Actos

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Actos 15 mg tablets 
Actos 30 mg tablets 
Actos 45 mg tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Actos 15 mg tablets 
Each tablet contains 15 mg of pioglitazone (as hydrochloride). 
 
Excipient with known effect 
Each tablet contains 92.87 mg of lactose monohydrate (see section 4.4). 
 
Actos 30 mg tablets 
Each tablet contains 30 mg of pioglitazone (as hydrochloride). 
 
Excipient with known effect 
Each tablet contains 76.34 mg of lactose monohydrate (see section 4.4). 
 
Actos 45 mg tablets 
Each tablet contains 45 mg of pioglitazone (as hydrochloride). 
 
Excipient with known effect 
Each tablet contains 114.51 mg of lactose monohydrate (see section 4.4). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet 
 
Actos 15 mg tablets 
The tablets are white to off-white, round, convex and marked ‘15’ on one face and ‘ACTOS’ on the 
other face. 
 
Actos 30 mg tablets 
The tablets are white to off-white, round, flat and marked ‘30’ on one face and ‘ACTOS’ on the other 
face. 
 
Actos 45 mg tablets 
The tablets are white to off-white, round, flat and marked ‘45’ on one face and ‘ACTOS’ on the other 
face. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Pioglitazone is indicated as second or third line treatment of type 2 diabetes mellitus as described 
below: 

 



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as monotherapy 
- in adult 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 adult patients (particularly overweight patients) with insufficient 

glycaemic control despite maximal tolerated dose of monotherapy with metformin 
- a sulphonylurea, only in adult 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 adult 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 adult patients 
with insufficient glycaemic control on insulin for whom metformin is inappropriate because of 
contraindications or intolerance (see section 4.4). 
 
After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assess 
adequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show an adequate 
response, pioglitazone should be discontinued. In light of potential risks with prolonged therapy, 
prescribers should confirm at subsequent routine reviews that the benefit of pioglitazone is maintained 
(see section 4.4). 
 
4.2 Posology and method of administration 
 
Posology 
 
Pioglitazone treatment may be initiated at 15 mg or 30 mg once daily. The dose may be increased in 
increments up to 45 mg 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. 
 
Special populations 
Elderly 
No dose adjustment is necessary for elderly patients (see section 5.2). Physicians should start 
treatment with the lowest available dose and increase the dose gradually, particularly when 
pioglitazone is used in combination with insulin (see section 4.4 Fluid retention and cardiac failure). 
 
Renal impairment 
No dose 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. 
 
Hepatic impairment 
Pioglitazone should not be used in patients with hepatic impairment (see sections 4.3 and 4.4). 
 
Paediatric population 
The safety and efficacy of Actos in children and adolescents under 18 years of age have not been 
established. No data are available. 
 



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Method of administration 
 
Pioglitazone tablets are taken orally once daily with or without food. Tablets should be swallowed 
with a glass of water. 
 
4.3 Contraindications 
 
Pioglitazone is contraindicated in patients with: 
 
- hypersensitivity to the active substance or to any of the excipients listed in section 6.1 
- cardiac failure or history of cardiac failure (NYHA stages I to IV) 
- hepatic impairment 
- diabetic ketoacidosis 
- current bladder cancer or a history of bladder cancer  
- uninvestigated macroscopic haematuria 

 
4.4 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 or the elderly), 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 post-marketing cases of cardiac failure reported when pioglitazone was used 
in combination with insulin or 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 both associated with fluid retention, 
concomitant administration may increase the risk of oedema. Post marketing cases of peripheral 
oedema and cardiac failure have also been reported in patients with concomitant use of pioglitazone 
and nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors. 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.  
 
Elderly 
 
Combination use with insulin should be considered with caution in the elderly because of increased 
risk of serious heart failure. 
 
In light of age- related risks (especially bladder cancer, fractures and heart failure), the balance of 
benefits and risks should be considered carefully both before and during treatment in the elderly. 
 
Bladder cancer 
 
Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials 
with pioglitazone (19 cases from 12,506 patients, 0.15%) than in control groups (7 cases from 
10,212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, p=0.029). After excluding patients in whom 
exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 
7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups. Epidemiological studies have 
also suggested a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, 
although not all studies identified a statistically significant increased risk. 



