Date of approval.
Date of revision.
Sevelamer Carbonate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Sevelamer Carbonate Tablets
English name: Sevelamer Carbonate Tablets
Chinese Pinyin: Tansuan Siweilamu Pian [Ingredients
The main ingredient of this product: Sevelamer Carbonate
Chemical Name: Poly(acrylamide-co-N,N’-diallyl-1,3-diamino-2-hydroxypropane) carbonate
Chemical structure formula.
a, b = number of primary amine groups (a + b = 9) c = number of cross-linking groups (c = 1) m = very large number to indicate an extended polymeric network structure
Molecular formula.
Sevelamer carbonate is a highly cross-linked polymer with a molecular formula expressed as follows.
(C3H7N – nH2CO3)810z (C9H18N2O – nH2CO3)95z (where z is a very large number)
Molecular weight.
Sevelamer carbonate is a highly cross-linked polymer of varying sizes, where each particle can be considered as a molecule. Therefore, the molecular weight is equal to the weight of the particle itself. Since the particle density is independent of the particle size, the particle weight is proportional to the particle size. Therefore, the molecular weight distribution of the cross-linked polymer is a function of the particle size distribution.
Properties
This product is white or off-white film-coated tablets, after removing the coating appears white or off-white.
Indications
This product is used to control hyperphosphatemia in adult patients with chronic kidney disease (CKD) who are on dialysis treatment.
Specification
0.8 g
Dosage and Administration
Dose
Starting dose.
The recommended starting dose of this product is 0.8 g or 1.6 g per dose, taken three times daily with meals. The specific dose is determined according to clinical needs and the patient’s serum phosphorus level (Table 1).
Table 1: Starting dose in dialysis patients
Serum phosphorus level 0.8 g tablet> 1.78 mmol/l and< 2.42 mmol/l (> 5.5 and< 7.5 mg/dL) 1 tablet three times daily with meals> 2.42 mmol/l (³ 7.5 mg/dL) 2 tablets three times daily with meals Dose adjustment.
Serum phosphorus levels must be monitored and the need for dose adjustment is determined based on serum phosphorus level attainment. Dose adjustments should be made at 2-4 week intervals, with each dose adjustment being 0.8 g (one additional tablet per meal) until an acceptable serum phosphorus level is achieved. Thereafter, regular monitoring is performed.
Dosing method
Tablets should be swallowed whole and should not be crushed, chewed or broken into pieces prior to administration.
[Adverse Reactions].
Clinical trial experience
There are few data on the safety of this product. However, considering that the active ingredient of this product is the same as that of Sevelamer hydrochloride, the adverse effect profile of both drugs should be similar. Also, in a crossover study involving hemodialysis patients, where treatment lasted 8 weeks and there was no washout period between the two groups, adverse reactions occurred in the sevelamer carbonate tablet group similar to those in the sevelamer hydrochloride group.
The safety of sevelamer (carbonic acid or hydrochloride) was studied in several clinical trials including 969 hemodialysis patients treated for 4 to 50 weeks (724 patients treated with sevelamer hydrochloride and 245 patients treated with sevelamer carbonate) and 97 peritoneal dialysis patients treated for 12 weeks (all treated with sevelamer hydrochloride).
The most frequent (≥ 5% of patients) adverse reactions that were potentially or likely to be associated with sevelamer were gastrointestinal disorders (by systemic organ). The majority of these adverse reactions were mild to moderate in severity. Data on adverse reactions in these trials that were likely or probably associated with sevelamer are listed below by frequency of occurrence. The reported incidence was categorized as very common (≥ 1/10), common (≥ 1/100, <1/10), occasional (≥ 1/1000, <1/100), rare (≥ 1/10,000, <1/1000), very rare (<1/10,000), and unknown (could not be assessed based on available data).
Gastrointestinal Disorders Very Common: Nausea, vomiting, epigastric pain, constipation Common: Diarrhea, dyspepsia, bloating, abdominal pain Postmarketing Experience: The following adverse reactions have been reported in patients treated with Sevelam after marketing approval: hypersensitivity, pruritus, rash, hypokinesia, intestinal obstruction/incomplete intestinal obstruction, and intestinal perforation.
