When a pharmaceutical company changes an SPC or PIL, 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.
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 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.
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.
- 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.
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
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.
7. MARKETING AUTHORISATION HOLDER
Takeda Global Research and Development Centre (Europe) Ltd
61 Aldwych
London
WC2B 4AE
United Kingdom
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%).
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.
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.
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.
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 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.
4. CLINICAL PARTICULARS
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.
Weight gain:
5. PHARMACOLOGICAL PROPERTIES
Pioglitazone is indicated in the treatment of type 2 diabetes mellitus:
- in patients (particularly overweight patients) inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance
- 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.
- 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).
PIOGLITAZONE IN TRIPLE ORAL COMBINATION THERAPY WITH METFORMIN AND SULPHONYLUREA
Common: weight increased, blood creatine phosphokinase increased
Very common: hypoglycaemia
Musculoskeletal and connective tissue disorders
Common: arthralgia
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