ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Glubrava 15 mg/850 mg film-coated tablets.
2.
Each tablet contains 15 mg of pioglitazone (as hydrochloride) and 850 mg of metformin
hydrochloride.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet
The tablets are white to off-white, oblong, film-coated, embossed ‘15 / 850’ on one face and ‘4833M’
on the other.
4.
Glubrava is indicated in the treatment of type 2 diabetes mellitus patients, particularly overweight
patients, who are unable to achieve sufficient glycaemic control at their maximally tolerated dose of
oral metformin alone.
Dosage in adults
The usual dose of Glubrava is 30 mg/day pioglitazone plus 1700 mg/day of metformin hydrochloride
(this dosage is achievable with one tablet of Glubrava 15 mg/850 mg, taken twice a day).
Dose titration with pioglitazone (added to the optimal dose of metformin) should be considered before
the patient is switched to Glubrava.
When clinically appropriate, direct change from metformin monotherapy to Glubrava may be
considered.
Taking Glubrava with, or just after food, may reduce gastrointestinal symptoms associated with
metformin.
Elderly
As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal
function, elderly patients taking Glubrava should have their renal function monitored regularly (see
sections 4.3 and 4.4).
Patients with renal impairment
Glubrava should not be used in patients with renal failure or renal dysfunction (creatinine clearance<
60 ml/min)(see sections 4.3 and 4.4).
2
Patients with hepatic impairment
Glubrava should not be used in patients with hepatic impairment (see sections 4.3 and 4.4).
Children and adolescents
There are no data available on the use of pioglitazone in patients under 18 years of age and therefore
the use of Glubrava in this age group is not recommended.
Glubrava is contraindicated in patients with:
-
Hypersensitivity to the active substances or to any of the excipients
-
Cardiac failure or history of cardiac failure (NYHA stages I to IV)
-
Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure,
recent myocardial infarction, shock
-
Hepatic impairment
-
Acute alcohol intoxication, alcoholism
-
Diabetic ketoacidosis or diabetic pre-coma
-
Renal failure or renal dysfunction (creatinine clearance <60 ml/min) (see section 4.4).
-
Acute conditions with the potential to alter renal function such as:
-
Dehydration
-
Severe infection
-
Shock
-
Intravascular administration of iodinated contrast agents (see section 4.4)
-
Lactation
There is no clinical experience of pioglitazone in triple combination with other oral antidiabetic
agents.
Lactic acidosis
Lactic acidosis is a very rare, but serious, metabolic complication that can occur due to metformin
accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in
diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be
reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis,
prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with
hypoxia.
Diagnosis
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by
coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5mmol/l,
and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment
with the medicinal product should be discontinued and the patient hospitalised immediately (see
section 4.9).
Renal Function
As metformin is excreted by the kidney, serum creatinine concentrations should be determined
regularly:
-
at least once a year in patients with normal renal function
3
-
at least two to four times a year in patients with serum creatinine levels at the upper limits of
normal and in elderly subjects
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be
exercised in situations where renal function may become impaired, for example when initiating
antihypertensive therapy or diuretic therapy and when starting treatment with a NSAID.
Fluid retention and cardiac failure
Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. When
treating patients who have at least one risk factor for development of congestive heart failure (e.g.
prior myocardial infarction or symptomatic coronary artery disease), physicians should start with the
lowest available dose and increase the dose gradually. Patients should be observed for signs and
symptoms of heart failure, weight gain or oedema particularly those with reduced cardiac reserve.
There have been cases of cardiac failure reported from the market when pioglitazone was used in
combination with insulin or in patients with a history of cardiac failure. Since insulin and pioglitazone
are associated with fluid retention, concomitant administration of insulin and Glubrava may increase
the risk of oedema. Glubrava should be discontinued if any deterioration in cardiac status occurs.
A cardiovascular outcome study of pioglitazone has been performed in patients under 75 years with
type 2 diabetes mellitus and pre-existing major macrovascular disease. Pioglitazone or placebo was
added to existing antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed an
increase in reports of heart failure, however this did not lead to an increase in mortality in this study.
Caution should be exercised in patients over 75 years because of the limited experience in this patient
group.
Monitoring of Liver Function
There have been rare reports of hepatocellular dysfunction during post-marketing experience with
pioglitazone (see section 4.8). It is recommended, therefore, that patients treated with Glubrava
undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation
of therapy with Glubrava in all patients. Therapy with Glubrava should not be initiated in patients with
increased baseline liver enzyme levels (ALT >2.5 X upper limit of normal) or with any other evidence
of liver disease.
Following initiation of therapy with Glubrava, it is recommended that liver enzymes be monitored
periodically according to clinical judgement. If ALT levels are increased to 3 X upper limit of normal
during Glubrava therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels
remain >3 X the upper limit of normal, therapy should be discontinued. If any patient develops
symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting,
abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision
whether to continue the patient on therapy with Glubrava should be guided by clinical judgement
pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.
Weight Gain
In clinical trials with pioglitazone there was evidence of dose related weight gain, which may be due
to fat accumulation and in some cases associated with fluid retention. In some cases weight increase
may be a symptom of cardiac failure,
therefore weight should be closely monitored.
