Actos

1.

NAME OF THE MEDICINAL PRODUCT

Actos 15 mg tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipients:

Each tablet contains 92.87 mg of lactose monohydrate (see section 4.4).

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Tablet.

The tablets are white to off-white, round, convex and marked ‘15’ on one face and ‘ACTOS’ on the

other face.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Pioglitazone is indicated in the treatment of type 2 diabetes mellitus:

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).

4.2 Posology and method of administration

Posology

Pioglitazone may be initiated at 15 mg or 30 mg once daily. The dose may be increased in increments

up to 45 mg once daily.

2

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).

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 Actos in children and adolescents under 18 years of age have not been

established. No data are available.

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)

-

diabetic ketoacidosis.

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), 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 associated with fluid retention,

concomitant administration may increase the risk of oedema. Pioglitazone should be discontinued if

any deterioration in cardiac status occurs.

A cardiovascular outcome study of pioglitazone has been performed in patients under 75 years with

type 2 diabetes mellitus and pre-existing major macrovascular disease. Pioglitazone or placebo was

added to existing antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed an

increase in reports of heart failure, however this did not lead to an increase in mortality in this study.

3

-

hepatic impairment

Caution should be exercised in patients over 75 years because of the limited experience in this patient

group in this study.

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.

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.

4

Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated

with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%)

versus comparator (1.5%).

The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with

pioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observed

excess risk of fractures for women in this dataset on pioglitazone is therefore 0.8 fractures per

100 patient years of use.

In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years)

of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures

per 100 patient years) of female patients treated with comparator. No increase in fracture rates was

observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).

The risk of fractures should be considered in the long term care of women treated with pioglitazone.

As a consequence of enhancing insulin action, pioglitazone treatment in patients with polycystic

ovarian syndrome may result in resumption of ovulation. These patients may be at risk of pregnancy.

Patients should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if

pregnancy occurs, the treatment should be discontinued (see section 4.6).

Pioglitazone should be used with caution during concomitant administration of cytochrome P450 2C8

inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored

closely. Pioglitazone dose adjustment within the recommended posology or changes in diabetic

treatment should be considered (see section 4.5).

Actos tablets contain lactose monohydrate and therefore should not be administered to patients with

rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose

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) 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

5

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

Actos 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

Combination

Mono-

therapy

with

metformin

with

sulpho-

nylurea

with

metformin

and sulpho-

nylurea

with insulin

Infections and

infestations

upper respiratory

tract infection

common

bronchitis

common

sinusitis

uncommon uncommon uncommon

uncommon

Blood and

lymphatic

system disorders

anaemia

common

Metabolism and

nutrition

disorders

hypo-glycaemia

uncommon

very

common

appetite increased

uncommon

Nervous system

disorders

hypo-aesthesia

common

headache

common

uncommon

6

Adverse

reaction

Frequency of adverse reactions of pioglitazone by treatment regimen

Combination

Mono-

therapy

with

metformin

with

sulpho-

nylurea

with

metformin

and sulpho-

nylurea

with insulin

dizziness

common

insomnia

uncommon uncommon uncommon

uncommon

Eye disorders

visual

disturbance 1

common

uncommon

macular oedema 2

not known not known

not known

Ear and

labyrinth

disorders

vertigo

uncommon

Cardiac

disorders

heart failure 3

common

Respiratory,

thoracic and

mediastinal

disorders

dyspnoea

common

Gastrointestinal

disorders

flatulence

uncommon

common

Skin and

subcutaneous

tissue disorders

sweating

uncommon

Musculoskeletal

and connective

tissue disorders

fracture bone 4

common

arthralgia

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

oedema

very

7

Adverse

reaction

Frequency of adverse reactions of pioglitazone by treatment regimen

Combination

Mono-

therapy

with

metformin

with

sulpho-

nylurea

with

metformin

and sulpho-

nylurea

with insulin

common

fatigue

uncommon

Investigations

weight increased 5

common

blood creatine

phospho-kinase

increased

common

increased lactic

dehydro-genase

uncommon

Alanine

aminotransferase

increased 6

not known not known

not known

1 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.

