Minor formatting change to section 4.1.

A variation to update the Actos SmPC and PIL was recently approved.  The application sought to add the unique product identifier data to the labelling (needed as a result of FMD) and as part of the submission, minor corrections to typos and formatting were also made. 

Minor addition to Setion 4.8

Text in red has been added.
...

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)

Section 4.4 addition of the following text:
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

Some epidemiological studies have suggested a similarly increased risk of fracture in both men and women.

Section 4.4 amendment of wording as follows:

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

Section 4.8 Addition of the following text:
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.

Section 4.8 Removal of the word "rarely" and replacement of  the word "but" with "and" 
Heart failure has been reported (rarely) with marketing use of pioglitazone, (but) and more frequently when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure.

The Actos SmPCs contains updated information in the following section:

7. Marketing Authourisation Holders has been updated from;

Takeda Global Research and Development Centre (Europe) Ltd

61 Aldwych

London WC2B 4AE

United Kingdom

To

Takeda Pharma A/S

Langebjerg 1

DK-4000 Roskilde

Denmark

Section 4.8 Undesirable effects

Under new adverse reaction class of immune system disorders ‘Hypersensitivity and allergic reactions’ have been added with a frequency of ‘Not known’.

In addition a footnote states ‘Postmarketing reports of hypersensitivity reactions in patients treated with pioglitazone have been reported. These reactions include anaphylaxis, angioedema, and urticaria’

4.1

Therapeutic indications -Pioglitazone is indicated as second or

third line treatment of type 2 diabetes mellitus as described below. Added

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).

Added

4.2.Posology and method of administration - Elderly:

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).







4.3 Contraindications- Current bladder

cancer or a history of bladder cancer and ‐ Uninvestigated macroscopic

haematuria. Added







4.4 Special warnings and precautions for use-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. Added

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. Available epidemiological data also

suggest a small increased risk of bladder cancer in diabetic patients treated

with pioglitazone in particular in patients treated for the longest durations

and with the highest cumulative doses. A possible risk after short term

treatment cannot be excluded. 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. Added

4.8 Undesirable effects Under

Neoplasms benign, malignant and unspecified (including cysts and

polyps)‐bladder cancer has been added as an Uncommon effect. Added.







10. Date of revision of the text 22 December

2011. updated

In section 5.3 Preclinical safety data, the following wording has been added

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.

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

Others:

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse event reports of bone fracture from randomised, controlled, double blind clinical trials in over 8100 pioglitazone and 7400 comparator treated patients, on treatment for up to 3.5 years.

Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus 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%).

4.1    Therapeutic indications

Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus patients with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance (see section 4.4).

4.2    Posology and method of administration

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.

4.3    Contraindications

-                Diabetic ketoacidosis.

4.4   Special warnings and precautions for use

A cardiovascular outcome study of pioglitazone has been performed in patients under 75 years with type 2 diabetes mellitus and pre-existing major macrovascular disease. Pioglitazone or placebo was added to existing antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed an increase in reports of heart failure, however this did not lead to an increase in mortality in this study.  Caution should be exercised in patients over 75 years because of the limited experience in this patient group.

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.

 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.

4.8        Undesirable effects

PIOGLITAZONE IN COMBINATION THERAPY WITH INSULIN

Metabolism and nutrition disorders

 Common:       hypoglycaemia

 General disorders and administration site conditions

 Very common: oedema

 Infections and infestations

 Common:       bronchitis

 Investigations

 Common:       weight increase

 Musculoskeletal system and connective tissue disorders

 Common:       back pain, arthralgia

 Respiratory, thoracic and mediastinal disorders

 Common:       dyspnoea

 Cardiac disorders

 Common:       heart failure

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.

5.1   Pharmacodynamic properties

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.

In PROactive, a cardiovascular outcome study, 5238 patients with type 2 diabetes mellitus and pre-existing major macrovascular disease were randomised to pioglitazone or placebo in addition to existing antidiabetic and cardiovascular therapy, for up to 3.5 years. The study population had an average age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third of patients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligible patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous cardiac intervention or coronary artery bypass graft, acute coronary syndrome, coronary artery disease, or peripheral arterial obstructive disease. Almost half of the patients had a previous myocardial infarction and approximately 20% had had a stroke. Approximately half of the study population had at least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates).

Although the study failed regarding its primary endpoint, which was a composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation, coronary revascularisation and leg revascularisation, the results suggest that there are no long-term cardiovascular concerns regarding use of pioglitazone. However, the incidences of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.

4.      CLINICAL PARTICULARS

4.1    Therapeutic indications

Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus patients with insufficient glycaemic control on insulin for whom metformin is inappropriate because of contraindications or intolerance (see section 4.4).

 4.2    Posology and method of administration

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.

4.3    Contraindications

-                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. Patients should be observed for signs and symptoms of heart failure, weight gain or oedema particularly those with reduced cardiac reserve. There have been cases of cardiac failure reported from the market when pioglitazone was used in combination with 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.  Caution should be exercised in patients over 75 years because of the limited experience in this patient group.

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.

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.

4.8        Undesirable effects

PIOGLITAZONE IN COMBINATION THERAPY WITH INSULIN

Metabolism and nutrition disorders

 Common:       hypoglycaemia

 General disorders and administration site conditions

 Very common: oedema

 Infections and infestations

 Common:       bronchitis

 Investigations

 Common:       weight increase

 Musculoskeletal system and connective tissue disorders

 Common:       back pain, arthralgia

 Respiratory, thoracic and mediastinal disorders

 Common:       dyspnoea

 Cardiac disorders

 Common:       heart failure

 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.

5.      PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

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.

In PROactive, a cardiovascular outcome study, 5238 patients with type 2 diabetes mellitus and pre-existing major macrovascular disease were randomised to pioglitazone or placebo in addition to existing antidiabetic and cardiovascular therapy, for up to 3.5 years. The study population had an average age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third of patients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligible patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous cardiac intervention or coronary artery bypass graft, acute coronary syndrome, coronary artery disease, or peripheral arterial obstructive disease. Almost half of the patients had a previous myocardial infarction and approximately 20% had had a stroke. Approximately half of the study population had at least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates).

Although the study failed regarding its primary endpoint, which was a composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation, coronary revascularisation and leg revascularisation, the results suggest that there are no long-term cardiovascular concerns regarding use of pioglitazone. However, the incidences of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.

4.1     Therapeutic indications

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

as monotherapy

-          in patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance 

as dual oral therapy in combination with

-          metformin, in patients (particularly overweight patients) with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin

-          a sulphonylurea, only in patients who show intolerance to metformin or for whom metformin is contraindicated, with insufficient glycaemic control despite maximal tolerated dose of monotherapy with a sulphonylurea. 

as triple oral therapy in combination with

-          metformin and a sulphonylurea, in patients (particularly overweight patients) with insufficient glycaemic control despite dual oral therapy. 

4.5     Interaction with other medicinal products and other forms of interaction

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). 

4.8     Undesirable effects 

PIOGLITAZONE IN TRIPLE ORAL COMBINATION THERAPY WITH METFORMIN AND SULPHONYLUREA 

Investigations 

Common:          weight increased, blood creatine phosphokinase increased 

Metabolism and nutrition disorders 

Very common:  hypoglycaemia 

Musculoskeletal and connective tissue disorders

Common:          arthralgia