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Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks 
include age, smoking history, exposure to some occupational or chemotherapy agents 
e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria 
should be investigated before starting pioglitazone therapy.  
 
Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria 
or other symptoms such as dysuria or urinary urgency develop during treatment. 
 
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, the medicinal product 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. 



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Others 
 
An increased incidence in bone fractures in women was seen in a pooled analysis of adverse reactions 
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%). 
 
Some epidemiological studies have suggested a similarly increased risk of fracture in both men and 
women. 
 
The risk of fractures should be considered in the long term care of patients treated with pioglitazone 
(see section 4.8). 
 
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, total lactase deficiency or glucose-galactose 
malabsorption. 
 
4.5 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 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) 



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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 Fertility, pregnancy and lactation 
 
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.  
 
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. 
 
Fertility 
 
In animal fertility studies there was no effect on copulation, impregnation or fertility index. 
 
4.7 Effects on ability to drive and use machines 
 
Actos has no or negligible influence on the ability to drive and use machines. However patients who 
experience visual disturbance should be cautious when driving or using machines.  
 
4.8 Undesirable effects 
 
Tabulated list of adverse reactions 
 
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 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). Within each system organ 
class, adverse reactions are presented in order of decreasing incidence followed by decreasing 
seriousness. 
 

Adverse reaction Frequency of adverse reactions of pioglitazone by treatment regimen 

 
 

Mono-
therapy 

Combination 
 

with 
metformin 

 
with 

sulpho-
nylurea 

 
with 

metformin 
and sulpho-

nylurea 

 
with insulin 

Infections and 
infestations 

 

upper respiratory 
tract infection 

common common common common common 

bronchitis     common 
sinusitis uncommon uncommon uncommon uncommon uncommon 



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Adverse reaction Frequency of adverse reactions of pioglitazone by treatment regimen 

 
 

Mono-
therapy 

Combination 
 

with 
metformin 

 
with 

sulpho-
nylurea 

 
with 

metformin 
and sulpho-

nylurea 

 
with insulin 

Neoplasms benign, 
malignant and 
unspecified 
(including cysts 
and polyps) 

 

bladder cancer uncommon uncommon uncommon uncommon uncommon 
Blood and 
lymphatic system 
disorders 

 

anaemia  common    
Immune System 
Disorders 

 

hypersensitivity and 
allergic reactions1 

not known not known not known not known not known 

Metabolism and 
nutrition disorders 

 

hypo-glycaemia   uncommon very 
common 

common 

appetite increased   uncommon   
Nervous system 
disorders 

 

hypo-aesthesia common common common common common 
headache  common uncommon   
dizziness   common   
insomnia uncommon uncommon uncommon uncommon uncommon 
Eye disorders  
visual disturbance2 common common uncommon   
macular oedema not known not known not known not known not known 
Ear and labyrinth 
disorders 

 

vertigo   uncommon   
Cardiac disorders  
heart failure3     common 
Respiratory, 
thoracic and 
mediastinal 
disorders 

 

dyspnoea     common 
Gastrointestinal 
disorders 

 

flatulence  uncommon common   
Skin and 
subcutaneous 
tissue disorders 

 

sweating   uncommon   



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Adverse reaction Frequency of adverse reactions of pioglitazone by treatment regimen 

 
 

Mono-
therapy 

Combination 
 

with 
metformin 

 
with 

sulpho-
nylurea 

 
with 

metformin 
and sulpho-

nylurea 

 
with insulin 

Musculoskeletal 
and connective 
tissue disorders 

 

fracture bone4 common common common common common 
arthralgia  common  common common 
back pain     common 
Renal and urinary 
disorders 

 

haematuria  common    
glycosuria   uncommon   
proteinuria   uncommon   
Reproductive 
system and breast 
disorders 

 

erectile dysfunction  common    
General disorders 
and administration 
site conditions 

 

Oedema5     very 
common 

fatigue   uncommon   
Investigations  
weight increased6 common common common common common 
blood creatine 
phospho-kinase 
increased 

   common  

increased lactic 
dehydro-genase 

  uncommon   

alanine 
aminotransferase 
increased7 

not known not known not known not known not known 

 
Description of selected adverse reactions 
 
1 Postmarketing reports of hypersensitivity reactions in patients treated with pioglitazone have been 
reported. These reactions include anaphylaxis, angioedema, and urticaria.  
 

