Annex I Summary of Product Characteristics

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Actos 15 mg tablets.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 15 mg of pioglitazone as hydrochloride.

For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Tablet.

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Pioglitazone is indicated only in oral combination treatment of type 2 diabetes mellitus in patients with insufficient glycaemic control despite maximal tolerated dose of oral monotherapy with either metformin or a sulphonylurea:

- in combination with metformin only in obese patients.

- in combination with a sulphonylurea only in patients who show intolerance to metformin or for whom metformin is contraindicated.

4.2 Posology and method of administration

Treatment should only be initiated by a physician experienced in the treatment of type 2 diabetes. Experience from clinical trials with pioglitazone is currently limited to 18 months. The long-term benefits of therapy with pioglitazone have not been demonstrated (see section 5.1).

Pioglitazone tablets are taken orally once daily with or without food.

Dosage in adults:

Combination with metformin Pioglitazone in combination with metformin may be used at the dose of 15 mg or 30 mg once daily. The current metformin dose can be continued upon initiation of pioglitazone therapy.

Combination with sulphonylurea Pioglitazone in combination with sulphonylurea may be used at the dose of 15 mg or 30 mg once daily. The current sulphonylurea dose can be continued upon initiation of pioglitazone therapy. If patients report hypoglycaemia, the dose of sulphonylurea should be decreased.

Elderly:

No dosage adjustment is necessary for elderly patients (see section 5.2).

Patients with renal impairment:

No dosage adjustment is necessary in patients with impaired renal function (creatinine clearance > 4 ml/min) (see section 5.2). No information is available from dialysed patients therefore pioglitazone should not be used in such patients.

Patients with hepatic impairment:

Pioglitazone should not be used in patients with hepatic impairment (see section 4.4).

Children and adolescents:

There are no data available on the use of pioglitazone in patients under 18 years of age, and therefore its use is not recommended in this age group.

4.3 Contraindications

Pioglitazone is contraindicated in patients with:

- known hypersensitivity to pioglitazone or to any of the excipients of the tablet - cardiac failure or history of cardiac failure (NYHA stages I to IV) - hepatic impairment.

Pioglitazone is also contraindicated for use in combination with insulin.

4.4 Special warnings and special precautions for use

There is no clinical experience with pioglitazone in triple combination with other oral antidiabetics.

Pioglitazone should not be used in monotherapy.

Fluid retention and cardiac failure:

Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. Patients should be observed for signs and symptoms of heart failure, particularly those with reduced cardiac reserve. Pioglitazone should be discontinued if any deterioration in cardiac status occurs. There have been cases of cardiac failure reported from the market when pioglitazone was used in combination with insulin. Therefore pioglitazone is contraindicated in combination with insulin. There also have been cases of cardiac failure reported from the market when pioglitazone was used in patients with a history of cardiac failure. Since NSAIDs and pioglitazone are associated with fluid retention, concomitant administration may increase the risk of oedema.

Monitoring of liver function:

There have been rare reports of hepatocellular dysfunction during post-marketing experience. 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 every two months for the first twelve months, and periodically thereafter. If ALT levels are increased to 3 X upper limit of normal during pioglitazone therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain > 3 X the upper limit of normal, therapy should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with pioglitazone should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

Weight gain:

In clinical trials with pioglitazone there was evidence of weight gain, 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.

Anaemia:

There was a small reduction in haemoglobin and in haematocrit during therapy with pioglitazone, consistent with haemodilution. Anaemia was reported as an adverse event in less than 0.1 % of patients treated with pioglitazone or placebo in all clinical trials.

Others:

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).

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.

4.6 Pregnancy and lactation

Use in pregnancy:

No clinical data on exposed pregnancies are available. 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. 4

Use in breast-feeding:

Pioglitazone has been shown to be present in the milk of lactating rats. It is not known whether pioglitazone is secreted in human milk. Therefore, pioglitazone should not be administered to breast-feeding women.

4.7 Effects on ability to drive and use machines

No effects on ability to drive and use machines have been observed.