Haematology
There was a small reduction in mean haemoglobin (4 % relative reduction) and haematocrit (4.1 %
relative reduction) during therapy with pioglitazone, consistent with haemodilution. Similar changes
were seen in metformin (haemoglobin 3 - 4 % and haematocrit 3.6 – 4.1 % relative reductions) treated
patients in comparative controlled trials with pioglitazone.
4
Hypoglycaemia
Patients receiving pioglitazone in dual oral therapy with a sulphonylurea may be at risk for dose-
related hypoglycaemia, and a reduction in the dose of the sulphonylurea may be necessary.
Eye disorders
Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual
acuity have been reported with thiazolidinediones, including pioglitazone. Many of these patients
reported concurrent peripheral oedema. It is unclear whether or not there is a direct association
between pioglitazone and macular oedema but prescribers should be alert to the possibility of macular
oedema if patients report disturbances in visual acuity; an appropriate ophthalmological referral should
be considered.
Surgery
As Glubrava contains metformin hydrochloride, the treatment should be discontinued 48 hours before
elective surgery with general anaesthesia and should not be usually resumed earlier than 48 hours
afterwards.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast agents in radiological studies can lead to renal
failure. Therefore, due to the metformin active substance, Glubrava should be discontinued prior to,
or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has
been re-evaluated and found to be normal (see section 4.5).
Polycystic ovarian syndrome
As a consequence of enhancing insulin action, pioglitazone treatment in patients with polycystic
ovarian syndrome may result in resumption of ovulation. These patients may be at risk of pregnancy.
Patients should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if
pregnancy occurs, the treatment should be discontinued (see section 4.6).
Others
An increased incidence in bone fractures in women was seen in a pooled analysis of adverse event
reports of bone fracture from randomised, controlled, double blind clinical trials in over 8100
pioglitazone and 7400 comparator treated patients, on treatment for up to 3.5 years.
Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated
with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%)
versus comparator (1.5%).
The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with
pioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The
observed excess risk of fractures for women in this dataset on pioglitazone is therefore 0.8 fractures
per 100 patient years of use.
In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years)
of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures
per 100 patient years) of female patients treated with comparator. No increase in fracture rates was
observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).
The risk of fractures should be considered in the long term care of women treated with pioglitazone.
5
Pioglitazone should be used with caution during concomitant administration of cytochrome P450 2C8
inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored
closely. Pioglitazone dose adjustment within the recommended posology or changes in diabetic
treatment should be considered (see section 4.5).
There have been no formal interaction studies for
Glubrava.
The following statements reflect the
information available on the individual active substances (pioglitazone and metformin).
Interaction studies have shown that pioglitazone
has no relevant effect on either the pharmacokinetics
or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Studies in man suggest
no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4.
In vitro
studies have shown
no inhibition of any subtype of cytochrome P450. Interactions with substances metabolised by these
enzymes, e.g. oral contraceptives, cyclosporin, calcium channel blockers, and HMGCoA reductase
inhibitors are not to be expected.
Co-administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported
to result in a 3-fold increase in AUC of pioglitazone. Since there is a potential for an increase in dose-
related adverse events, a decrease in the dose of pioglitazone may be needed when gemfibrozil is
concomitantly administered. Close monitoring of glycaemic control should be considered (see section
4.4)
.
Co-administration of pioglitazone with rifampicin (an inducer of cytochrome P450 2C8) is
reported to result in a 54% decrease in AUC of pioglitazone. The pioglitazone dose may need to be
increased when rifampicin is concomitantly administered. Close monitoring of glycaemic control
should be considered (see section 4.4).
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of
fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of Glubrava (see
section 4.4). Avoid consumption of alcohol and medicinal products containing alcohol.
Intravascular administration of iodinated contrast agents in radiological studies may lead to renal
failure, resulting in metformin accumulation and risk of lactic acidosis. Metformin should be
discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only
after renal function has been re-evaluated and found to be normal.
Cationic drugs that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with
metformin by competing for common renal tubular transport systems. A study conducted in seven
normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased
metformin systemic exposure (AUC) by 50% and C
max
by 81%. Therefore, close monitoring of
glycaemic control, dose adjustment within the recommended posology and changes in diabetic
treatment should be considered when cationic drugs that are eliminated by renal tubular secretion are
co-administered.
Combinations requiring precautions for use
Glucocorticoids (given by systemic and local routes), beta-2-agonists, and diuretics have intrinsic
hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring
performed, especially at the beginning of treatment. If necessary, the dosage of the
antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal
product and on its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. If necessary, the dosage of the
antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal
product and on its discontinuation.
6
For Glubrava no preclinical or clinical data on exposed pregnancies or lactation are available.
Risk related to pioglitazone
There are no adequate human data from the use of pioglitazone in pregnant women. Animal studies
have not shown teratogenic effects but have shown foetotoxicity related to the pharmacologic action
(see section 5.3).
Risk related to metformin
Animal studies have not revealed teratogenic effects. Small clinical trials have not revealed
metformin to have malformative effects.
