Sevelamer

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SEVELAMER SEVELAMER

Composition:

Active substance: sevelamer;

One film-coated tablet contains 800 mg of sevelamer hydrochloride;

Excipients: colloidal anhydrous silicon dioxide, stearic acid, purified water;

Coating mixture: polyvinyl alcohol, polyethylene glycol (macrogol), talc, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets

Main physicochemical properties: film-coated tablets of white or almost white color, oval-shaped with a biconvex surface.

Pharmacotherapeutic group.

Medicinal products for the treatment of hyperkalemia and hyperphosphatemia.

ATC code V03AE02.

Pharmacological properties.

Pharmacodynamics.

The medicinal product contains sevelamer – a phosphate-binding polymer that is not absorbed and contains no metals or calcium. Sevelamer contains numerous amines separated by one carbon atom from the main polymer chain, which bind protons in the stomach. These protonated amines bind negatively charged ions, such as dietary phosphate, in the intestine. By binding phosphate in the gastrointestinal tract and reducing its absorption, sevelamer decreases serum phosphate concentration.

Clinical trials have demonstrated that sevelamer is effective in reducing serum phosphorus levels in patients undergoing hemodialysis or peritoneal dialysis.

Sevelamer reduces the incidence of hypercalcemia episodes in patients compared to those treated with calcium-based phosphate binders, likely because the product itself does not contain calcium. The effect of sevelamer on phosphate and calcium levels has been shown to be maintained throughout the study period, including one year of follow-up.

Sevelamer binds bile acids in experimental animal models in vitro and in vivo. Binding of bile acids by ion-exchange resins is a well-established method for lowering blood cholesterol. In clinical studies with sevelamer, mean levels of both total cholesterol and low-density lipoprotein cholesterol (LDL-C) decreased by 15–31%. Cholesterol reduction was observed within 2 weeks of treatment and persisted during long-term therapy. Levels of triglycerides, high-density lipoprotein cholesterol (HDL-C), and albumin were unchanged during sevelamer treatment.

In clinical studies involving patients on hemodialysis, sevelamer had no clinically significant effect on intact parathyroid hormone (iPTH). However, in a 12-week study involving patients on peritoneal dialysis, a relative reduction in iPTH levels was observed compared to patients receiving calcium acetate. Patients with secondary hyperparathyroidism should receive sevelamer as part of a comprehensive treatment regimen, which may include additional calcium, 1,25-dihydroxyvitamin D3, or one of its analogs to reduce iPTH levels.

In a one-year clinical trial, sevelamer did not have an adverse effect on bone mineralization compared to calcium carbonate.

Pharmacokinetics.

Sevelamer hydrochloride is not absorbed from the gastrointestinal tract, as evidenced by pharmacokinetic studies of single doses in healthy volunteers. Pharmacokinetic studies have not been conducted in patients with renal insufficiency.

Clinical characteristics.

Indications.

Sevelamer is indicated for the treatment of hyperphosphatemia in adult patients undergoing hemodialysis or peritoneal dialysis.

Sevelamer is indicated for use as part of a comprehensive treatment regimen including calcium supplements, 1,25-dihydroxyvitamin D3, or one of its analogs for the control of renal osteodystrophy.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Hypophosphatemia.

Intestinal obstruction.

Interaction with other medicinal products and other forms of interaction.

Dialysis.

Studies on interactions with other medicinal products in patients undergoing dialysis have not been conducted.

Ciprofloxacin.

In interaction studies involving healthy volunteers, sevelamer hydrochloride reduced the bioavailability of ciprofloxacin by approximately 50% when administered concomitantly. Therefore, Sevelamer should not be taken simultaneously with ciprofloxacin.

Antiarrhythmic and anticonvulsant medicinal products.

Patients receiving antiarrhythmic medicinal products to control arrhythmias and anticonvulsant medicinal products to prevent seizures were not included in clinical trials. Therefore, Sevelamer should be prescribed with caution in patients taking antiarrhythmic and anticonvulsant medicinal products.

Levothyroxine.

During post-marketing surveillance, very rare cases of increased thyroid-stimulating hormone (TSH) levels have been reported in patients concurrently taking sevelamer hydrochloride and levothyroxine. Careful monitoring of TSH levels is recommended in patients receiving both medicinal products.

Use of cyclosporine, mycophenolate mofetil, and tacrolimus in transplant recipients.

