ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Votrient 200 mg film-coated tablets
2.
Each film-coated tablet contains 200 mg pazopanib (as hydrochloride).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Capsule-shaped, pink, film-coated tablet with GS JT debossed on one side.
4.
CLINIC AL PARTICULARS
Votrient is indicated for the first line treatment of advanced Renal Cell Carcinoma (RCC) and for
patients who have received prior cytokine therapy for advanced disease.
Votrient treatment should only be initiated by a physician experienced in the administration of
anti-cancer agents.
Adults
The recommended dose of pazopanib is 800 mg once daily.
Dose modifications
Dose modification should be in 200 mg increments in a stepwise fashion based on individual
tolerability in order to manage adverse reactions. The dose of pazopanib should not exceed 800 mg.
Paediatric population
Pazopanib is not recommended for use in children and adolescents below 18 years of age due to
insufficient data on safety and efficacy.
Elderly
There are limited data of 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 older
individuals cannot be ruled out.
2
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
The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully
established (see section 4.4). Administration of pazopanib to patients with mild or moderate hepatic
impairment should be undertaken with caution and close monitoring due to potentially increased
exposure to the medicinal product. Insufficient data are available in patients with mild hepatic
impairment to provide a dose adjustment recommendation but a reduced pazopanib dose of 200 mg
once daily is recommended in patients with moderate hepatic impairment (see section 5.2).
Pazopanib is contraindicated in patients with severe hepatic impairment (see section 4.3).
Method of administration
Pazopanib should be taken without food, at least one hour before or two hours after a meal (see section
5.2). Votrient film-coated tablets should be taken whole with water and not broken or crushed (see
section 5.2).
Hypersensitivity to the active substance or to any of the excipients.
Severe hepatic impairment.
Hepatic effects
Cases of hepatic failure (including fatalities) have been reported during use of pazopanib. The safety
and pharmacokinetics of pazopanib have not been fully established in patients with pre-existing
hepatic impairment. Administration of pazopanib to patients with mild or moderate hepatic
impairment should be undertaken with caution and close monitoring. A reduced pazopanib dose of
200 mg once daily is recommended in patients with moderate hepatic impairment (see section 4.2).
Insufficient data are available in patients with mild hepatic impairment to provide a dose adjustment
recommendation. Pazopanib is contraindicated in patients with severe hepatic impairment (see section
4.3).
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.
Monitor serum liver tests before initiation of treatment with pazopanib and at least once every 4 weeks
for the first 4 months of treatment, and as clinically indicated. Periodic monitoring should then
continue after this time period.
•
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
3
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.
Hypertension
Blood pressure should be well controlled prior to initiating pazopanib. Patients should be monitored
for hypertension and treated as needed with standard anti-hypertensive therapy (see section 4.8).
Hypertension occurs early in the course of treatment (88 % occurring in first 18 weeks). In the case of
persistent hypertension despite anti-hypertensive therapy, the pazopanib dose may be reduced (see
section 4.2). Temporary suspension is recommended in patients if hypertension is severe and persists
despite anti-hypertensive therapy and pazopanib dose reduction. Pazopanib treatment may be resumed
once hypertension is appropriately controlled.
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). Pazopanib should be used with caution in patients who are at
increased risk for any of these events. A treatment decision should be made based upon the assessment
of individual patient’s benefit/risk.
Haemorrhagic events
In clinical studies with pazopanib haemorrhagic events have been reported (see section 4.8).
Pazopanib is not recommended 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).
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.
4
Heart failure
The safety and pharmacokinetics of pazopanib in patients with moderate to severe heart failure has not
been studied.
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.
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).
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.
Grapefruit juice should be avoided during treatment with pazopanib (see section 4.5).
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.
Co-administration of pazopanib with strong inhibitors of the CYP3A4 family (e.g., ketoconazole,
itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
5
telithromycin, voriconazole) may increase pazopanib concentrations. Grapefruit juice contains an
inhibitor of CYP3A4 and may also increase plasma concentrations of pazopanib.
Administration of 1,500 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 C
max
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.
Concurrent administration of a single dose of pazopanib eye drops (at a low dose of 400 µg (80 µl of
5 mg/ml)) with the strong CYP3A4 inhibitor and P-gp inhibitor, ketoconazole, in healthy volunteers
resulted in a 2.2- and 1.5-fold increase in mean AUC
(0-t)
and C
max
values, respectively. Inhibition of
P-gp and/or BCRP by ketoconazole likely contributed to the increased exposure to pazopanib. At
present no dosing recommendations can be made for either potent specific inhibitors of CYP3A4 or
ketoconazole.
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).
Combination with strong CYP3A4, P-gp or BCRP inhibitors should therefore be avoided, or selection
of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4, 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 alternate
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 C
max
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/m
2
(CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of
25 % and 31 % in paclitaxel AUC and C
max
, respectively.
Based on
in vitro
IC
50
and
in vivo
plasma C
max
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.
rosuvastatin).
6
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 C
max
. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after a
meal.
Pregnancy
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 women 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 and avoid becoming
pregnant while receiving treatment with pazopanib.
Breast-feeding
The safe use of pazopanib during lactation has not been established. It is not known whether
pazopanib is excreted in human milk. There are no animal data on the excretion of pazopanib in
animal milk. A risk to the suckling 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).
No studies on the effects on the ability to drive and use machines have been performed. 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.
Pooled data from the pivotal RCC study (VEG105192, n=290), extension study (VEG107769, n=71)
and the supportive Phase II study (VEG102616, n=225) was evaluated in the overall evaluation of
safety and tolerability of pazopanib (total n=586) in subjects with RCC (see section 5.1).
The most important serious adverse reactions were transient ischaemic attack, ischaemic stroke,
myocardial ischaemia, cardiac dysfunction, gastrointestinal perforation and fistula, QT prolongation
and pulmonary, gastrointestinal and cerebral haemorrhage, all adverse reactions being reported in
< 1 % of treated patients.
Fatal events that were considered possibly related to pazopanib included gastrointestinal haemorrhage,
pulmonary haemorrhage/haemoptysis, abnormal hepatic function, intestinal perforation and ischemic
stroke.
7
The most common adverse reactions (experienced by at least 10 % of the patients) of any grade
included: diarrhoea, hair colour change, hypertension, nausea, fatigue, anorexia, vomiting, dysgeusia,
elevated alanine aminotransferase and elevated aspartate aminotransferase.
Treatment related adverse reactions, all grades, which were reported in RCC patients 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
not known
(cannot be estimated from the available data)
Categories have been assigned based on absolute frequencies in the clinical study data. Within each
system organ class, adverse reactions with the same frequency are presented in order of decreasing
seriousness.