However, Glubrava should not be used during pregnancy and in women of child-bearing age not using
contraceptive measures. If a patient wishes to become pregnant or if a pregnancy occurs, treatment
with Glubrava should be discontinued.
Both pioglitazone and metformin have been shown to be present in the milk of lactating rats. It is not
known whether breast-feeding will lead to exposure of the infant to the medicinal product. Glubrava
must therefore not be used in women who are breast-feeding (see section 4.3).
No effects on ability to drive and use machines have been observed.
Clinical trials have been conducted with Glubrava tablets and co-administered pioglitazone and
metformin (see section 5.1). Bioequivalence of Glubrava with co-administered pioglitazone and
metformin has also been demonstrated (see section 5.2).
Adverse reactions reported in excess (>0.5%) of placebo and as more than an isolated case in patients
receiving pioglitazone in combination with metformin in double-blind studies are listed below as
MedDRA preferred term by system organ class and absolute frequency. Frequencies are defined as:
common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (>1/10000, < 1/1000); very rare
(< 1/10000); isolated reports; not known (cannot be estimated from the available data). Within each
frequency grouping, undesirable effects are presented in order of decreasing seriousness.
PIOGLITAZONE IN COMBINATION THERAPY WITH METFORMIN
Blood and lymphatic system disorders
Common:
anaemia
Eye disorders
Common:
visual disturbance
Gastrointestinal disorders
Uncommon:
flatulence
Metabolism and nutrition disorders
7
Common:
weight increased
Musculoskeletal system and connective tissue disorders
Common:
arthralgia
Nervous system disorders
Common:
headache
Renal and urinary disorders
Common:
haematuria
Reproductive system and breast disorders
Common:
erectile dysfunction
In active comparator controlled trials oedema was reported in 6.3% of patients treated with metformin
and pioglitazone, whereas the addition of sulphonylurea to metformin treatment resulted in oedema in
2.2% of patients. The reports of oedema were generally mild to moderate and usually did not require
discontinuation of treatment.
In active comparator controlled trials mean weight increase with pioglitazone given as monotherapy
was 2 – 3 kg over one year. In combination trials pioglitazone added to metformin resulted in mean
weight increase over one year of 1.5 kg.
Visual disturbance has been reported mainly early in treatment and is related to changes in blood
glucose due to temporary alteration in the turgidity and refractive index of the lens as seen with other
hypoglycaemic agents.
In clinical trials with pioglitazone the incidence of elevations of ALT greater than three times the
upper limit of normal was equal to placebo but less than that seen in metformin or sulphonylurea
comparator groups. Mean levels of liver enzymes decreased with treatment with pioglitazone. Rare
cases of elevated liver enzymes and hepatocellular dysfunction have occurred in post-marketing
experience. Although in very rare cases fatal outcome has been reported, causal relationship has not
been established.
In controlled clinical trials the incidence of reports of heart failure with pioglitazone treatment was the
same as in placebo, metformin and sulphonylurea treatment groups, but was increased when used in
combination therapy with insulin. In an outcome study of patients with pre-existing major
macrovascular disease, the incidence of serious heart failure was 1.6% higher with pioglitazone than
with placebo, when added to therapy that included insulin. However, this did not lead to an increase
in mortality in this study. Heart failure has been reported rarely with marketing use of pioglitazone,
but more frequently when pioglitazone was used in combination with insulin or in patients with a
history of cardiac failure.
Additional information on the individual active substances of the fixed dose combination
Pioglitazone
In double blind placebo controlled clinical trials with pioglitazone upper respiratory tract infection and
hypoaesthesia were common; sinusitis and insomnia were uncommon.
8
POST-MARKETING DATA
Eye disorders
Macular oedema:
not known
Metformin
Metabolism and nutrition disorders
Very rare: Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of
metformin. Consideration of such aetiology is recommended if a patient presents with megaloplastic
anaemia.
Very rare:
Nervous system disorders
Common: Taste disturbance
Gastrointestinal disorders
Very common: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and
loss of appetite. These undesirable effects occur most frequently during initiation of therapy and
resolve spontaneously in most cases.
Hepatobiliary disorders
Isolated reports: Liver function tests abnormalities or hepatitis resolving upon metformin
discontinuation.
Skin and subcutaneous tissue disorders
Very rare: Skin reactions such as erythema, pruritis, urticaria.
A pooled analysis was conducted of adverse event reports of bone fractures from randomised,
comparator controlled, double blind clinical trials in over 8100 patients in the pioglitazone-treated
groups and 7400 in the comparator-treated groups of up to 3.5 years duration. A higher rate of
fractures was observed in women taking pioglitazone (2.6%) versus comparator (1.7%). No increase
in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).
In the 3.5 year PROactive study, 44/870 (5.1%) of pioglitazone-treated female patients experienced
fractures compared to 23/905 (2.5%) of female patients treated with comparator. No increase in
fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).
No data are available with regard to overdose of Glubrava.
Patients have taken pioglitazone at higher than the recommended highest dose of 45 mg daily. The
maximum reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not
associated with any symptoms.
A large overdose of metformin (or coexisting risks of lactic acidosis) may lead to lactic acidosis which
is a medical emergency and must be treated in hospital.