Contraindications
1. Contraindicated in patients with hypersensitivity to any of the components of this product.
2. Contraindicated in patients with hypophosphatemia.
3.Forbidden in patients with intestinal obstruction.
Precautions】
The safety and efficacy of this product has not been established in patients with
Dysphagia
Swallowing disorder
Severe gastrointestinal dysfunction, including untreated or severe gastroparesis, retention of gastric contents, or abnormal or irregular bowel movements
Active inflammatory bowel disease
Major gastrointestinal surgery
Therefore, this product should be used with caution in the above patients.
Intestinal obstruction and intestinal blockage/incomplete bowel obstruction
Intestinal obstruction and intestinal occlusion/incomplete bowel occlusion have been observed in rare cases during treatment with sevelamer hydrochloride. Sevelamer hydrochloride has the same active ingredients as Sevelamer carbonate. The initial symptom may be constipation. Patients with constipation should be closely monitored while using this product for treatment. Treatment with this product should be re-evaluated in patients experiencing severe constipation or other gastrointestinal symptoms.
Fat-soluble vitamins
Vitamin A, D, E and K levels may be low in patients with chronic kidney disease (CKD) depending on dietary intake and the severity of the disease the patient has. It cannot be excluded that this product may be combined with the intake of fat-soluble vitamins contained in food. Serum levels of vitamins A, D, E, and K should be monitored regularly in patients who do not consume supplemental vitamins but take this product. Vitamin supplements are recommended when necessary. In patients on peritoneal dialysis, monitoring of fat-soluble vitamins and folic acid is recommended because vitamin A, D, E, and K levels were not measured in peritoneal dialysis patients in a clinical trial.
Folic acid deficiency
There are insufficient data to exclude the possibility of folic acid deficiency during long-term treatment with this product.
Hypocalcemia/hypercalcemia
Hypocalcemia or hypercalcemia may occur in patients with chronic kidney disease (CKD). This product does not contain any calcium component. Therefore, serum calcium levels should be monitored regularly and supplemented with calcium if necessary.
Metabolic acidosis
Patients with chronic kidney disease are at risk of developing metabolic acidosis. Serum bicarbonate and chloride levels should therefore be monitored.
Peritonitis
Patients on dialysis are at risk of developing dialysis-related infections. Peritonitis is a known complication in patients undergoing peritoneal dialysis, and in a clinical trial with sevelamer hydrochloride, a substantially higher number of cases of peritonitis were reported in the sevelamer group compared to the control group. Patients undergoing peritoneal dialysis should be closely monitored to ensure proper application of aseptic technique, and any signs and symptoms associated with peritonitis should be rapidly identified and managed.
Dysphagia and asphyxia
There have been rare reports of dysphagia or esophageal pill retention on sevelamer carbonate tablets, with individual patients requiring hospitalization or intervention. Most of these patients have been associated with dysphagia or esophageal abnormalities. Caution should be exercised when administering sevelamer carbonate to patients with dysphagia.
Antiarrhythmic and antiepileptic drugs
Particular caution should be exercised when prescribing this product to patients taking concomitant antiarrhythmic and antiepileptic drugs (see [Drug Interactions]).
Hypothyroidism
In hypothyroid patients taking concomitant sevelamer carbonate and levothyroxine, thyroid-stimulating hormone (TSH) levels and signs of hypothyroidism should be monitored closely. (See [Drug Interactions]).
Long-term chronic treatment
In a one-year clinical trial, no evidence of accumulation of this product was found. However, the possibility of absorption and accumulation during long-term chronic treatment (> 1 year) cannot be completely excluded (see [Pharmacokinetics]).
Hyperparathyroidism
This product is not indicated for the control of hyperparathyroidism. In patients with secondary hyperparathyroidism, this product should be used in the context of multiple therapeutic routes of application, including calcium supplementation, 1,25-dihydroxyvitamin D3, or one of its analogs, to reduce whole segment parathyroid hormone (iPTH) levels.
Inflammatory Gastrointestinal Disorders
Cases of severe inflammatory diseases of the gastrointestinal tract (including severe complications such as bleeding, perforation, ulceration, necrosis, and colitis) associated with sevelamer crystals have been reported. However, a causal relationship between sevelamer crystals causing such diseases has not been established. Sevelamer carbonate should be re-evaluated in patients presenting with severe gastrointestinal symptoms.