8
Table 1: Treatment-related adverse reactions reported in RCC studies (n=586)
System Organ
Class
Frequency
(all grades)
Adverse Reactions
All Grades
n (%)
Grade 3
n (%)
Grade 4
n (%)
Blood and
lymphatic system
disorders
Common
Thrombocytopenia
25 (4 %)
3 (< 1 %)
3 (< 1 %)
Common
Neutropenia
17 (3 %)
4 (< 1 %)
2 (< 1 %)
Common
Leukopenia
14 (2 %)
1 (< 1 %)
0
Endocrine
disorders
Common
Hypothyroidism
23 (4 %)
0
0
Very common Decreased appetite
e
122 (21 %)
6 (1 %)
0
Metabolism and
nutrition
disorders
Uncommon
Hypophosphataemia
4 (< 1 %)
2 (< 1 %)
0
Uncommon
Hypomagnesaemia
3 (< 1 %)
0
0
Very common Dysgeusia
c
92 (16 %)
0
0
Common
Headache
41 (7 %)
0
0
Common
Dizziness
19 (3 %)
0
1 (< 1 %)
Common
Lethargy
12 (2 %)
1 (< 1 %)
0
Common
Paraesthesia
12 (2 %)
2 (< 1 %)
0
Nervous system
disorders
Uncommon
Peripheral sensory
neuropathy
5 (< 1 %)
0
0
Uncommon
Hypoaesthesia
4 (< 1 %)
0
0
Uncommon
Transient ischaemic
attack
3 (< 1 %)
2 (< 1 %)
0
Uncommon
Cerebrovascular
accident
1 (< 1 %)
0
1 (< 1 %)
Uncommon
Ischaemic stroke
1 (< 1 %)
0
0
Eye disorders
Uncommon
Eyelash discolouration 3 (< 1 %)
0
0
Uncommon
Bradycardia
3 (< 1 %)
0
0
Cardiac disorders
Uncommon
Cardiac dysfunction
4 (< 1 %)
1 (< 1 %)
1 (< 1 %)
Uncommon
Myocardial infarction 2 (< 1 %)
0
2 (< 1 %)
Uncommon
Myocardial ischaemia 1 (< 1 %)
1 (< 1 %)
0
Very common Hypertension
225 (38 %)
34 (6%)
0
Common
Hot flush
11 (2 %)
0
0
Vascular
disorders
Uncommon
Flushing
5 (< 1 %)
0
0
Uncommon
Haemorrhage
1 (< 1 %)
0
0
Uncommon
Hypertensive crisis
1 (< 1 %)
0
1 (< 1 %)
Common
Epistaxis
16 (3 %)
0
0
Respiratory,
thoracic and
mediastinal
disorders
Common
Dysphonia
15 (3 %)
0
0
Uncommon
Pulmonary embolism 4 (< 1 %)
1 (< 1 %)
3 (< 1 %)
Uncommon
Haemoptysis
3 (< 1 %)
0
0
Uncommon
Pulmonary
haemorrhage
1 (< 1 %)
0
0
Very common Diarrhoea
286 (49 %)
19 (3 %)
2 (< 1 %)
Very common Nausea
161 (27 %)
3 (< 1 %)
0
Gastrointestinal
disorders
Very common Vomiting
89 (15 %)
7 (1 %)
1 (< 1 %)
Very common Abdominal pain
a
60 (10 %)
8 (1 %)
0
Common
Dyspepsia
24 (4 %)
2 (< 1 %)
0
Common
Stomatitis
24 (4 %)
0
0
Common
Flatulence
20 (3 %)
0
0
9
Common
Abdominal distension 15 (3 %)
0
0
Uncommon
Mouth ulceration
4 (< 1 %)
1 (< 1 %)
0
Uncommon
Frequent bowel
movements
3 (< 1 %)
0
0
Uncommon
Gastrointestinal
haemorrhage
3 (< 1 %)
1 (< 1 %)
0
Uncommon
Rectal haemorrhage
3 (< 1 %)
1 (< 1 %)
0
Uncommon
Large intestine
perforation
2 (< 1 %)
1 (< 1 %)
0
Uncommon
Mouth haemorrhage
2 (< 1 %)
0
0
Uncommon
Enterocutaneous
fistula
1 (< 1 %)
0
0
Uncommon
Haematemesis
1 (< 1 %)
0
0
Uncommon
Haematochezia
1 (< 1 %)
0
0
Uncommon
Haemorrhoidal
haemorrhage
1 (< 1 %)
0
0
Uncommon
Ileal perforation
1 (< 1 %)
0
1 (< 1 %)
Uncommon
Melaena
1 (< 1 %)
0
0
Uncommon
Oesophageal
haemorrhage
1 (< 1 %)
0
1 (< 1 %)
Uncommon
Pancreatitis
1 (< 1 %)
0
0
Uncommon
Peritonitis
1 (< 1 %)
0
0
Uncommon
Retroperitoneal
haemorrhage
1 (< 1 %)
0
0
Uncommon
Upper gastrointestinal
haemorrhage
1 (< 1 %)
0
0
Common
Hepatic function
abnormal
20 (3 %)
6 (1 %)
0
Common
Hyperbilirubinaemia
18 (3 %)
2 (< 1 %)
1 (< 1 %)
Hepatobiliary
disorders
Uncommon
Hepatotoxicity
5 (< 1 %)
3 (< 1 %)
0
Uncommon
Jaundice
2 (< 1 %)
1 (< 1 %)
0
Uncommon
Hepatic failure
1 (< 1 %)
0
1 (< 1 %)
Uncommon
Hepatitis
1 (< 1 %)
1 (< 1 %)
0
Very common Hair colour change
231 (39 %)
1 (< 1 %)
0
Common
Rash
52 (9 %)
3 (< 1 %)
0
Common
Alopecia
50 (9 %)
0
0
Common
Palmar-plantar
erythrodysaesthesia
syndrome
43 (7 %)
7 (1 %)
0
Common
Skin
hypopigmentation
25 (4 %)
0
0
Skin and
subcutaneous
disorders
Common
Erythema
15 (3 %)
0
0
Common
Pruritus
13 (2 %)
0
0
Common
Skin depigmentation
13 (2 %)
0
0
Common
Dry skin
12 (2 %)
0
0
Common
Hyperhidrosis
9 (2 %)
0
0
Uncommon
Photosensitivity
reaction
7 (1 %)
0
0
Uncommon
Skin exfoliation
7 (1 %)
0
0
Uncommon
Rash vesicular
3 (< 1 %)
0
0
Uncommon
Pruritus generalised
2 (< 1 %)
1 (< 1 %)
0
Uncommon
Rash papular
2 (< 1 %)
0
0
Uncommon
Plantar erythema
1 (< 1 %)
0
0
10
Uncommon
Rash erythematous
1 (< 1 %)
0
0
Uncommon
Rash generalised
1 (< 1 %)
0
0
Uncommon
Rash macular
1 (< 1 %)
0
0
Uncommon
Rash pruritic
1 (< 1 %)
0
0
Musculoskeletal
and connective
tissue disorders
Common
Myalgia
15 (3 %)
2 (< 1 %)
0
Common
Muscle spasms
12 (2 %)
0
0
Renal and
urinary disorders
Common
Proteinuria
40 (7 %)
5 (< 1 %)
0
Uncommon
Haemorrhage urinary
tract
1 (< 1 %)
0
0
Reproductive
system and breast
disorders
Uncommon
Menorrhagia
1 (< 1 %)
0
0
Uncommon
Metrorrhagia
1 (< 1 %)
0
0
Uncommon
Vaginal haemorrhage 1 (< 1 %)
0
0
Very common Fatigue
139 (24 %)
16 (3 %)
0
Common
Asthenia
41 (7 %)
8 (1 %)
0
General disorders
and
administration
site conditions
Common
Mucosal inflammation 27 (5 %)
2 (< 1 %)
0
Common
Oedema
b
19 (3 %)
0
0
Common
Chest pain
14 (2 %)
2 (< 1 %)
0
Uncommon
Mucous membrane
disorder
1 (< 1 %)
0
0
Very common Alanine
aminotransferase
increased
83 (14%)
28 (5 %)
4 (< 1 %)
Very common Aspartate
aminotransferase
increased
72 (12%)
17 (3 %)
3 (< 1 %)
Common
Weight decreased
38 (6 %)
2 (< 1 %)
0
Common
Blood creatinine
increased
13 (2 %)
2 (< 1 %)
0
Common
Blood bilirubin
increased
11 (2 %)
1 (< 1 %)
1 (< 1 %)
Common
White blood cell count
decreased
d