4.8 Undesirable effects

Adverse reactions with suspected (at least possible) relationship to treatment reported in excess of reports with placebo and as more than an isolated case in patients receiving pioglitazone in combination with sulphonylurea or metformin in double-blind studies are listed below, by system organ class and absolute frequency. Frequencies are defined as: common > 1/100, < 1/10; uncommon > 1/1000, < 1/100.

PIOGLITAZONE IN COMBINATION WITH METFORMIN

Red blood cell disorders

Common: anaemia

Metabolism and nutritional

Common: weight increase

Central and peripheral nervous system

Common: headache

Vision orders

Common: vision abnormal

Gastrointestinal system

Uncommon: flatulence

Musculoskeletal system

Common: arthralgia

Urinary system

Common: haematuria

Reproductive disorders

Common: impotence

PIOGLITAZONE IN COMBINATION WITH SULPHONYLUREA

Metabolism and nutritional

Common: weight increase Uncommon: glycosuria, hypoglycaemia, increase in lactic dehydrogenase, appetite increase

Central and peripheral nervous system

Common: dizziness Uncommon: headache, vertigo

Vision disorders

Uncommon: vision abnormal

Gastrointestinal system

Common: flatulence

Skin and appendages

Uncommon: sweating

Urinary system

Uncommon: proteinuria

Body as a whole

Uncommon: fatigue

In double-blind studies, oedema occurred in 5.9 % of patients treated with pioglitazone + sulphonylurea (sulphonylurea alone 1.9 %) and in 6.0 % of patients treated with pioglitazone + metformin (metformin alone 2.5 %). The reports of oedema were generally mild to moderate and usually did not require discontinuation of treatment.

During treatment with pioglitazone there was a small increase in total cholesterol which was mostly accounted for by an increase in the HDL cholesterol.

In clinical trials with pioglitazone the incidence of elevations of ALT greater than three times the upper limit of normal was equal to placebo (0.2 %). The incidence of all adverse events relating to liver and biliary systems was also low (pioglitazone 1.1 %, placebo 0.9 %). Isolated cases of elevated liver enzymes and hepatocellular dysfunction have occurred in post-marketing experience, although causal relationship has not been established.

Heart failure was not reported as an adverse event during double-blind clinical studies of pioglitazone in combination with sulphonylurea or metformin, but was reported with an incidence of 1.1 % during studies of pioglitazone in combination with insulin.

After 60 weeks of treatment, pioglitazone was associated with a mean increase of 5.4 % in weight in combination with metformin and a mean increase of 5.5 % in combination with sulphonylurea.

4.9 Overdose

One case of overdose with pioglitazone has been reported. A patient took 120 mg/day for four days, then 180 mg/day for seven days. The patient did not report any clinical 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: antihyperglycaemic, ATC code: A10 BG 03.

Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to act via activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leading to increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment with pioglitazone has been shown to reduce hepatic glucose output and to increase peripheral glucose disposal in the case of insulin resistance.

Fasting and postprandial glycaemic control is improved in patients with type 2 diabetes mellitus. The improved glycaemic control is associated with a reduction in both fasting and postprandial plasma insulin concentrations.

There is no direct effect of pioglitazone on beta-cell function.

The weight increase seen on pioglitazone therapy has been shown in a small study to be due to decreased visceral fat and increased subcutaneous fat. This change in body composition on pioglitazone was 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 no statistically significant increases in LDL-cholesterol levels.

An outcome study has not been conducted with pioglitazone, and therefore the long-term benefits associated with improved metabolic control have not been demonstrated. The efficacy of pioglitazone in combination with sulphonylureas or metformin has not been compared to the combination of sulphonylureas plus metformin.

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 %).

Metabolism:

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This is predominantly via cytochrome P450 3A4 and 2C9 although multiple other isoforms are 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. It is therefore not expected that inducers or inhibitors of P450 isoenzymes will alter pioglitazone or active metabolites in a significant way.