2 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 treatments. 
 
3 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. In this study in patients receiving pioglitazone and insulin, a higher 

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percentage of patients with heart failure was observed in patients aged ≥ 65 years compared with 
those less than 65 years (9.7% compared to 4.0%). In patients on insulin with no pioglitazone the 
incidence of heart failure was 8.2% in those ≥ 65 years compared to 4.0% in patients less than 
65 years. Heart failure has been reported with marketing use of pioglitazone, and more frequently 
when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure 
(see section 4.4). 
 
4 A pooled analysis was conducted of adverse reactions of bone fractures from randomised, 
comparator controlled, double blind clinical trials in over 8,100 patients in the pioglitazone-treated 
groups and 7,400 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%). 
Post-marketing, bone fractures have been reported in both male and female patients (see section 4.4) 
 
5 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. 
 
6 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. 
 
7 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. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In clinical studies, 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. 
 
 

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5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins; 
ATC code: A10BG03. 
 
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 significantly different to glibenclamide. 
 
In PROactive, a cardiovascular outcome study, 5,238 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 



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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 medicinal products (beta blockers, angiotensin-converting enzyme (ACE) 
inhibitors, angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, acetylsalicylic 
acid, 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. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with Actos 
in all subsets of the paediatric population in type 2 diabetes mellitus. See section 4.2 for information 
on paediatric use. 
 
5.2 Pharmacokinetic properties 
 
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%). 
 
Biotransformation 
 
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. 
 
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). 
 



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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. 
 
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 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. 
 
Environmental Risk Assessment (ERA): 
No environmental impact is anticipated from the clinical use of pioglitazone. 
 



14 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Carmellose calcium 
Hyprolose 
Lactose monohydrate 
Magnesium stearate 
 
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, 84, 90, 98, 112 and 196 tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements for disposal. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S 
Dybendal Alle 10, 
DK-2630 Taastrup 
Denmark 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/00/150/001 
EU/1/00/150/002 
EU/1/00/150/003 
EU/1/00/150/004 
EU/1/00/150/005 
EU/1/00/150/006 
EU/1/00/150/007 
EU/1/00/150/008 
EU/1/00/150/009 
EU/1/00/150/010 
EU/1/00/150/011 
EU/1/00/150/012 
EU/1/00/150/013 
EU/1/00/150/014 



15 

EU/1/00/150/015 
EU/1/00/150/016 
EU/1/00/150/017 
EU/1/00/150/018 
EU/1/00/150/019 
EU/1/00/150/020 
EU/1/00/150/021 
EU/1/00/150/022 
EU/1/00/150/023 
EU/1/00/150/024 
EU/1/00/150/025 
EU/1/00/150/026 
EU/1/00/150/027 
EU/1/00/150/028 
EU/1/00/150/029 
EU/1/00/150/030 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 13/10/2000 
Date of latest renewal: 31/08/2010 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
 

http://www.ema.europa.eu/


16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 

USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE 

AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 



17 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
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 OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 

 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 



18 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

 
 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



20 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Actos 15 mg tablets 
 
pioglitazone  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 15 mg pioglitazone (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
30 tablets 
50 tablets 
56 tablets 
84 tablets 
90 tablets 
98 tablets 
112 tablets 
196 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 



21 

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 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S 
Dybendal Alle 10 
DK-2630 Taastrup  
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/00/150/007 14 tablets 
EU/1/00/150/001 28 tablets 
EU/1/00/150/016 30 tablets 
EU/1/00/150/002 50 tablets 
EU/1/00/150/009 56 tablets 
EU/1/00/150/017 84 tablets 
EU/1/00/150/018 90 tablets 
EU/1/00/150/003 98 tablets 
EU/1/00/150/025 112 tablets 
EU/1/00/150/026 196 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Actos 15 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 



