Label update is based on data from Phase IIIb DIALIZE trial
Today, the US Food and Drug Administration (FDA) approved a label update in the US for AstraZeneca’s LOKELMA® (sodium zirconium cyclosilicate) to include a dosing regimen specifically to treat hyperkalemia in patients with end-stage renal disease on chronic hemodialysis.
The approval by the US FDA was based on positive results from the Phase IIIb DIALIZE trial, the first ever randomized, placebo-controlled trial to evaluate a potassium binder in patients on stable hemodialysis. The DIALIZE trial showed that a significantly higher proportion of patients in the LOKELMA group (41.2%) met the primary endpoint and were classified as responders (maintained serum potassium 4-5 mmol/L during at least three out of four hemodialysis sessions after the long interdialytic interval [LIDI] of the last four weeks of treatment and did not require urgent rescue therapy) compared to patients in the placebo group (1.0%), making it a statistically significant (P<0.001) and clinically meaningful improvement. Rescue therapy was defined as any urgent therapeutic intervention considered necessary to reduce serum potassium for severe hyperkalemia (serum potassium >6.0 mmol/L). The safety profile of LOKELMA observed in DIALIZE was consistent with previous trials.
LOKELMA is a potassium binder indicated for the treatment of hyperkalemia in adults. LOKELMA should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action. This is the first label update for LOKELMA in the US following its FDA approval in 2018 to treat adults with hyperkalemia. The label update now includes a dosing regimen for patients on chronic hemodialysis with a starting dose of 5 g once daily on non-dialysis days and a starting dose of 10 g once daily on non-dialysis days in patients with serum potassium greater than 6.5 mmol/L.
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “More than 500,000 patients in the US are living with dialysis-dependent end-stage renal disease and could be at risk for dangerously high levels of potassium. With this FDA approved update, the LOKELMA label now includes important dosing guidance for treating hyperkalemia in patients on hemodialysis.”
LOKELMA is currently approved in the US, EU, Canada, Hong Kong, China, Russia and Japan for the treatment of patients with hyperkalemia. LOKELMA recently received a positive opinion from The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) on a dosing and administration label update to include patients with hyperkalemia on stable hemodialysis. A final decision is expected from the European Commission in the near-future.
IMPORTANT SAFETY INFORMATION FOR LOKELMA® 5 g and 10 g (sodium zirconium cyclosilicate)
WARNINGS AND PRECAUTIONS:
- Gastrointestinal Adverse Events in Patients with Motility Disorders: Avoid LOKELMA in patients with severe constipation, bowel obstruction or impaction, including abnormal post-operative bowel motility disorders. LOKELMA has not been studied in patients with these conditions and it may be ineffective and may worsen gastrointestinal conditions.
- Edema: Each 5-g dose of LOKELMA contains approximately 400 mg of sodium, but the extent of absorption by the patient is unknown. In clinical trials of LOKELMA in patients who were not on dialysis, edema was observed and was generally mild to moderate in severity and was more commonly seen in patients treated with 15 g once daily. Monitor for signs of edema, particularly in patients who should restrict their sodium intake or are prone to fluid overload (eg, heart failure or renal disease). Advise patients to adjust dietary sodium, if appropriate. Increase the dose of diuretics as needed.
In a clinical trial of LOKELMA in patients on chronic hemodialysis in which most patients were treated with doses of 5 g to 10 g once daily on non-dialysis days, there was no difference in the mean change from baseline in interdialytic weight gain (a measure of fluid retention) between the LOKELMA and placebo groups.
- Hypokalemia in Patients on Hemodialysis: Patients on hemodialysis may be prone to acute illness that can increase the risk of hypokalemia on LOKELMA (eg, illnesses associated with decreased oral intake, diarrhea). Consider adjusting LOKELMA dose based on potassium levels in these settings.