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 relevance of this finding is unknown. There was no tumorigenic response in mice of either sex. Hyperplasia of the urinary bladder was not seen in dogs or monkeys treated for up to 12 months.

In an animal model of familial adenomatous polyposis (FAP), treatment with two other thiazolidinediones increased tumour multiplicity in the colon. The relevance of this finding is unknown.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Carmellose calcium, hydroxypropylcellulose, lactose monohydrate and magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

No special precautions for storage.

6.5 Nature and contents of container

Aluminium/aluminium blisters, packs of 28, 50 and 98 tablets.

6.6 Instructions for use and handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Takeda Europe R & D Centre Limited Savannah House

11-12 Charles II Street London SW1Y 4QU United Kingdom

8. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

1. NAME OF THE MEDICINAL PRODUCT

Actos 30 mg tablets.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 30 mg of pioglitazone as hydrochloride.

For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Tablet.

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

- in combination with metformin only in obese patients.

- in combination with a sulphonylurea only in patients who show intolerance to metformin or for whom metformin is contraindicated.

4.2 Posology and method of administration

Pioglitazone tablets are taken orally once daily with or without food.

Dosage in adults:

Elderly:

No dosage adjustment is necessary for elderly patients (see section 5.2).

Patients with renal impairment:

Patients with hepatic impairment:

Pioglitazone should not be used in patients with hepatic impairment (see section 4.4).

Children and adolescents:

There are no data available on the use of pioglitazone in patients under 18 years of age, and therefore its use is not recommended in this age group.

4.3 Contraindications

Pioglitazone is contraindicated in patients with:

- known hypersensitivity to pioglitazone or to any of the excipients of the tablet - cardiac failure or history of cardiac failure (NYHA stages I to IV) - hepatic impairment.

Pioglitazone is also contraindicated for use in combination with insulin.

4.4 Special warnings and special precautions for use

There is no clinical experience with pioglitazone in triple combination with other oral antidiabetics.

Pioglitazone should not be used in monotherapy.

Fluid retention and cardiac failure:

Monitoring of liver function:

Weight gain:

Anaemia:

Others:

4.5 Interaction with other medicinal products and other forms of interaction

4.6 Pregnancy and lactation

Use in pregnancy:

Use in breast-feeding:

4.7 Effects on ability to drive and use machines

No effects on ability to drive and use machines have been observed.

4.8 Undesirable effects

PIOGLITAZONE IN COMBINATION WITH METFORMIN

Red blood cell disorders

Common: anaemia

Metabolism and nutritional

Common: weight increase

Central and peripheral nervous system

Common: headache

Vision orders

Common: vision abnormal

Gastrointestinal system

Uncommon: flatulence

Musculoskeletal system

Common: arthralgia

Urinary system

Common: haematuria

Reproductive disorders

Common: impotence

PIOGLITAZONE IN COMBINATION WITH SULPHONYLUREA

Metabolism and nutritional

Common: weight increase Uncommon: glycosuria, hypoglycaemia, increase in lactic dehydrogenase, appetite increase

Central and peripheral nervous system

Common: dizziness Uncommon: headache, vertigo

Vision disorders

Uncommon: vision abnormal

Gastrointestinal system

Common: flatulence

Skin and appendages

Uncommon: sweating

Urinary system

Uncommon: proteinuria

Body as a whole

Uncommon: fatigue

During treatment with pioglitazone there was a small increase in total cholesterol which was mostly accounted for by an increase in the HDL cholesterol.

After 60 weeks of treatment, pioglitazone was associated with a mean increase of 5.4 % in weight in combination with metformin and a mean increase of 5.5 % in combination with sulphonylurea.

4.9 Overdose

One case of overdose with pioglitazone has been reported. A patient took 120 mg/day for four days, then 180 mg/day for seven days. The patient did not report any clinical 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: antihyperglycaemic, ATC code: A10 BG 03.

Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to act via activation of specific nuclear receptors (peroxisome proliferator activated 16

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.