22 

 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



23 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Actos 30 mg tablets 
 
pioglitazone  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 30 mg pioglitazone (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
30 tablets 
50 tablets 
56 tablets 
84 tablets 
90 tablets 
98 tablets 
112 tablets 
196 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 



24 

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 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S 
Dybendal Alle 10 
DK-2630 Taastrup 
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/00/150/008 14 tablets 
EU/1/00/150/004 28 tablets 
EU/1/00/150/019 30 tablets 
EU/1/00/150/005 50 tablets 
EU/1/00/150/010 56 tablets 
EU/1/00/150/020 84 tablets 
EU/1/00/150/021 90 tablets 
EU/1/00/150/006 98 tablets 
EU/1/00/150/027 112 tablets 
EU/1/00/150/028 196 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Actos 30 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 



25 

 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



26 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Actos 45 mg tablets 
 
pioglitazone  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 45 mg pioglitazone (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
30 tablets 
50 tablets 
56 tablets 
84 tablets 
90 tablets 
98 tablets 
112 tablets 
196 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 



27 

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 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S 
Dybendal Alle 10 
DK-2630 Taastrup 
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/00/150/011 14 tablets 
EU/1/00/150/012 28 tablets 
EU/1/00/150/022 30 tablets 
EU/1/00/150/013 50 tablets 
EU/1/00/150/014 56 tablets 
EU/1/00/150/023 84 tablets 
EU/1/00/150/024 90 tablets 
EU/1/00/150/015 98 tablets 
EU/1/00/150/029 112 tablets 
EU/1/00/150/030 196 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Actos 45 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 



28 

 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



29 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Actos 15 mg tablets 
 
pioglitazone  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda (logo)  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
FOR CALENDARISED PACKS: 
 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 
 



30 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS  
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Actos 30 mg tablets 
 
pioglitazone  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda (logo)  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. OTHER 
 
FOR CALENDARISED PACKS: 
 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 



31 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS  
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Actos 45 mg tablets 
 
pioglitazone  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda (logo)  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
FOR CALENDARISED PACKS: 
 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 



32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



33 

Package Leaflet: Information for the patient 
 

Actos 15 mg tablets 
Actos 30 mg tablets 
Actos 45 mg tablets 

pioglitazone 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Actos is and what it is used for 
2. What you need to know before you take Actos 
3. How to take Actos 
4. Possible side effects 
5. How to store Actos 
6. Contents of the pack and other information 
 
 
1. What Actos is and what it is used for 
 
Actos contains pioglitazone. It is an anti-diabetic medicine used to treat type 2 (non-insulin 
dependent) diabetes mellitus in adults, when metformin is not suitable or has failed to work 
adequately. This is the diabetes that usually develops in adulthood. 
 
Actos helps 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. Your doctor will check whether Actos is working 3 to 
6 months after you start taking it. 
 
Actos may be used on its own in patients who are unable to take metformin, and where treatment with 
diet and exercise has failed to control blood sugar or may be added to other therapies (such as 
metformin, sulphonylurea or insulin) which have failed to provide sufficient control of blood sugar. 
 
 
2. What you need to know before you take Actos 
 
Do not take Actos 
- if you are allergic to pioglitazone or any of the other ingredients of this medicine (listed in 

section 6). 
- if you have heart failure or have had heart failure in the past.  
- if you have liver disease.  
- if you have had diabetic ketoacidosis (a complication of diabetes causing rapid weight loss, 

nausea or vomiting). 
- if you have or have ever had bladder cancer. 
- if you have blood in your urine that your doctor has not checked. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Actos (also see section 4) 



34 

- if you retain water (fluid retention) or have heart failure problems, in particular if you are over 
75 years old. If you take anti-inflammatory medicines which can also cause fluid retention and 
swelling, you must also tell your doctor. 

- if you have a special type of diabetic eye disease called macular oedema (swelling of the back 
of the eye). 

- if you have cysts on your ovaries (polycystic ovary syndrome). There may be an increased 
possibility of becoming pregnant because you may ovulate again when you take Actos. If this 
applies to you, use appropriate contraception to avoid the possibility of an unplanned 
pregnancy. 

