Actos tablets
- Name:
Actos tablets
- Company:
Takeda Products Ireland Ltd
- Active Ingredients:
- Legal Category:
Product subject to medical prescription which may be renewed (B)
Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 12/07/19

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Takeda Products Ireland Ltd

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Updated on 12 July 2019 PIL
Reasons for updating
- Change to section 4 - possible side effects
- Change to section 6 - manufacturer
- Change to section 6 - date of revision
Updated on 12 July 2019 SPC
Reasons for updating
- Change to section 4.1 - Therapeutic indications
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
Minor formatting change to section 4.1.
Updated on 18 October 2018 SPC
Reasons for updating
- Change to section 10 - Date of revision of the text
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
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.
Updated on 10 June 2016 SPC
Reasons for updating
- New SPC for new product
Legal category: Product subject to medical prescription which may be renewed (B)
Updated on 10 June 2016 SPC
Reasons for updating
- Change to section 4.8 - Undesirable effects
- Change to section 10 - Date of revision of the text
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
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)
5 Oedema was reported in 6–9% of patients treated with pioglitazone over one year in controlled clinical trials. The oedema rates for comparator groups (sulphonylurea, metformin) were 2–5%. The reports of oedema were generally mild to moderate and usually did not require discontinuation of treatment.
Updated on 8 June 2016 PIL
Reasons for updating
- New PIL for new product
Updated on 8 June 2016 PIL
Reasons for updating
- Change to side-effects
- Change to date of revision
Updated on 13 May 2016 SPC
Reasons for updating
- Change to section 2 - Qualitative and quantitative composition
- Change to section 3 - Pharmaceutical form
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 10 - Date of revision of the text
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
Change to section |
Details of change |
|
There have been some formatting changes. |
2. Qualitative and quantitative composition |
Text in red added and text in blue removed:
Actos 15mg tablets Each tablet contains 15 mg of pioglitazone (as hydrochloride).
Excipients with known effect: Each tablet contains 92.87 mg of lactose monohydrate (see section 4.4).
Actos 30mg tablets Each tablet contains 30mg of pioglitazone (as hydrochloride).
Excipients with known effect: Each tablet contains 76.34 mg of lactose monohydrate (see section 4.4).
Actos 45mg tablets Each tablet contains 45mg of pioglitazone (as hydrochloride).
Excipients with known effect: Each tablet contains 114.51 mg of lactose monohydrate (see section 4.4).
For the full list of excipients, see section 6.1.
|
3. Pharmaceutical Form |
Tablet.
Actos 15mg tablets The
Actos 30mg tablets The
Actos 45mg tablets The
|
4.4 Special warnings and precautions for use |
Text in red added and text in blue removed: …
Bladder
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.
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.
... |
10. Date of revision of the text |
Updated text in red:
28th April 2016 |
Updated on 12 May 2016 PIL
Reasons for updating
- Change to packaging
- Change to date of revision
- Change of active ingredient
Updated on 30 June 2014 PIL
Reasons for updating
- Change to, or new use for medicine
- Change to warnings or special precautions for use
- Change of contraindications
- Change to storage instructions
- Change to side-effects
- Change to information about driving or using machinery
- Change to how the medicine works
- Change to further information section
- Change to date of revision
- Change to MA holder contact details
- Change to improve clarity and readability
- Improved electronic presentation
Updated on 30 June 2014 SPC
Reasons for updating
- Change to section 2 - Qualitative and quantitative composition
- Change to section 4.1 - Therapeutic indications
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.6 - Pregnancy and lactation
- Change to section 4.7 - Effects on ability to drive and use machines
- Change to section 4.8 - Undesirable effects
- Change to Section 4.8 – Undesirable effects - how to report a side effect
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 5.3 - Preclinical safety data
- Change to section 7 - Marketing authorisation holder
- Change to section 9 - Date of renewal of authorisation
- Change to section 10 - Date of revision of the text
- Correction of spelling/typing errors
- Change to MA holder contact details
- Change to improve clarity and readability
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
Section 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- Addition of the highlighted text:
Excipients with known effect:
- Replacement of the word ‘a’ with ‘the’:
For a the full list of excipients, see section 6.1
Section 4.1 Therapeutic indications
- Formatting change to subscript of the highlighted text in the final paragraph of the section:
HbA1c
Section 4.2 Posology and method of administration
- Formatting of subheading 'Paediatric population' to convert to italics, and removal of underline.