10 (2 %)
1 (< 1 %)
0
Common
Lipase increased
9 (2 %)
4 (< 1 %)
1 (< 1 %)
Common
Blood pressure
increased
6 (1 %)
0
0
Investigations
Common
Blood thyroid
stimulating hormone
increased
6 (1 %)
0
0
Common
Gamma-
glutamyltransferase
increased
6 (1 %)
1 (< 1 %)
1 (< 1 %)
Common
Hepatic enzyme
increased
6 (1 %)
2 (< 1 %)
0
Uncommon
Aspartate
aminotransferase
5 (< 1 %)
2 (< 1 %)
0
Uncommon
Blood urea increased
5 (< 1 %)
1 (< 1 %)
0
Uncommon
Electrocardiogram QT
prolonged
5(< 1 %)
1 (< 1 %)
0
Uncommon
Blood amylase
increased
4 (< 1 %)
0
0
Uncommon
Blood glucose
decreased
4 (< 1 %)
0
0
11
Uncommon
Alanine
aminotransferase
3 (< 1 %)
2 (< 1 %)
0
Uncommon
Transaminase
increased
3 (< 1 %)
1 (< 1 %)
0
Uncommon
Blood pressure
diastolic increased
2 (< 1 %)
0
0
Uncommon
Thyroid function test
abnormal
2 (< 1 %)
0
0
Uncommon
Blood pressure
systolic increased
1 (< 1 %)
0
0
Uncommon
Liver function test
abnormal
1 (< 1 %)
0
0
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
Pazopanib doses up to 2,000 mg have been evaluated in clinical studies without dose-limiting toxicity.
There is no specific antidote for overdose with pazopanib and treatment of overdose should consist of
general supportive measures.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: 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)-α and –β, and stem cell factor receptor (c-KIT), with IC
50
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-β receptors in cells.
In vivo
, pazopanib
inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in various animal
models, and the growth of multiple human tumour xenografts in mice.
Clinical studies
The safety and efficacy of pazopanib in RCC were evaluated in a randomized, double-blind, placebo-
controlled multi-centre study. Patients (N= 435) with locally advanced and/or metastatic RCC were
randomized to receive pazopanib 800 mg once daily or placebo. The primary objective of the study
was to evaluate and compare the two treatment arms for progression-free survival (PFS) and the
principle secondary endpoint is overall survival (OS). The other objectives were to evaluate the overall
response rate and duration of response.
From the total of 435 patients in this study, 233 patients were treatment naïve and 202 were second
line patients who received one prior IL-2 or INFα-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
12
(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-naïve 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 naïve and cytokine pre-treated).
Table 2: Overall efficacy results by independent assessment
P value
(one-sided)
PFS
Overall* ITT N = 290 N = 145
Median (months) 9.2 4.2 0.46 (0.34, 0.62) <0.0000001
Response rate N = 290 N = 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-Naïve and Cytokine Pre-
treated Populations.
Pazopanib
Placebo
HR (95% CI)
Figure 1: Kaplan-Meier curve for progression-free survival by independent assessment for the overall
population (treatment-naïve and cytokine pre-treated populations)
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
13
Endpoints/Study Population
Figure 2: Kaplan-Meier curve for progression-free survival by independent assessment for the
treatment-naïve population
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
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.
At the time of the analysis for the primary endpoint, the overall survival data were not sufficiently
mature.
No statistical differences were observed between treatment groups for Global Quality of Life using
EORTC QLQ-C30 and EuroQoL EQ-5D.
In a Phase 2 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.
Paediatric population
14
The European Medicines Agency has waived the obligation to submit the results of studies with
Votrient in all subsets of the paediatric population in Renal Cell Carcinoma (see section 4.2 for
information on paediatric use).
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
.
5.2 Pharmacokinetic properties
Absorption
:
Upon oral administration of a single pazopanib 800 mg dose to patients with solid
tumours, maximum plasma concentration (C
max
) of approximately 19 ± 13 µg/ml were obtained after
median 3.5 hours (range 1.0-11.9 hours) and an AUC
∞
of approximately 650 ± 500 µg.h/ml was
obtained. Daily dosing results in 1.23- to 4-fold increase in AUC
T
.
There was no consistent increase in AUC or C
max
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 C
max
.
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 C
max
by
approximately 2 fold and decreased t
max
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 μg/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:
In subjects with moderate hepatic impairment the median pazopanib C
max
and
AUC(0-6 hr) normalized to a dose of 800 mg once daily were both increased 2-fold compared to those
in subjects with normal hepatic function. Based on safety, tolerability and pharmacokinetic data, the
15
dosage of pazopanib should be reduced to 200 mg once daily in subjects with moderate hepatic
impairment (see section 4.2). Data are not available in subjects with mild hepatic impairment.
