Pioglitazone Actavis

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Pioglitazone Actavis 15 mg tablets 
Pioglitazone Actavis 30 mg tablets 
Pioglitazone Actavis 45 mg tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Pioglitazone Actavis 15 mg tablets 
Each tablet contains 15 mg of pioglitazone (as hydrochloride). 
 
Excipients with known effect: 
Each tablet contains 37.77 mg of lactose monohydrate (see section 4.4). 
 
Pioglitazone Actavis 30 mg tablets 
Each tablet contains 30 mg of pioglitazone (as hydrochloride). 
 
Excipients with known effect: 
Each tablet contains 75.54 mg of lactose monohydrate (see section 4.4). 
 
Pioglitazone Actavis 45 mg tablets 
Each tablet contains 45 mg of pioglitazone (as hydrochloride). 
 
Excipients with known effect: 
Each tablet contains 113.31 mg of lactose monohydrate (see section 4.4). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
 
Pioglitazone Actavis 15 mg tablets 
The tablets are white, round, flat, bevelled, 5.5 mm in diameter and engraved with ‘TZ15’ on one 
side. 
 
Pioglitazone Actavis 30 mg tablets 
The tablets are white, round, flat, bevelled, 7 mm in diameter and engraved with ‘TZ30’ on one side. 
 
Pioglitazone Actavis 45 mg tablets 
The tablets are white, round, flat, bevelled, 8 mm in diameter and engraved with ‘TZ45’ on one side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Pioglitazone is indicated as second or third line treatment of type 2 diabetes mellitus as described 
below: 
 
as monotherapy 
- in adult patients (particularly overweight patients) inadequately controlled by diet and exercise 

for whom metformin is inappropriate because of contraindications or intolerance. 
 



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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 population 
 
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 section 4.3 and 4.4). 
 
Paediatric population 
 
The safety and efficacy of pioglitazone 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 
- 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 12506 patients, 0.15%) than in control groups (7 cases from 
10212 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). 
 
Pioglitazone Actavis 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 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. 
 
Breastfeeding 
 
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 
 
Pioglitazone Actavis has no or negligible effect 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 
 
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 frequency 
grouping, adverse reactions are presented in order of decreasing incidence and 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 

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

 

bladder cancer uncommon uncommon uncommon uncommon uncommon 
Respiratory, 
thoracic and 
mediastinal 
disorders 

 

dyspnoea     common 



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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 

Gastrointestinal 
disorders 

 

flatulence  uncommon common   
Skin and 
subcutaneous 
tissue disorders 

 

sweating   uncommon   
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.  
 



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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 
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. 
 
4 A pooled analysis was conducted of adverse reactions 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%). 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. 



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Hypoglycaemia may occur in combination with sulphonylureas or insulin. Symptomatic and general 
supportive measures should be taken in case of overdose. 
 
 
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 significant different to glibenclamide. 



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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 medicinal products (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. 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
pioglitazone 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 



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administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) or with 
rifampicin (an inducer of cytochrome P450 2C8) is reported to increase or decrease, respectively, the 
plasma concentration of pioglitazone (see section 4.5). 
 
Elimination 
 
Following oral administration of radiolabelled pioglitazone to man, recovered label was mainly in 
faeces (55%) and a lesser amount in urine (45%). In animals, only a small amount of unchanged 
pioglitazone can be detected in either urine or faeces. The mean plasma elimination half-life of 
unchanged pioglitazone in man is 5 to 6 hours and for its total active metabolites 16 to 23 hours. 
 
Elderly 
 
Steady state pharmacokinetics are similar in patients age 65 and over and young subjects. 
 
Patients with renal impairment 
 
In patients with renal impairment, plasma concentrations of pioglitazone and its metabolites are lower 
than those seen in subjects with normal renal function, but oral clearance of parent substance is 
similar. Thus free (unbound) pioglitazone concentration is unchanged. 
 
Patients with hepatic impairment 
 
Total plasma concentration of pioglitazone is unchanged, but with an increased volume of 
distribution. Intrinsic clearance is therefore reduced, coupled with a higher unbound fraction of 
pioglitazone. 
 
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. 
 



14 

Environmental Risk Assessment: no environmental impact is anticipated from the clinical use of 
pioglitazone. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Carmellose calcium 
Hydroxypropylcellulose 
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 and 100 tablets. 
 
