Pioglitazone – New contra-indications and warnings

Pioglitazone – New contra-indications and warnings following European review of bladder cancer risk

(Actos, Glustin, Competact, Glubrava, Tandemact)

Pioglitazone belongs to the class of medicines known as ‘thiazolidinediones’ and is used in the treatment of type 2 diabetes as second-line therapy (see Summary of Product Characteristics for licensed indications). Pioglitazone (Actos and Glustin) was first authorised through a centralised European assessment procedure in 2000 with subsequent authorisation of combination products with metformin (Competact and Glubrava) and glimepiride (Tandemact) in 2006 and 2007.

The risk of bladder cancer in association with pioglitazone has been kept under close review since the marketing authorisation was first granted in 2000. As part of the ongoing evaluation of this issue, the marketing authorisation holder, Takeda, is conducting a number of post-authorisation studies, including a ten-year epidemiological study (Kaiser Permanente Northern California study (KPNC)) aimed at identifying incident malignancies associated with pioglitazone treatment in a cohort of diabetic patients. While initial study reports had not confirmed a clear association between the use of pioglitazone and the occurrence of bladder cancer, the third interim report did provide a signal of a potential increased risk in those with the longest exposure and highest cumulative dose. Subsequently and following increased reporting of cases of bladder cancer in France and the US, a European-wide review of pioglitazone-containing medicines was initiated in March 2011. The European Medicines Agency’s Committee for Human Medicinal Products (CHMP) reviewed all available data on the occurrence of bladder cancer, including results of preclinical studies, clinical studies, epidemiological studies and spontaneous reports. The CHMP also considered the advice from its Scientific Advisory Group on Diabetes/Endocrinology.

The CHMP concluded that the evidence from the different sources shows that there is a small increased risk of bladder cancer with pioglitazone. Recently available data from epidemiological studies (third interim analysis of the KPNC cohort and nested case control studies, French CNAMTS cohort study and studies conducted in the GPRD database) point to a small increased risk (relative risk ranging from 1.15 to 1.33 across studies) of bladder cancer in diabetic patients treated with pioglitazone, in particular in patients treated for the longest durations and with the highest cumulative doses. Additionally, in a meta-analysis of randomized controlled clinical trials, 19 out of 12,506 patients taking pioglitazone had bladder cancer (0.15%) compared with 7 out of 10,212 patients not taking pioglitazone (0.07%) (HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whom exposure to the 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. A possible risk after short term treatment cannot be excluded.

The CHMP concluded that there are some patients who cannot be adequately treated by other therapies and who could benefit from pioglitazone subject to additional monitoring requirements and further risk minimisation measures as outlined below.

Advice to Healthcare Professionals

• Use of pioglitazone is now contraindicated in patients with:

– current active bladder cancer or

– a history of bladder cancer or

– uninvestigated macroscopic haematuria.

• Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment. Any unexplained 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.

• In light of age-related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully before initiating treatment in the elderly.

• Prescribers should review the treatment of patients currently on pioglitazone and new patients after 3 to 6 months treatment (and regularly thereafter) to ensure that only patients who are deriving sufficient benefit continue to take it. Pioglitazone should be discontinued in patients who do not respond adequately to treatment (e.g. insufficient reduction in HbA1c).

• Prescribers should consider risk factors for bladder cancer (such as age, smoking and exposure to certain chemicals or treatments) before starting pioglitazone and in those already taking it.

• Patients currently on pioglitazone should be advised to have their treatments evaluated by their doctor at their next scheduled appointment.

• Any suspected adverse reactions with use of pioglitazone should be reported to the Irish Medicines Board.

Key Message:

There is a small increased risk of bladder cancer with the use of pioglitazone; epidemiological data suggest a relative risk of around 1.2 (ranging from 1.15 to 1.33 for ever use across studies). The benefit-risk balance remains positive in a limited population of type 2 diabetics. Prescribers are advised to carefully select patients based on individual patient’s risk factors and to periodically review the efficacy of the patient’s treatment in order to optimise the benefit-risk margin at the individual patient level by ensuring that only patients who are deriving sufficient benefit continue to take pioglitazone.