Section 4.3 Contraindications
- Addition of the highlighted text:
hypersensitivity to the active substance or to any of the excipients listed in 6.1
Section 4.4 Special warnings and precautions for use
- Formatting of the following subheadings to add underline:
Fluid retention and cardiac failure
Elderly
Bladder Cancer
Monitoring of liver function
Weight gain
Haematology
Hypoglycaemia
Eye disorders
Others
Section 4.6 Fertility, pregnancy and lactation
Formatting of highlighted subheading :
Pregnancy changed to non-italics, and underline added.
Formatting of highlighted subheading :
Breast-feeding changed to non-italics, hyphen and underline added.
Formatting of highlighted text, addition of hyphen:
breast‑feeding
Formatting of highlighted subheading :
Fertility changed to non-italics, and underline added.
Section 4.7 Effects on ability to drive and use machines
Replacement of the word ‘effect’ with ‘influence’:
Actos has no or negligible effect influence on the ability to drive and use machines.
Section 4.8 Undesirable effects
Addition of the following subheading text underlined:
Tabulated list of adverse reactions
Amendment to wording in the following paragraph with insertion of highlighted text and deletion of crossed out text:
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 system organ class, adverse reactions are presented in order of decreasing incidence and followed by decreasing seriousness.
Formatting of table
Addition of the following subheading text underlined:
Description of selected adverse reactions
Insertion of the following paragraph:
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to Pharmacovigilance Section, Irish Medicines Board, Kevin O'Malley House, Earlsfort Centre, Earlsfort Terrace, IRL – Dublin 2. Tel: +353 1 6764971, Fax: +353 1 6767836, Website: www.imb.ie. e-mail:imbpharmacovigilance@imb.ie.
Section 5.1 Pharmacodynamic properties
In the following paragraph, amendment of ‘significant’ to ‘significantly’ (highlighted):
In clinical trials of up to two years duration, pioglitazone reduced total plasma triglycerides and free fatty acids, and increased HDL cholesterol levels, compared with placebo, metformin or gliclazide. Pioglitazone did not cause statistically significant increases in LDL cholesterol levels compared with placebo, whilst reductions were observed with metformin and gliclazide. In a 20-week study, as well as reducing fasting triglycerides, pioglitazone reduced post prandial hypertriglyceridaemia through an effect on both absorbed and hepatically synthesised triglycerides. These effects were independent of pioglitazone’s effects on glycaemia and were statistically significantly different to glibenclamide.
Formatting of subheading Paediatric population to remove italics, and addition of underline
Section 5.2 Pharmacokinetic properties
Formatting of the following subheadings to add underline and remove italics:
Absorption
Distribution
Biotransformation
Elimination
Elderly
Patients with renal impairment
Patients with hepatic impairment
Under the subheading Distribution, text has been amended from ‘l’ to ‘L’ in the following sentence: The estimated volume of distribution in humans is 0.25 L/kg.
Section 5.3 Preclinical safety data
Formatting of the following with amendments highlighted and addition of underline:
Environmental Risk Assessment (ERA):
Nno environmental impact is anticipated from the clinical use of pioglitazone.
Section 7. MARKETING AUTHORISATION HOLDER
MA holder address amended to:
Takeda Pharma A/S
Dybendal Alle 10,
DK-2630 Taastrup
Denmark
Section 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- Amendment of wording with insertion of ‘latest’ as follows:
Date of last latest renewal:
Section 10. DATE OF REVISION OF THE TEXT
Updated to 16/06/2014
Updated on 29 November 2013 PIL
Reasons for updating
- Change to warnings or special precautions for use
- Change of distributor details
Updated on 29 November 2013 SPC
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to Section 4.8 – Undesirable effects - how to report a side effect
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
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.