The most effective method to remove lactate and metformin is haemodialysis.
9
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Combinations of oral blood glucose lowering drugs
,
ATC code:
A10BD05.
Glubrava combines two antihyperglycaemic agents with complementary mechanisms of action to
improve glycaemic control in patients with type 2 diabetes: pioglitazone, a member of the
thiazolidinedione class and metformin hydrochloride, a member of the biguanide class.
Thiazolidinediones act primarily by reducing insulin resistance and biguanides act primarily by
decreasing endogenous hepatic glucose production.
Pioglitazone and metformin combination
The fixed dose combination tablet of pioglitazone 15 mg/metformin 850 mg BID (N=201),
pioglitazone 15 mg BID (N=189), and metformin 850 mg BID (N=210) were evaluated in type 2
diabetes mellitus patients with mean baseline HbA1C of 9.5% in a randomised double-blind, parallel-
group study. Previous anti-diabetic medication was discontinued for 12 weeks prior to baseline
measurements. After 24 weeks of treatment, the primary endpoint of mean change from baseline in
HbA1c was -1.83% in the combination group versus -0.96% in the pioglitazone group (p<0.0001) and
-0.99% in the metformin group (p<0.0001).
The safety profile seen in this study reflected the known adverse reactions seen with the individual
products and did not suggest any new safety issues.
Pioglitazone
Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to act
via activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leading
to increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment with
pioglitazone has been shown to reduce hepatic glucose output and to increase peripheral glucose
disposal in the case of insulin resistance.
Fasting and postprandial glycaemic control is improved in patients with type 2 diabetes mellitus. The
improved glycaemic control is associated with a reduction in both fasting and postprandial plasma
insulin concentrations. A clinical trial of pioglitazone
vs
. gliclazide as monotherapy was extended to
two years in order to assess time to treatment failure (defined as appearance of HbA
1c
8.0% after the
first six months of therapy). Kaplan-Meier analysis showed shorter time to treatment failure in
patients treated with gliclazide, compared with pioglitazone. At two years, glycaemic control (defined
as HbA
1c
8.0%) was sustained in 69% of patients treated with pioglitazone, compared with 50% of
patients on gliclazide. In a two-year study of combination therapy comparing pioglitazone with
gliclazide when added to metformin, glycaemic control measured as mean change from baseline in
HbA
1c
was similar between treatment groups after one year. The rate of deterioration of HbA
1c
during
the second year was less with pioglitazone than with gliclazide.
In a placebo controlled trial, patients with inadequate glycaemic control despite a three month insulin
optimisation period were randomised to pioglitazone or placebo for 12 months. Patients receiving
pioglitazone had a mean reduction in HbA
1c
of 0.45% compared with those continuing on insulin
alone, and a reduction of insulin dose in the pioglitazone treated group.
HOMA analysis shows that pioglitazone improves beta cell function as well as increasing insulin
sensitivity. Two-year clinical studies have shown maintenance of this effect.
10
In one year clinical trials, pioglitazone consistently gave a statistically significant reduction in the
albumin/creatinine ratio compared to baseline.
The effect of pioglitazone (45 mg monotherapy
vs
. placebo) was studied in a small 18-week trial in
type 2 diabetics. Pioglitazone was associated with significant weight gain. Visceral fat was
significantly decreased, while there was an increase in extra-abdominal fat mass. Similar changes in
body fat distribution on pioglitazone have been accompanied by an improvement in insulin sensitivity.
In most clinical trials, reduced total plasma triglycerides and free fatty acids, and increased
HDL-cholesterol levels were observed as compared to placebo, with small, but not clinically
significant increases in LDL-cholesterol levels. In clinical trials of up to two years duration,
pioglitazone reduced total plasma triglycerides and free fatty acids, and increased HDL-cholesterol
levels, compared with placebo, metformin or gliclazide. Pioglitazone did not cause statistically
significant increases in LDL-cholesterol levels compared with placebo, whilst reductions where
observed with metformin and gliclazide. In a 20-week study, as well as reducing fasting triglycerides,
pioglitazone reduced postprandial hypertriglyceridaemia through an effect on both absorbed and
hepatically synthesised triglycerides. These effects were independent of pioglitazone’s effects on
glycaemia and were statistically significantly different to glibenclamide.
In PROactive, a cardiovascular outcome study, 5238 patients with type 2 diabetes mellitus and pre-
existing major macrovascular disease were randomised to pioglitazone or placebo in addition to
existing antidiabetic and cardiovascular therapy, for up to 3.5 years. The study population had an
average age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third of
patients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligible
patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous
cardiac intervention or coronary artery bypass graft, acute coronary syndrome, coronary artery disease,
or peripheral arterial obstructive disease. Almost half of the patients had a previous myocardial
infarction and approximately 20% had had a stroke. Approximately half of the study population had
at least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving
cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II antagonists, calcium channel
blockers, nitrates, diuretics, aspirin, statins, fibrates).
