Regulatory Decision Summary for Lokelma

The potassium-lowering effects of Lokelma have been demonstrated in two randomized, double-blind, placebo-controlled trials in patients with hyperkalemia. Both studies tested the initial effect of Lokelma to correct hyperkalemia during a 48-hour period and then, the effect on maintenance of normokalemia (serum potassium levels between 3.5 and 5.0 mmol/L). The studies included patients with chronic kidney disease (58%), heart failure (10%), diabetes mellitus (62%) and taking renin-angiotensin-aldosterone system inhibitors (68%). Two additional open-label studies examined long-term safety and efficacy of Lokelma for up to 12 months.

In the placebo-controlled trials, Lokelma 10g three times daily (TID) was proven to effectively and safely reduce serum potassium into the normokalemic range within 48 hours (correction phase) in patients with hyperkalemia. This effect was observed regardless of baseline serum potassium levels, although the extent of reduction observed was greater in patients with higher baseline levels. The majority of patients maintained normokalemia thereafter under Lokelma being administered as a single daily dose (QD) in both placebo-controlled and long-term studies (maintenance phase). During the maintenance phase, the Lokelma dose administered was established as the minimal effective dose in individual patients, to prevent recurrence of hyperkalemia.

Lokelma has high selectivity for potassium and therefore, does not have clinically significant effects on serum calcium and magnesium. Each 5g of Lokelma contains approximately 364mg of sodium and this drug preferentially captures potassium in exchange for hydrogen and sodium cations. Therefore, treatment with Lokelma increased the risk of edema which was reported as the most common adverse drug reaction in placebo-controlled trials, incidence of 5.7% with Lokelma compared to 1.7% with placebo. Gastrointestinal (GI) disorders such as constipation and nausea were also common. Caution should be taken particularly in patients who should restrict their sodium or are prone to fluid overload associated with comorbidities (e.g., heart failure or renal disease). Other less common (<1%) adverse drug reactions included congestive cardiac failure, diarrhea, vomiting and gastroenteritis. The assessment of long-term safety and efficacy of Lokelma based on a study with an open-label design did not show new or significant safety signals up to 12 months.

Lokelma is an insoluble, inorganic compound that is not absorbed or metabolized by the body. Drug-drug interactions are expected with other medications for which the bioavailability is known to be pH dependent, as Lokelma increases gastric pH and this information was provided in the Product Monograph. There is limited clinical trial experience of Lokelma in patients with serum potassium concentrations greater than 6.5 mmol/L.

Lokelma should not be used as an emergency treatment for life-threatening hyperkalemia and this information was stated in the Product Monograph. Lokelma has not been studied in patients with severe GI disorders, history of major GI surgery, hepatic impairment or on dialysis treatment. Its use should be avoided in case of severe constipation, bowel obstruction or impaction. Lokelma is not recommended during pregnancy and breastfeeding. Cautionary statements have been included in the Product Monograph to address all these issues and uncertainties.

A Risk Management Plan (RMP) for Lokelma was submitted. Upon review, the RMP was considered to be acceptable. The RMP was designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product.

In conclusion, the data on quality, safety and efficacy demonstrated that Lokelma had a favourable benefit/risk profile.

For more information on Health Canadas decision, please view the Summary Basis of Decision.