Perfosen

Pharmacology: Mechanism of Action: Patients with chronic kidney disease (CKD) retain phosphorus and can develop hyperphosphatemia. When the product of serum calcium and phosphorus concentrations (Ca x P) exceeds 55 mg²/dL², there is an increased risk that ectopic calcification will occur. Hyperphosphatemia plays a role in the development of secondary hyperparathyroidism in renal insufficiency. Treatment of hyperphosphatemia includes reduction of intestinal phosphate absorption with phosphate binders, and removal of phosphate with dialysis. Sevelamer carbonate taken with meals has been shown to control serum phosphorus concentrations to patients with CKD who are on dialysis.
Pharmacodynamics: In addition to effects on serum phosphorus levels, Sevelamer hydrochloride has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acid binding by ion exchange is a well-established method of lowering blood cholesterol. Because Sevelamer binds bile acids, it may interfere with normal fat absorption and thus may reduce adsorption of fat-soluble vitamins such as A, D and K. in clinical trials of Sevelamer hydrochloride, both the mean total and LDL, cholesterol declined by 15-31%. This effect is observed after 2 weeks. Triglycerides, HDL cholesterol and albumin did not change.
Clinical efficacy and safety: In two randomized, cross over clinical trials, sevelamer carbonate in both tablet and powder formulations when administered three times per day has been shown to be therapeutically equivalent to sevelamer hydrochloride and therefore effective in controlling serum phosphorus in CKD patients on hemodialysis. The first study demonstrated that sevelamer carbonate tablets dosed three times per day was equivalent to sevelamer hydrochloride tablets dosed three times per day in 79 hemodialysis patients treated over two randomized 8-week treatment periods (mean serum phosphorus timeweighted averages were 1.5 ± 0.3 mmol/l for both sevelamer carbonate and sevelamer hydrochloride). The second study demonstrated that sevelamer carbonate powder dosed three times per day was equivalent to sevelamer hydrochloride tablets dosed three times per day in 31 hyper phosphatemic (defined as serum phosphorus levels ≥1.78 mmol/l) hemodialysis patients over two randomized 4-week treatment periods (mean serum phosphorus time-weighted averages were 1.6 ± 0.5 mmol/l for sevelamer carbonate powder and 1.7 ± 0.4 mmol/l for sevelamer hydrochloride tablets). In the clinical trials in hemodialysis patients, sevelamer alone did not have a consistent and clinically significant effect on iPTH. In a 12-week study involving peritoneal dialysis patients however, similar iPTH reductions were seen compared with patients receiving calcium acetate. In patients with secondary hyperparathyroidism sevelamer carbonate should be used within the context of a multiple therapeutic approach, which could include calcium as supplements, 1,25-dihydroxy Vitamin D3 or one of its analogues to lower the iPTH levels. Sevelamer has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acid binding by ion exchange resins is a well-established method of lowering blood cholesterol. In clinical trials of sevelamer, both the mean total-cholesterol and LDL-cholesterol declined by 15-39%. The decrease in cholesterol has been observed after 2 weeks of treatment and is maintained with long-term treatment. Triglycerides, HDL-cholesterol and albumin levels did not change following 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 does not contain calcium and decreases the incidence of hypercalcemic episodes as compared to patients using calcium-based phosphate binders alone. The effects of sevelamer on phosphorus and calcium were proven to be maintained throughout a study with one year follow-up. This information was obtained from studies in which sevelamer hydrochloride was used.
Pharmacokinetics: A mass balance study using 14C-sevelamer hydrochloride, in 16 healthy male and female volunteers showed that Sevelamer hydrochloride is not systemically absorbed. No absorption studies have been performed in patients with renal disease.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Rats were given sevelamer hydrochloride by diet at 0.3, 1, or 3 g/kg/day. There was an increased incidence of urinary bladder transitional cell papilloma in male rats of the high dose group (human equivalent dose twice the maximum clinical trial dose of 13 g). Mice received dietary administration of Sevelamer hydrochloride at doses of up to 9 g/kg/day (human equivalent dose 3 times the maximum clinical trial dose). There was no increased incidence of tumors observed in mice.
In an in vitro mammalian cytogenetic caused a statistically significant increase in the number of structural chromosome aberrations. Sevelamer hydrochloride was not mutagenic in the Ames bacterial mutation assay.
Sevelamer hydrochloride did not impair the fertility of male or female rats in a dietary administration study in which the females were treated from 14 days prior to mating through gestation and the males were treated for 28 days prior to mating.
Developmental Toxicity: In pregnant rats given dietary doses of 0.5, 1.5 or 4.5 g/kg/day of Sevelamer hydrochloride during organogenesis, reduced or irregular ossification of fetal bones, probably due to a reduced absorption of fat-soluble vitamin D, occurred in mid and high-dose groups (human equivalent doses approximately equal to 3-4 times the maximum clinical trial dose of 13 g). in pregnant rabbits given oral doses of 100, 500 or 1,000 mg/kg/day of Sevelamer hydrochloride by gavage during organogenesis, an increase of early resorptions occurred in the high-dose group.