Pazopanib is contraindicated in patients with severe hepatic impairment (see section 4.3).
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 pharmacologic effects (rodents). Proliferative hepatic
lesions (eosinophilic foci and adenoma) were seen in female mice at exposures 2.5 times human
exposure based on AUC.
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
Carcinogenicity studies with pazopanib have not been performed.
6.
6.1 List of excipients
Tablet core
Magnesium stearate
Microcrystalline cellulose
Povidone (K30)
Sodium starch glycolate (type A)
Tablet coating
Hypromellose
Iron oxide red (E172)
Macrogol 400
Polysorbate 80
Titanium dioxide (E171)
16
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
HDPE bottles with polypropylene child resistant closures containing either 30 or 90 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Glaxo Group Limited
Berkeley Avenue
Greenford
Middlesex
UB6 0NN
United Kingdom.
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/.
17
1.
Votrient 400 mg film-coated tablets
2.
Each film-coated tablet contains 400 mg pazopanib (as hydrochloride).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Capsule-shaped, white, film-coated tablet with GS UHL debossed on one side.
4.
CLINIC AL PARTICULARS
Votrient is indicated for the first line treatment of advanced Renal Cell Carcinoma (RCC) and for
patients who have received prior cytokine therapy for advanced disease.
Votrient treatment should only be initiated by a physician experienced in the administration of
anti-cancer agents.
Adults
The recommended dose of pazopanib is 800 mg once daily.
Dose modifications
Dose modification should be in 200 mg increments in a stepwise fashion based on individual
tolerability in order to manage adverse reactions. The dose of pazopanib should not exceed 800 mg.
Paediatric population
Pazopanib is not recommended for use in children and adolescents below 18 years of age due to
insufficient data on safety and efficacy.
Elderly
There are limited data of 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 older
individuals cannot be ruled out.
18
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
The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully
established (see section 4.4). Administration of pazopanib to patients with mild or moderate hepatic
impairment should be undertaken with caution and close monitoring due to potentially increased
exposure to the medicinal product. Insufficient data are available in patients with mild hepatic
impairment to provide a dose adjustment recommendation but a reduced pazopanib dose of 200 mg
once daily is recommended in patients with moderate hepatic impairment (see section 5.2).
Pazopanib is contraindicated in patients with severe hepatic impairment (see section 4.3).
Method of administration
Pazopanib should be taken without food, at least one hour before or two hours after a meal (see section
5.2). Votrient film-coated tablets should be taken whole with water and not broken or crushed (see
section 5.2).
Hypersensitivity to the active substance or to any of the excipients.
Severe hepatic impairment.
Hepatic effects
Cases of hepatic failure (including fatalities) have been reported during use of pazopanib. The safety
and pharmacokinetics of pazopanib have not been fully established in patients with pre-existing
hepatic impairment. Administration of pazopanib to patients with mild or moderate hepatic
impairment should be undertaken with caution and close monitoring. A reduced pazopanib dose of
200 mg once daily is recommended in patients with moderate hepatic impairment (see section 4.2).
Insufficient data are available in patients with mild hepatic impairment to provide a dose adjustment
recommendation. Pazopanib is contraindicated in patients with severe hepatic impairment (see section
4.3).
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.
Monitor serum liver tests before initiation of treatment with pazopanib and at least once every 4 weeks
for the first 4 months of treatment, and as clinically indicated. Periodic monitoring should then
continue after this time period.
•
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
19
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.
Hypertension
Blood pressure should be well controlled prior to initiating pazopanib. Patients should be monitored
for hypertension and treated as needed with standard anti-hypertensive therapy (see section 4.8).
Hypertension occurs early in the course of treatment (88 % occurring in first 18 weeks). In the case of
persistent hypertension despite anti-hypertensive therapy, the pazopanib dose may be reduced (see
section 4.2). Temporary suspension is recommended in patients if hypertension is severe and persists
despite anti-hypertensive therapy and pazopanib dose reduction. Pazopanib treatment may be resumed
once hypertension is appropriately controlled.
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). Pazopanib should be used with caution in patients who are at
increased risk for any of these events. A treatment decision should be made based upon the assessment
of individual patient’s benefit/risk.
Haemorrhagic events
In clinical studies with pazopanib haemorrhagic events have been reported (see section 4.8).
Pazopanib is not recommended 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).
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.
20
Heart failure
The safety and pharmacokinetics of pazopanib in patients with moderate to severe heart failure has not
been studied.
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.
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).
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.
Grapefruit juice should be avoided during treatment with pazopanib (see section 4.5).
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.
Co-administration of pazopanib with strong inhibitors of the CYP3A4 family (e.g., ketoconazole,
itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
21
telithromycin, voriconazole) may increase pazopanib concentrations. Grapefruit juice contains an
inhibitor of CYP3A4 and may also increase plasma concentrations of pazopanib.
Administration of 1,500 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 C
max
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.
Concurrent administration of a single dose of pazopanib eye drops (at a low dose of 400 µg (80 µl of
5 mg/ml)) with the strong CYP3A4 inhibitor and P-gp inhibitor, ketoconazole, in healthy volunteers
resulted in a 2.2- and 1.5-fold increase in mean AUC
(0-t)
and C
max
values, respectively. Inhibition of
P-gp and/or BCRP by ketoconazole likely contributed to the increased exposure to pazopanib. At
present no dosing recommendations can be made for either potent specific inhibitors of CYP3A4 or
ketoconazole.
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).
Combination with strong CYP3A4, P-gp or BCRP inhibitors should therefore be avoided, or selection
of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4, 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 alternate
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 C
max
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/m
2
(CYP3A4 and CYP2C8 substrate) once weekly resulted in a mean increase of
25 % and 31 % in paclitaxel AUC and C
max
, respectively.
Based on
in vitro
IC
50
and
in vivo
plasma C
max
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.
rosuvastatin).
22
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 C
max
. Therefore, pazopanib should be administered at least 1 hour before or 2 hours after
a meal.
Pregnancy
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 women 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 and avoid becoming
pregnant while receiving treatment with pazopanib.
Breast-feeding
The safe use of pazopanib during lactation has not been established. It is not known whether
pazopanib is excreted in human milk. There are no animal data on the excretion of pazopanib in
animal milk. A risk to the suckling 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).
No studies on the effects on the ability to drive and use machines have been performed. 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.
Pooled data from the pivotal RCC study (VEG105192, n=290), extension study (VEG107769, n=71)
and the supportive Phase II study (VEG102616, n=225) was evaluated in the overall evaluation of
safety and tolerability of pazopanib (total n=586) in subjects with RCC (see section 5.1).