[For Pregnant and Lactating Women].
Pregnancy:
No data are available on the use of sevelamer in women who are pregnant. Animal studies have shown some reproductive toxicity in rats given high doses of sevelamer (see [Pharmacologic Toxicology]). Studies have also shown that sevelamer can reduce the absorption of several vitamins, including folic acid (see [Pharmacologic Toxicology]), but the potential risk to humans is unknown and should be used with caution. If indeed needed, it should be considered for use during pregnancy only if the benefits to the mother and fetus clearly outweigh the potential risks to the fetus.
Nursing Women.
It is not known whether sevelamer can be secreted in human breast milk. Based on the non-absorption characteristics of sevelamer, it is presumed that it is unlikely to be secreted in breast milk. However, the decision to continue/stop breastfeeding or to continue/stop treatment with this product should still be made after fully weighing the benefits of breastfeeding for the infant and the benefits and potential risks of this product for the mother.
Fertility.
No data are available on the effect of sevelamer on fertility. Animal studies have shown that sevelamer failed to impair fertility in male and female rats when applied at 2 times the human equivalent dose (maximum clinical trial dose of 13 g/day) based on relative body surface area comparisons.
Pediatric Dosage]
The safety and efficacy of this product have not been established in children younger than 18 years of age; therefore, this product is not recommended for use in children younger than 18 years of age.
Geriatric use]
A sufficient number of subjects aged ≥65 years were not enrolled in clinical trials of this product, so it has not been determined whether their response differs from that of younger subjects. Other reports of clinical experience have not found differences in response to the drug between older and younger patients. In conclusion, doses for elderly patients should be carefully selected, usually starting with the lowest dose.
[Drug Interactions].
In human drug interaction studies, drug-drug interactions of sevelamer carbonate with warfarin and digoxin were investigated. The interaction of sevelamer hydrochloride (containing the same active ingredient as sevelamer carbonate) with ciprofloxacin, digoxin, warfarin, enalapril, metoprolol, and iron was studied.
– Ciprofloxacin
In a trial with 15 healthy subjects, concomitant administration of a single dose of 2.8 g of sevelamer hydrochloride reduced the bioavailability of ciprofloxacin by approximately 50%. Therefore, this product should not be taken concomitantly with ciprofloxacin.
– Digoxin
Nineteen healthy subjects received 2.4 g of sevelamer hydrochloride three times daily with meals for 2 days. Sevelamer did not alter the pharmacokinetics of a single dose of digoxin.
Eighteen healthy subjects received 9.6 g of sevelamer carbonate once daily with meals; sevelamer did not alter the pharmacokinetics of a single dose of digoxin.
– Warfarin
Fourteen healthy subjects received 2.4 g of sevelamer hydrochloride three times daily with meals for 2 days; sevelamer did not alter the pharmacokinetics of a single dose of warfarin.
Fourteen healthy subjects received 9.6 g of sevelamer carbonate once daily with meals. Sevelamer did not alter the pharmacokinetics of a single dose of warfarin.
– Enalapril
Twenty-eight healthy subjects received 2.4 g of a single dose of sevelamer hydrochloride. Sevelamer hydrochloride did not alter the pharmacokinetics of a single dose of enalapril.
– Metoprolol
Thirty-one healthy subjects received a single dose of 2.4 g of sevelamer hydrochloride, and sevelamer hydrochloride did not alter the pharmacokinetics of a single dose of metoprolol.
– Iron
23 healthy subjects received 2.8 g of a single dose of sevelamer hydrochloride. Sevelamer hydrochloride did not alter the absorption of ferrous ions in a single dose of 200 mg dry ferrous sulfate tablets.
– Proton pump inhibitors
In post-marketing experience, very rare events of elevated phosphate levels have been reported in patients receiving proton pump inhibitors administered in combination with sevelamer carbonate.
– Other Combination Therapy
No empirical data are available on the avoidance of interactions between sevelamer carbonate and most coadministered drugs. Elevated thyroid stimulating hormone (TSH) markers have been reported in patients receiving both sevelamer hydrochloride and levothyroxine after the introduction of sevelamer carbonate, but are extremely rare. Serum levels of TSH and signs of hypothyroidism need to be monitored in patients receiving both drugs.