2 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.

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. Heart failure has been reported rarely with marketing use of pioglitazone, but

more frequently when pioglitazone was used in combination with insulin or in patients with a history

of cardiac failure.

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%).

5 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.

8

6 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.

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.

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 HbA 1c ≥ 8.0% after the

first six months of therapy). Kaplan-Meier analysis showed shorter time to treatment failure in patients

treated with gliclazide, compared with pioglitazone. At two years, glycaemic control (defined as

HbA 1c < 8.0%) was sustained in 69% of patients treated with pioglitazone, compared with 50% of

patients on gliclazide. In a two-year study of combination therapy comparing pioglitazone with

gliclazide when added to metformin, glycaemic control measured as mean change from baseline in

HbA 1c was similar between treatment groups after one year. The rate of deterioration of HbA 1c during

the second year was less with pioglitazone than with gliclazide.

In a placebo controlled trial, patients with inadequate glycaemic control despite a three month insulin

optimisation period were randomised to pioglitazone or placebo for 12 months. Patients receiving

pioglitazone had a mean reduction in HbA 1c of 0.45% compared with those continuing on insulin

alone, and a reduction of insulin dose in the pioglitazone treated group.

HOMA analysis shows that pioglitazone improves beta cell function as well as increasing insulin

sensitivity. Two-year clinical studies have shown maintenance of this effect.

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.

9

In most clinical trials, reduced total plasma triglycerides and free fatty acids, and increased HDL-

cholesterol levels were observed as compared to placebo, with small, but not clinically significant

increases in LDL-cholesterol levels.

In clinical trials of up to two years duration, pioglitazone reduced total plasma triglycerides and free

fatty acids, and increased HDL cholesterol levels, compared with placebo, metformin or gliclazide.

Pioglitazone did not cause statistically significant increases in LDL cholesterol levels compared with

placebo, whilst reductions were observed with metformin and gliclazide. In a 20-week study, as well

as reducing fasting triglycerides, pioglitazone reduced post prandial hypertriglyceridaemia through an

effect on both absorbed and hepatically synthesised triglycerides. These effects were independent of

pioglitazone’s effects on glycaemia and were statistically significant different to glibenclamide.

In PROactive, a cardiovascular outcome study, 5238 patients with type 2 diabetes mellitus and pre-

existing major macrovascular disease were randomised to pioglitazone or placebo in addition to

existing antidiabetic and cardiovascular therapy, for up to 3.5 years. The study population had an

average age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third of

patients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligible

patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous

cardiac intervention or coronary artery bypass graft, acute coronary syndrome, coronary artery disease,

or peripheral arterial obstructive disease. Almost half of the patients had a previous myocardial

infarction and approximately 20% had had a stroke. Approximately half of the study population had at

least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving

cardiovascular 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 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

10

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).

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.

11

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: no environmental impact is anticipated from the clinical use of

pioglitazone.

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.

7.

MARKETING AUTHORISATION HOLDER

Takeda Global Research and Development Centre (Europe) Ltd

61 Aldwych

London

WC2B 4AE

United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/00/150/001

EU/1/00/150/002

12

EU/1/00/150/003

EU/1/00/150/007

EU/1/00/150/009

EU/1/00/150/016

EU/1/00/150/017

EU/1/00/150/018

EU/1/00/150/025

EU/1/00/150/026

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13/10/2000

Date of last renewal: 13/10/2005

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

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

13

1.

NAME OF THE MEDICINAL PRODUCT

Actos 30 mg tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipients:

Each tablet contains 76.34 mg of lactose monohydrate (see section 4.4).

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Tablet.

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

face.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Pioglitazone is indicated in the treatment of type 2 diabetes mellitus:

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).

4.2 Posology and method of administration

Posology

Pioglitazone may be initiated at 15 mg or 30 mg once daily. The dose may be increased in increments

up to 45 mg once daily.

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