The most important serious adverse reactions were transient ischaemic attack, ischaemic stroke,
myocardial ischaemia, cardiac dysfunction, gastrointestinal perforation and fistula, QT prolongation
and pulmonary, gastrointestinal and cerebral haemorrhage, all adverse reactions being reported in
< 1 % of treated patients.
Fatal events that were considered possibly related to pazopanib included gastrointestinal haemorrhage,
pulmonary haemorrhage/haemoptysis, abnormal hepatic function, intestinal perforation and ischemic
stroke.
23
The most common adverse reactions (experienced by at least 10 % of the patients) of any grade
included: diarrhoea, hair colour change, hypertension, nausea, fatigue, anorexia, vomiting, dysgeusia,
elevated alanine aminotransferase and elevated aspartate aminotransferase.
Treatment related adverse reactions, all grades, which were reported in RCC patients 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
not known
(cannot be estimated from the available data)
Categories have been assigned based on absolute frequencies in the clinical study data. Within each
system organ class, adverse reactions with the same frequency are presented in order of decreasing
seriousness.
24
Table 1: Treatment-related adverse reactions reported in RCC studies (n=586)
System Organ
Class
Frequency
(all grades)
Adverse Reactions
All Grades
n (%)
Grade 3
n (%)
Grade 4
n (%)
Blood and
lymphatic system
disorders
Common
Thrombocytopenia
25 (4 %)
3 (< 1 %)
3 (< 1 %)
Common
Neutropenia
17 (3 %)
4 (< 1 %)
2 (< 1 %)
Common
Leukopenia
14 (2 %)
1 (< 1 %)
0
Endocrine
disorders
Common
Hypothyroidism
23 (4 %)
0
0
Very common Decreased appetite
e
122 (21 %)
6 (1 %)
0
Metabolism and
nutrition
disorders
Uncommon
Hypophosphataemia
4 (< 1 %)
2 (< 1 %)
0
Uncommon
Hypomagnesaemia
3 (< 1 %)
0
0
Very common Dysgeusia
c
92 (16 %)
0
0
Common
Headache
41 (7 %)
0
0
Common
Dizziness
19 (3 %)
0
1 (< 1 %)
Common
Lethargy
12 (2 %)
1 (< 1 %)
0
Common
Paraesthesia
12 (2 %)
2 (< 1 %)
0
Nervous system
disorders
Uncommon
Peripheral sensory
neuropathy
5 (< 1 %)
0
0
Uncommon
Hypoaesthesia
4 (< 1 %)
0
0
Uncommon
Transient ischaemic
attack
3 (< 1 %)
2 (< 1 %)
0
Uncommon
Cerebrovascular
accident
1 (< 1 %)
0
1 (< 1 %)
Uncommon
Ischaemic stroke
1 (< 1 %)
0
0
Eye disorders
Uncommon
Eyelash discolouration 3 (< 1 %)
0
0
Uncommon
Bradycardia
3 (< 1 %)
0
0
Cardiac disorders
Uncommon
Cardiac dysfunction
4 (< 1 %)
1 (< 1 %)
1 (< 1 %)
Uncommon
Myocardial infarction 2 (< 1 %)
0
2 (< 1 %)
Uncommon
Myocardial ischaemia 1 (< 1 %)
1 (< 1 %)
0
Very common Hypertension
225 (38 %)
34 (6%)
0
Common
Hot flush
11 (2 %)
0
0
Vascular
disorders
Uncommon
Flushing
5 (< 1 %)
0
0
Uncommon
Haemorrhage
1 (< 1 %)
0
0
Uncommon
Hypertensive crisis
1 (< 1 %)
0
1 (< 1 %)
Common
Epistaxis
16 (3 %)
0
0
Respiratory,
thoracic and
mediastinal
disorders
Common
Dysphonia
15 (3 %)
0
0
Uncommon
Pulmonary embolism 4 (< 1 %)
1 (< 1 %)
3 (< 1 %)
Uncommon
Haemoptysis
3 (< 1 %)
0
0
Uncommon
Pulmonary
haemorrhage
1 (< 1 %)
0
0
Very common Diarrhoea
286 (49 %)
19 (3 %)
2 (< 1 %)
Very common Nausea
161 (27 %)
3 (< 1 %)
0
Gastrointestinal
disorders
Very common Vomiting
89 (15 %)
7 (1 %)
1 (< 1 %)
Very common Abdominal pain
a
60 (10 %)
8 (1 %)
0
Common
Dyspepsia
24 (4 %)
2 (< 1 %)
0
Common
Stomatitis
24 (4 %)
0
0
Common
Flatulence
20 (3 %)
0
0
25
Common
Abdominal distension 15 (3 %)
0
0
Uncommon
Mouth ulceration
4 (< 1 %)
1 (< 1 %)
0
Uncommon
Frequent bowel
movements
3 (< 1 %)
0
0
Uncommon
Gastrointestinal
haemorrhage
3 (< 1 %)
1 (< 1 %)
0
Uncommon
Rectal haemorrhage
3 (< 1 %)
1 (< 1 %)
0
Uncommon
Large intestine
perforation
2 (< 1 %)
1 (< 1 %)
0
Uncommon
Mouth haemorrhage
2 (< 1 %)
0
0
Uncommon
Enterocutaneous
fistula
1 (< 1 %)
0
0
Uncommon
Haematemesis
1 (< 1 %)
0
0
Uncommon
Haematochezia
1 (< 1 %)
0
0
Uncommon
Haemorrhoidal
haemorrhage
1 (< 1 %)
0
0
Uncommon
Ileal perforation
1 (< 1 %)
0
1 (< 1 %)
Uncommon
Melaena
1 (< 1 %)
0
0
Uncommon
Oesophageal
haemorrhage
1 (< 1 %)
0
1 (< 1 %)
Uncommon
Pancreatitis
1 (< 1 %)
0
0
Uncommon
Peritonitis
1 (< 1 %)
0
0
Uncommon
Retroperitoneal
haemorrhage
1 (< 1 %)
0
0
Uncommon
Upper gastrointestinal
haemorrhage
1 (< 1 %)
0
0
Common
Hepatic function
abnormal
20 (3 %)
6 (1 %)
0
Common
Hyperbilirubinaemia
18 (3 %)
2 (< 1 %)
1 (< 1 %)
Hepatobiliary
disorders
Uncommon
Hepatotoxicity
5 (< 1 %)
3 (< 1 %)
0
Uncommon
Jaundice
2 (< 1 %)
1 (< 1 %)
0
Uncommon
Hepatic failure
1 (< 1 %)
0
1 (< 1 %)
Uncommon
Hepatitis
1 (< 1 %)
1 (< 1 %)
0
Very common Hair colour change
231 (39 %)
1 (< 1 %)
0
Common
Rash
52 (9 %)
3 (< 1 %)
0
Common
Alopecia
50 (9 %)
0
0
Common
Palmar-plantar
erythrodysaesthesia
syndrome
43 (7 %)
7 (1 %)
0
Common
Skin
hypopigmentation
25 (4 %)
0
0
Skin and
subcutaneous
disorders
Common
Erythema
15 (3 %)
0
0
Common
Pruritus
13 (2 %)
0
0
Common
Skin depigmentation
13 (2 %)
0
0
Common
Dry skin
12 (2 %)
0
0
Common
Hyperhidrosis
9 (2 %)
0
0
Uncommon
Photosensitivity
reaction
7 (1 %)
0
0
Uncommon
Skin exfoliation
7 (1 %)
0
0
Uncommon
Rash vesicular
3 (< 1 %)
0
0
Uncommon
Pruritus generalised
2 (< 1 %)
1 (< 1 %)
0
Uncommon
Rash papular
2 (< 1 %)
0
0
Uncommon
Plantar erythema
