Continuing Education Activity

Chronic kidney disease (CKD) presents a significant clinical challenge due to complications such as hyperphosphatemia, which is closely linked to secondary hyperparathyroidism, vascular calcification, and increased cardiovascular morbidity and mortality. Sevelamer, a non-calcium, nonmetal phosphate binder, is approved by the US Food and Drug Administration (FDA) and is used to manage hyperphosphatemia in CKD patients, especially those on dialysis. Unlike calcium-based binders, sevelamer lowers serum phosphate levels without causing hypercalcemia, thereby reducing the risk of vascular calcification, which is a significant concern for these patients.

In addition to controlling phosphate levels, sevelamer offers benefits such as improved lipid profiles and potentially lower all-cause mortality. Clinical studies highlight sevelamer's value as a multifaceted therapeutic agent due to its effects on lipid metabolism and mortality reduction. Sevelamer's favorable safety profile, with a lower risk of calcium overload-related complications, makes it particularly suitable for patients at higher risk of cardiovascular events. KDIGO guidelines recommend sevelamer for CKD stages 3 to 5, and it is also used off-label in pediatrics to reduce phosphate absorption in nutritional formulas. This activity reviews the mechanism of action, clinical efficacy, and expanding role of sevelamer in CKD management, offering healthcare providers the latest evidence and practical insights to enhance patient outcomes.

Objectives:

• Identify patients with chronic kidney disease who would benefit from sevelamer therapy to manage hyperphosphatemia, especially those at risk of cardiovascular complications.
• Implement appropriate monitoring protocols for serum phosphate, calcium, bicarbonate, and parathyroid hormone levels in patients receiving sevelamer therapy.
• Select alternative formulations of sevelamer, such as powder packets, for patients who cannot tolerate tablet forms.
• Collaborate with pharmacists to ensure accurate dosing, medication reconciliation, and management of drug interactions with sevelamer.

Indications

Chronic kidney disease (CKD) is a complex condition that poses significant challenges, profoundly affecting patients' quality of life and mortality. This impact is secondary to numerous manifestations stemming from the progressive decline in glomerular filtration rate and its associated consequences.[1] In advanced CKD, phosphate clearance decreases, leading to its accumulation in the body.[2] While some phosphate originates endogenously, most is absorbed through the gastrointestinal (GI) tract. The concept of using phosphate binders emerged in the mid-twentieth century, with various agents such as aluminum-based, calcium-based, and lanthanum-based binders being used. However, due to adverse effects, particularly in the CKD population, the search for more effective medications continued.

FDA-Approved Indications

The US Food and Drug Administration (FDA) has approved sevelamer, a nonabsorbable, polymer-based phosphate binder, for managing hyperphosphatemia in patients with CKD and aged 6 and older.[3][4] The Kidney Disease Improving Global Outcomes (KDIGO) 2017 clinical practice guidelines recommend using phosphate binders to manage hyperphosphatemia in CKD patients stages 3 to 5. Sevelamer is included among the recommended phosphate binders for this purpose.[5] The KDIGO 2023 guidelines continue to endorse this practice outlined in the 2017 guidelines for managing hyperphosphatemia.

Off-Label Uses

Sevelamer is used off-label in pediatrics to pretreat oral or enteral nutrition formulas, such as expressed breast milk or cow's milk, to reduce phosphate burden in individuals with hyperphosphatemia due to renal disease.[6] Additionally, sevelamer may help lower serum lipid levels, potentially due to its ability to chelate bile acids within the GI tract.[7]

Mechanism of Action

Sevelamer is a calcium- and metal-free phosphate-binding agent that works within the intraluminal GI tract to effectively bind dietary phosphate and reduce its absorption.[8] Sevelamer exists in 2 forms—sevelamer hydrochloride and sevelamer carbonate. The primary difference between these forms is their respective effects on serum bicarbonate levels.

