NAME OF THE MEDICINAL PRODUCT
Actos ▼ tablets. 2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 15 mg, 30 mg or 45 mg of pioglitazone as hydrochloride.
For a full list of excipients, see 6.1. 3. PHARMACEUTICAL
The tablets are white to off-white, round, convex and marked ‘15’ on one face and ‘ACTOS’ on the other
The tablets are white to off-white, round, flat and marked ‘30’ on one face and ‘ACTOS’ on the other face.
The tablets are white to off-white, round, flat and marked ‘45’ on one face and ‘ACTOS’ on the other face. 4. CLINICAL
Pioglitazone is indicated in the treatment of type 2 diabetes mellitus:
- in patients (particularly overweight patients) inadequately controlled by diet and exercise
for whom metformin is inappropriate because of contraindications or intolerance
as dual oral therapy
in combination with
- metformin, in patients (particularly overweight patients) with insufficient glycaemic
control despite maximal tolerated dose of monotherapy with metformin
- a sulphonylurea, only in patients who show intolerance to metformin or for whom
metformin is contraindicated, with insufficient glycaemic control despite maximal tolerated dose of monotherapy with a sulphonylurea.
as triple oral therapy
in combination with
- metformin and a sulphonylurea, in patients (particularly overweight patients) with insufficient
glycaemic control despite dual oral therapy.
Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus patients with
insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications
or intolerance (see section 4.4). 4.2
Posology and method of administration
Pioglitazone tablets are taken orally once daily with or without food.
Pioglitazone may be initiated at 15mg or 30mg once daily. The dose may be increased in increments up to
45mg once daily.
In combination with insulin, the current insulin dose can be continued upon initiation of pioglitazone
therapy. If patients report hypoglycaemia, the dose of insulin should be decreased. Elderly:
No dosage adjustment is necessary for elderly patients (see section 5.2). Patients with renal impairment:
No dosage adjustment is necessary in patients with impaired renal function (creatinine clearance > 4 ml/min)
(see section 5.2). No information is available from dialysed patients therefore pioglitazone should not be
used in such patients. Patients with hepatic impairment:
Pioglitazone should not be used in patients with hepatic impairment (see section 4.4). Children and adolescents:
There are no data available on the use of pioglitazone in patients under 18 years of age, and therefore its use
is not recommended in this age group. 4.3 Contraindications
Pioglitazone is contraindicated in patients with:
hypersensitivity to the active substance or to any of the excipients
cardiac failure or history of cardiac failure (NYHA stages I to IV)
Special warnings and precautions for use
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 insulinor in patients with a history
of cardiac failure; patients should be observed for signs and symptoms of heart failure, weight gain and
oedema when pioglitazone is used in combination with insulin. Since insulin and pioglitazone are associated
with fluid retention, concomitant administration may increase the risk of oedema. Pioglitazone 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 (see section
4.8). It is recommended, therefore, that patients treated with pioglitazone undergo periodic monitoring of
liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with pioglitazone in all
patients. Therapy with pioglitazone 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 pioglitazone, it is recommended that liver enzymes be monitored
periodically based on clinical judgement. If ALT levels are increased to 3 X upper limit of normal during
pioglitazone 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 pioglitazone 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. Part of the treatment of diabetes is
dietary control. Patients should be advised to adhere strictly to a calorie-controlled diet. 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) and to a lesser extent
sulphonylurea and insulin (haemoglobin 1 – 2 % and haematocrit 1 – 3.2 % relative reductions) treated
patients in comparative controlled trials with pioglitazone. Hypoglycaemia
As a consequence of increased insulin sensitivity, patients receiving pioglitazone in dual or triple oral
therapy with a sulphonylurea or in dual therapy with insulin may be at risk for dose-related hypoglycaemia,
and a reduction in the dose of the sulphonylurea or insulin 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. 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
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.
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).
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).
Actos tablets contain lactose monohydrate and therefore should not be administered to patients with rare
hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
Interaction with other medicinal products and other forms of interaction
Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or
pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Co-administration of pioglitazone
with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea. Studies in man
suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4. In vitro
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).