1 (< 1 %)
0
0
26
Uncommon
Rash erythematous
1 (< 1 %)
0
0
Uncommon
Rash generalised
1 (< 1 %)
0
0
Uncommon
Rash macular
1 (< 1 %)
0
0
Uncommon
Rash pruritic
1 (< 1 %)
0
0
Musculoskeletal
and connective
tissue disorders
Common
Myalgia
15 (3 %)
2 (< 1 %)
0
Common
Muscle spasms
12 (2 %)
0
0
Renal and
urinary disorders
Common
Proteinuria
40 (7 %)
5 (< 1 %)
0
Uncommon
Haemorrhage urinary
tract
1 (< 1 %)
0
0
Reproductive
system and breast
disorders
Uncommon
Menorrhagia
1 (< 1 %)
0
0
Uncommon
Metrorrhagia
1 (< 1 %)
0
0
Uncommon
Vaginal haemorrhage 1 (< 1 %)
0
0
Very common Fatigue
139 (24 %)
16 (3 %)
0
Common
Asthenia
41 (7 %)
8 (1 %)
0
General disorders
and
administration
site conditions
Common
Mucosal inflammation 27 (5 %)
2 (< 1 %)
0
Common
Oedema
b
19 (3 %)
0
0
Common
Chest pain
14 (2 %)
2 (< 1 %)
0
Uncommon
Mucous membrane
disorder
1 (< 1 %)
0
0
Very common Alanine
aminotransferase
increased
83 (14%)
28 (5 %)
4 (< 1 %)
Very common Aspartate
aminotransferase
increased
72 (12%)
17 (3 %)
3 (< 1 %)
Common
Weight decreased
38 (6 %)
2 (< 1 %)
0
Common
Blood creatinine
increased
13 (2 %)
2 (< 1 %)
0
Common
Blood bilirubin
increased
11 (2 %)
1 (< 1 %)
1 (< 1 %)
Common
White blood cell count
decreased
d
10 (2 %)
1 (< 1 %)
0
Common
Lipase increased
9 (2 %)
4 (< 1 %)
1 (< 1 %)
Common
Blood pressure
increased
6 (1 %)
0
0
Investigations
Common
Blood thyroid
stimulating hormone
increased
6 (1 %)
0
0
Common
Gamma-
glutamyltransferase
increased
6 (1 %)
1 (< 1 %)
1 (< 1 %)
Common
Hepatic enzyme
increased
6 (1 %)
2 (< 1 %)
0
Uncommon
Aspartate
aminotransferase
5 (< 1 %)
2 (< 1 %)
0
Uncommon
Blood urea increased
5 (< 1 %)
1 (< 1 %)
0
Uncommon
Electrocardiogram QT
prolonged
5(< 1 %)
1 (< 1 %)
0
Uncommon
Blood amylase
increased
4 (< 1 %)
0
0
Uncommon
Blood glucose
decreased
4 (< 1 %)
0
0
27
Uncommon
Alanine
aminotransferase
3 (< 1 %)
2 (< 1 %)
0
Uncommon
Transaminase
increased
3 (< 1 %)
1 (< 1 %)
0
Uncommon
Blood pressure
diastolic increased
2 (< 1 %)
0
0
Uncommon
Thyroid function test
abnormal
2 (< 1 %)
0
0
Uncommon
Blood pressure
systolic increased
1 (< 1 %)
0
0
Uncommon
Liver function test
abnormal
1 (< 1 %)
0
0
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
Pazopanib doses up to 2,000 mg have been evaluated in clinical studies without dose-limiting toxicity.
There is no specific antidote for overdose with pazopanib and treatment of overdose should consist of
general supportive measures.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: 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)-α and –β, and stem cell factor receptor (c-KIT), with IC
50
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-β receptors in cells.
In vivo
, pazopanib
inhibited VEGF-induced VEGFR-2 phosphorylation in mouse lungs, angiogenesis in various animal
models, and the growth of multiple human tumour xenografts in mice.
Clinical studies
The safety and efficacy of pazopanib in RCC were evaluated in a randomized, double-blind, placebo-
controlled multi-centre study. Patients (N= 435) with locally advanced and/or metastatic RCC were
randomized to receive pazopanib 800 mg once daily or placebo. The primary objective of the study
was to evaluate and compare the two treatment arms for progression-free survival (PFS) and the
principle secondary endpoint is overall survival (OS). The other objectives were to evaluate the overall
response rate and duration of response.
From the total of 435 patients in this study, 233 patients were treatment naïve and 202 were second
line patients who received one prior IL-2 or INFα-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
28
(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-naïve 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 naïve and cytokine pre-treated).
Table 2: Overall efficacy results by independent assessment
P value
(one-sided)
PFS
Overall* ITT N = 290 N = 145
Median (months) 9.2 4.2 0.46 (0.34, 0.62) <0.0000001
Response rate N = 290 N = 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-Naïve and Cytokine Pre-
treated Populations.
Pazopanib
Placebo
HR (95% CI)
Figure 1: Kaplan-Meier curve for progression-free survival by independent assessment for the overall
population (treatment-naïve and cytokine pre-treated populations)
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
29
Endpoints/Study Population
Figure 2: Kaplan-Meier curve for progression-free survival by independent assessment for the
treatment-naïve population
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
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.
At the time of the analysis for the primary endpoint, the overall survival data were not sufficiently
mature.
No statistical differences were observed between treatment groups for Global Quality of Life using
EORTC QLQ-C30 and EuroQoL EQ-5D.
In a Phase 2 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.
30
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
Votrient in all subsets of the paediatric population in Renal Cell Carcinoma (see section 4.2 for
information on paediatric use).
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
.