The packs with 14, 28, 56, 84 and 98 tablets contain blisters with abbreviations for days of the week 
printed on the blister (Mon., Tue., Wed., Thu., Fri., Sat., Sun.). 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf.  
Reykjavíkurvegi 76-78 
220 Hafnarfjörður 
Iceland 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/12/755/001 
EU/1/12/755/002 
EU/1/12/755/003 
EU/1/12/755/004 
EU/1/12/755/005 
EU/1/12/755/006 
EU/1/12/755/007 



15 

EU/1/12/755/008 
EU/1/12/755/009 
EU/1/12/755/010 
EU/1/12/755/011 
EU/1/12/755/012 
EU/1/12/755/013 
EU/1/12/755/014 
EU/1/12/755/015 
EU/1/12/755/016 
EU/1/12/755/017 
EU/1/12/755/018 
EU/1/12/755/019 
EU/1/12/755/020 
EU/1/12/755/021 
EU/1/12/755/022 
EU/1/12/755/023 
EU/1/12/755/024 
EU/1/12/755/025 
EU/1/12/755/026 
EU/1/12/755/027 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
15/03/2012 
 
 
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/. 
 



16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER 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. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Actavis Ltd. 
BLB016 Bulebel Industrial Estate 
Zejtun ZTN 3000 
Malta 
 
 
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 
 
At the time of granting the marketing authorisation, the submission of periodic safety update reports is 
not required for this medicinal product. However, the marketing authorisation holder shall submit 
periodic safety update reports for this medicinal product if the product is included in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and 
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. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
 
• Additional risk minimisation measures 
 
The MAH shall provide an educational pack targeting all physicians who are expected to 
prescribe/use Pioglitazone. Prior to distribution of the prescriber guide in each Member State, the 
MAH must agree the content and format of the educational material, together with a communication 
plan, with the national competent authority. 
 
• This educational pack is aimed at strengthening awareness of important identified risks of 

bladder cancer and heart failure and the overall recommendations intended to optimise the 
benefit-risk margin at the patient level.  



18 

• The physician educational pack should contain: The Summary of Product Characteristics, 
package leaflet, and a Prescriber Guide. 

 
The Prescriber Guide should highlight the following: 
• Patient selection criteria including that Pioglitazone should not be used as first line therapy and 

emphasising the need for regular review of treatment benefit. 
• The risk of bladder cancer and relevant risk minimisation advice. 
• The risk of heart failure and relevant risk minimisation advice. 
• Caution in use in the elderly in light of age related risks (in particular bladder cancer, fractures 

and heart failure). 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



21 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pioglitazone Actavis 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 
100 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 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



22 

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 
 
Actavis Group PTC ehf. 
220 Hafnarfjörður 
Iceland 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/12/755/001 [14 tablets] 
EU/1/12/755/002 [28 tablets] 
EU/1/12/755/003 [30 tablets] 
EU/1/12/755/004 [50 tablets] 
EU/1/12/755/005 [56 tablets] 
EU/1/12/755/006 [84 tablets] 
EU/1/12/755/007 [90 tablets] 
EU/1/12/755/008 [98 tablets] 
EU/1/12/755/009 [100 tablets] 
 
13. MANUFACTURER’S BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Pioglitazone Actavis 15 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



23 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pioglitazone Actavis 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 
100 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 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



24 

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 
 
Actavis Group PTC ehf. 
220 Hafnarfjörður 
Iceland 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/12/755/010 [14 tablets] 
EU/1/12/755/011 [28 tablets] 
EU/1/12/755/012 [30 tablets] 
EU/1/12/755/013 [50 tablets] 
EU/1/12/755/014 [56 tablets] 
EU/1/12/755/015 [84 tablets] 
EU/1/12/755/016 [90 tablets] 
EU/1/12/755/017 [98 tablets] 
EU/1/12/755/018 [100 tablets] 
 
13. MANUFACTURER’S BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Pioglitazone Actavis 30 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



25 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pioglitazone Actavis 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 
100 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 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



26 

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 
 
Actavis Group PTC ehf. 
220 Hafnarfjörður 
Iceland 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/12/755/019 [14 tablets] 
EU/1/12/755/020 [28 tablets] 
EU/1/12/755/021 [30 tablets] 
EU/1/12/755/022 [50 tablets] 
EU/1/12/755/023 [56 tablets] 
EU/1/12/755/024 [84 tablets] 
EU/1/12/755/025 [90 tablets] 
EU/1/12/755/026 [98 tablets] 
EU/1/12/755/027 [100 tablets] 
 
13. MANUFACTURER’S BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Pioglitazone Actavis 45 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



27 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pioglitazone Actavis 15 mg tablets 
 
pioglitazone 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. (logo) 
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
Lot 
 