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). 4.6
Pregnancy and lactation
Use in pregnancy:
There are no adequate human data to determine the safety of pioglitazone during pregnancy. 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. The relevance
of such a mechanism in humans is unclear and pioglitazone should not be used in pregnancy. Use in breast-feeding:
Pioglitazone has been shown to be present in the milk of lactating rats. It is not known whether pioglitazone
is secreted in human milk. Therefore, pioglitazone should not be administered to breast-feeding women. 4.7
Effects on ability to drive and use machines
No effects on ability to drive and use machines have been observed. 4.8 Undesirable
Adverse reactions reported in excess (> 0.5 %) of placebo and as more than an isolated case in patients
receiving pioglitazone in double-blind studies are listed below as MedDRA preferred term by system organ
class and absolute frequency. Frequencies are defined as: very common >1/10; common > 1/100, < 1/10;
uncommon > 1/1000, < 1/100; rare > 1/10000, < 1/1000; very rare < 1/10000; not known (cannot be
estimated from the available data). Within each frequency grouping, undesirable effects are presented in
order of decreasing seriousness. PIOGLITAZONE MONOTHERAPY
Infection and infestations
Common: upper respiratory tract infection
Uncommon: sinusitis Investigations
Nervous system disorders
Uncommon: insomnia PIOGLITAZONE IN COMBINATION THERAPY WITH METFORMIN Blood and lymphatic system disorders
Common: visual disturbance Gastrointestinal disorders
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 PIOGLITAZONE IN COMBINATION THERAPY WITH SULPHONYLUREA
Ear and labyrinth disorders
Uncommon: vertigo Eye disorders
Uncommon: visual disturbance Gastrointestinal disorders
Common: flatulence General disorders and administration site conditions
Uncommon: fatigue Investigations
Common: weight increased
Uncommon: increased lactic dehydrogenase Metabolism and nutritional disorders
Uncommon: appetite increased, hypoglycaemia Nervous system disorders
Renal and urinary disorders
Uncommon: glycosuria, proteinuria Skin and subcutaneous tissue disorders
PIOGLITAZONE IN TRIPLE ORAL COMBINATION THERAPY WITH METFORMIN AND
Common: weight increased, blood creatine phosphokinase increased Metabolism and nutrition disorders
Musculoskeletal and connective tissue disorders
Common: arthralgia PIOGLITAZONE IN COMBINATION THERAPY WITH INSULIN Metabolism and nutrition disorders
Common: hypoglycaemia General disorders and administration site conditions
Very common: oedema Infections and infestations
Common: bronchitis Investigations
Common: weight increase Musculoskeletal system and connective tissue disorders
Common: back pain, arthralgia Respiratory, thoracic and mediastinal disorders
Common: dyspnoea Cardiac disorders
Macular oedema: not known
Oedema was reported in 6 – 9 % of patients treated with pioglitazone over one year in controlled clinical
trials. The oedema rates for comparator groups (sulphonylurea, metformin) were 2 – 5 %. 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. This is similar to that seen in a sulphonylurea active comparator group. In combination
trials pioglitazone added to metformin resulted in mean weight increase over one year of 1.5 kg and added to
a sulphonylurea of 2.8 kg. In comparator groups addition of sulphonylurea to metformin resulted in a mean
weight gain of 1.3 kg and addition of metformin to a sulphonylurea a mean weight loss of 1.0 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
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.
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%). 4.9 Overdose
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.
Hypoglycaemia may occur in combination with sulphonylureas or insulin. Symptomatic and general
supportive measures should be taken in case of overdose.
Pharmacotherapeutic group: oral blood glucose lowering drugs; Thiazolidinediones; ATC code: A10 BG 03. 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 HbA1c ≥ 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 HbA1c < 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 HbA1c was similar between treatment groups after one
year. The rate of deterioration of HbA1c 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 HbA1c 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. 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 were observed with metformin and gliclazide. In a 20-week study, as well as reducing fasting triglycerides, pioglitazone reduced post prandial hypertriglyceridaemia through an effect on both absorbed and hepatically synthesised triglycerides. These effects were independent of pioglitazone’s effects on glycaemia and were statistically significant 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 incidences of oedema, weight gain and heart failure
were increased. No increase in mortality from heart failure was observed. 5.2 Pharmacokinetic
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.
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).
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.
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. 5.3
Preclinical safety data
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 relevance of
this finding is unknown. There was no tumorigenic response in mice of either sex. Hyperplasia of the
urinary bladder was not seen in dogs or monkeys treated 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.
List of excipients
Magnesium stearate 6.2 Incompatibilities
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, 84, 90 and 98 tablets.
Not all pack sizes may be marketed. 6.6
Special precautions for disposal
No special requirements. 7.
MARKETING AUTHORISATION HOLDER
Takeda Global Research and Development Centre (Europe) Ltd
United Kingdom 8.
MARKETING AUTHORISATION NUMBER(S)
EU/1/00/150/001 - Actos 15mg x 28
EU/1/00/150/004 - Actos 30mg x 28
EU/1/00/150/012 - Actos 45mg x 28 9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 13-10-2000
Date of last renewal: 13-10-2005 10.
DATE OF REVISION OF THE TEXT
24 Feb 2009
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