Sevelamer sache - vista

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SEVELAMER SACHET-VISTA (SEVELAMER SACHET-VISTA)

Composition:

Active substance: sevelamer carbonate;

1 sachet contains 2.4 g of sevelamer carbonate;

Excipients: microcrystalline cellulose, sodium carmellose, sucralose, lemon flavor, orange flavor, iron oxide yellow (E 172).

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: powder from almost white to yellow color.

Pharmacotherapeutic group. Medicinal products for the treatment of hyperkalemia and hyperphosphatemia. ATC code V03A E02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The medicinal product contains sevelamer – a non-absorbed, metal- and calcium-free phosphate-binding polymer. Sevelamer contains numerous amines separated by one carbon atom from the polymer's main chain, which bind protons in the stomach. These protonated amines bind negatively charged ions, such as dietary phosphate, in the intestine.

Pharmacodynamic effects

By binding phosphate in the gastrointestinal tract and reducing its absorption, sevelamer lowers serum phosphate concentration. Regular monitoring of serum phosphorus levels is required during treatment with phosphate binders.

Clinical efficacy and safety

In two randomized, crossover clinical studies, sevelamer carbonate (in both tablet and powder forms) was shown to be therapeutically equivalent to sevelamer hydrochloride and thus effective in controlling serum phosphorus levels in patients with chronic kidney disease (CKD) undergoing hemodialysis. These studies also demonstrated that sevelamer carbonate in tablet and powder forms is therapeutically equivalent to sevelamer hydrochloride.

Results from the first study showed that sevelamer carbonate in tablets administered three times daily was equivalent to sevelamer hydrochloride in tablets administered three times daily in 79 hemodialysis patients who received randomized treatment for 8 weeks (mean time-averaged serum phosphorus levels were 1.5 ± 0.3 mmol/L for both sevelamer carbonate and sevelamer hydrochloride). Results from the second study demonstrated that sevelamer carbonate in powder form administered three times daily was equivalent to sevelamer hydrochloride in tablets administered three times daily in 31 hemodialysis patients with hyperphosphatemia (defined as serum phosphorus level ≥ 1.78 mmol/L) who received randomized treatment for 4 weeks (mean time-averaged serum phosphorus levels were 1.6 ± 0.5 mmol/L for sevelamer carbonate powder and 1.7 ± 0.4 mmol/L for sevelamer hydrochloride tablets).

In clinical studies involving hemodialysis patients, sevelamer alone did not consistently or clinically significantly affect intact parathyroid hormone (iPTH). However, in a 12-week study involving patients on peritoneal dialysis, a reduction in iPTH levels was observed, similar to that seen in 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.

Sevelamer has been shown to bind 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 levels. In clinical studies with sevelamer, mean levels of both total cholesterol and low-density lipoprotein cholesterol (LDL-C) decreased by 15–39%. Cholesterol reduction was observed within 2 weeks of treatment and was maintained during long-term therapy. Levels of triglycerides, high-density lipoprotein cholesterol (HDL-C), and albumin were unchanged after sevelamer treatment.

Because sevelamer binds bile acids, it may interfere with the absorption of fat-soluble vitamins such as A, D, E, and K.

Sevelamer is calcium-free and reduces the incidence of hypercalcemia compared to calcium-based phosphate binders. The effects of sevelamer on phosphorus and calcium have been shown to be sustained throughout the study period, including one year of follow-up. This information was obtained from studies using sevelamer hydrochloride. Pediatric population.

The safety and efficacy of sevelamer carbonate in pediatric patients with hyperphosphatemia due to CKD were evaluated in a multicenter study with a 2-week randomized, placebo-controlled, fixed-dose period, followed by a 6-month open-label dose-titration period (ODT) with a single group. A total of 101 patients (aged 6 to 18 years, with body surface area ranging from 0.8 to 2.4 m²) were randomized in the study: 49 patients received sevelamer carbonate and 51 received placebo for 2 weeks. After this period, all patients received sevelamer carbonate during a 26-week dose-finding period. In the study, sevelamer carbonate reduced serum phosphorus levels with a mean difference of 0.90 mg/dL compared to placebo and secondary efficacy endpoints. In pediatric patients with hyperphosphatemia secondary to CKD, sevelamer carbonate significantly reduced serum phosphorus levels compared to placebo during the 2-week fixed-dose period. The treatment response was maintained in pediatric patients receiving sevelamer carbonate throughout the 6-month open-label dose-titration period. 27% of pediatric patients achieved a target serum phosphorus level at the end of treatment. These rates were 23% and 15% in subgroups of patients undergoing hemodialysis and peritoneal dialysis, respectively. Body surface area did not influence the treatment response during the 2-week fixed-dose period; however, no treatment response was observed in children with baseline phosphorus levels < 7.0 mg/dL. Most adverse reactions reported as related or possibly related to sevelamer carbonate occurred in the gastrointestinal tract. No new risks or safety signals were identified during the use of sevelamer carbonate in the study.

