (< 1 %)	0	0
Respiratory, thoracic and mediastinal disorders	Common	Epistaxis	50 (4 %)	1 (< 1 %)	0
	Common	Dysphonia	48 (4 %)	0	0
	Common	Dyspnoea	42 (4 %)	8 (< 1 %)	1 (< 1 %)
	Common	Haemoptysis	15 (1 %)	1 (< 1 %)	0
	Uncommon	Rhinorrhoea	8 (< 1 %)	0	0
	Uncommon	Pulmonary haemorrhage	2 (< 1 %)	0	0
	Uncommon	Pneumothorax	1 (< 1 %)	0	0
Gastrointestinal disorders	Very common	Diarrhoea	614 (53 %_)	65 (6 %)	2 (< 1 %)
	Very common	Nausea	386 (34 %)	14 (1%)	0
	Very common	Vomiting	225 (20 %)	18 (2 %)	1 (< 1 %)
	Very common	Abdominal paina	139 (12 %)	15 (1 %)	0
	Common	Stomatitis	96 (8 %)	4 (< 1 %)	0
	Common	Dyspepsia	83 (7 %)	2 (< 1 %)	0
	Common	Flatulence	43 (4 %)	0	0
	Common	Abdominal distension	36 (3 %)	2 (< 1 %)	0
	Common	Mouth ulceration	28 (2 %)	3 (< 1 %)	0
	Common	Dry mouth	27 (2 %)	0	0
	Uncommon	Pancreatitis	8 (< 1 %)	4 (< 1 %)	0
	Uncommon	Rectal haemorrhage	8 (< 1 %)	2 (< 1 %)	0
	Uncommon	Haematochezia	6 (< 1 %)	0	0
	Uncommon	Gastrointestinal haemorrhage	4 (< 1 %)	2 (< 1 %)	0
	Uncommon	Melaena	4 (< 1 %)	1(< 1 %)	0
	Uncommon	Frequent bowel movements	3 (< 1 %)	0	0
	Uncommon	Anal haemorrhage	2 (< 1 %)	0	0
	Uncommon	Large intestine perforation	2 (< 1 %)	1 (< 1 %)	0
	Uncommon	Mouth haemorrhage	2 (< 1 %)	0	0
	Uncommon	Upper gastrointestinal haemorrhage	2 (< 1 %)	1 (< 1 %)	0
	Uncommon	Enterocutaneous fistula	1 (< 1 %)	0	0
	Uncommon	Haematemesis	1 (< 1 %)	0	0
	Uncommon	Haemorrhoidal haemorrhage	1 (< 1 %)	0	0
	Uncommon	Ileal perforation	1 (< 1 %)	0	1 (< 1 %)
	Uncommon	Oesophageal haemorrhage	1 (< 1 %)	0	0
	Uncommon	Retroperitoneal haemorrhage	1 (< 1 %)	0	0
Hepatobiliary disorders	Common	Hyperbilirubinaemia	38 (3 %)	2 (< 1 %)	1 (< 1 %)
	Common	Hepatic function abnormal	29 (3 %)	13 (1 %)	2 (< 1 %)
	Common	Hepatotoxicity	18 (2 %)	11(< 1 %)	2 (< 1 %)
	Uncommon	Jaundice	3 (< 1 %)	1 (< 1 %)	0
	Uncommon	Drug induced liver injury	2 (< 1 %)	2 (< 1 %)	0
	Uncommon	Hepatic failure	1 (< 1 %)	0	1 (< 1 %)
Skin and subcutaneous disorders	Very common	Hair colour change	404 (35 %)	1 (< 1 %)	0
	Very common	Palmar-plantar erythrodysaesthesia syndrome	206 (18 %)	39 (3 %)	0
	Very common	Alopecia	130 (11 %)	0	0
	Very common	Rash	129 (11 %)	7 (< 1 %)	0
	Common	Skin hypopigmentation	52 (5 %)	0	0
	Common	Dry skin	50 (4 %(	0	0
	Common	Pruritus	29 (3 %)	0	0
	Common	Erythema	25 (2 %)	0	0
	Common	Skin depigmentation	20 (2 %)	0	0
	Common	Hyperhidrosis	17 (1 %)	0	0
	Uncommon	Nail disorders	11 (< 1 %)	0	0
	Uncommon	Skin exfoliation	10 (< 1 %)	0	0
