Benefits Outweigh Risks for Weight Loss Drug Mysimba

The European Medicines Agency (EMA) has concluded a review of the weight loss drug naltrexone/bupropion (Mysimba), which was prompted by concerns about potential long-term cardiovascular risks. The scientific assessment of the EMA’s Committee for Medicinal Products for Human Use (CHMP) was that available data suggested that the benefits of its authorized indication “continue to outweigh its risks.” However, the cardiovascular safety of the drug in patients treated for longer than 12 months has not been fully determined and “remains uncertain,” the drug regulator said.

Naltrexone/bupropion was granted marketing authorization in 2015 as a medicine to be used along with diet and exercise to help manage weight in adults with obesity, defined as a BMI of 30 kg/m² or more, or those who are overweight (BMI between 27 and 30) and have weight-related co-morbidities such as type 2 diabetes, dyslipidemia, or controlled hypertension. 

Each tablet contains 8 mg naltrexone hydrochloride, equivalent to 7.2 mg of naltrexone, and 90 mg bupropion hydrochloride, equivalent to 78 mg of bupropion. Treatment should be discontinued after 16 weeks if patients have not lost at least 5% of their initial body weight, and thereafter the need for continued treatment should be re-evaluated annually.

Long Term Cardiovascular Risk 

At the time of authorization, the CHMP noted uncertainties regarding the long-term effects of naltrexone/bupropion on the cardiovascular system. Studies to date have shown no cardiovascular safety concerns when the drug is used for up to 12 months. However, the data available are not sufficient to fully determine the cardiovascular safety beyond this time.

The drug has been subject to several reviews and variations of marketing authorization due to concerns about various side effects and interactions with other opioid-containing medications.

The current review was initiated in September 2023 at the request of the European Commission (EC) under Article 20 of EC regulations, which triggers the procedure for medicines that have been authorized via the centralized procedure in case of quality, safety, or efficacy issues. The CHMP highlighted the remaining concern regarding the potential long-term cardiovascular risk. Its opinion, following a review of available data, has concluded that the benefits of naltrexone/bupropion in its authorized indication continue to outweigh its risks. However, the cardiovascular safety of the combination drug in patients treated for longer than 12 months has not been fully determined and remains uncertain.

During the review, the CHMP considered all available data in relation to the cardiovascular safety of naltrexone/bupropion, including data from clinical studies and from clinical practice, as well as data from spontaneous reports of side effects and from the literature. Clinical and literature data in relation to the effectiveness of the medicine were also considered.

Trial to Report in 2028

The EMA said that an ongoing prospective, pragmatic, randomized, placebo-controlled study (INFORMUS) has been proposed by the manufacturer to evaluate the long-term cardiovascular safety of naltrexone/bupropion beyond the 12‑month period. The CHMP said the trial was appropriate to generate evidence about this risk in the long term, with results expected in 2028. Its evaluation is a condition for continuing marketing authorization and the company must provide annual reports on the progress of the study.

Meanwhile, healthcare professionals were advised that treatment with naltrexone/bupropion should be discontinued if there are concerns with the safety or tolerability of ongoing treatment, including concerns about increased blood pressure. Patients should be reviewed annually, and physicians should discuss whether the combination remains beneficial for them, taking into account any changes to the patient’s cardiovascular risk and whether weight loss has been maintained.

To minimize potential cardiovascular risks with long-term use of the drug, the existing recommendations have now been clarified and reinforced, the EMA said. The product information, as well as the checklist for healthcare professionals, is being updated to reflect the outcome of this review. A letter including these recommendations will be sent in due course to healthcare professionals prescribing, dispensing, or administering the medicine.

The CHMP opinion will now be forwarded to the EC, which will issue a final legally binding decision applicable in all EU Member States.