Sevelamer carbonate (Perfosen) is indicated for the control of serum phosphorus in patient with chronic kidney disease (CKD) on dialysis. It is also indicated for the control of hyperphosphatemia in adult patients receiving hemodialysis. It is also approved for adult CKD patients not on dialysis with serum phosphorus >1.78 mmol/L (5.5 mg/dL).

Because of the rapid reaction with the hydrochloric acid in the stomach, the dosing of Perfosen powder or tablet is anticipated to be similar to that of the Sevelamer hydrochloride salt or tablet.
General Dosing Information: Perfosen should be given three times a day with meals.
Patients Not taking a Phosphate Binder: The Recommended starting dose of Perfosen is 0.8 to 1.6 g with meals based on serum phosphorus level. Table 1 provided recommended starting doses of Perfosen for patients not taking a phosphate binder. (See Table 1.)

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Switching from Sevelamer Hydrochloride Tablets: For patients switching from sevelamer hydrochloride tablets to sevelamer carbonate tablets or powder, use the same dose in grams. Further titration may be necessary to achieve desired phosphorus levels. The highest daily dose of sevelamer carbonate studied was 14 grams in CKD patients on dialysis.
Switching between Sevelamer Carbonate Tablets and Powder: Use the same dose in grams. Further titration may be necessary to achieve desired phosphorus levels.
Switching from calcium acetate: In a study 84 CKD patients on hemodialysis, a similar reduction in serum phosphorus was seen with equivalent dose (approximately mg for mg) of sevelamer hydrochloride and calcium acetate.
Table 2 gives recommended starting dose of Perfosen on a patient's current calcium acetate dose. (See Table 2.)

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Dose Titration for all Patients Taking Perfosen: Titrate the Perfosen dose by 0.8 g three times per day with meals at two-week intervals as necessary with the goal of controlling serum phosphorus within the target range. Or as prescribed by the physician.

Sevelamer hydrochloride, which contains the same active moiety as Sevelamer carbonate, has been given to normal healthy volunteers in doses of up to 14 grams per day for eight days with no adverse effects. In CKD patients on dialysis, the maximum doses studied was 14 grams of Sevelamer carbonate and 13 grams of Sevelamer hydrochloride. There are no reports of one dosage with sevelamer carbonate or Sevelamer hydrochloride in patients. Since Sevelamer is not absorbed, the risk of systemic toxicity is low.

Sevelamer carbonate is contraindicated in patients with bowel obstruction. Sevelamer carbonate is contraindicated in patients with known hypersensitivity to sevelamer carbonate, sevelamer hydrochloride, or to any of the excipients.

Use in Pregnancy: Sevelamer carbonate is not absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug. Clinical Considerations Sevelamer carbonate may decrease serum levels of fat-soluble vitamins and folic acid in pregnant women.
Use in Lactation: Sevelamer carbonate is not absorbed systemically by the mother following oral administration, and breastfeeding is not expected to result in exposure of the child to Sevelamer carbonate. Clinical Considerations Sevelamer carbonate may decrease serum levels of fat-soluble vitamins and folic acid in pregnant women.
Use in Children: The safety and efficacy of Sevelamer carbonate in lowering serum phosphorus levels was studied in patients 6 years of age and older with CKD. In this study, Sevelamer carbonate was apparently less effective in children with a low baseline serum phosphorus, which described children <13 years of age and children not on dialysis. Given its mechanism of action, Sevelamer carbonate is expected to be effective in lowering serum phosphorus levels in pediatric patients with CKD. Most adverse events that were reported as related, or possibly related, to sevelamer carbonate were gastrointestinal in nature. No new risks or safety signals were identified with the use of sevelamer carbonate in the trial. Sevelamer carbonate has not been studied in pediatric patients below 6 years of age.
Use in the Elderly: Clinical studies of Sevelamer carbonate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