Pharmacokinetics.

Pharmacokinetic studies of sevelamer carbonate have not been conducted. Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, is not absorbed from the gastrointestinal tract, as confirmed in an absorption study involving healthy volunteers.

In clinical studies lasting up to 1 year, there was no evidence of sevelamer accumulation. However, possible absorption and accumulation of sevelamer during long-term chronic treatment (> 1 year) cannot be completely ruled out.

Clinical characteristics.

Indications.

Indicated for the control of hyperphosphatemia:

• in adult patients undergoing hemodialysis or peritoneal dialysis;
• in adult patients with chronic kidney disease (CKD) not on dialysis, with serum phosphorus levels > 1.78 mmol/L;
• in pediatric patients (> 6 years of age and body surface area (BSA) > 0.75 m²) with chronic kidney disease.

The medicinal product should be used as part of a comprehensive therapeutic approach, which may include calcium supplements, 1,25-dihydroxyvitamin D3, or one of its analogs, to control the progression 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.

Interaction studies of the drug 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 ciprofloxacin was co-administered with sevelamer hydrochloride. Therefore, the medicinal product should not be taken simultaneously with ciprofloxacin.

Cyclosporine, mycophenolate mofetil, and tacrolimus in transplant patients.

In patients who have undergone organ transplantation, decreased levels of cyclosporine, mycophenolate mofetil, and tacrolimus have been reported when administered concomitantly with sevelamer hydrochloride, although without any clinical consequences (e.g., no graft rejection). Interaction cannot be ruled out; therefore, careful monitoring of blood concentrations of mycophenolate mofetil, cyclosporine, and tacrolimus is necessary during and after concomitant use of these agents.

Levothyroxine.

Very rare cases of hypothyroidism have been reported in patients concurrently taking sevelamer hydrochloride—which contains the same active component as sevelamer carbonate—and levothyroxine. Therefore, careful monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients taking sevelamer carbonate and levothyroxine.

Antiarrhythmic and anticonvulsant medicinal products.

Patients taking antiarrhythmic drugs to control arrhythmias and anticonvulsant drugs to prevent seizures were not included in clinical trials. Therefore, reduced absorption cannot be excluded. Antiarrhythmic drugs should be administered at least one hour before or three hours after sevelamer carbonate, and monitoring of blood levels should be considered.

Proton pump inhibitors.

During post-marketing use, very rare cases of increased phosphate levels have been reported in patients taking proton pump inhibitors concomitantly with sevelamer carbonate. Proton pump inhibitors should be prescribed with caution to patients who are concurrently using sevelamer. Serum phosphate levels should be monitored and the dose of sevelamer adjusted accordingly.

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 a clinically significant impact on safety and efficacy, that product should be taken at least one hour before or three hours after sevelamer. Otherwise, the physician should consider the need for monitoring blood levels of such drugs.

Digoxin, warfarin, enalapril, and metoprolol.

In drug interaction studies involving healthy volunteers, sevelamer hydrochloride—which contains the same active component as sevelamer carbonate—did not affect the bioavailability of digoxin, warfarin, enalapril, and metoprolol.

Special precautions for use.

The efficacy and safety of sevelamer have not been established in adult patients with chronic kidney disease not on dialysis who have serum phosphorus levels < 1.78 mmol/L. Therefore, the drug is not currently recommended for use in such patients.

The efficacy and safety of sevelamer have not been studied in patients with the following conditions:

• Dysphagia (difficulty swallowing);
• Swallowing disorders;
• Severe gastrointestinal motility disorders, including untreated or severe gastric paresis, gastric content retention, and difficult or irregular defecation;
• Active inflammatory bowel disease;
• History of major gastrointestinal surgery.

Therefore, sevelamer should be initiated in such patients only after careful assessment of the benefit-risk ratio. If treatment is initiated, patients with these conditions should be closely monitored. The continued need for sevelamer should be re-evaluated in patients who develop severe constipation or other serious gastrointestinal symptoms.

Intestinal obstruction and complete or partial bowel obstruction.