	Uncommon	Photosensitivity reaction	7 (< 1 %)	0	0
	Uncommon	Rash erythematous	6 (< 1 %)	0	0
	Uncommon	Skin disorder	5 (< 1 %)	0	0
	Uncommon	Rash macular	4 (< 1 %)	0	0
	Uncommon	Rash pruritic	3 (< 1 %)	0	0
	Uncommon	Rash vesicular	3 (< 1 %)	0	0
	Uncommon	Pruritus generalised	2 (< 1 %)	1 (< 1 %)	0
	Uncommon	Rash generalised	2 (< 1 %)	0	0
	Uncommon	Rash papular	2 (< 1 %)	0	0
	Uncommon	Plantar erythema	1 (< 1 %)	0	0
Musculoskeletal and connective tissue disorders	Common	Arthralgia	48 (4 %)	8 (< 1 %)	0
	Common	Myalgia	35 (3 %)	2 (< 1 %)	0
	Common	Muscle spasms	25 (2 %)	0	0
	Uncommon	Musculoskeletal pain	9 (< 1 %)	1 (< 1 %)	0
Renal and urinary disorders	Common	Proteinuria	135 (12 %)	32 (3 %)	0
	Uncommon	Haemorrhage urinary tract	1 (< 1 %)	0	0
Reproductive system and breast disorders	Uncommon	Menorrhagia	3 (< 1 %)	0	0
	Uncommon	Vaginal haemorrhage	3 (< 1 %)	0	0
	Uncommon	Metrorrhagia	1 (< 1 %)	0	0
General disorders and administration site conditions	Very common	Fatigue	415 (36 %)	65 (6 %)	1 (< 1 %)
	Common	Mucosal inflammation	86 (7 %)	5 (< 1 %)	0
	Common	Asthenia	82 (7 %)	20 (2 %)	1 (< 1 %)
	Common	Oedemab	72 (6 %)	1 (< 1 %)	0
	Common	Chest pain	18 (2 %)	2 (< 1 %)	0
	Uncommon	Chills	4 (< 1 %)	0	0
	Uncommon	Mucous membrane disorder	1 (< 1 %)	0	0
Investigations	Very common	Alanine aminotransferase increased	246 (21 %)	84 (7 %)	14 (1 %)
	Very common	Aspartate aminotransferase increased	211 (18 %)	51 (4 %)	10 (< 1 %)
	Common	Weight decreased	96 (8 %)	7 (< 1 %)	0
	Common	Blood bilirubin increased	61 (5 %)	6 (< 1 %)	1 (< 1 %)
	Common	Blood creatinine increased	55 (5 %)	3 (< 1 %)	0
	Common	Lipase increased	51 (4 %)	21 (2 %)	7 (< 1 %)
	Common	White blood cell count decreasedd	51 (4 %)	3 (< 1 %)	0
	Common	Blood thyroid stimulating hormone increased	36 (3 %)	0	0
	Common	Amylase increased	35 (3 %)	7 (< 1 %)	0
	Common	Gamma-glutamyltransferase increased	31 (3 %)	9 (< 1 %)	4 (< 1 %)
	Common	Blood pressure increased	15 (1 %)	2 (< 1 %)	0
	Common	Blood urea increased	12 (1 %)	1 (< 1 %)	0
	Common	Liver function test abnormal	12 (1 %)	6 (< 1 %)	1 (< 1 %)
	Uncommon	Hepatic enzyme increased	11 (< 1 %)	4 (< 1 %)	3 (< 1 %)
	Uncommon	Blood glucose decreased	7 (< 1 %)	0	1 (< 1 %)
	Uncommon	Electrocardiogram QT prolonged	7 (< 1 %)	2 (< 1 %)	0
	Uncommon	Transaminase increased	7 (< 1 %)	1 (< 1 %)	0
	Uncommon	Thyroid function test abnormal	3 (< 1 %)	0	0
	Uncommon	Blood pressure diastolic increased	2 (< 1 %)	0	0
	Uncommon	Blood pressure systolic increased	1 (< 1 %)	0	0

