Lokelma

Lokelma is part of the drug class:

• Drugs for treatment of hyperkalemia and hyperphosphatemia

Lokelma is a powder for oral suspension. The active ingredient in Lokelma is sodium zirconium cyclosilicate, a potassium binder. Sodium zirconium cyclosilicate is a non-absorbed zirconium silicate that preferentially exchanges potassium for hydrogen and sodium. Lokelma is a free flowing, odorless, insoluble white powder for oral suspension. It has a mean particle size of 20 µm and includes no more than 3% of particles with a diameter below 3 µm. Each 5 g of sodium zirconium cyclosilicate contains 400 mg of sodium.

The chemical formula of sodium zirconium cyclosilicate is Na~1.5H~0.5ZrSi3O9•2–3H2O.

Figure 1: Crystal Structure of Sodium Zirconium Cyclosilicate

Mechanism of Action

Lokelma (sodium zirconium cyclosilicate) is a non-absorbed zirconium silicate that preferentially captures potassium in exchange for hydrogen and sodium. In vitro, Lokelma has a high affinity for potassium ions, even in the presence of other cations such as calcium and magnesium. Lokelma increases fecal potassium excretion through binding of potassium in the lumen of the gastrointestinal tract. Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, thereby lowering serum potassium levels.

Pharmacodynamics

In a study in healthy adult subjects, Lokelma administered as 5 g or 10 g once daily for four days caused a dose-dependent increase in fecal potassium excretion. Corresponding dose-dependent decreases in urinary potassium excretion and serum potassium were also observed.

In patients with hyperkalemia treated with Lokelma 10 g three times a day for up to 48 hours, reductions in serum potassium were observed one hour after initiation of therapy; serum potassium concentrations continued to decline over the 48-hour treatment period [see Clinical Studies (14.2)]. In patients not continuing Lokelma, potassium levels increased. Patients with higher starting serum potassium levels or receiving a higher dose have greater reductions in serum potassium.

Lokelma causes a small dose-dependent increase in serum bicarbonate concentrations (1.1 mmol/L at 5 g once daily, 2.3 mmol/L at 10 g once daily and 2.6 mmol/L at 15 g once daily as compared with a mean increase of 0.6 mmol/L in patients treated with placebo). The clinical significance of this finding is unclear.

Pharmacokinetics

Lokelma is an inorganic, insoluble compound that is not subject to enzymatic metabolism. In a clinical study in patients with hyperkalemia in which zirconium concentrations were measured in the urine and blood, zirconium concentrations were similar in treated and untreated patients (i.e., either undetectable or around the lower limit of quantification of the assay). An in vivo mass balance study in rats showed that Lokelma was recovered in the feces with no evidence of systemic absorption.

Thirty-nine (39) drugs were tested to determine potential interactions with Lokelma.

Sixteen (16) drugs tested did not show an in vitro interaction with Lokelma (allopurinol, apixaban, aspirin, captopril, cyclosporine, digoxin, ethinyl estradiol, lisinopril, magnesium, metformin, phenytoin, prednisone, propranolol, quinapril, spironolactone and ticagrelor).

Nine (9) of the 23 drugs that showed an in vitro interaction were subsequently tested in vivo in healthy volunteers. Losartan, glipizide and levothyroxine did not show any changes in exposure when co-administered with Lokelma. However, there was an increase in systemic exposure to weak acids such as furosemide and atorvastatin, and a decrease in systemic exposure to weak bases such as dabigatran when co-administered with Lokelma, as shown in Figure 2. These changes are consistent with the hypothesis that Lokelma, by elevating gastric pH, affects the systemic exposure of co-administered drugs whose solubility is pH-dependent [see Drug Interactions (7)].

Figure 2: Effects of Lokelma on the Pharmacokinetic Exposures of Other Orally Administered Medications

In the U.S.

• Lokelma

Available Dosage Forms:

• Powder for Suspension

Therapeutic Class: Gastrointestinal Agent

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of sodium zirconium cyclosilicate in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of sodium zirconium cyclosilicate in the elderly.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Dabigatran Etexilate

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bowel blockage or impaction or
• Constipation, severe—Use has not been studied in patients with these conditions. This medicine may not work properly and may worsen these conditions.

• Heart failure or
• Kidney disease—Use with caution. May increase risk for more side effects.