- if you have a problem with your liver or heart. Before you start taking Actos you will have a 
blood sample taken to check your liver function. This check may be repeated at intervals. Some 
patients with long-standing type 2 diabetes mellitus and heart disease or previous stroke who 
were treated with Actos 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).  

 
If you take Actos with other medicines for diabetes, it is more likely that your blood sugar could fall 
below the normal level (hypoglycaemia).  
 
You may also experience a reduction in blood count (anaemia). 
 
Broken bones 
A higher number of bone fractures was seen in patients, particularly women taking pioglitazone. Your 
doctor will take this into account when treating your diabetes. 
 
Children and adolescents 
Use in children and adolescents under 18 years is not recommended. 
 
Other medicines and Actos 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription. 
 
You can usually continue to take other medicines whilst you are being treated with Actos. However, 
certain medicines are especially likely to affect the amount of sugar in your blood: 
- gemfibrozil (used to lower cholesterol) 
- rifampicin (used to treat tuberculosis and other infections) 
Tell your doctor or pharmacist if you are taking any of these. Your blood sugar will be checked, and 
your dose of Actos may need to be changed. 
 
Actos with food and drink 
You may take your tablets with or without food. You should swallow the tablets with a glass of water.  
 
Pregnancy and breast-feeding 
Tell your doctor if  
- you are, you think you might be or are planning to become pregnant.  
- you are breast-feeding or if you are planning to breast-feed your baby.  
Your doctor will advise you to discontinue this medicine. 
 
Driving and using machines 
This medicine will not affect your ability to drive or use machines but take care if you experience 
abnormal vision. 
 
Actos contains lactose monohydrate  
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking Actos. 
 



35 

 
3. How to take Actos 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
The usual starting dose is one tablet of 15 mg or of 30 mg of pioglitazone to be taken once daily. Your 
doctor may increase the dose to a maximum of 45 mg once a day. Your doctor will tell you the dose to 
take. 
 
If you have the impression that the effect of Actos is too weak, talk to your doctor.  
 
When Actos is taken in combination with other medicines used to treat diabetes (such as insulin, 
chlorpropamide, glibenclamide, gliclazide, tolbutamide) your doctor will tell you whether you need to 
take a smaller dose of your medicines. 
 
Your doctor will ask you to have blood tests periodically during treatment with Actos. This is to 
check that your liver is working normally. 
 
If you are following a special diet for diabetes, you should continue with this while you are taking 
Actos. 
 
Your weight should be checked at regular intervals; if your weight increases, inform your doctor. 
 
If you take more Actos 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. Your blood sugar could fall below the normal level and can be 
increased by taking sugar. It is recommended that you carry some sugar lumps, sweets, biscuits or 
sugary fruit juice. 
 
If you forget to take Actos 
Take Actos 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 Actos 
Actos should be used every day to work properly. If you stop using Actos, your blood sugar may go 
up. Talk to your doctor before stopping this treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
In particular, patients have experienced the following serious side effects: 
 
Heart failure has been experienced commonly (may affect up to 1 in 10 people) in patients taking 
Actos in combination with insulin. Symptoms are unusual shortness of breath or rapid increase in 
weight or localised swelling (oedema). If you experience any of these, especially if you are over the 
age of 65, seek medical advice straight away. 
 
Bladder cancer has been experienced uncommonly (may affect up to 1 in 100 people) in patients 
taking Actos. Signs and symptoms include blood in your urine, pain when urinating or a sudden need 
to urinate. If you experience any of these, talk to your doctor as soon as possible. 
 



36 

Localised swelling (oedema) has also been experienced very commonly (may affect more than 
1 in 10 people) in patients taking Actos in combination with insulin. If you experience this side effect, 
talk to your doctor as soon as possible. 
 
Broken bones have been reported commonly (may affect up to 1 in 10 people) in female patients 
taking Actos and have also been reported in male patients (frequency cannot be estimated from the 
available data) taking Actos. If you experience this side effect, talk to your doctor as soon as possible. 
 