Intestinal obstruction and complete or partial bowel obstruction have been reported very rarely in patients treated with sevelamer hydrochloride (capsules/tablets), which contains the same active component as sevelamer carbonate. Constipation may be a precursor symptom. Patients with constipation should be closely monitored during treatment. The appropriateness of sevelamer therapy should be re-evaluated in patients who develop severe constipation or symptoms of other serious gastrointestinal disorders.

Deficiency of fat-soluble vitamins and folic acid.

In patients with CKD, low levels of vitamins A, D, E, and K may occur depending on dietary intake and disease severity. It is possible that sevelamer may bind fat-soluble vitamins present in ingested food. Therefore, in patients not receiving these vitamins as supplements, levels of vitamins A, D, E, and K should be monitored, and supplementation should be provided as needed according to recommendations.

Patients with CKD not on dialysis are recommended to take vitamin D (approximately 400 IU of native vitamin D daily), for example, as part of a multivitamin preparation taken separately from sevelamer. Additional monitoring of fat-soluble vitamin and folic acid levels is recommended in patients on peritoneal dialysis, as levels of vitamins A, D, E, and K were not measured in such patients during clinical trials.

Currently, there are insufficient data to exclude the possibility of folic acid deficiency during long-term treatment with sevelamer carbonate. In patients who are not taking additional folic acid but are receiving sevelamer, folic acid levels should be regularly assessed.

Hypocalcemia/hypercalcemia.

Hypocalcemia or hypercalcemia may develop in patients with CKD. The drug does not contain calcium. Serum calcium levels should be monitored at regular intervals, and elemental calcium should be administered if hypocalcemia develops.

Metabolic acidosis.

Patients with chronic kidney failure are prone to developing metabolic acidosis. Therefore, careful monitoring of serum bicarbonate levels is recommended. Peritonitis.

Patients undergoing dialysis are at risk of infection related to the dialysis modality. Peritonitis is a known complication in patients on peritoneal dialysis (PD). In a clinical trial, a higher incidence of peritonitis was observed in the sevelamer hydrochloride treatment group compared to the control group. 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.

Hypothyroidism.

Careful monitoring is recommended in patients with hypothyroidism who are concomitantly taking sevelamer carbonate and levothyroxine.

Hyperparathyroidism.

Sevelamer is not indicated for the control of hyperparathyroidism. In patients with secondary hyperparathyroidism, the drug should be used as part of a multifaceted therapeutic approach, which may include calcium supplements, 1,25-dihydroxyvitamin D3, or one of its analogs to reduce PTH levels.

Inflammatory gastrointestinal disorders.

Published reports describe cases of serious inflammatory conditions affecting various parts of the gastrointestinal tract (including serious complications such as bleeding, perforation, ulcers, necrosis, colitis, and formation of thick/blind bowel), associated with the presence of sevelamer crystals. However, a causal relationship between sevelamer crystals and the development of such disorders has not been demonstrated. Sevelamer carbonate treatment should be re-evaluated in patients who develop serious gastrointestinal symptoms.

Important information about excipients.

This medicine contains less than 1 mmol of sodium (23 mg) per sachet, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy.

There is no information or limited data on the use of sevelamer in pregnant women. Animal studies have shown some reproductive toxicity when sevelamer was administered to animals at high doses. It has also been shown that sevelamer reduces the absorption of certain vitamins, including folic acid. The potential risk to humans is unknown. The drug may be prescribed to pregnant women only if absolutely necessary and after careful evaluation of the benefit-risk ratio for the pregnant woman and the fetus.

Breastfeeding.

It is unknown whether sevelamer or its metabolites are excreted in human milk. The lack of sevelamer absorption suggests that excretion into breast milk is unlikely. The decision to continue or discontinue breastfeeding or to continue or discontinue sevelamer carbonate therapy should be made taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Fertility.

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

Ability to affect reaction speed when driving or operating machinery.

The medicinal product has no effect or has a negligible effect on the ability to drive or operate machinery.

Dosage and administration.

Doses.

Initial dose.

The recommended initial dose of sevelamer carbonate is 2.4 g or 4.8 g per day, depending on clinical requirements and serum phosphorus levels.

The medicinal product should be taken 3 times a day with meals (see Table 1).

Table 1

• With subsequent titration, see section "Titration and Maintenance Dose".

Children/adolescents (> 6 years and body surface area > 0.75 m²)

The recommended initial dose of sevelamer carbonate for children is 2.4 g to 4.8 g per day, depending on the patient's body surface area.