5.2 Pharmacokinetic properties
Absorption
:
Upon oral administration of a single pazopanib 800 mg dose to patients with solid
tumours, maximum plasma concentration (C
max
) of approximately 19 ± 13 µg/ml were obtained after
median 3.5 hours (range 1.0-11.9 hours) and an AUC
∞
of approximately 650 ± 500 µg.h/ml was
obtained. Daily dosing results in 1.23- to 4-fold increase in AUC
T
.
There was no consistent increase in AUC or C
max
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 C
max
.
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 C
max
by
approximately 2 fold and decreased t
max
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 μg/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:
In subjects with moderate hepatic impairment the median pazopanib C
max
and
AUC(0-6 hr) normalized to a dose of 800 mg once daily were both increased 2-fold compared to those
31
in subjects with normal hepatic function. Based on safety, tolerability and pharmacokinetic data, the
dosage of pazopanib should be reduced to 200 mg once daily in subjects with moderate hepatic
impairment (see section 4.2). Data are not available in subjects with mild hepatic impairment.
Pazopanib is contraindicated in patients with severe hepatic impairment (see section 4.3).
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 pharmacologic effects (rodents). Proliferative hepatic
lesions (eosinophilic foci and adenoma) were seen in female mice at exposures 2.5 times human
exposure based on AUC.
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
Carcinogenicity studies with pazopanib have not been performed.
6.
6.1 List of excipients
Tablet core
Magnesium stearate
Microcrystalline cellulose
Povidone (K30)
Sodium starch glycolate (type A)
Tablet coating
Hypromellose
Macrogol 400
Polysorbate 80
Titanium dioxide (E171)
32
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.5
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.6
Nature and contents of container
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
No special requirements.
7.
Glaxo Group Limited
Berkeley Avenue
Greenford
Middlesex
UB6 0NN
United Kingdom.
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu/.
33
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
34
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Glaxo Operations UK Ltd (trading as Glaxo Wellcome Operations)
Priory Street
Ware
Hertfordshire
SG12 0DJ
United Kingdom
Glaxo Wellcome, S.A.
Avda. Extremadura, 3
09400 Aranda De Duero, Burgos
Spain
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 7.2 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 2 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
⋅
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
⋅
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
35
⋅
At the request of the EMEA
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of studies within the
specified time frame. The results of which shall be taken into account in the risk benefit balance
during the assessment of the application for a renewal.
Clinical aspects
1)
Submit the study report for VEG108844 (a study of pazopanib versus sunitinib in the treatment of
subjects with locally advanced and/or metastatic renal cell carcinoma) by February 2012.
2)
Submit a pooled analysis of data from study VEG108844 and VEG113078 (a study to evaluate
efficacy and safety of pazopanib versus sunitinib for the treatment of Asian subjects with locally
advanced and/or metastatic renal cell carcinoma - a sub study of VEG108844). The studies should
be appropriately powered to demonstrate non-inferiority with a margin of 1.22. A discussion on
the applicability of the efficacy data from VEG113078 to the European population should be
provided by June 2012.
36
ANNEX III
LABELLING AND PACKAGE LEAFLET
37
A. LABELLING
38
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON – 200 mg film-coated tablets
1.
Votrient 200 mg film-coated tablets
pazopanib
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 200 mg pazopanib (as hydrochloride)
3.
LIST OF EXCIPIENTS
4.
30 film-coated tablets
90 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
39
Glaxo Group Ltd, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
votrient 200 mg
40
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE LABEL – 200 mg film-coated tablets
1.
Votrient 200 mg film-coated tablets
Pazopanib
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 200 mg pazopanib (as hydrochloride)
3.
LIST OF EXCIPIENTS
4.
30 film-coated tablets
90 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
41
Glaxo Group Ltd, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
42
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON – 400 mg film-coated tablets
1.
Votrient 400 mg film-coated tablets
Pazopanib
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 400 mg pazopanib (as hydrochloride)
3.
LIST OF EXCIPIENTS
4.
30 film-coated tablets
60 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
43
Glaxo Group Ltd, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
votrient 400 mg
44
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE LABEL – 400 mg film-coated tablets
1.
Votrient 400 mg film-coated tablets
pazopanib
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 400 mg pazopanib (as hydrochloride)
3.
LIST OF EXCIPIENTS
4.
30 film-coated tablets
60 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
45
Glaxo Group Ltd, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
46
B. PACKAGE LEAFLET
47
PACKAGE LEAFLET: INFORMATION FOR THE USER
Votrient 200 mg film-coated tablets
Votrient 400 mg film-coated tablets
Pazopanib
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Votrient is and what it is used for
2.
Before you take Votrient
4.
Possible side effects
5.
How to store Votrient
6.
Further information
1.
What Votrient is and what it is used for
Votrient is a type of medicine called a
protein kinase inhibitor.
It is used to treat kidney cancer that is
advanced or has spread to other organs. It works by preventing the activity of proteins that are
involved in the growth and spread of cancer cells.
2.
Before you take Votrient
Don’t take Votrient
-
if you are allergic
(
hypersensitive
) to pazopanib or any of the other ingredients of Votrient
(listed in Section 6).
-
Check with your doctor
if you think this applies to you. Don’t take Votrient.
Take special care with Votrient
Before you take Votrient
your doctor needs to know:
-
if you have
heart disease
-
if you have
liver disease
-
if you have had
stomach or bowel problems
such as
perforation
(hole) or
fistula
(abnormal
passages forming between parts of the intestine).
-
Tell your doctor
if any of these apply to you. Your doctor will decide whether Votrient is
suitable for you. You may need
extra tests
to check that your heart and liver are working
properly.
Votrient is not recommended for people aged under 18.
It is not yet known how well it works in
this age group.
High blood pressure and Votrient
48
-
If you have any further questions, ask your doctor or pharmacist.
3.
How to take Votrient
-
if you have had problems with
bleeding, blood clots or narrowing of the arteries
Votrient can raise your blood pressure. Your blood pressure will be checked before you take Votrient
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 Votrient 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 may need to look out for
Votrient can make some conditions worse or cause serious side effects, such as heart conditions,
bleeding and thyroid probems. You must look out for certain symptoms while you are taking Votrient
to reduce the risk of any problems. See ‘
Conditions you need to look out for’
in Section 4.
Other medicines and Votrient
Tell your doctor or pharmacist if you are taking any other medicines, have taken any recently, or if
you start new ones. This includes herbal medicines and other medicines you’ve bought without a
prescription.
Some medicines may affect how Votrient works or make it more likely that you’ll have side effects.
Votrient 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
)
-
Tell your doctor
or pharmacist if you take any of these.
Food and drink with Votrient
Don’t take Votrient 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.