Although the study failed regarding its primary endpoint, which was a composite of all-cause
mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation,
coronary revascularisation and leg revascularisation, the results suggest that there are no long-term
cardiovascular concerns regarding use of pioglitazone. However, the incidence of oedema, weight
gain and heart failure were increased. No increase in mortality from heart failure was observed.
Metformin
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial
plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via three mechanisms:
-
in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and
utilisation
-
by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin
increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and
GLUT-4).
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid
metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term
clinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.
11
-
by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood
glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with
metformin after failure of diet alone showed:
-
a significant reduction of the absolute risk of any diabetes-related complication in the metformin
group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years),
p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1
events/1,000 patient-years), p=0.0034
-
a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5
events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017
-
a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000
patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), and versus the
combined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years
(p=0.021)
-
a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000
patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).
5.2 Pharmacokinetic properties
Glubrava
Bioequivalence studies in healthy volunteers have shown Glubrava to be bioequivalent to the
administration of pioglitazone and metformin given as separate tablets.
Food had no effect on the AUC and C
max
of pioglitazone when Glubrava was administered to healthy
volunteers. However, in the case of metformin, in the fed state the mean AUC and C
max
were lower
(13% and 28% respectively). Tmax was delayed by food by approximately 1.9 h for pioglitazone and
0.8 h for metformin.
The following statements reflect the pharmacokinetic properties of the individual active substances of
Glubrava.
Pioglitazone
Absorption
Following oral administration, pioglitazone is rapidly absorbed, and peak plasma concentrations of
unchanged pioglitazone are usually achieved 2 hours after administration. Proportional increases of
the plasma concentration were observed for doses from 2 – 60 mg. Steady state is achieved after
4-7 days of dosing. Repeated dosing does not result in accumulation of the compound or metabolites.
Absorption is not influenced by food intake. Absolute bioavailability is greater than 80 %.
Distribution
The estimated volume of distribution in humans is 0.25 l/kg.
Pioglitazone and all active metabolites are extensively bound to plasma protein (> 99 %).
Metabolism
Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups.
This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesser
degree. Three of the six identified metabolites are active (M-II, M-III, and M-IV). When activity,
concentrations and protein binding are taken into account, pioglitazone and metabolite M-III
contribute equally to efficacy. On this basis M-IV contribution to efficacy is approximately three-fold
that of pioglitazone, whilst the relative efficacy of M-II is minimal.
12
In vitro
studies have shown no evidence that pioglitazone inhibits any subtype of cytochrome P450.
There is no induction of the main inducible P450 isoenzymes 1A, 2C8/9, and 3A4 in man.
Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics
or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Concomitant
administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) or with
rifampicin (an inducer of cytochrome P450 2C8) is reported to increase or decrease, respectively, the
plasma concentration of pioglitazone (see section 4.5).
Elimination
Following oral administration of radiolabelled pioglitazone to man, recovered label was mainly in
faeces (55%) and a lesser amount in urine (45%). In animals, only a small amount of unchanged
pioglitazone can be detected in either urine or faeces. The mean plasma elimination half-life of
unchanged pioglitazone in man is 5 to 6 hours and for its total active metabolites 16 to 23 hours.
Elderly
Steady state pharmacokinetics are similar in patients age 65 and over and young subjects.
Patients with renal impairment
In patients with renal impairment, plasma concentrations of pioglitazone and its metabolites are lower
than those seen in subjects with normal renal function, but oral clearance of parent substance is
similar. Thus free (unbound) pioglitazone concentration is unchanged.
Patients with hepatic impairment
Total plasma concentration of pioglitazone is unchanged, but with an increased volume of distribution.
Intrinsic clearance is therefore reduced, coupled with a higher unbound fraction of pioglitazone.
Metformin
Absorption
After an oral dose of metformin, t
max
is reached in 2.5 h. Absolute bioavailability of a 500 mg
metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed
fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the
pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing
schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than
1 g/ml. In controlled clinical trials, maximum metformin plasma levels (C
max
) did not exceed
4 g/ml, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following administration
of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min
prolongation of time to peak plasma concentration was observed. The clinical relevance of this
decrease is unknown.
Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower
than the plasma peak and appears at approximately the same time. The red blood cells most likely
represent a secondary compartment of distribution. The mean V
d
ranged between 63 – 276 l.
13
Metabolism
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination
Renal clearance of metformin is 400 ml/min, indicating that metformin is eliminated by glomerular
filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is
approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to
that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of
metformin in plasma.
5.3 Preclinical safety data
No animal studies have been conducted with the combined products in Glubrava. The following data
are findings in studies performed with pioglitazone or metformin individually.
Pioglitazone
In toxicology studies, plasma volume expansion with haemodilution, anaemia, and reversible eccentric
cardiac hypertrophy was consistently apparent after repeated dosing of mice, rats, dogs, and monkeys.
In addition, increased fatty deposition and infiltration were observed. These findings were observed
across species at plasma concentrations 4 times the clinical exposure. Foetal growth restriction was
apparent in animal studies with pioglitazone. This was attributable to the action of pioglitazone in
diminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during
pregnancy thereby reducing the availability of metabolic substrates for foetal growth.