Updated on 16 May 2013 PIL
Reasons for updating
- Change to marketing authorisation holder
Updated on 16 May 2013 SPC
Reasons for updating
- Change to section 7 - Marketing authorisation holder
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
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
Updated on 10 January 2013 PIL
Reasons for updating
- Change to side-effects
Updated on 10 January 2013 SPC
Reasons for updating
- Change to section 4.8 - Undesirable effects
- Change to section 10 - Date of revision of the text
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
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’
Updated on 20 January 2012 PIL
Reasons for updating
- Change to side-effects
Updated on 19 January 2012 SPC
Reasons for updating
- Change to section 4.1 - Therapeutic indications
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
- Change to section 10 - Date of revision of the text
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
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
Updated on 8 February 2011 PIL
Reasons for updating
- Change to date of revision
Updated on 17 November 2010 PIL
Reasons for updating
- PIL Submitted in error
- Change to date of revision
Updated on 16 November 2010 SPC
Reasons for updating
- Change to section 2 - Qualitative and quantitative composition
- Change to section 4.1 - Therapeutic indications
- Change to section 4.2 - Posology and method of administration
- Change to section 4.6 - Pregnancy and lactation
- Change to section 4.7 - Effects on ability to drive and use machines
- Change to section 4.8 - Undesirable effects
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 5.3 - Preclinical safety data
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
Updated SmPC wording (main changes to be aware of) |
Summary of change |
2 QUALITATIVE AND QUANTITATIVE COMPOSITION Excipients: Each 15 mg tablet contains 92.87 mg of lactose monohydrate (see section 4.4). Each 30 mg tablet contains 76.34 mg of lactose monohydrate (see section 4.4). Each 45 mg tablet contains 114.51 mg of lactose monohydrate (see section 4.4). |
Lactose content has been added to this section |
4.1 Therapeutic indications 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. |
Change to wording to include indicated in ADULT patients.
|
4.2 Posology and method of administration 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. |
Restructured |
4.6 Fertility, pregnancy and lactation Fertility In animal fertility studies there was no effect on copulation, impregnation or fertility index |
Information on animal fertility has been added to this section |
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. |
Information for patients who experience visual disturbances has been added |
4.8 Undesirable effects |
No new events have been reported, but the information is now presented in a table |
5.2 Pharmacokinetic properties Metabolism section has been re-worded to Biotransformation |
Addition of Biotransformation |
5.3 Preclinical safety data Environmental Risk Assessment: no environmental impact is anticipated from the clinical use of pioglitazone. |
Information in bold has been added to this section |
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu |
Added at the end of the SmPC |
Updated on 28 April 2010 PIL
Reasons for updating
- Change to marketing authorisation holder
Updated on 21 April 2010 SPC
Reasons for updating
- Change to section 5.3 - Preclinical safety data
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
In section 5.3 Preclinical safety data, the following wording has been added
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.
Updated on 12 May 2009 SPC
Reasons for updating
- Change to section 3 - Pharmaceutical form
- Change to marketing authorisation holder address
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
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.
7. MARKETING AUTHORISATION HOLDER
Takeda Global Research and Development Centre (
61 Aldwych
WC2B 4AE
Updated on 12 May 2009 PIL
Reasons for updating
- Change to marketing authorisation holder address
Updated on 10 October 2007 PIL
Reasons for updating
- Change to side-effects
Updated on 6 September 2007 SPC
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
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%).
A pooled analysis was conducted of adverse event reports 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%).
Updated on 28 February 2007 PIL
Reasons for updating
- New PIL for medicines.ie
Updated on 26 February 2007 SPC
Reasons for updating
- Change to section 4.1 - Therapeutic indications
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
- Change to section 5 - Pharmacological properties
- Change to section 5.1 - Pharmacodynamic properties
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
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
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
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 HbA1c 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.
Updated on 6 February 2007 SPC
Reasons for updating
- Change to section 4.1 - Therapeutic indications
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.8 - Undesirable effects
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 4.4 - Special warnings and precautions for use
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
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).
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.
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
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 HbA1c 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.
Updated on 8 November 2006 SPC
Reasons for updating
- Change to section 4.1 - Therapeutic indications
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.8 - Undesirable effects
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
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
Updated on 9 October 2006 SPC
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
- Change to section 7 - Marketing authorisation holder
Legal category: Product subject to medical prescription which may be renewed (B)
Free text change information supplied by the pharmaceutical company
WC2R 3DA
Updated on 4 September 2006 SPC
Reasons for updating
- New SPC for new product
Legal category: Product subject to medical prescription which may be renewed (B)