There is no information on dosing regimens applicable to all drugs when reduced bioavailability of an oral drug would have a significant clinical impact on its safety and efficacy. However, the drug should be administered at least one hour before or three hours after administration of sevelamer carbonate, and the blood levels of the drug should be monitored.
Patients taking antiarrhythmic drugs to control cardiac arrhythmias and antiepileptic drugs to control seizure disorders were excluded from the study in clinical trials. Therefore, special caution should be exercised when giving sevelamer carbonate to patients taking such drugs concomitantly.
In organ transplant patients, reduced blood levels of cyclosporine, mescaline mofetil and tacrolimus were observed when administered concomitantly with this product, but no associated clinical consequences (i.e., graft rejection) were observed. However, the possibility of drug interactions cannot be ruled out, so regular monitoring of blood concentrations of cyclosporine, mescaline mofetil and tacrolimus should be considered when these drugs are used together and after discontinuation of this product.
[Drug overdose].
Overdose of sevelamer carbonate or sevelamer hydrochloride has not been reported in patients.
No adverse reactions have been reported in healthy volunteers taking sevelamer hydrochloride (same active ingredient as sevelamer carbonate) at a maximum dose of 14 g/day for 8 days. In patients with chronic kidney disease (CKD) on dialysis, the maximum study dose of sevelamer carbonate was 14 g and sevelamer hydrochloride was 13 g. Because sevelamer is not absorbed, the risk of systemic toxicity is low.
[Clinical Trial].
Sevelamer controls serum phosphorus levels in dialysis patients with chronic kidney disease (CKD) as determined primarily by the binding of carbonate to phosphate. Six clinical trials have used sevelamer hydrochloride and two clinical trials have used sevelamer carbonate. The sevelamer hydrochloride trials included one double-blind, placebo-controlled, two-week trial (sevelamer group N=24); two open, uncontrolled, 8-week trials (sevelamer group N=220) and three positive drug-controlled, open trials with treatment periods of 8 to 52 weeks (sevelamer group N=256). The sevelamer carbonate study included a double-blind, positive drug-controlled, crossover trial with two 8-week treatment periods using sevelamer carbonate tablets (N=79) in patients receiving hemodialysis and an 8-week, double-blind, placebo-controlled trial in Chinese hemodialysis patients. Four positive drug-controlled trials (one sevelamer carbonate trial and three sevelamer hydrochloride trials) and one placebo-controlled trial of sevelamer carbonate are described below.
Crossover trial of sevelamer carbonate 0.8 g tablets and sevelamer hydrochloride 0.8 g tablets
Seventy-nine patients with chronic kidney disease (CKD) stage 5 receiving hemodialysis were randomized to receive sevelamer carbonate 0.8 g tablets and sevelamer hydrochloride 0.8 g tablets for 8 weeks each after first entering a 5-week pretreatment with sevelamer hydrochloride, with no drug washout period between the two drug treatments. The trial dose for the crossover period was determined according to the dose of sevelamer hydrochloride during the pretreatment period according to the gram-for-gram principle. At the end of the two crossover periods, blood phosphorus levels were similar. In both treatment groups, the actual average daily dose was 6 g/day with meals. 39 patients who completed the study crossover period were enrolled in a 2-week washout period during which patients were not allowed to take any phosphorus binding agents; this trial confirmed the activity of sevelamer.
Parallel Trial of Sevelamer Carbonate versus Placebo in Chinese Hemodialysis Patients
In a double-blind, placebo-controlled trial, 205 Chinese hemodialysis patients who developed hyperphosphatemia (serum phosphorus level > 1.78 mmol/L [5.5 mg/dL]) after a 2-week phosphorus-binding agent elution period were randomized to receive 8 weeks of sevelamer carbonate (N=135) or placebo (N=70). Sevelamer carbonate significantly reduced serum phosphorus levels compared with placebo (0.69 mmol/L [2.12 mg/dL] versus 0.06 mmol/L [0.20 mg/dL] for sevelamer carbonate versus placebo, respectively, p<0.0001). The mean prescribed daily dose of sevelamer carbonate was 4.5 g/day (range 2.4 ~9.6 g/day).