Sevelamer hydrochloride lowers serum bicarbonate by releasing a hydrochloride molecule when binding to phosphate, which can contribute to acidosis—a condition frequently encountered in patients with CKD. Hence, certain formulations of sevelamer hydrochloride were withdrawn from the US market in October 2009.[9] Sevelamer carbonate does not exhibit this effect.[10]

The polymeric amine structure of sevelamer has been shown to effectively bind bile acids, which is a well-established mechanism for reducing serum total and low-density lipoprotein cholesterol (LDL-C). This mechanism is similar to that of bile acid-binding resins, which also lower cholesterol levels.[9][11] Clinical trials with sevelamer hydrochloride have consistently demonstrated a significant reduction in total cholesterol levels, from 15% to 30%. However, triglycerides, high-density lipoprotein (HDL) cholesterol, and albumin levels remain unaltered.[9]

Pharmacokinetics

Absorption: Sevelamer is not absorbed systemically, and its primary site of action occurs within the intraluminal space of the GI tract.

Distribution: Sevelamer is not distributed in the body due to its nonabsorbable nature.

Metabolism: Sevelamer is a nonabsorbable medication, so it does not undergo metabolism within the body.

Elimination: Sevelamer is excreted unchanged in the feces.[12]

Administration

Available Dosage Forms and Strengths

Sevelamer is administered orally, with therapy initiation requiring consideration of the patient's prior exposure to phosphate binders, distinguishing between those who are phosphate binder-naive and those already receiving treatment.[9] The medication is orally administered concomitantly with meals and is available in 2 distinct formulations—tablets and suspension powder. 

• Tablet: Available as 400 mg (sevelamer hydrochloride only) and 800 mg (sevelamer carbonate or sevelamer hydrochloride).
• Suspension powder: Available in packets for oral suspension in 800 mg or 2400 mg (sevelamer carbonate only).

The dosing equivalence between sevelamer carbonate and sevelamer hydrochloride is maintained on a milligram-to-milligram basis. Therefore, when transitioning between these formulations, keeping the same prescribed dosage is recommended.[9]

Finally, when considering tablet formulations, it is important to avoid crushing or smashing pills, especially in patients with dysphagia, as this can significantly increase the risk of aspiration and complications. Tablets should also not be crushed for administration via nasogastric or other enteral tubes due to the risk of tube occlusion. However, one study suggests that crushing pills might be feasible under certain conditions.[13]

Sevelamer hydrochloride tablets are indicated for controlling serum phosphorus in patients with CKD who are on dialysis. However, the safety and efficacy of these tablets in CKD patients who are not on dialysis have not been studied.

Adult Dosage

Management of hyperphosphatemia in patients with chronic kidney disease: For phosphate binder-naive patients, the initial dosing is as follows:

• Serum phosphate levels greater than 9 mg/dL: 1600 mg of sevelamer administered orally 3 times daily with meals.
• Serum phosphate levels between 7.5 and 9 mg/dL: 1200-1600 mg of sevelamer administered orally 3 times daily with meals.
• Serum phosphate levels between 5.5 and 7.5 mg/dL: 800 mg of sevelamer administered orally 3 times daily with meals.

Dosage adjustments for sevelamer involve titrating the doses, with 400 to 800 mg increments per meal at 2-week intervals as required to attain the desired serum phosphorus levels. Clinical studies suggest that the average prescribed daily dose for adults is approximately 7.2 g.[9] The maximum daily dose studied in adult CKD patients undergoing dialysis was 14 g.

Maintenance dosage: The objective is to maintain a serum phosphate level of 5.5 mg/dL or lower.

• Serum phosphate levels for 5.5 mg/dL: The dosage of sevelamer should be increased by 400 to 800 mg per meal.
• Serum phosphate levels between 3.5 and 5.5 mg/dL: The current dosage of sevelamer should be continued.
• Serum phosphate less than 3.5 mg/dL: The dosage of sevelamer should be decreased by 400 to 800 mg per meal.