Do not drink grapefruit juice
while you are being treated with Votrient as this may increase the
chance of side effects.
Pregnancy and breast-feeding
Votrient is not recommended if you are pregnant.
The effect of Votrient 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 Votrient, to prevent pregnancy
-
If you do become pregnant during treatment
with Votrient, tell your doctor
Don’t breast-feed while taking Votrient
. It is not known whether the ingredients in Votrient pass
into breast-milk. Talk to your doctor about this.
Driving and using machines
Votrient 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.
49
3.
How to take Votrient
Always take Votrient exactly as your doctor has told you.
Check with your doctor or pharmacist if
you’re not sure.
How much to take
The usual dose
is two Votrient 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 Votrient 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 Votrient 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 it affects
the way the medicine is absorbed and may increase the chance of side effects.
If you take too much Votrient
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 Votrient
Don't take the extra tablets to make up for a missed dose. Just take your next dose at the usual time.
Don’t stop Votrient without advice
Take Votrient for as long as your doctor recommends. Don’t stop unless your doctor advises you to.
4.
Possible side effects
Like all medicines, Votrient can cause side effects, although not everybody gets them.
Conditions you need to look out for
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.
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
50
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
-
taste disturbance or loss of taste
-
lack of energy
-
changes in hair colour
-
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
Common side effects
These may affect
up to 1 in 10
people:
-
indigestion, bloating, flatulence
-
weight loss
-
nose bleed
-
feeling weak or tired
-
abnormal drowsiness
-
difficulty in sleeping
-
headache
-
dizziness
-
hot flushes
-
swelling caused by fluid of face, hands, ankles, feet or eyelids
-
tingling or numbness of the hands, arms, legs or feet
-
skin rash, redness, itching, dry skin
-
loss of skin pigment
-
redness and swelling of the palms of the hands or soles of the feet
-
excessive sweating
-
muscle or chest pain, muscle spasms
-
unusual hair loss or thinning
-
hoarseness
-
Tell your doctor
or pharmacist if any of these effects become troublesome.
51
Common side effects that may show up in your blood or urine tests:
-
under-active thyroid gland
-
abnormal liver function
-
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
-
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, rectum or intestine), or the lung,
kidneys, mouth, 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
-
rashes which may be itchy or inflamed (flat or raised spots or blisters)
-
frequent bowel movements
-
increased sensitivity of the skin to sunlight
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
52
If you get side effects
Tell your doctor or pharmacist
if any of the side effects listed becomes
severe or troublesome
, or if
you notice any side effects not listed in this leaflet.
5
.
How to store Votrient
Keep out of the reach and sight of children.
Do not use Votrient 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.
If you have unwanted tablets, don’t put them in waste water or household rubbish. Ask your
pharmacist how to dispose of medicines you don’t need. This will help to protect the environment.
6.
Further information
What Votrient contains
The active substance in Votrient
is
pazopanib hydrochloride. Votrient tablets come in different
strengths.
Votrient 200 mg: each tablet contains 200 mg pazopanib.
Votrient 400 mg: each tablet contains 400 mg pazopanib.
The other ingredients in the 200 mg and 400 mg tablets are: hypromellose, macrogol 400, magnesium
stearate, microcrystalline cellulose, polysorbate 80, povidone (K30), sodium starch glycolate (type A),
titanium dioxide (E171). The 200 mg tablets also contain iron oxide red (E172).
What Votrient looks like and contents of the pack
Votrient 200 mg film-coated tablets are capsule-shaped, pink with GS JT marked on one side. They
are supplied in bottles of 30 or 90 tablets.
Votrient 400 mg film-coated tablets are capsule-shaped, white with GS UHL marked on one side.
They are supplied in bottles of 30 or 60 tablets.
Not all pack sizes or tablet strengths may be available in your country.
Marketing Authorisation Holder
Glaxo Group Ltd, Berkeley Avenue, Greenford, Middlesex UB6 0NN, United Kingdom.
Manufacturer
Glaxo Operations UK Ltd (trading as Glaxo Wellcome Operations), Priory Street, Ware,
Hertfordshire, SG12 0DJ, United Kingdom.
Glaxo Wellcome, S.A., Avda. Extremadura, 3, 09400 Aranda De Duero, Burgos, Spain
53
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 (0)2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Belgique/Belgien
Tél/Tel: + 32 (0)2 656 21 11
България
ГлаксоСмитКлайн ЕООД
Teл.: + 359 2 953 10 34
Magyarország
GlaxoSmithKline Kft.
Tel.: + 36 1 225 5300
Česká republika
GlaxoSmithKline s.r.o.
Tel: + 420 222 001 111
gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00
dk-info@gsk.com
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 6938100
nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel.: + 49 (0)89 36044 8701
produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00
firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti OÜ
Tel: + 372 6676 900
estonia@gsk.com
Österreich
GlaxoSmithKline Pharma GmbH
Tel: + 43 (0)1 97075 0
at.info@gsk.com
Ελλάδα
GlaxoSmithKline A.E.B.E.
Τηλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o.
Tel.: + 48 (0)22 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700
es-ci@gsk.com
Portugal
GlaxoSmithKline – Produtos Farmacêuticos, Lda.
Tel: + 351 21 412 95 00
FI.PT@gsk.com
France
Laboratoire GlaxoSmithKline
Tél.: + 33 (0)1 39 17 84 44
diam@gsk.com
România
GlaxoSmithKline (GSK) S.R.L.
Tel: + 4021 3028 208
Ireland
GlaxoSmithKline (Ireland) Limited
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0)1 280 25 00
medical.x.si@gsk.com
54
Ísland
GlaxoSmithKline ehf.
Sími: + 354 530 3700
Slovenská republika
GlaxoSmithKline Slovakia s. r. o.
Tel: + 421 (0)2 48 26 11 11
recepcia.sk@gsk.com
Italia
GlaxoSmithKline S.p.A.
Tel: + 39 (0)45 9218 111
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 (0)10 30 30 30
Finland.tuoteinfo@gsk.com
Κύπρος
GlaxoSmithKline Cyprus Ltd
Τηλ: + 357 22 39 70 00
Sverige
GlaxoSmithKline AB
Tel: + 46 (0)8 638 93 00
info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687
lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
Tel: + 44 (0)800 221441
customercontactuk@gsk.com
Lietuva
GlaxoSmithKline Lietuva UAB
Tel: + 370 5 264 90 00
info.lt@gsk.com
This leaflet was last approved in
This medicine has been given “conditional approval”.
This means that there is more evidence to come about this medicine.
The European Medicines Agency will review new information on the medicine every year and this
leaflet will be updated as necessary.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
55
Source: European Medicines Agency
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