There is no direct effect of pioglitazone on beta-cell function.

5.2 Pharmacokinetic properties

Absorption:

Distribution:

The estimated volume of distribution in humans is 0.25 l/kg.

Pioglitazone and all active metabolites are extensively bound to plasma protein (> 99 %).

Metabolism:

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. It is therefore not expected that inducers or inhibitors of P450 isoenzymes will alter pioglitazone or active metabolites in a significant way.

Elimination:

Elderly:

Steady state pharmacokinetics are similar in patients age 65 and over and young subjects.

Patients with renal impairment:

Patients with hepatic impairment:

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.

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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Carmellose calcium, hydroxypropylcellulose, lactose monohydrate and magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

No special precautions for storage.

6.5 Nature and contents of container

Aluminium/aluminium blisters, packs of 28, 50 and 98 tablets.

6.6 Instructions for use and handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Takeda Europe R & D Centre Limited Savannah House 11-12 Charles II Street London SW1Y 4QU United Kingdom

8. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10. DATE OF REVISION OF THE TEXT

ANNEX II

A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OF THE MARKETING AUTHORISATION

A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE

Takeda Ireland Limited, Bray Business Park, Kilruddery, Co. Wicklow, Ireland. Manufacturing Authorisation issued on 21 December 1998 by the Irish Medicines Board, Earlsfort Centre, Earlsfort Terrace, Dublin 2, Ireland.

B. CONDITIONS OF THE MARKETING AUTHORISATION

• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER

Medicinal product subject to restricted medical prescription (see Annex I, Summary of Product Characteristics, section 4.2).

ANNEX III

LABELLING AND PACKAGE LEAFLET

A. LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING

1. NAME OF THE MEDICINAL PRODUCT

Actos 15 mg tablets pioglitazone

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 15 mg pioglitazone (as hydrochloride).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

28 tablets

5. METHOD AND, IF NECESSARY, ROUTE(S) OF ADMINISTRATION

For oral use. Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

Expiry date: {month/year}

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 25

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Europe R & D Centre Ltd Savannah House 11-12 Charles II Street London SW1Y 4QU United Kingdom

12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

EU/0/00/000/000

13. MANUFACTURER’S BATCH NUMBER

Batch number: {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

1. NAME OF THE MEDICINAL PRODUCT

Actos 15 mg tablets pioglitazone

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 15 mg pioglitazone (as hydrochloride).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

50 tablets

5. METHOD AND, IF NECESSARY, ROUTE(S) OF ADMINISTRATION

For oral use. Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

Expiry date: {month/year}

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Europe R & D Centre Ltd Savannah House 11-12 Charles II Street 27

London SW1Y 4QU United Kingdom

12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

EU/0/00/000/000

13. MANUFACTURER’S BATCH NUMBER

Batch number: {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

1. NAME OF THE MEDICINAL PRODUCT

Actos 15 mg tablets pioglitazone

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 15 mg pioglitazone (as hydrochloride).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

98 tablets

5. METHOD AND, IF NECESSARY, ROUTE(S) OF ADMINISTRATION

For oral use. Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

Expiry date: {month/year}

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Europe R & D Centre Ltd Savannah House 11-12 Charles II Street 29

London SW1Y 4QU United Kingdom

12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

EU/0/00/000/000

13. MANUFACTURER’S BATCH NUMBER

Batch number: {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

1. NAME OF THE MEDICINAL PRODUCT

Actos 15 mg tablets pioglitazone

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Takeda (logo)

3. EXPIRY DATE

Expiry date: {month/year}

4. BATCH NUMBER

Batch number: {number}

5. ABBREVIATIONS FOR DAYS OF THE WEEK (PACK SIZES OF 28 AND 98 TABLETS ONLY)

MON TUE WED THU FRI SAT SUN

PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING

1. NAME OF THE MEDICINAL PRODUCT

Actos 30 mg tablets pioglitazone

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 30 mg pioglitazone (as hydrochloride).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

