Novartis will revise the product information for its hypertension drug Rasilez (aliskiren) to take account of new European Medicines Agency (EMA) drug interaction warnings.

A risk-benefit review from the EMA’s Committee for Medicinal Products for Human Use (CHMP) concluded that aliskiren-containing medicines may interact harmfully with ACE inhibitors or ARBs.

The CHMP review followed Novartis’ decision in December 2011 to abandon the ALTITUDE trial of Rasilez used in combination with those medications.

While confirming that Rasilez is suitable for the treatment of essential hypertension (where no external risk factors present), the CHMP requested two changes in the product information in the EU:

• A contraindication against its use with an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) in patients with diabetes and/or moderate to severe renal impairment.

• A warning against its use in any patients who are taking an ACE inhibitor or an ARB, asking the doctor to assess the balance of risk and benefit carefully.

Novartis will inform doctors in the EU of these changes, which will also affect combination products containing aliskiren such as Rasilamlo and Rasitrio.

David Epstein, Division Head of Novartis Pharmaceuticals, commented: “Patient safety continues to be the highest priority for Novartis, and we are working closely with the CHMP, EMA and other health authorities worldwide to continue to provide Rasilez and combination products containing aliskiren to the most appropriate patient population who would benefit.”

The ALTITUDE study was a large-scale trial of Rasilez used in combination with an ACE inhibitor or ARB in a specific population of patients with type 2 diabetes and renal impairment to reduce the risk of cardiovascular and renal events.

Novartis halted the trial in December after the Data Monitoring Committee concluded from preliminary interim data that the combination in these patients not only did not reduce the risk of such events, but actually increased it.

The company warned doctors worldwide not to prescribe aliskiren-containing products to patients with diabetes who were receiving an ACE inhibitor or ARB. This warning remains in place outside the EU pending further discussions.

Rasilez (Tekturna in the US) was approved in the EU and the US in 2007 for treatment of hypertension as a monotherapy or in combination with other drugs. It is available in tablet form in all EU Member States except Estonia, Latvia, Lithuania and Romania.

The EMA has started a review into the balance of benefits and risks of aliskiren-containing medicines after Novartis’ decision to end the ALTITUDE study. 

Novartis terminated the study following a recommendation from the independent Data Monitoring Committee (DMC) after a seventh interim review of data identified higher adverse effects when treatments were added to an ACE or ARB drug.

The DMC has now asked Novartis to provide additional analysis to the CHMP in order to assess the impacts of the ALTITUDE study and determine the need for regulatory action.

The Phase III, placebo-controlled trial was the first to investigate Rasilez for more than a year in patients with type II diabetes and renal impairment. More than 8,600 patients from 36 countries were included in the study into the potential benefits to reduce the risk of cardiovascular and renal events.

But the DMC found that patients were not likely to benefit from the treatment when it was added to standard anti-hypertensives. Those in study which received Rasilez in addition to standard care were also found to be at an increased risk after 18-24 months of non-fatal stroke, renal complications, hyperkalaemia and hypotension in this high-risk study population.

While the EMA’s review is ongoing, the CHMP recommends, as a precautionary measure, that doctors should not prescribe aliskiren-containing medicines to diabetic patients in combination with ACE inhibitors or ARBs.

Since 2007, eight aliskiren-containing medicines that have been authorised for use in the European Union: Rasilamlo, Rasilez, Rasilez HCT, Rasitrio, Riprazo, Riprazo HCT, Sprimeo, Sprimeo HCT.