5. OTHER (FOR CALENDARISED PACKS SIZES OF 14, 28, 56, 84 AND 98 TABLETS 

ONLY) 
 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 



28 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pioglitazone Actavis 30 mg tablets 
 
pioglitazone 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. (logo) 
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
Lot 
 
5. OTHER (FOR CALENDARISED PACKS SIZES OF 14, 28, 56, 84 AND 98 TABLETS 

ONLY) 
 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 



29 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pioglitazone Actavis 45 mg tablets 
 
pioglitazone 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. (logo) 
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
Lot 
 
5. OTHER (FOR CALENDARISED PACKS SIZES OF 14, 28, 56, 84 AND 98 TABLETS 

ONLY) 
 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



31 

Package leaflet: Information for the user 
 

Pioglitazone Actavis 15 mg, 30 mg and 45 mg tablets 
Pioglitazone Actavis 15 mg tablets 
Pioglitazone Actavis 30 mg tablets 
Pioglitazone Actavis 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 Pioglitazone Actavis is and what it is used for 
2. What you need to know before you take Pioglitazone Actavis 
3. How to take Pioglitazone Actavis 
4. Possible side effects 
5. How to store Pioglitazone Actavis 
6. Contents of the pack and other information 
 
 
1. What Pioglitazone Actavis is and what it is used for 
 
Pioglitazone Actavis contains pioglitazone. It is an anti-diabetic medicine used to treat type 2 
(non-insulin dependent) diabetes mellitus, when metformin is not suitable or has failed to work 
adequately. This is the diabetes that usually develops in adulthood. 
 
Pioglitazone Actavis 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 
Pioglitazone Actavis is working 3 to 6 months after you start taking it. 
 
Pioglitazone Actavis 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 Pioglitazone Actavis  
 
Do not take Pioglitazone Actavis 
- if you are hypersensitive (allergic) to pioglitazone or any of the other ingredients of 

Pioglitazone Actavis (see section 6 for a list of ingredients). 
- 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. 
 



32 

Warnings and precautions 
Talk to your doctor before you start to take this medicine: 
- if you retain water (fluid retention) or have heart failure problems and 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 Pioglitazone 
Actavis. 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 Pioglitazone Actavis 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 pioglitazone and insulin experienced the development of 
heart failure. Inform your doctor as soon as possible if you experience signs of heart failure 
such as unusual shortness of breath or rapid increase in weight or localised swelling (oedema). 

 
If you take Pioglitazone Actavis 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 under 18 years is not recommended. 
 
Other medicines and Pioglitazone Actavis 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
You can usually continue to take other medicines whilst you are being treated with Pioglitazone 
Actavis. 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 Pioglitazone Actavis may need to be changed. 
 
Pioglitazone Actavis 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 breastfeeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. 
Your doctor will advise you to discontinue this medicine. 
 
Driving and using machines 
Pioglitazone will not affect your ability to drive or use machines but take care if you experience 
abnormal vision. 
 
Pioglitazone Actavis contains lactose monohydrate 
If you have been told by your doctor that you have intolerance to some sugars, contact your doctor 
before taking Pioglitazone Actavis. 



33 

 
 
3. How to take Pioglitazone Actavis  
 
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 Pioglitazone Actavis is too weak, talk to your doctor. 
 
Pioglitazone Actavis can be taken with or without food. 
 
When Pioglitazone Actavis 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 Pioglitazone Actavis. 
This is to check that your liver is working normally. 
 
If you are following a diabetic diet, you should continue with this while you are taking Pioglitazone 
Actavis. 
 
Your weight should be checked at regular intervals; if your weight increases, inform your doctor. 
 
If you take more Pioglitazone Actavis 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 Pioglitazone Actavis 
Take Pioglitazone Actavis 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. 
For the 14, 28, 56, 84 and 98 tablets pack sizes, you can check the day on which you last took a tablet 
of Pioglitazone Actavis by referring to the calendar printed on the blister. 
 
If you stop taking Pioglitazone Actavis  
Pioglitazone Actavis should be used every day to work properly. If you stop using Pioglitazone 
Actavis, 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 (up to 1 in 10 people) in patients taking pioglitazone 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. 
 



34 

Bladder cancer has been experienced uncommonly (up to 1 in 100 people) in patients taking 
pioglitazone. 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. 
 
Localised swelling (oedema) has also been experienced very commonly in patients taking 
pioglitazone in combination with insulin. If you experience this side effect, talk to your doctor as 
soon as possible. 
 