28 tablets

5. METHOD AND, IF NECESSARY, ROUTE(S) OF ADMINISTRATION

For oral use. Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

Expiry date: {month/year}

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 32

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Europe R & D Centre Ltd Savannah House 11-12 Charles II Street London SW1Y 4QU United Kingdom

12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

EU/0/00/000/000

13. MANUFACTURER’S BATCH NUMBER

Batch number: {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

1. NAME OF THE MEDICINAL PRODUCT

Actos 30 mg tablets pioglitazone

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 30 mg pioglitazone (as hydrochloride).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

50 tablets

5. METHOD AND, IF NECESSARY, ROUTE(S) OF ADMINISTRATION

For oral use. Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

Expiry date: {month/year}

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Europe R & D Centre Ltd Savannah House 11-12 Charles II Street 34

London SW1Y 4QU United Kingdom

12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

EU/0/00/000/000

13. MANUFACTURER’S BATCH NUMBER

Batch number: {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

1. NAME OF THE MEDICINAL PRODUCT

Actos 30 mg tablets pioglitazone

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 30 mg pioglitazone (as hydrochloride).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

98 tablets

5. METHOD AND, IF NECESSARY, ROUTE(S) OF ADMINISTRATION

For oral use. Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

Expiry date: {month/year}

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Takeda Europe R & D Centre Ltd Savannah House 11-12 Charles II Street 36

London SW1Y 4QU United Kingdom

12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS

EU/0/00/000/000

13. MANUFACTURER’S BATCH NUMBER

Batch number: {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

1. NAME OF THE MEDICINAL PRODUCT

Actos 30 mg tablets pioglitazone

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Takeda (logo)

3. EXPIRY DATE

Expiry date: {month/year}

4. BATCH NUMBER

Batch number: {number}

5. ABBREVIATIONS FOR DAYS OF THE WEEK (PACK SIZES OF 28 AND 98 TABLETS ONLY)

MON TUE WED THU FRI SAT SUN

B. PACKAGE LEAFLET

PACKAGE LEAFLET ACTOS 15 MG TABLETS (Pioglitazone)

Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have further questions, please ask your doctor or your pharmacist. - This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours.

In this leaflet:

1. What Actos 15 mg tablets are and what they are used for 2. Before you take Actos 15 mg tablets 3. How to take Actos 15 mg tablets 4. Possible side effects 5. Storing Actos 15 mg tablets

[Name of the medicinal product] Actos 15 mg tablets (Pioglitazone)

[Full statement of the active substance(s) and excipient(s)] The active substance in Actos 15 mg tablets is pioglitazone. Each tablet contains 15 mg pioglitazone. The other ingredients are lactose monohydrate, hydroxypropylcellulose, carmellose calcium and magnesium stearate.

[Name and address of the marketing authorisation holder and of the manufacturing authorisation holder responsible for batch release, if different] Marketing authorisation holder: Takeda Europe R & D Centre Limited, Savannah House, 11- 12 Charles II Street, London SW1Y 4QU, United Kingdom.

Manufacturer: Takeda Ireland Limited, Bray Business Park, Kilruddery, County Wicklow, Ireland.

1. WHAT ACTOS 15 MG TABLETS ARE AND WHAT THEY ARE USED FOR [Pharmaceutical form and contents; pharmacotherapeutic group] Actos 15 mg tablets are white to off white, round, convex tablets marked 15 on one face. The tablets are supplied in blister packs of 28, 50 or 98 tablets.

[Therapeutic indications] Actos 15 mg tablets are an anti-diabetic medicine used to treat type 2 (non-insulin dependent) diabetes mellitus. This is the diabetes that usually develops in adulthood.

Actos 15 mg tablets 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.

Actos 15 mg tablets should be used only with metformin or a sulphonylurea which are also oral anti-diabetic medicines.

2. BEFORE YOU TAKE ACTOS 15 MG TABLETS [List of information necessary before taking the medicinal product]

[Contraindications]

Do not take Actos 15 mg tablets:

- If you are hypersensitive (allergic) to pioglitazone or any of the other ingredients of Actos 15 mg tablets. - If you have heart failure. - If you have liver disease. - If you are also taking insulin.