Pioglitazone was devoid of genotoxic potential in a comprehensive battery of
in vivo
and
in vitro
genotoxicity assays. An increased incidence of hyperplasia (males and females) and tumours (males)
of the urinary bladder epithelium was apparent in rats treated with pioglitazone for up to 2 years.
The formation and presence of urinary calculi with subsequent irritation and hyperplasia was
postulated as the mechanistic basis for the observed tumourigenic response in the male rat. A
24-month mechanistic study in male rats demonstrated that administration of pioglitazone resulted in
an increased incidence of hyperplastic changes in the bladder. Dietary acidification significantly
decreased but did not abolish the incidence of tumours. The presence of microcrystals exacerbated the
hyperplastic response but was not considered to be the primary cause of hyperplastic changes. The
relevance to humans of the tumourigenic findings in the male rat cannot be excluded.
There was no tumorigenic response in mice of either sex. Hyperplasia of the urinary bladder was not
seen in dogs or monkeys treated with pioglitazone for up to 12 months.
In an animal model of familial adenomatous polyposis (FAP), treatment with two other
thiazolidinediones increased tumour multiplicity in the colon. The relevance of this finding is
unknown.
Metformin
Preclinical data for metformin reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction.
14
6.
6.1 List of excipients
Tablet Core
Microcrystalline cellulose
Povidone (K30)
Croscarmellose sodium
Magnesium stearate
Film Coat
Hypromellose
Macrogol 8000
Talc
Titanium dioxide.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Aluminium/aluminium blisters, packs of 14, 28, 30, 50, 56, 60, 90, 98 and 180 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Takeda Global Research and Development Centre (Europe) Ltd
61 Aldwych
London
WC2B 4AE
United Kingdom
8.
EU/1/07/421/001-009
9.
11 December 2007
15
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
17
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Takeda Italia Farmaceutici S.p.A
Via Crosa, 86
28065 Cerano (NO)
Italy
Takeda Ireland Limited
Bray Business Park
Kilruddery
County Wicklow
Ireland
Lilly S.A.
Avda. de la Industria 30
28108 Alcobendas
Madrid
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 medical prescription.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 9.0, presented in
Module 1.8.1. of the Marketing Authorisation, 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 9.0, of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation 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, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
18
o
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
o
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
o
At the request of the EMEA
PSURs
The PSUR cycle of Glubrava 15 mg/850 mg film-coated tablets will correspond to the one attributed
to the cross-referenced product, Competact, until otherwise specified.
19
ANNEX III
LABELLING AND PACKAGE LEAFLET
20
A. LABELLING
21
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Glubrava 15 mg/850 mg film-coated tablets
Pioglitazone (as hydrochloride)
Metformin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 15 mg pioglitazone (as hydrochloride) and 850 mg metformin hydrochloride.
3.
LIST OF EXCIPIENTS
4.
14 tablets
28 tablets
30 tablets
50 tablets
56 tablets
60 tablets
90 tablets
98 tablets
180 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For 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
Expiry date: {month/year}
22
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Takeda Global Research and Development Centre (Europe) Ltd
61 Aldwych
London
WC2B 4AE
United Kingdom
EU/1/07/421/001 14 tablets
EU/1/07/421/002 28 tablets
EU/1/07/421/003 30 tablets
EU/1/07/421/004 50 tablets
EU/1/07/421/005 56 tablets
EU/1/07/421/006 60 tablets
EU/1/07/421/007 90 tablets
EU/1/07/421/008 98 tablets
EU/1/07/421/009 180 tablets
13. BATCH NUMBER
Batch number: {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Glubrava15 mg/850 mg tablets.
23
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Glubrava15 mg/850 mg tablets
Pioglitazone (as HCl)
Metformin hydrochloride
2.
Takeda (logo)
3.
EXPIRY DATE
Expiry date: {month/year}
4.
BATCH NUMBER
Batch number: {number}
5.
OTHER (FOR CALENDARISED PACKS)
MON 1
MON 2
TUE 1
TUE 2
WED 1
WED 2
FRI 1
FRI 2
SAT 1
SAT 2
SUN 1
SUN 2
24
THU 1
THU 2
B. PACKAGE LEAFLET
25
PACKAGE LEAFLET: INFORMATION FOR THE USER
GLUBRAVA 15 mg/850 mg FILM-COATED TABLETS
Pioglitazone/Metformin hydrochloride
Read all of this leaflet carefully before you start taking this medicine
-
If you have any further questions, ask your doctor or pharmacist.
-
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 Glubrava is and what it is used for
2.
Before you take Glubrava
4.
Possible side effects
5
How to store Glubrava
6.
Further information
1.
WHAT GLUBRAVA IS AND WHAT IT IS USED FOR
Glubrava tablets are an anti-diabetic medicine used to treat type 2 (non-insulin dependent) diabetes
mellitus. This is the diabetes that usually develops in adulthood.
Glubrava tablets help control the level of sugar in your blood when you have type 2 diabetes by
helping your body make better use of the insulin it produces.
2.
BEFORE YOU TAKE GLUBRAVA
Do not take Glubrava:
-
If you are allergic (hypersensitive) to pioglitazone, metformin or any of the other ingredients of
Glubrava tablets.