Blurred vision due to swelling (or fluid) at the back of the eye has also been reported in patients 
taking Actos (frequency cannot be estimated from the available data). If you experience this symptom 
for the first time, talk to your doctor as soon as possible. Also, if you already have blurred vision and 
the symptom gets worse, talk to your doctor as soon as possible. 
 
Allergic reactions have been reported with frequency not known (cannot be estimated from the 
available data) in patients taking Actos. If you have a serious allergic reaction, including hives and 
swelling of the face, lips, tongue, or throat that may cause difficulty in breathing or swallowing stop 
taking this medicine and talk to your doctor as soon as possible. 
 
The other side effects that have been experienced by some patients taking Actos are: 
 
common (may affect up to 1 in 10 people) 
- respiratory infection 
- abnormal vision 
- weight gain 
- numbness 
 
uncommon (may affect up to 1 in 100 people) 
- inflammation of the sinuses (sinusitis)  
- difficulty sleeping (insomnia) 
 
not known (frequency cannot be estimated from the available data) 
- increase in liver enzymes 
- allergic reactions 
 
The other side effects that have been experienced by some patients when Actos is taken with other 
antidiabetic medicines are: 
 
very common (may affect more than 1 in 10 people) 
- decreased blood sugar (hypoglycaemia)  
 
common (may affect up to 1 in 10 people) 
- headache 
- dizziness  
- joint pain 
- impotence 
- back pain 
- shortness of breath 
- small reduction in red blood cell count 
- flatulence 
 



37 

uncommon (may affect up to 1 in 100 people) 
- sugar in urine, proteins in urine 
- increase in enzymes 
- spinning sensation (vertigo) 
- sweating 
- tiredness 
- increased appetite 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store Actos 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and the blister pack after 
“EXP”. The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage precautions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Actos contains 
− The active substance in Actos is pioglitazone.  

Each Actos 15 mg tablet contains 15 mg of pioglitazone (as hydrochloride). 
Each Actos 30 mg tablet contains 30 mg of pioglitazone (as hydrochloride). 
Each Actos 45 mg tablet contains 45 mg of pioglitazone (as hydrochloride). 

− The other ingredients are lactose monohydrate, hyprolose, carmellose calcium and magnesium 
stearate. See section 2 “Actos contains lactose monohydrate”. 

 
What Actos looks like and contents of the pack 
− Actos 15 mg tablets are white to off-white, round, convex tablets marked ‘15’ on one face and 

‘ACTOS’ on the other face. 
− Actos 30 mg tablets are white to off-white, round, flat tablets marked ‘30’ on one face and 

‘ACTOS’ on the other face. 
− Actos 45 mg tablets are white to off-white, round, flat tablets marked ‘45’ on one face and 

‘ACTOS’ on the other face. 
The tablets are supplied in blister packs of 14, 28, 30, 50, 56, 84, 90, 98, 112 or 196 tablets. Not all 
the pack sizes may be marketed. 
 
Marketing authorisation holder 
Takeda Pharma A/S 
Dybendal Alle 10 
DK-2630 Taastrup 
Denmark 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


38 

Manufacturer 
Takeda Ireland Limited, Bray Business Park, Kilruddery, County Wicklow, Ireland. 
Lilly S.A, Avda. de la Industria 30, 28108 Alcobendas (Madrid), Spain 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Takeda Belgium 
Tél/Tel: +32 2 464 06 11 
takeda-belgium@takeda.com  
 

Lietuva 
Eli Lilly Holdings Limited atstovybė 
Tel. +370 (5) 2649600 
 

България 
Такеда България 
Тел.: + 359 2 958 27 36; + 359 2 958 15 29 
 

Luxembourg/Luxemburg 
Takeda Belgium 
Tél/Tel: +32 2 464 06 11 
takeda-belgium@takeda.com  
 

Česká republika 
ELI LILLY ČR, s.r.o. 
Tel: +420 234 664 111 
 

Magyarország 
Lilly Hungária Kft. 
Tel: +36 1 328 5100 
 

Danmark 
Takeda Pharma A/S 
Tlf: +45 46 77 11 11 
 

Malta 
Takeda Italia S.p.A. 
Tel: +39 06 502601 

Deutschland 
Takeda GmbH 
Tel: 0800 825 3325 
medinfo@takeda.de  
 

Nederland 
Eli Lilly Nederland B.V.  
Tel: +31 (0) 30 60 25 800 
 

Eesti 
Takeda Pharma AS 
Tel: +372 617 7669 
 
 