[Appropriate precautions for use; special warnings] Take special care with Actos 15 mg tablets:

Tell your doctor before you start to take this medicine: - If you are planning to become pregnant. - If you are breast-feeding. - If you have polycystic ovary syndrome. There may be an increased possibility of your becoming pregnant because of how your medicine works. - If you have a problem with your liver or heart. - If you already take a sulphonylurea with metformin. This is because triple combination therapy is not recommended. - If you are under 18 years of age because use in such patients is not recommended.

[Interactions with food and drink] Taking Actos 15 mg tablets with food and drink: You may take your tablets with or after a meal or on an empty stomach. You should swallow the tablets with a glass of water.

[Use by pregnant or breast-feeding women] Pregnancy: Ask your doctor or pharmacist for advice before taking any medicine.

Breast-feeding: Ask your doctor or pharmacist for advice before taking any medicine.

[Effects on the ability to drive or to use machines] Driving and using machines: Pioglitazone will not affect your ability to drive or operate machinery.

[Interaction with other medicinal products] Taking other medicines: Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed.

You can usually continue to take other medicines whilst you are being treated with Actos 15 mg tablets.

3. HOW TO TAKE ACTOS 15 MG TABLETS [Instructions for proper use]

[Dosage] One tablet should be taken once daily. If necessary your doctor may tell you to take a different dose. If you have the impression that the effect of Actos 15 mg tablets is too weak, talk to your doctor.

[Method and/or route(s) of administration] Actos 15 mg tablets can be taken with or without food.

As Actos 15 mg tablets is taken in combination with other medicines used to treat diabetes (such as chlorpropamide, glibenclamide, gliclazide, tolbutamide) your doctor will tell you whether you need to take a smaller dose of your medicines.

[Frequency of administration]

[Duration of treatment] Your doctor will prescribe Actos 15 mg tablets in combination with another oral anti-diabetic medicine

Your doctor will ask you to have blood tests every two months during the first year of taking Actos 15 mg tablets and thereafter at regular intervals. 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 Actos 15 mg tablets.

Your weight should be checked at regular intervals; if your weight increases, inform your doctor.

[Symptoms in case of overdose and actions to be taken] If you take more Actos 15 mg tablets than you should: If you accidentally take too many tablets, or if someone else or a child takes your medicine, talk to a doctor or pharmacist immediately.

[Actions to be taken when one or more doses have been missed] If you forget to take Actos 15 mg tablets: Try to take Actos 15 mg tablets daily as prescribed. However if you miss a dose, just carry on with the next dose as normal. Do not take an extra tablet to make up for the one you missed.

[Indication of the risk of withdrawal effects]

4. POSSIBLE SIDE EFFECTS [Description of side effects] Like all medicines, Actos 15 mg tablets can have side effects.

The following side effects have been experienced by some patients taking Actos 15 mg tablets:

- localised swelling (oedema) - weight gain - headache - dizziness - vertigo - abnormal vision - flatulence - joint pain - impotence - sweating - fatigue - decreased blood sugar (hypoglycaemia), sugar in urine, proteins in urine, blood in urine - in rare cases, impaired liver function - a small reduction in red blood cell count.

If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.

5. STORING ACTOS 15 MG TABLETS [Storage conditions and expiry date]

Keep out of the reach and sight of children.

Do not use after the expiry date stated on the carton.