Broken bones have been reported commonly (up to 1 in 10 people) in female patients taking 
pioglitazone and have also been reported in male patients (frequency cannot be estimated from the 
available data) taking pioglitazone. 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 (frequency not known) has also been 
reported in patients taking pioglitazone. 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 (frequency not known) in patients taking Pioglitazone Actavis. 
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 pioglitazone: 
 
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 pioglitazone 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 (wind) 
 



35 

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 Pioglitazone Actavis  
 
Keep out of the sight and reach of children. 
 
Do not use Pioglitazone Actavis after the expiry date which is stated on the carton and the blister pack 
after the word “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 to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Pioglitazone Actavis contains 
- The active substance is pioglitazone.  
 Each tablet contains 15 mg, 30 mg or 45 mg of pioglitazone (as hydrochloride). 
 Each tablet contains 15 mg of pioglitazone (as hydrochloride).  
 Each tablet contains 30 mg of pioglitazone (as hydrochloride). 
 Each tablet contains 45 mg of pioglitazone (as hydrochloride). 
- The other ingredients are lactose monohydrate, hydroxypropylcellulose, carmellose calcium 

and magnesium stearate. 
 
What Pioglitazone Actavis looks like and contents of the pack 
Pioglitazone Actavis 15 mg tablets are white, round, flat, bevelled, 5.5 mm in diameter and engraved 
with ‘TZ15’ on one side. 
Pioglitazone Actavis 30 mg tablets are white, round, flat, bevelled, 7 mm in diameter and engraved 
with ‘TZ30’ on one side. 
Pioglitazone Actavis 45 mg tablets are white, round, flat, bevelled, 8 mm in diameter and engraved 
with ‘TZ45’ on one side. 
 
The tablets are supplied in aluminium blister packs of 14, 28, 30, 50, 56, 84, 90, 98 and 100 tablets.  
The packs with 14, 28, 56, 84 and 98 tablets contain blisters with abbreviations for days of the week 
printed on the blister (Mon, Tue, Wed, Thu, Fri, Sat, Sun). 
 
Not all the pack sizes may be marketed. 
 



36 

Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder 
Actavis Group PTC ehf.  
Reykjavíkurvegi 76-78 
220 Hafnarfjörður 
Iceland 
 
Manufacturer 
Actavis Ltd. 
BLB 016 Bulebel Industrial Estate 
Zejtun ZTN 3000 
Malta 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Actavis Group PTC ehf. 
IJsland / Islande / Island 
 

Lietuva 
UAB "Sicor Biotech" 
Tel: +370 5 266 0203 
 

България 
Актавис ЕАД 
Teл.: +359 2 489 95 85 
 

Luxembourg/Luxemburg 
Actavis Group PTC ehf. 
Islande / Island 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251 007 111 
 

Magyarország 
Teva Gyógyszergyár Zrt. 
Tel.: +36 1 288 6400 
 

Danmark 
Teva Denmark A/S 
Tlf: +45 44 98 55 11 
 

Malta 
Actavis Ltd. 
Tel: +35621693533 
 

Deutschland 
Actavis Group PTC ehf. 
Island 
 

Nederland 
Aurobindo Pharma B.V. 
Tel: +31 (0)35 542 99 33 
 

Eesti 
UAB "Sicor Biotech" Eesti filiaal  
Tel: +372 661 0801 
 

Norge 
Teva Norway AS 
Tlf: +47 66 77 55 90 
 

Ελλάδα 
Specifar ABEE 
Τηλ: +30 210 5401500 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43(0)1 97007 0 
 

España 
Actavis Group PTC ehf. 
Islandia 
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel: +48 22 345 93 00 
 

France 
Actavis Group PTC ehf. 
Islande 
 

Portugal 
Aurovitas, Unipessoal, Lda 
Tel: +351 214 185 104 
 



37 

Hrvatska 
Pliva Hrvatska d.o.o.  
Tel: +385 1 37 20 000  
 

România 
Teva Pharmaceuticals S.R.L 
Tel: +40 21 230 65 24 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 51 321740 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 1 58 90 390 
 

Ísland 
Actavis Group PTC ehf. 
Sími: +354 550 3300 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o 
Tel: +421 2 57 26 79 11 
 

Italia 
Aurobindo Pharma (Italia) s.r.l. 
Tel: +39 0296392601 
 

Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +358 (0)20 180 5900 
 

Κύπρος 
Specifar ABEE  
Τηλ: +30 210 5401500 
Ελλάδα 
 

Sverige 
Teva Sweden AB 
Tel: +46 42 12 11 00 
 

Latvija 
UAB "Sicor Biotech" filiāle Latvijā 
Tel: +371 673 23 666 
 

United Kingdom 
Actavis UK Limited 
Tel: +44 1271 385257 
 

 
This leaflet was last revised in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/.  
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER 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