Crossover trial of sevelamer hydrochloride with positive drug control in hemodialysis patients
Eighty-four patients with chronic kidney disease (CKD) on hemodialysis developed hyperphosphatemia after first receiving a two-week phosphorus-binding agent clearance (serum phosphorus> 1.94
mmol/L [6.0 mg/dL]) when randomized to a crossover trial to receive sevelamer hydrochloride and a positive control drug for 8 weeks each. Treatment periods were separated by a two-week washout period with phosphorus-binding agents. Patients started treatment with three daily doses with meals. At three different time points during each 8-week treatment period, the dose of sevelamer hydrochloride may be gradually increased to control serum phosphorus, and the dose of the positive control drug may be changed to control serum phosphorus levels. Both treatments resulted in a significant reduction in mean serum phosphorus values of approximately 0.65 mmol/L (2 mg/dL) (Table 2).
Table 2. Mean serum phosphorus values (mmol/L [ mg/dL]) at baseline and endpoint
Sevelamer hydrochloride (N = 81) Calcium acetate (N = 83) Baseline at the end of the elution period 2.71 (8.4) 2.58 (8.0) Endpoint 2.07 (6.4) 1.91 (5.9) Change from baseline to endpoint (95% confidence interval) -0.65 (-2.0)* (-0.81 [-2.5], -0.48 [-1.5]) -0.68 (- 2.1)* (-0.84 [-2.6], -0.55 [-1.7])* p < 0.0001, compared to the treatment group
The distribution of responses can be seen in Figure 1. sevelamer hydrochloride was similar to the distribution of positive controls. In both treatment groups, the median response was a decrease in serum phosphorus levels of approximately 0.65 mmol/L [2 mg/dL]. Blood phosphorus levels decreased by 0.32 mmol/L [1 mg/dL] to 0.97 mmol/L [3 mg/dL] in approximately 50% of subjects.
Figure 1 Percentage of patients with a decrease in serum phosphorus no less than the X-axis value (Y-axis) compared to baseline (mg/dL)*
*Translating mg/dL to mmol/L multiplies by 0.3229
At the end of treatment, the mean daily dose of sevelamer hydrochloride was 4.9 g (range 0.0 to 12.6 g).
– Sevelamer hydrochloride versus calcium-based phosphate binding agents in hemodialysis patients
Two hundred patients with chronic kidney disease (CKD) on hemodialysis who developed hyperphosphatemia (serum phosphorus >1.78 mmol/L [5.5 mg/dL]) after a two-week period of phosphorus-binding agent elution were randomized to receive either sevelamer hydrochloride 0.8 g tablets (N = 99) or calcium-based phosphorus-binding agent (N = 101). The results of the last observation carryover at week 52 showed that both sevelamer and calcium significantly reduced mean serum phosphorus values (Table 3).
Table 3. Mean values of baseline serum phosphorus (mmol/L [mg/dL]) and calcium-phosphorus product to treatment endpoints
Sevelamer hydrochloride
(N = 94) Control calcium
(N = 98) Baseline mean serum phosphorus values
Change in mean serum phosphorus from baseline to treatment endpoint 2.42 (7.5) -0.68 (-2.1) 2.34 (7.3) -0.58 (-1.8) Mean baseline calcium-phosphorus product
Change in mean calcium-phosphorus product from baseline to treatment endpoint 5.69 (70.5) -1.57 (-19.4) 5.52 (68.4) -1.15 (-14.2) 61% of sevelamer hydrochloride patients and 73% of control patients completed all 52 weeks of treatment.
Figure 2 shows the curve of the change in serum phosphorus relative to the baseline period for those who completed the trial, showing the durability of response in patients who could receive continuous treatment.
Figure 2. Mean change in serum phosphorus compared to baseline for patients who completed 52 weeks of treatment*
*Translating mg/dL to mmol/L multiplies by 0.3229
At the end of treatment, the mean daily dose of sevelamer hydrochloride was 6.5 g (range 0.8 to 13 g).