[Where appropriate, warning against certain visible signs of deterioration]

This leaflet was last approved on {date}

Further information

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

België/Belgique/Belgien Luxembourg/Luxemburg Eli Lilly Benelux S.A., Eli Lilly Benelux S.A., Rue de l’ Etuve 52/1, Stoofstraat, Rue de l’ Etuve 52/1, Stoofstraat, B-1000 Bruxelles, Brussel B-1000 Bruxelles, Brussel Tél/Tel: +32 (0)2 548 8484 Tél/Tel: +32 (0)2 548 8484

Danmark Nederland Eli Lilly Danmark A/S, Eli Lilly Nederland B.V., Nybrovej 110, Krijtwal 17-23, DK-2800 Lyngby NL-3432 ZT, Nieuwegein Tlf: +45 45 26 60 00 Tel: +31-(0) 30 60 25 800

Deutschland Österreich Takeda Pharma GmbH Takeda Pharma Ges m.b.H Viktoriaallee 3-5 Seidengasse 33-35, D-52066 Aachen. A-1070 Wien Tel: +49 (0)241 941-0 Tel: +43 (1) 524 40 64

Ελλάδα Portugal ΦΑPΜΑΣΕPΒ-ΛΙΛΛΥ Α.Ε.Β.Ε Lilly Farma Produtos Farmacêuticos, Lda 15° χλμ Εθνικής Οδού Αθηvώv – Λαμίας, Rua Dr António Loureiro Borges, 4-Piso 3 GR- 145 64 Κηφισιά. Arquiparque-Miraflores, Τηλ: +30 (0)1 629 4600 P-1495-131 Algés Tel: +351 21 412 6600

España Suomi/Finland Lilly, S.A. Avda. de la Industria, 30 Oy Eli Lilly Finland Ab, E-28108 Alcobendas, Madrid Rajatorpantie 41 C Råtorpsvägen, Tel: +34 (91) 663 50 00 FIN-01640 Vantaa / Vanda Puh/Tln: +358 (0)9 8545250

France Sverige Laboratoires Takeda Eli Lilly Sweden AB, 15, Quai de Dion Bouton Box 30037, F-92816 Puteaux Cedex S-10425 Stockholm. Tél: +33 (0)1 46 25 16 16 Tln: +46 (0)8 737 88 00

Ireland United Kingdom Takeda Europe R & D Centre Limited, Takeda UK Ltd, Savannah House, Takeda House, The Mercury Centre 11/12 Charles II Street, Wycombe Lane London, SW1Y 4QU-U.K. Wooburn Green, High Wycombe Tel: +44 (0)20 7484 9000 Buckinghamshire HP10 0HH-UK Tel: +44 (0)1628 537 900

Italia Takeda Italia Farmaceutici SpA

Via Elio Vittorini I-129- Roma Tel: +39 06 5026 01

PACKAGE LEAFLET ACTOS 30 MG TABLETS (Pioglitazone)

In this leaflet:

1. What Actos 30 mg tablets are and what they are used for 2. Before you take Actos 30 mg tablets 3. How to take Actos 30 mg tablets 4. Possible side effects 5. Storing Actos 30 mg tablets

[Name of the medicinal product] Actos 30 mg tablets (Pioglitazone)

[Full statement of the active substance(s) and excipient(s)] The active substance in Actos 30 mg tablets is pioglitazone. Each tablet contains 30 mg pioglitazone. The other ingredients are lactose monohydrate, hydroxypropylcellulose, carmellose calcium and magnesium stearate.

Manufacturer: Takeda Ireland Limited, Bray Business Park, Kilruddery, County Wicklow, Ireland.

1. WHAT ACTOS 30 MG TABLETS ARE AND WHAT THEY ARE USED FOR [Pharmaceutical form and contents; pharmacotherapeutic group] Actos 30 mg tablets are white to off white, round, flat tablets marked 30 on one face. The tablets are supplied in blister packs of 28, 50 or 98 tablets.

[Therapeutic indications] Actos 30 mg tablets are an anti-diabetic medicine used to treat type 2 (non-insulin dependent) diabetes mellitus. This is the diabetes that usually develops in adulthood.

Actos 30 mg tablets 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.

Actos 30 mg tablets should be used only with metformin or a sulphonylurea which are also oral anti-diabetic medicines.

