Regulatory Decision Summary for Regiocit

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

sodium chloride, sodium citrate

Therapeutic area:

Blood Substitutes And Perfusion Solutions

Type of submission:

New Drug Submission

Control number:

225953
What was the purpose of this submission?

 

This New Drug Submission (NDS) was filed to obtain market authorisation for Regiocit (sodium chloride and sodium citrate) solution, for use as a replacement solution for regional citrate anticoagulation (RCA) of the extracorporeal circuit in patients treated with continuous renal replacement therapy, particularly when systemic anticoagulation with heparin is contraindicated, e.g., in patients with increased bleeding risks. This NDS was reviewed according to the Submission Relying on Third Party Data (SRTD) regulatory pathway.

 

Why was the decision issued?

 

Continuous renal replacement therapy (CRRT) is used in the treatment of patients with acute kidney injury (AKI), to replace the normal blood-filtering function of the kidneys until kidney function improves. The effectiveness of CRRT depends, in part, upon avoiding interruptions to hemofiltration. Since a major cause of such interruptions is hemofilter and extracorporeal circuit clotting, measures to avoid clotting are often employed. Systemic anticoagulation is sometimes administered using unfractionated heparin (UFH), however, heparin use increases the risk of serious bleeding, particularly since patients with AKI often have major comorbidities, such as sepsis or trauma, which may themselves predispose to increased bleeding risk. Thus, strategies which minimize external circuit and hemofilter clotting while avoiding the unnecessary risks of systemic anticoagulation offer potential clinical benefit.

Calcium plays an essential role in multiple steps of the coagulation cascade. Citrate prevents clotting by binding to calcium, thus preventing it from being available to the coagulation cascade. In current clinical practice, regional citrate anticoagulation (RCA) is employed to prolong hemofilter life during CRRT, while avoiding systemic anticoagulation. This approach has been endorsed in international professional guidance, such as the Kidney Disease Improving Global Outcomes (KDIGO) Acute Kidney Injury guidelines (2012). The KDIGO guidelines recommend that for patients not at increased bleeding risk and who are not already receiving systemic anticoagulation, anticoagulation should be used during CRRT, and that RCA rather than a systemic anticoagulation regimen is recommended in patients who do not have contraindications to citrate. RCA is commonly used as anticoagulation in patients receiving CRRT in Canada.

Regiocit is a dilute citrate-containing replacement solution for use during CRRT. Currently, there are no citrate-containing replacement solutions approved for use in CRRT in Canada. The use of RCA during CRRT in Canada currently requires off-label compounding of citrate-containing solutions, using concentrated citrate solutions that are approved for use in plasma apheresis and for administration of other blood products.

This New Drug Submission (NDS) was assessed through the Submission Relying on Third-Party Data (SRTD) regulatory pathway. In the NDS, the sponsor has provided evidence from the medical literature that demonstrates the effectiveness of Regiocit solution for prevention of circuit clotting during CRRT, based on two randomized controlled trials (RCTs), supported by an open-label observational study. The two RCTs randomised a total of 133 patients to study treatment, with 73 receiving citrate replacement solution; the supportive observational trial evaluated 43 patients treated with UFH and 37 patients treated with RCA at a single academic centre. Together, the studies, demonstrated that administration of a solution of sodium citrate and sodium chloride corresponding to that contained in Regiocit results in hemofilter lifespan and effective CRRT delivery equal to or superior to that observed with a systemic anticoagulation regimen using UFH.

The safety of RCA with Regiocit was deemed acceptable. However, during RCA, systemic electrolyte and acid-base status requires careful monitoring, and serum calcium and magnesium losses due to RCA during CRRT, or other electrolyte imbalances observed, must be promptly corrected with systemic infusion of appropriate replacement fluids. Citrate is metabolised to bicarbonate in the liver and also by skeletal muscles and in the renal cortex, and if it is not metabolised effectively, citrate may accumulate, leading to systemic hypocalcemia and metabolic acidosis. On the other hand, metabolic alkalosis may occur if excess citrate enters the circulation and is then metabolised rapidly to bicarbonate. With RCA during CRRT, the need for close monitoring of acid-base balance and electrolyte levels, particularly calcium levels, and prompt correction of any imbalances, is well documented in several sections of the Product Monograph. In addition, the Product Monograph states that administration of RCA using Regiocit during CRRT should only be administered under the direction of a physician experienced in the use of CRRT.

A Risk Management Plan (RMP) was submitted and considered acceptable.

Overall, the benefit risk assessment of Regiocit is considered favourable for prevention of extracorporeal circuit and hemofilter clotting, in order to facilitate continuous renal replacement therapy for patients with acute kidney injury, under the proposed conditions of use.

 

Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.