Switching from calcium acetate: When transitioning from calcium acetate to sevelamer, appropriate dosing adjustments are necessary to ensure effective management of hyperphosphatemia.

• A dose of 800 mg of sevelamer hydrochloride or sevelamer carbonate should be substituted for 667 mg of calcium acetate.
• A dose of 1600 mg of sevelamer hydrochloride or sevelamer carbonate should be substituted for 1334 mg of calcium acetate.
• A dose of 2400 mg of sevelamer hydrochloride or sevelamer carbonate should be substituted for 2001 mg of calcium acetate.[14]

Specific Patient Populations

Hepatic impairment: No dosage adjustments are necessary.

Renal impairment: No dosage adjustments are required, as sevelamer is not absorbed and does not necessitate changes in dosing for CKD patients, including those on hemodialysis or peritoneal dialysis.

Pregnancy considerations: No dosage adjustment is needed. However, repletion of folic acid and fat-soluble vitamins may be necessary, as sevelamer can interfere with their absorption by binding bile acids.

Breastfeeding considerations: The administration of sevelamer to lactating mothers does not lead to drug excretion in breast milk or cause any detrimental effects on the breastfed infant.[15]

Pediatric patients: For off-label use in pediatric patients with CKD, sevelamer hydrochloride or sevelamer carbonate can be administered as pretreatment to lower phosphate levels before consuming dairy or breast milk. For this purpose, 800 mg of sevelamer hydrochloride or sevelamer carbonate (in tablet or powder form) should be mixed with up to 400 mL of breast milk, 100 mL of infant formula, tube feeding, or cow's milk. After the sevelamer is added, the mixture should be allowed to stand for 10 minutes before pouring off the liquid for feeding, leaving the sediment at the bottom. Clinical observations show reductions in phosphate levels of more than 85% in breast milk, 42% in cow's milk, 48% in tube feeding, and 68% in infant formula.[6]

Adverse Effects

The primary GI adverse effects are attributed to sevelamer's action in the intraluminal space and its binding of phosphate and bile acids. Common adverse effects include gastrointestinal intolerance, vomiting, nausea, diarrhea, dyspepsia, abdominal pain, nasopharyngitis, limb pain, pruritus, arthralgia, and bronchitis.[16][17] 

Other less commonly reported adverse effects include rash, flatulence, constipation, ileus, intestinal obstruction, intestinal perforation, worsening GI bleeding, necrosis, ulcers, and colitis.[18][19] These adverse events warrant careful consideration, especially in populations at higher risk for these complications.[20][21][22] Notably, addressing constipation before initiating sevelamer treatment on patients is advisable.[9][16] Metabolic acidosis may occur with sevelamer hydrochloride use. Additionally, some reports have noted an increased incidence of peritonitis in patients undergoing peritoneal dialysis who are prescribed sevelamer.[23]

Drug-Drug Interactions

Healthcare providers should consider administering oral medications separately from sevelamer if decreased bioavailability might significantly impact the safety or effectiveness of the concurrent drugs (such as cyclosporine, tacrolimus, and levothyroxine). The duration of separation should be adjusted based on the absorption properties of the medications and whether they are immediate-release or extended-release. Close monitoring of the clinical response and blood concentrations of the concomitant medications is essential.

The binding affinity of sevelamer to bile acids and oleic acid may affect the absorption of fat-soluble vitamins, such as A, D, E, and K. Therefore, it is advisable to consider appropriate supplementation, especially for individuals with CKD who need vitamin D.[24]

Contraindications

As with any medication, the presence of a hypersensitivity reaction to the drug, one of its components, or its formulation is a contraindication. Additionally, sevelamer is contraindicated in cases of bowel obstruction due to potential GI adverse effects.[25] In addition, it is worth mentioning that the Canadian labeling of the medication contraindicates its use in hypophosphatemia and ulcerative colitis, GI bleeding, perforation, and necrosis.[18][19]

Monitoring

Serum biochemical parameters, including bicarbonate, calcium, phosphorus, parathyroid hormone (PTH), and chloride levels, should be regularly monitored.