 

†Treatment related adverse reaction reported during post marketing period (spontaneous case reports and serious adverse reactions from all pazopanib clinical trials).

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}

 

 

 

Addition of the following paragraph to section 5.1 Pharmacodynamic properties:

 

The safety, efficacy and quality of life of pazopanib versus sunitinib has been evaluated in a randomized, 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 randomized to receive either pazopanib 800 mg once daily continuously or sunitinib 50 mg once daily in 6‑week cycles of dosing with 4 weeks on treatment followed by 2 weeks without treatment.

The primary objective of this study was to evaluate and compare PFS in patients treated with pazopanib to those treated with sunitinib. Demographic characteristics were similar between the treatment arms. Disease characteristics at initial diagnosis and at screening were balanced between the treatment arms with the majority of patients having clear cell histology and Stage IV disease.

VEG108844 achieved its primary endpoint of PFS and demonstrated that pazopanib was non-inferior to sunitinib, as the upper bound of the 95 % CI for the hazard ratio was less than the protocol-specified non-inferiority margin of 1.25. Overall efficacy results are summarised in Table 4.

Table 4: Overall efficacy results (VEG108844)

 

Endpoint	Pazopanib 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)	28.4 (26.2, 35.6)	29.3 (25.3, 32.5)	0.908a (0.762, 1.082)

HR = Hazard Ratio; PFS = Progression-free Survival; ^a P value = 0.275 (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)).

 

 

And the deletion of the end paragraph in section 5.1 Pharmacodynamic properties:

 

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme.

This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on the product every year and this SmPC will be updated as necessary.

 

 

 

Summary of changes the for PACKAGE LEAFLET

 

The following QRD changes to section 2 of the Leaflet:

 

Don’tDo not take Votrient

 -       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. Don’t take Votrient.

Take special care with Votrient

Warnings and precautions

 

 

An update ot the following side effects in Section 4 Possible side effects

 

Very common side effects

-        general pain

-        unusual hair loss or thinning

-        scaly red skin rash

-        redness  and swelling of the palms of the hands or soles of the feet

 

Very common side effect that may show up in your blood tests

-        decrease in the number of blood platelets (cells that help blood to clot)

-        decrease in the number of white blood cells

 

Common side effects

-    heart failure

-        weakness

-        skin disordersrash

-        redness and swelling of the palms of the hands or soles of the feet, nail problems

-        tumour pain

-        unusual hair loss or thinning

-    shortness of breath

-    coughing up blood

-         

Common side effects that may show up in your blood or urine tests:

-          decrease in the number of blood platelets (cells that help blood to clot)

-        decrease in the number of white blood cells

Uncommon side effects

-          coughing up blood

-        stools contain blood

-        decreased feeling or sensitivity, especially in the skin

4.4       Special warnings and precautions for use

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.

 

Thrombotic Microangiopathy

 

Thrombotic microangiopathy (TMA) has been reported in clinical trials of pazopanib as monotherapy, in combination with bevacizumab, and in combination with topotecan (sees 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.

 

4.8       Undesirable effects

System Organ Class	Frequency (all grades)	Adverse Reactions	All Grades n (%)	Grade 3 n (%)	Grade 4 n (%)
	Rare	Thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome) †	not known	not known	not known
	Uncommon	Ischaemic stroke	1 (< 1 %)	0