2. BEFORE YOU TAKE ACTOS 30 MG TABLETS [List of information necessary before taking the medicinal product]

[Contraindications]

Do not take Actos 30 mg tablets:

- If you are hypersensitive (allergic) to pioglitazone or any of the other ingredients of Actos 30 mg tablets. - If you have heart failure. - If you have liver disease. - If you are also taking insulin.

[Appropriate precautions for use; special warnings] Take special care with Actos 30 mg tablets:

[Interactions with food and drink] Taking Actos 30 mg tablets with food and drink: You may take your tablets with or after a meal or on an empty stomach. You should swallow the tablets with a glass of water.

[Use by pregnant or breast-feeding women] Pregnancy: Ask your doctor or pharmacist for advice before taking any medicine.

Breast-feeding: Ask your doctor or pharmacist for advice before taking any medicine.

[Effects on the ability to drive or to use machines] Driving and using machines: Pioglitazone will not affect your ability to drive or operate machinery.

[Interaction with other medicinal products] Taking other medicines: Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed.

You can usually continue to take other medicines whilst you are being treated with Actos 30 mg tablets.

3. HOW TO TAKE ACTOS 30 MG TABLETS [Instructions for proper use]

[Dosage] One tablet should be taken once daily. If necessary your doctor may tell you to take a different dose. If you have the impression that the effect of Actos 30 mg tablets is too weak, talk to your doctor.

[Method and/or route(s) of administration] Actos 30 mg tablets can be taken with or without food.

As Actos 30 mg tablets is taken in combination with other medicines used to treat diabetes (such as chlorpropamide, glibenclamide, gliclazide, tolbutamide) your doctor will tell you whether you need to take a smaller dose of your medicines.

[Frequency of administration]

[Duration of treatment] Your doctor will prescribe Actos 30 mg tablets in combination with another oral anti-diabetic medicine

Your doctor will ask you to have blood tests every two months during the first year of taking Actos 30 mg tablets and thereafter at regular intervals. 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 Actos 30 mg tablets.

Your weight should be checked at regular intervals; if your weight increases, inform your doctor.

[Symptoms in case of overdose and actions to be taken] If you take more Actos 30 mg tablets than you should: If you accidentally take too many tablets, or if someone else or a child takes your medicine, talk to a doctor or pharmacist immediately.

[Actions to be taken when one or more doses have been missed] If you forget to take Actos 30 mg tablets: Try to take Actos 30 mg tablets daily as prescribed. However if you miss a dose, just carry on with the next dose as normal. Do not take an extra tablet to make up for the one you missed.

[Indication of the risk of withdrawal effects]

4. POSSIBLE SIDE EFFECTS [Description of side effects] Like all medicines, Actos 30 mg tablets can have side effects.

The following side effects have been experienced by some patients taking Actos 30 mg tablets:

If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.

5. STORING ACTOS 30 MG TABLETS [Storage conditions and expiry date]

Keep out of the reach and sight of children.

Do not use after the expiry date stated on the carton.

[Where appropriate, warning against certain visible signs of deterioration]

This leaflet was last approved on {date}

Further information

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

Danmark Nederland Eli Lilly Danmark A/S, Eli Lilly Nederland B.V., Nybrovej 110, Krijtwal 17-23, DK-2800 Lyngby NL-3432 ZT, Nieuwegein Tlf: +45 45 26 60 00 Tel: +31-(0) 30 60 25 800

Deutschland Österreich Takeda Pharma GmbH Takeda Pharma Ges m.b.H Viktoriaallee 3-5 Seidengasse 33-35, D-52066 Aachen. A-1070 Wien Tel: +49 (0)241 941-0 Tel: +43 (1) 524 40 64

France Sverige Laboratoires Takeda Eli Lilly Sweden AB, 15, Quai de Dion Bouton Box 30037, F-92816 Puteaux Cedex S-10425 Stockholm. Tél: +33 (0)1 46 25 16 16 Tln: +46 (0)8 737 88 00

Italia Takeda Italia Farmaceutici SpA

Via Elio Vittorini I-129- Roma Tel: +39 06 5026 01