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 -Competact is indicated as second line treatment of type 2 diabetes mellitus adult paitents. 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). Added,
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
Most of the changes do not alter the meaning of the licence and are either rewording, re-positioning or re-formatting of the previous text.
The updated Competact SmPC contains additional information to the following sections:
Updated SmPC wording (main changes to be aware of)
Summary of change
4.4 Special Warnings and Precautions for use
Monitoring of liver function
Addition of elevated liver enzymes and that there have been some fatal reports.
4.7 Effects on ability to drive and use machines
Competact 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.
Following wording has been added, previous wording was ’ No effects on ability to drive and use machines have been observed.’
4.8 Undesirable effects
At the initiation of the treatment abdominal pain, diarrhoea, loss of appetite, nausea and vomiting may occur, these reactions are very common but usually disappear spontaneously in most cases. Lactic acidosis is a serious reaction which may occur in less than 1 case per 10,000 patients (see section 4.4) and other reactions such as bone fracture, weight increase and oedema may occur in less than 1 case per 10 patients (see section 4.4).
No new events have been reported, but the information is now presented in a table and the following wording added to introduction of section
5.1 Pharmacodynamic properties
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Competact in all subsets of the paediatric population in Type 2 Diabetes Mellitus. See section 4.2 for information on paediatric use.
Following wording has been added
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
The following information has been added to the sections listed below; Section 4. 8. Undesirable effects-''
Section 4. 8. Undesirable effects-''
Clinical trials have been conducted with Competact tablets and co-administered pioglitazone and metformin (see section 5.1). Bioequivalence of Competact with co-administered pioglitazone and metformin has also been demonstrated (see section 5.2).’’
Section 5.1 Pharmacodynamic properties
‘’Pioglitazone and metformin combination
The fixed dose combination tablet of pioglitazone 15 mg/metformin 850 mg BID (N=201), pioglitazone 15 mg BID (N=189), and metformin 850 mg BID (N=210) were evaluated in type 2 diabetes mellitus patients with mean baseline HbA1C of 9.5% in a randomised double-blind, parallel-group study. Previous anti-diabetic medication was discontinued for 12 weeks prior to baseline measurements. After 24 weeks of treatment, the primary endpoint of mean change from baseline in HbA1c was -1.83% in the combination group versus -0.96% in the pioglitazone group (p<0.0001) and -0.99% in the metformin group (p<0.0001).
The safety profile seen in this study reflected the known adverse reactions seen with the individual products and did not suggest any new safety issues.’’
7. MARKETING AUTHORISATION HOLDER
Takeda Global Research and Development Centre (Europe) Ltd
61 Aldwych
London WC2B 4AE
United Kingdom
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 incidence of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.
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%).
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%).