In patients who have undergone organ transplantation, decreased levels of cyclosporine, mycophenolate mofetil, and tacrolimus have been observed when administered concomitantly with sevelamer hydrochloride; however, without any clinical consequences (e.g., transplant rejection). The possibility of interaction cannot be excluded; therefore, careful monitoring of blood concentrations of mycophenolate mofetil, cyclosporine, and tacrolimus is necessary during combination therapy and after discontinuation.

Digoxin, warfarin, enalapril, and metoprolol.

In drug interaction studies involving healthy volunteers, sevelamer hydrochloride had no effect on the bioavailability of digoxin, warfarin, enalapril, or metoprolol.

Proton pump inhibitors.

During post-approval use, there have been reports of very rare cases of increased phosphate levels in patients taking proton pump inhibitors concomitantly with sevelamer hydrochloride.

Bioavailability.

Sevelamer is not absorbed and may affect the bioavailability of other medicinal products. When administering any medicinal product for which reduced bioavailability could have clinically significant effects on safety and efficacy, that medicinal product should be taken at least 1 hour before or 3 hours after administration of Sevelamer. Otherwise, the physician should consider the need for monitoring blood levels of these medicinal products.

Special precautions for use.

The efficacy and safety of sevelamer have not been studied in patients:

• with swallowing disorders;
• with active inflammatory bowel disease;
• with gastrointestinal motility disorders, including untreated or severe gastric paresis, delayed gastric emptying, and irregular defecation;
• with a history of major gastrointestinal surgery.

Therefore, sevelamer should be used with caution in such patients.

Intestinal obstruction and complete or partial bowel obstruction.

Intestinal obstruction and complete or partial bowel obstruction have been reported very rarely in patients during treatment with sevelamer hydrochloride. Constipation may be a warning sign of this condition. Patients with constipation should be closely monitored during treatment. The continued need for sevelamer therapy should be reassessed in patients who develop severe constipation or symptoms of other serious gastrointestinal disorders.

Fat-soluble vitamins.

Patients with chronic kidney disease (CKD) may have low levels of vitamins A, D, E, and K, depending on dietary intake and disease severity. Sevelamer may bind fat-soluble vitamins present in ingested food. Therefore, in patients not receiving additional supplementation of these vitamins, levels of vitamins A, D, and E should be monitored, and vitamin K status should be assessed by measuring prothrombin time. Supplementation should be considered as needed according to clinical guidelines.

Additional monitoring of fat-soluble vitamin and folic acid levels is recommended in patients undergoing peritoneal dialysis, as levels of vitamins A, D, E, and K were not measured in such patients during clinical trials.

Folate deficiency.

Currently, there is insufficient data regarding the potential for folate deficiency during long-term sevelamer therapy.

Hypocalcemia/hypercalcemia.

Patients with CKD may develop hypocalcemia or hypercalcemia. Sevelamer does not contain calcium. Serum calcium levels should be monitored regularly, and elemental calcium should be supplemented if hypocalcemia develops.

Metabolic acidosis.

Patients with chronic kidney disease are prone to metabolic acidosis. In several studies, worsening acidosis and lower serum bicarbonate levels were observed in patients switching from other phosphate binders to sevelamer, compared to those receiving calcium-based phosphate binders. Therefore, careful monitoring of serum bicarbonate levels is recommended.

Peritonitis.

Patients undergoing dialysis are at risk of infections specific to the type of dialysis. Peritonitis is a known complication in patients undergoing peritoneal dialysis (PD). Several cases of peritonitis were reported in clinical trials using sevelamer hydrochloride. Therefore, careful monitoring of patients on PD is necessary to ensure proper use of aseptic techniques and prompt recognition and treatment of any signs or symptoms associated with peritonitis.

Dysphagia and choking.

Rare cases of difficulty swallowing sevelamer tablets have been reported. Most of these cases occurred in patients with concomitant conditions such as swallowing disorders or esophageal pathology. Sevelamer should be used with caution in patients with dysphagia.

Hypothyroidism.

Careful monitoring is recommended in patients with hypothyroidism who are concurrently taking sevelamer hydrochloride and levothyroxine.

Long-term use.

As data on sevelamer use beyond one year are not yet available, potential absorption and accumulation of sevelamer during prolonged treatment cannot be completely ruled out.

Hyperparathyroidism.