The frequency of measuring serum calcium, phosphorus, and PTH may vary based on the severity of abnormalities, the rate of CKD progression, and the administration of therapies for CKD-associated mineral and bone disorders.

According to the KDIGO 2017 guidelines:

• For CKD stages 3a to 3b, serum calcium and phosphate should be assessed every 6 to 12 months. The frequency of PTH levels should be measured based on baseline levels and CKD progression.
• For CKD stage 4, serum calcium and phosphate should be evaluated every 3 to 6 months, while PTH should be measured every 6 to 12 months.
• For CKD stage 5 and end-stage renal disease, serum calcium and phosphate should be monitored every 1 to 3 months, and PTH levels should be assessed every 3 to 6 months.

Additionally, periodic assessments of 24-hour urinary calcium, phosphorus, magnesium, and alkaline phosphatase should be performed every 12 months or more frequently if PTH levels are elevated. Creatinine, blood urea nitrogen, albumin, and intact PTH should be monitored every 3 to 12 months, with the frequency adjusted based on the severity of CKD. In practice, these tests are often conducted more frequently.

Monitoring of bicarbonate levels is recommended for patients receiving sevelamer hydrochloride, especially those with CKD who are not undergoing hemodialysis or are on peritoneal dialysis. A noncontrolled cross-sectional study found that 22% of patients on peritoneal dialysis experienced metabolic acidosis associated with the treatment.[26]

Toxicity

Due to the nonsystemic nature of the mode of action of sevelamer, instances of systemic intoxication have not been reported. However, routine monitoring of phosphate levels is crucial for determining the necessity for dosage adjustments. Notably, sevelamer bears a resemblance to other medications in appearance. A notable case report highlighted metformin intoxication caused by the visual similarity between metformin and sevelamer tablets.[12][27]

Enhancing Healthcare Team Outcomes

Hyperphosphatemia is a common complication in individuals with CKD, often resulting in adverse clinical outcomes. The use of phosphate binders is crucial in managing these complications. Sevelamer, a phosphate binder, has demonstrated superior efficacy in controlling phosphate levels compared to alternative binders, primarily due to its more favorable adverse effect profile that does not constrain its utility. However, vigilant monitoring of phosphate, calcium, bicarbonate, and PTH levels is warranted during sevelamer therapy to ensure optimal patient outcomes and prevent potential complications.

Clinicians should carefully review the patient's medical history before prescribing sevelamer, as it may lead to severe complications in those with GI disorders. Effective communication with other healthcare providers, such as nephrologists, gastroenterologists, and speech therapists (for dysphagia patients), is crucial to minimize these risks. A comprehensive interprofessional healthcare team must be actively involved in managing sevelamer therapy to ensure patient safety and therapeutic success.

The primary care provider or nephrologist typically initiates sevelamer therapy. Nursing staff should possess a comprehensive understanding of the drug's adverse event profile and play a key role in monitoring both adverse effects and therapeutic efficacy during follow-up appointments. Pharmacists contribute by verifying dosages, recommending adjustments, performing medication reconciliation to prevent drug interactions, and suggesting alternative formulations when appropriate. When switching between different phosphate binders or various formulations of sevelamer, engaging pharmacy services is crucial to ensure accurate dosage adjustments. Notably, it is also important to emphasize that sevelamer tablets should not be crushed. If a patient is unable to take tablets, sevelamer powder packets may be an appropriate alternative.

Through cohesive collaboration across various disciplines, optimal sevelamer therapy can be achieved while minimizing associated risks. This interprofessional approach ensures comprehensive care that addresses all aspects of the patient's condition, ultimately leading to improved clinical outcomes and an enhanced quality of life for individuals with CKD.

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Disclosure: Antoine Kharsa declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Rout declares no relevant financial relationships with ineligible companies.