-
If you recently had a heart attack, have severe circulatory problems including shock, or
breathing difficulties.
-
If you drink alcohol excessively (either every day or only from time to time).
-
If you have diabetic ketoacidosis (complication of diabetes with rapid weight loss, nausea or
vomiting).
-
If you have a problem with your kidneys.
-
If you have a severe infection or are dehydrated.
-
If you are going to have a certain type of X-ray with an injectable dye. You will need to stop
taking Glubrava tablets at the time of and for a few days after the procedure.
-
If you are breast-feeding.
26
-
Keep this leaflet. You may need to read it again.
3.
How to take Glubrava
-
If you have heart failure.
-
If you have liver disease.
Take special care with Glubrava
Tell your doctor before you start to take this medicine:
-
If you have a special type of diabetic eye disease called macular oedema (swelling of the back
of the eye).
-
If you are planning to become pregnant.
-
If you are going to have an operation under general anaesthetic, as you may need to stop taking
Glubrava for a couple of days before and after the procedure.
-
If you have polycystic ovary syndrome. There may be an increased possibility of your
becoming pregnant because of how your medicine works.
-
If you are under 18 years of age because use in such patients is not recommended.
-
If you already take any other tablets to treat diabetes.
Taking other medicines:
Please let your doctor know if you already take cimetidine, glucocorticoids, beta-2-agonists, diuretics
or ACE inhibitors. Please tell your doctor or pharmacist if you are taking or have recently taken any
other medicines, including medicines obtained without a prescription.
Pregnancy and breast-feeding:
Tell your doctor if you are, you think you might be or are planning to become pregnant. Your doctor
will advise you to discontinue this medicine. You should not use Glubrava if you are breast-feeding or
are planning to breast-feed your baby.
Driving and using machines:
This medicine will not affect your ability to drive or operate machinery.
3.
HOW TO TAKE GLUBRAVA
Always take Glubrava tablets exactly as your doctor has told you. You should check with your doctor
or pharmacist if you are not sure. The usual dose is one tablet taken twice daily. If necessary your
doctor may tell you to take a different dose.
You should take the tablets with or just after food to reduce the chance of an upset stomach.
If you are following a diabetic diet, you should continue with this while you are taking Glubrava
tablets.
Your weight should be checked at regular intervals; if your weight increases, inform your doctor.
Some patients with long-standing type 2 diabetes mellitus and heart disease or previous stroke who
were treated with pioglitazone and insulin experienced the development of heart failure. Inform your
doctor as soon as possible if you experience signs of heart failure such as unusual shortness of breath
or rapid increase in weight or localised swelling (oedema).
In clinical trials in which pioglitazone was compared to other oral anti diabetic drugs or placebo
(dummy pill), a higher number of bone fractures was seen in women (but not in men) taking
pioglitazone. Your doctor will take this into account when treating your diabetes.
Your doctor will ask you to have blood tests periodically during treatment with Glubrava. This is to
check that your liver is working normally. At least once a year (more often if you are elderly or have
kidney problems) your doctor will check that your kidneys are working normally.
27
If you take more Glubrava tablets than you should:
If you accidentally take too many tablets, or if someone else or a child takes your medicine, talk to a
doctor or pharmacist immediately.
If you forget to take Glubrava:
Try to take Glubrava tablets daily as prescribed. However if you miss a dose, just carry on with the
next dose as normal. Do not take a double dose to make up for a forgotten tablet.
If you stop taking Glubrava:
Do not stop taking Glubrava tablets without first discussing it with your doctor.
If you have any further questions on the use of Glubrava tablets ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Glubrava can have side effects.
Some patients experience the following side effects whilst taking pioglitazone and/or metformin (the
two active substances of Glubrava).
Very rarely patients taking metformin have experienced a condition called lactic acidosis (excess of
lactic acid in your blood), particularly those whose kidneys are not working properly. Symptoms
include feeling cold and uncomfortable, severe nausea and vomiting, abdominal pain, unexplained
weight loss, or rapid breathing.
If you experience some of these symptoms stop taking Glubrava
and consult a doctor immediately.
Blurred vision due to swelling (or fluid) at the back of the eye has been reported. If you experience
these symptoms for the first time or if they get worse talk to your doctor as soon as possible.
Between 1 in 10 and 1 in 100 patients experience
-
localised swelling (oedema)
-
weight gain
-
headache
-
respiratory infection
-
abnormal vision
-
joint pain
-
impotence
-
blood in urine
-
anaemia
Between 1 in 100 and 1 in 1000 patients experience
-
sinusitis
-
flatulence
Between 1 in 1000 and 1 in 10000 patients experience
-
impaired liver function
Less than 1 in 10,000 patients experience
-
a condition called lactic acidosis (excess of lactic acid in your blood) due to metformin,
particularly those whose kidneys are not working properly
-
blurred vision due to swelling (or fluid) in the back of the eye.
28
-
insomnia
5.
HOW TO STORE GLUBRAVA
Keep out of the reach and sight of children.
Do not use Glubrava after the expiry date which is stated on the carton and blister.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Glubrava Tablets contain
The active substances are 15 mg pioglitazone (as hydrochloride) and 850 mg metformin
hydrochloride.