The medicinal product should be taken 3 times daily with meals or snacks (see Table 2).

Table 2

** With further titration, see section "Titration and Maintenance Dose".

For patients previously treated with phosphate binders (sevelamer hydrochloride or calcium-based agents), the medicinal product should be titrated in 1 g increments, and serum phosphorus levels should be monitored to ensure optimal daily doses.

Titration and Maintenance Dose.

Adults.

In adult patients, serum phosphorus levels should be monitored and the dose of sevelamer carbonate titrated in increments of 0.8 g three times daily (2.4 g/day) every 2–4 weeks until acceptable serum phosphorus levels are achieved, followed by regular monitoring thereafter. In clinical practice, treatment will be continuous due to the ongoing need to control serum phosphorus levels, and the daily dose in adults is expected to average approximately 6 g per day.

Children and adolescents (> 6 years of age and body surface area > 0.75 m²).

In children, serum phosphorus levels should be monitored and the dose of sevelamer carbonate titrated by gradual increments according to the patient's body surface area, administered three times daily, every 2–4 weeks until acceptable serum phosphorus levels are achieved, followed by regular monitoring thereafter (see Table 3).

Table 3

Pediatric dosing based on body surface area (m²).

Patients taking sevelamer carbonate should adhere to the prescribed diet.

Special patient groups.

Elderly patients.

Dose adjustment is not required for elderly patients.

Patients with hepatic impairment.

No studies have been conducted in patients with impaired liver function.

Method of administration.

For oral use.

The contents of each sachet – 2.4 g of powder – must be dissolved in 60 ml of water before administration. The suspension should be taken within 30 minutes after preparation. The medicinal product should be taken with food, not on an empty stomach.

As an alternative to water, the powder may be pre-mixed with a small amount of beverage or food (e.g., 100 grams/120 ml) and consumed within 30 minutes. Do not heat the powder (e.g., in a microwave oven) and do not add it to heated foods or liquids.

Children.

The safety and efficacy of sevelamer in children under 6 years of age or in children with body surface area less than 0.75 m² have not been established.

This medicinal product, SEVELAMER SACHE-VISTA, is not intended for use in children as initial therapy.

If lower doses of the medicinal product are required, sevelamer carbonate in another pharmaceutical form should be used.

Overdose.

Symptoms. Sevelamer hydrochloride, which contains the same active component as sevelamer carbonate, was administered to healthy volunteers at doses up to 14 g per day for 8 days; no adverse effects occurred. In patients with CKD, the maximum studied mean daily dose was 14.4 g of sevelamer carbonate as a single daily dose. Symptoms observed in case of overdose are similar to the adverse reactions described in the section "Adverse Reactions" and mainly include constipation and other known gastrointestinal disorders.

Treatment. If necessary, appropriate symptomatic treatment should be carried out.

Adverse reactions.

Summary of safety profile.

All adverse reactions that occurred most frequently (≥ 5% of patients) were classified as gastrointestinal disorders. Most of these adverse reactions were of mild or moderate severity.

List of adverse reactions (see Table 4).

The safety of sevelamer (in the form of carbonate and hydrochloride salts) was evaluated in multiple clinical studies involving 969 dialysis patients on hemodialysis, with treatment duration ranging from 4 to 50 weeks (724 patients received sevelamer hydrochloride and 245 patients received sevelamer carbonate), 97 patients on peritoneal dialysis with 12 weeks of treatment (all received sevelamer hydrochloride), and 128 non-dialysis patients with chronic kidney disease (CKD), with treatment duration from 8 to 12 weeks (79 patients received sevelamer hydrochloride and 49 patients received sevelamer carbonate).

Data on adverse reactions occurring during clinical studies or reported voluntarily during post-marketing use of the drug are presented in Table 4, categorized by frequency of occurrence. The data are classified as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from the available data).

Table 4

* Post-marketing use.

1 See warnings regarding inflammatory gastrointestinal disorders in section "Special precautions".

Children.

The overall safety profile in children and adolescents (aged 6 to 18 years) is similar to that in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

The suspension should be used within 30 minutes after preparation.

Storage conditions.

No special storage conditions required. Keep out of reach of children.

Packaging.

2.4 g of sevelamer carbonate per sachet; 20, 60 or 90 sachets in a cardboard box.

Prescription status. Prescription-only.

Manufacturer.

SINTON ESPAÑA, S.L.

Manufacturer's address and location of its business operations.

C/Castello, nᵒ1, Sant Boi de Llobregat, Barcelona, 08830, Spain