ADVERSE REACTIONS: The most common adverse reaction in non-dialysis patients with LOKELMA was mild to moderate edema. In placebo-controlled trials up to 28 days, edema was reported in 4.4%, 5.9%, 16.1% of non-dialysis patients treated with 5 g, 10 g, and 15 g of LOKELMA once daily, respectively vs 2.4% of non-dialysis patients receiving placebo.
DRUG INTERACTIONS: LOKELMA can transiently increase gastric pH. In general, oral medications with pH-dependent solubility should be administered at least 2 hours before or 2 hours after LOKELMA. Spacing is not needed if it has been determined the concomitant medication does not exhibit pH-dependent solubility.
INDICATION AND LIMITATION OF USE
LOKELMA is indicated for the treatment of hyperkalemia in adults.
LOKELMA should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action.
- Non-hemodialysis Patients
For initial treatment of hyperkalemia, the recommended starting dose is 10 g administered three times a day up to 48 hours. For maintenance treatment, the recommended starting dose is 10 g once daily. Monitor serum potassium and adjust dose of LOKELMA at 1-week intervals or longer in increments of 5 g based on serum potassium and desired target range. The recommended maintenance dose range is from 5 g every other day to 15 g daily. Discontinue or decrease the dose of LOKELMA if serum potassium is below the desired target range.
- Hemodialysis Patients
For patients on chronic hemodialysis, administer LOKELMA only on non‑dialysis days. The recommended starting dose is 5 g once daily on non-dialysis days. Consider a starting dose of 10 g once daily on non-dialysis days in patients with serum potassium greater than 6.5 mEq/L. Monitor serum potassium and adjust the dose of LOKELMA based on the pre‑dialysis serum potassium value after the long interdialytic interval and desired target range. During initiation and after dose adjustment, assess serum potassium after one week. Discontinue or decrease the dose of LOKELMA if serum potassium falls below the desired target range based on pre-dialysis value after the long interdialytic interval or the patient develops clinically significant hypokalemia. The recommended maintenance dose range is from 5 g to 15 g once daily, on non-dialysis days.
PLEASE READ FULL PRESCRIBING INFORMATION.
Hyperkalemia is characterized by high levels of potassium in the blood, generally classified as greater than 5 mmol/l. Many people living with chronic kidney disease (CKD) have hyperkalemia despite being on hemodialysis and often experience fluctuations in their potassium levels. Patients with high variability in potassium levels between dialysis sessions are at significant risk of arrhythmias which can lead to cardiac arrest. Hyperkalemia occurs in 23% to 47% of patients with CKD and/or heart failure with an estimated 700 million and 64 million people respectively, living with each condition worldwide.
DIALIZE is the first ever randomized, placebo-controlled trial to evaluate a potassium binder in patients on stable hemodialysis. The Phase IIIb, multicenter, double-blinded trial investigated the efficacy of LOKELMA versus placebo in 196 patients on hemodialysis with hyperkalemia. Patients were randomized to receive LOKELMA or placebo once daily on non-dialysis days for a treatment period of eight weeks. This included a four-week dose adjustment phase and a four-week evaluation phase on stable dose.
The full results of the DIALIZE trial were published in September 2019 in the Journal of the American Society of Nephrology.
LOKELMA® (sodium zirconium cyclosilicate) is an insoluble, non-absorbed sodium zirconium silicate, formulated as a powder for oral suspension, that acts as a highly selective potassium-removing medicine. It is administered orally as a suspension, is odorless, tasteless and stable at room temperature. It has been studied in three double-blinded, placebo-controlled trials, in one 11-month open label clinical trial and in one 12-month open label clinical trial in patients with hyperkalemia.
AstraZeneca in CVRM
Cardiovascular, Renal and Metabolism (CVRM) together forms one of AstraZeneca’s three therapy areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. The Company’s ambition is to modify or halt the natural course of CVRM diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and cardiovascular health for millions of patients worldwide.
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US-38712 Last Updated 4/20