Sevelamer is not indicated for the control of hyperparathyroidism. In patients with secondary hyperparathyroidism, sevelamer should be used as part of a comprehensive treatment regimen that may include calcium supplements, 1,25-dihydroxyvitamin D3, or its analogs to reduce intact PTH (iPTH) levels.

Serum chloride.

Serum chloride levels may increase during treatment with sevelamer, as chloride may exchange for phosphate in the intestinal lumen. Although clinically significant increases in serum chloride were not observed in clinical trials, this parameter should be monitored as part of routine monitoring in dialysis patients.

Inflammatory gastrointestinal disorders.

Cases of serious inflammatory disorders affecting various parts of the gastrointestinal tract (including serious complications such as bleeding, perforation, ulcers, necrosis, colitis, and fecal impaction in the colon and cecum), associated with the presence of sevelamer crystals, have been described in the scientific literature. However, a causal relationship between sevelamer crystals and the development of such disorders has not been established. The continued need for sevelamer hydrochloride therapy should be re-evaluated in patients who develop serious gastrointestinal symptoms.

Use during pregnancy or breastfeeding.

Pregnancy.

Safety studies in pregnant women have not been conducted. Animal studies have not shown evidence of embryotoxicity or fetotoxicity with sevelamer. Sevelamer may be prescribed to pregnant women only if clearly necessary and after careful assessment of the benefit-risk balance for both mother and fetus.

Breastfeeding.

The safety of sevelamer hydrochloride in breastfeeding women has not been established. Sevelamer should be used in breastfeeding women only if clearly necessary. The decision to continue or discontinue breastfeeding or to continue or discontinue the medication should be made by weighing the benefits of breastfeeding for the child against the benefits of therapy for the mother.

Fertility.

There are no data on the effect of sevelamer on human fertility. Animal studies have shown that sevelamer does not impair fertility in male or female animals at doses equivalent to twice the maximum clinical dose (13 g/day), adjusted for relative body surface area.

Ability to affect reaction speed when driving or operating machinery.

Sevelamer has no effect or a negligible effect on the ability to drive or operate machinery.

Dosage and Administration.

Doses.

Initial dose.

The recommended initial dose of sevelamer hydrochloride is 2.4 g or 4.8 g per day, depending on clinical requirements and serum phosphorus levels. Sevelamer should be taken 3 times a day with meals.

Table 1

For patients who have previously used phosphate-binding agents, sevelamer should be initiated gradually by increasing the dose by 1 g increments, with monitoring of serum phosphorus levels to ensure the optimal daily dose is administered.

Titration and maintenance dose.

Serum phosphorus levels should be carefully monitored, and the dose of sevelamer hydrochloride should be titrated by 0.8 g three times daily (2.4 g/day) with the goal of reducing serum phosphate to 1.76 mmol/L (5.5 mg/dL) or less. Serum phosphate should be monitored every two to three weeks until a stable level is achieved, and then on a regular basis thereafter.

The dosage range may vary from 1 to 5 tablets of 800 mg per meal, and the daily dose is expected to average approximately 7 g of sevelamer.

Renal impairment

The safety and efficacy of sevelamer hydrochloride have not been established in non-dialysis chronic kidney disease (CKD) patients.

Method of administration

Sevelamer tablets are intended for oral use.

Patients should take sevelamer with meals and adhere to their prescribed diet. Tablets should be swallowed whole, without crushing or chewing.

Children

The safety and efficacy of sevelamer in patients under 18 years of age have not been studied.

Overdose.

Sevelamer has been administered to healthy volunteers at doses up to 14 g (equivalent to 17 tablets of 800 mg) per day for eight days without adverse effects.

Adverse reactions

All adverse reactions most frequently observed (≥ 5% of patients) were classified as gastrointestinal disorders.

The safety of sevelamer was studied in clinical trials involving 244 hemodialysis patients treated for up to 54 weeks and 97 peritoneal dialysis patients treated for 12 weeks.

Adverse reactions that occurred during clinical trials or were voluntarily reported by patients during post-marketing use of the medicinal product are listed in the table below, categorized by frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Table 2

* Post-marketing experience with sevelamer hydrochloride.

1 See gastrointestinal disorders warning in section "Special precautions for use".

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging. 10 tablets per blister, 18 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of operations.

139 Saksaganskoho Street, Kyiv, 01032, Ukraine.