Norge 
Takeda AS 
Tlf: +47 6676 3030 
infonorge@takeda.com  
 

Ελλάδα 
ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε.  
Τηλ: +30 210 629 4600 
 

Österreich 
Takeda Pharma Ges.m.b.H 
Tel: +43(0)800 20 80 50 
 

España 
Lilly S.A. 
Tel: +34 (91) 663 50 00 
 

Polska 
Takeda Polska Sp. z o.o. 
Tel.: +48 22 608 13 00 

France 
Takeda France 
Tél: +33 1 46 25 16 16 
 

Portugal 
Lilly Portugal - Produtos Farmacêuticos, Lda 
Tel: +351 21 412 6600 
 

Hrvatska 
Takeda Pharmaceuticals Croatia d.o.o 
Tel: +385 1 377 88 96 
 
Ireland 
Takeda Products Ireland Limited 
Tel: +353 (0) 1 6420021 
 

România 
Eli Lilly România S.R.L. 
Tel: +40 21 4023000 
 
Slovenija 
Takeda GmbH, Podružnica Slovenija 
Tel.+ 386 (0) 59 082 480 
 

mailto:takeda%1Ebelgium@takeda.com
mailto:takeda%1Ebelgium@takeda.com
mailto:medinfo@takeda.de
mailto:infonorge@takeda.com


39 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
vistor@vistor.is  
 

Slovenská republika 
Takeda Pharmaceuticals Slovakia s.r.o. 
Tel: +421 (2) 20 602 600 
 
 

Italia 
Takeda Italia S.p.A. 
Tel: +39 06 502601 
 

Suomi/Finland 
Oy Eli Lilly Finland Ab  
Puh/Tel: +358 (0)9 8545250 
 

Κύπρος 
Takeda Pharma A/S 
Τηλ: +45 46 77 11 11 
 

Sverige 
Takeda Pharma AB 
Tel: +46 8 731 28 00 
infosweden@takeda.com 
 

Latvija 
Eli Lilly Holdings Limited pārstāvniecība 
Latvijā 
Tel: +371 6 7 364 000 
 

United Kingdom 
Takeda UK Ltd 
Tel: +44 (0)1628 537 900 
 

 
This leaflet was last approved in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 

mailto:vistor@vistor.is
mailto:infosweden@takeda.com
http://www.ema.europa.eu/


40 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 
 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S) 

 
 
 
 
 
 
 
 
 
 
 
 
 



41 

Scientific conclusions 
 
Taking into account the PRAC Assessment Report on the PSUR(s) for glimepiride / pioglitazone 
hydrochloride, metformin / pioglitazone, pioglitazone, the scientific conclusions of CHMP are as 
follows:  
 
The MAH provided updates on new information related to the important identified and important 
potential risks as listed in the summary of safety concerns. The data presented during the current 
reporting period did not provide new information that would allow for further reduction, mitigation, 
or characterisation of these risks. Based on the data presented, the risk minimisation measures in the 
approved product information are considered adequate for the listed safety concerns. 
Given the accumulation of data since the implementation of the additional risk minimisation 
measures, the PRAC agreed with the MAH’s proposal to remove the additional risk minimisation 
measures. As a consequence, the conditions or restrictions with regards to the safe and effective use 
of the medicinal product should be updated to remove the additional risk minimisation measures. The 
RMP has been updated in accordance. 
 
The CHMP agrees with the scientific conclusions made by the PRAC. 

 
Grounds for the variation to the terms of the Marketing Authorisation(s)  
 
On the basis of the scientific conclusions for glimepiride / pioglitazone hydrochloride, metformin / 
pioglitazone, pioglitazone the CHMP is of the opinion that the benefit-risk balance of the medicinal 
product(s) containing glimepiride / pioglitazone hydrochloride, metformin / pioglitazone, pioglitazone 
is unchanged subject to the proposed changes to the product information. 
 
The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)