The other ingredients are, microcrystalline cellulose, povidone (K 30), croscarmellose sodium
magnesium stearate, hypromellose, macrogol 8000, talc and titanium dioxide.
What Glubrava Tablets look like and contents of the pack
Glubrava tablets are white to off white, oblong, convex, film-coated tablets embossed ‘15 / 850’ on
one face and ‘4833M’ on the other. The tablets are supplied in blister packs of 14, 28, 30, 50, 56, 60,
90, 98 or 180 tablets.
Marketing Authorisation Holder and Manufacturer
Marketing authorisation holder: Takeda Global Research and Development Centre (Europe) Ltd,
61 Aldwych, London, WC2B 4AE, United Kingdom.
Manufacturer: Takeda Ireland Limited, Bray Business Park, Kilruddery, County Wicklow, Ireland.
Takeda Italia Farmaceutici SpA, Via Crosa, 86, I-28065 Cerano (NO), Italy.
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Takeda Global Research and Development
Centre (Europe) Ltd, Royaume-Uni
Tél/Tel: + 44 (0)203 116 8000
Luxembourg/Luxemburg
Takeda Global Research and Development
Centre (Europe) Ltd., Royaume-Uni
Tél/Tel: + 44 (0)203 116 8000
България
Takeda Global Research and Development
Centre (Europe) Ltd., Обединеното кралство
Teл.: + 44 (0)203 116 8000
Magyarország
Takeda Global Research and Development
Centre (Europe) Ltd., Nagy-Britannia
Tel.: + 44 (0)203 116 8000
Česká republika
Takeda Global Research and Development
Centre (Europe) Ltd., Velká Británie
Tel: + 44 (0)203 116 8000
Malta
Takeda Global Research and Development
Centre (Europe) Ltd., Ir-Renju Unit
Tel: + 44 (0)203 116 8000
Danmark
Takeda Global Research and Development
Nederland
Takeda Global Research and Development
29
Centre (Europe) Ltd., Storbritannien
Tlf: + 44 (0)203 116 8000
Centre (Europe) Ltd., Verenigd Koninkrijk
Tel: + 44 (0)203 116 8000
Deutschland
Takeda Pharma GmbH
Tel: + 49 (0) 241 941-0
Norge
Takeda Global Research and Development
Centre (Europe) Ltd., Storbritannia
Tlf: + 44 (0)203 116 8000
Eesti
Takeda Global Research and Development
Centre (Europe) Ltd., Ühendkuningriik
Tel: + 44 (0)203 116 8000
Österreich
Takeda Global Research and Development
Centre (Europe) Ltd., Vereinigtes Königreich
Tel: + 44 (0)203 116 8000
Ελλάδα
Takeda Global Research and Development
Centre (Europe) Ltd., Ηνωμένο Βασίλειο
Τηλ: + 44 (0)203 116 8000
Polska
Takeda Global Research and Development
Centre (Europe) Ltd., Wielka Brytania
Tel.: + 44 (0)203 116 8000
España
Takeda Farmacéutica España, S.A.
Tel: +34 931845730
Portugal
Takeda - Farmacêuticos Portugal, Unipessoal LDA
Tel: +351 21 464 3222
France
Laboratoires Takeda
Tél: +33 (0)1 46 25 16 16
România
Takeda Global Research and Development
Centre (Europe) Ltd., Marea Britanie
Tel: + 44 (0)203 116 8000
Ireland
Takeda Global Research and Development
Centre (Europe) Ltd., United Kingdom
Tel: + 44 (0)203 116 8000
Slovenija
Takeda Global Research and Development
Centre (Europe) Ltd., Velika Britanija
Tel: + 44 (0)203 116 8000
Ísland
Takeda Global Research and Development
Centre (Europe) Ltd., Bretland
Sími: + 44 (0)203 116 8000
Slovenská republika
Takeda Global Research and Development
Centre (Europe) Ltd., Veľká Británia
Tel: + 44 (0)203 116 8000
Italia
Takeda Italia Farmaceutici SpA
Tel: + 39 06 5026 01
Suomi/Finland
Takeda Global Research and Development
Centre (Europe) Ltd., Iso-Britannia
Puh/Tel: + 44 (0)203 116 8000
Κύπρος
Takeda Global Research and Development
Centre (Europe) Ltd., Ηνωμένο Βασίλειο
Τηλ: + 44 (0)203 116 8000
Sverige
Takeda Global Research and Development
Centre (Europe) Ltd., Storbritannien
Tel: + 44 (0)203 116 8000
Latvija
Takeda Global Research and Development
Centre (Europe) Ltd., Lielbritānija
Tel: + 44 (0)203 116 8000
United Kingdom
Takeda Global Research and Development
Centre (Europe) Ltd.
Tel: + 44 (0)203 116 8000
Lietuva
Takeda Global Research and Development
Centre (Europe) Ltd., Jungtinė Karalystė
Tel. + 44 (0)203 116 8000
30
This leaflet was last approved on {date}
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA) http://www.emea.europa.eu/
31
Source: European Medicines Agency
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