– In peritoneal dialysis patients, sevelamer hydrochloride versus positive controls
The 143 patients on peritoneal dialysis who developed hyperphosphatemia (serum phosphorus >1.78 mmol/L [5.5 mg/dL]) after two weeks of phosphorus-binding agent-eluting clearance were randomized to receive 12 weeks of open sevelamer hydrochloride (N=97) or calcium acetate (N=46). The mean daily dose of sevelamer hydrochloride at the end of treatment was 5.9 g (range, 0.8 to 14.3 g). Thirteen patients (14%) in the sevelamer group and nine patients (20%) in the positive control group withdrew from the trial, mainly due to gastrointestinal adverse effects. The change in serum phosphorus (0.52 mmol/L [1.6 mg/dL] from 2.42 mmol/L [7.5 mg/dL] at baseline) in the sevelamer hydrochloride group was statistically significant (p<0.001) and similar to the positive control group.
[Pharmacology and Toxicology].
Pharmacological effects
Sevelamer carbonate is a non-absorbable phosphate bound cross-linked polymer, containing no calcium or other metals; it contains multiple amine roots, each attached to the polymeric backbone by a carbon atom. The amine roots are present in the intestinal tract in protonated form and interact with phosphate molecules through ionic and hydrogen bonds. Sevelamer carbonate reduces serum phosphate concentrations by binding phosphate in the GI tract and reducing its absorption.
In addition to its effect on serum phosphate levels, sevelamer hydrochloride binds bile acids. Binding of bile acids with ion exchange resins is a proven method for lowering blood cholesterol. As sevelamer binds bile acids, it may interfere with normal fat absorption and thus reduce the absorption of fat-soluble vitamins such as A, D and K.
Toxicological studies
Genotoxicity.
In vitro mammalian chromosome aberration test results were positive for sevelamer hydrochloride under metabolically activated conditions. The Ames test for Sevelamer hydrochloride was negative.
Reproductive toxicity.
No significant effects of sevelamer hydrochloride on fertility were observed in female rats administered orally from 14 days prior to mating to gestation and in male rats administered orally 28 days prior to mating at a maximum tolerated dose of 4.5 g/kg/day (human equivalent dose equivalent to 3 times the maximum clinically tested dose of 13 g).
In the rat embryo-fetal development toxicity test, reduced or irregular ossification of fetuses was seen at doses of 1.5g/kg/day and 4.5g/kg/day of sevelamer hydrochloride (human equivalent doses were equivalent to or 3-4 times the maximum clinical test dose of 13g, respectively), probably due to reduced absorption of fat-soluble vitamin D. In an embryo-fetal developmental toxicity test in pregnant rabbits, an increase in early embryonic absorption was observed at doses of Sevelamer hydrochloride up to 1000 mg/kg/day (human equivalent dose equivalent to 2 times the maximum clinical trial dose).
Carcinogenicity.
Adulteration of sevelamer hydrochloride in rats up to 3 g/kg/day (human equivalent equivalent 2 times the maximum clinical trial dose of 13 g) resulted in an increased incidence of migratory cell papilloma of the bladder in male rats. No significant increase in tumor incidence was observed in mice given Sevelamer hydrochloride at 9 g/kg/day (human equivalent dose equivalent to 3 times the maximum clinical trial dose) by adulteration.
Pharmacokinetics]
The pharmacokinetics of sevelamer carbonate has not been tested. Sevelamer hydrochloride contains the same active ingredient as sevelamer carbonate. A pharmacokinetic trial was conducted using 14C sevelamer hydrochloride in 16 healthy male and female subjects, which showed no systemic absorption of sevelamer hydrochloride. Absorption tests have not been conducted on patients with renal disease.
Storage】 Seal and store in a dry place below 30℃.
Package】 Oral solid medicine in HDPE bottle, 30 tablets/bottle/box.
Expiration date】 36 months
Execution Standard
Approval number】
[Drug marketing license holder
Name: Nanjing Hengsheng Pharmaceutical Co.
Registered address: No. 18, Airport Road, Lishui Economic Development Zone, Nanjing
Zip code: 211200
Telephone number: 025-57212809
Fax number: 025-57226938
Website: www.hencer.com
Manufacturer
Company name: Nanjing Hengsheng Pharmaceutical Co.
Address: No. 18, Airport Road, Lishui Economic Development Zone, Nanjing
Postal code: 211200
Telephone number: 025-57212809
Fax number: 025-57226938
Web address: www.hencer.com