Medicines Safety Update

Summary

Recently published evidence suggests that drospirenone-containing oral contraceptives may be associated with an increased risk of venous thromboembolism compared with levonorgestrel-containing oral contraceptives. Health professionals should weigh the clinical needs of patients against the possible risk, and educate patients to recognise the signs and symptoms of venous thromboembolism.

New information about the risk of venous thromboembolism (VTE) is being included in the Product Information documents for drospirenone-containing combined oral contraceptives (Yaz, Yasmin) as a result of a recent safety review by the TGA.

Evidence of risk with drospirenone

Two recently published articles suggest a two- to three-fold increase in the risk of VTE (deep vein thrombosis and/or pulmonary embolism) in women taking drospirenone-containing contraceptives compared with those taking contraceptives containing the progestogen levonorgestrel.^1,2

Previous studies comparing VTE risk in women using drospirenone- or levonorgestrel-containing contraceptives had conflicting results.^3-6

Advice for health professionals

Health professionals are reminded that oral contraceptives are contraindicated in women with severe or multiple risk factor(s) for venous or arterial thrombosis. Risk factors include, for example, age >35 years, smoking and prolonged immobilisation.

The clinical needs of patients should be weighed against the possible slight increase in the risk of VTE, and patients should be educated to recognise the signs and symptoms of VTE. Health professionals are encouraged to report all adverse events associated with all oral contraceptives to the TGA.

Summary

Use of pioglitazone for more than a year may be associated with an increased risk of bladder cancer. Consider the risk of bladder cancer when prescribing pioglitazone. Avoid pioglitazone in patients with bladder cancer or a history of bladder cancer. Ask patients taking pioglitazone to report blood in the urine, urinary urgency, pain on urination, and back or abdominal pain.

Pioglitazone is used to treat type 2 diabetes mellitus inadequately controlled by diet and exercise. Recent studies have suggested a link between pioglitazone and bladder cancer. At the time of writing, Product Information documents for pioglitazone-containing medicines were being updated to reflect this new evidence.

Clinical evidence for bladder cancer risk with pioglitazone

In a cardiovascular outcomes study of patients with type 2 diabetes an increased incidence of bladder cancer was observed in subjects receiving pioglitazone (14 cases or 0.5%) compared with subjects in the placebo arm (5 cases or 0.2%).⁷After excluding patients in whom exposure to the study drug was <1 year at time of diagnosis of bladder cancer, there were six (0.2%) cases in the pioglitazone arm and two (0.1%) cases in the placebo arm.

Two recent observational cohort studies of diabetic patients ≥40 years of age have found an association between pioglitazone and bladder cancer (see table). In an interim analysis of a study conducted in the United States, the adjusted hazard ratio for bladder cancer in patients exposed to pioglitazone compared with other patients was 1.2 (95% confidence interval [CI] 0.9–1.5).⁸An unpublished French study (conducted by the government agency Agence Francaise de Securite Sanitaire des Produits de Sante) has confirmed these results.³In both studies, the effect was more pronounced in men than women.

Advice for health professionals

Until there is a better understanding of the link between bladder cancer and pioglitazone, it is prudent to avoid pioglitazone in patients with bladder cancer or a history of bladder cancer. This advice is based on the assumption that pioglitazone or a metabolite may affect bladder cancer initiation, promotion or progression, rather than on clinical evidence of deterioration in patients with bladder cancer or recurrence in patients with a history of bladder cancer.

Consider the risk of bladder cancer in the care of all patients treated with pioglitazone. Advise patients of a small absolute increased risk of bladder cancer with use of pioglitazone, and ask them to report any possible signs or symptoms of bladder cancer such as blood in the urine, urinary urgency, pain on urination, or back or abdominal pain.

Patients or healthcare professionals are encouraged to report cases of bladder cancer in patients who have taken pioglitazone – see 'What to report'.

Summary

Several safety-related changes and recommendations have been included in the recently updated Product Information for modafinil (Modavigil) as a result of a recent benefit–risk review by the TGA.

Modafinil is a wakefulness-promoting agent that has been available in Australia since July 2002. The precise mechanism of action is unclear.

The TGA has reviewed the available clinical trial data, national and international postmarketing spontaneous adverse event data and published literature relating to modafinil adverse drug reactions to 1 October 2010. This review was initiated because of postmarket reports of serious skin, psychiatric, nervous system and cardiovascular adverse events.
The TGA concluded that:

• some additional safety information should be included in the Product Information (see box)
• the benefits of modafinil continued to outweigh the risks for the indications to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy and in patients with obstructive sleep apnoea/hypopnoea syndrome as an adjunct to continuous positive airway pressure (CPAP)
• the indication to treat excessive sleepiness associated with moderate-to-severe chronic shift work sleep disorder should be revised to include only patients where non-pharmacological interventions (e.g. planned napping) are unsuccessful or inappropriate.

Important information when prescribing modafinil

Modafinil can improve the symptom of excessive sleepiness but does not treat the underlying cause. Therefore, when used to improve wakefulness in patients with obstructive sleep apnoea/hypopnoea syndrome, modafinil should only be used as an adjunct to CPAP.

Treatment with modafinil should be initiated and supervised by physicians with appropriate experience in the treatment of sleep disorders who have access to sleep laboratory diagnostic facilities. Modafinil is contraindicated in pregnancy.

The effectiveness of oral contraceptives may be impaired due to the induction of the metabolising enzyme cytochrome P450 3A4. Evaluate cardiovascular, psychiatric and substance abuse status before starting modafinil and monitor patients regularly for skinreactions, cardiovascular disease, psychiatric illness and signs of modafinil abuse. Start with the lowest recommended dose and monitor the patient at every dose adjustment. The updated Product Information for modafinil can be accessed from the TGA website (www.tga.gov.au).