Pregnancy: Sevelamer carbonate is not absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug. Clinical Considerations Sevelamer carbonate may decrease serum levels of fat-soluble vitamins and folic acid in pregnant women.
Lactation: Sevelamer carbonate is not absorbed systemically by the mother following oral administration, and breastfeeding is not expected to result in exposure of the child to Sevelamer carbonate. Clinical Considerations Sevelamer carbonate may decrease serum levels of fat-soluble vitamins and folic acid in pregnant women.

Gastrointestinal Adverse Events: Cases of dysphagia and esophageal tablet retention have been reported in association with use of the tablet formulation of sevelamer, some requiring hospitalization and intervention. Consider using sevelamer suspension in patients with a history of swallowing disorders.
Cases of bowel obstruction and perforation have also been reported with sevelamer use Patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders including severe constipation, or major GI tract surgery were not included in the Sevelamer carbonate clinical studies.
Monitor Serum Chemistries: Bicarbonate and chloride levels should be monitored.
Monitor for Reduced Vitamins, D, E, K (clotting factors) and Folic Acid Levels: In preclinical studies in rats and dogs, sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, reduced vitamins D, E, and K (coagulation parameters) and folic acid levels at doses of 6-10 times the recommended human dose. In short-term clinical trials, there was no evidence of reduction in serum levels of vitamins. However, in a one-year clinical trial, 25-hydroxyvitamin D (normal range 10 to 55 ng/mL) fell from 39 ± 22 mg/mL to 34 ± 22 ng/mL (p < 0.01) with sevelamer hydrochloride treatment. Most (approximately 75%) patients in sevelamer hydrochloride clinical trials were receiving vitamin supplements, which is typical of patients on dialysis.

There are no empirical data on avoiding drug interactions between Perfosen and most concomitant oral drugs. For oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy (e.g. cyclosporine, tacrolimus, levothyroxine), consider separation of the timing of the administration of the two drugs. The duration of the separation depends upon the absorption characteristics of the medication concomitantly administered, such as the time to reach peak systemic levels and whether the drug is an immediate release or an extended release product. Where possible consider monitoring clinical responses and/or blood levels of concomitant drugs that have a narrow therapeutic range. (See Table 3.)

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Sevelamer carbonate has been studied in human drug-drug interaction studies (9.6 grams once daily with a meal) with warfarin and digoxin. Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, has been studied in human drug-drug interaction studies (2.4-2.8 grams single dose or three times daily with meals or two times daily without meals) with ciprofloxacin, digoxin, enalapril, iron, metoprolol, mycophenolate mofetil and warfarin.
Co-administered single dose of 2.8 grams of Sevelamer hydrochloride in fasted state decreased the bioavailability of ciprofloxacin by approximately 50% in healthy subjects.
Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA Cmax and AUCO-12h by 36% and 26% respectively.
Sevelamer carbonate or Sevelamer hydrochloride did not alter the pharmacokinetics of a single dose of enalapril, digoxin, iron, metoprolol and warfarin when co-administered.
During post marketing experience, cases of increased thyroid stimulating hormone (TSH) levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Reduction in concentrations of cyclosporine and tacrolimus leading to dose increases has also been reported in patients co-administered with sevelamer hydrochloride without any clinical consequences (for example, graft rejection). The possibility of an interaction cannot be excluded with these drugs.

Inform patients to take Sevelamer carbonate with meals and adhere to their prescribed diets. For patients using an oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, advise the patient to take the oral medication at least one hour before or three hours after Sevelamer carbonate.
Advise patients to report new onset or worsening of existing constipation promptly to their physician.

Antidotes & Detoxifying Agents

V03AE02 - sevelamer ; Belongs to the class of drugs used in the treatment of hyperkalemia and hyperphosphatemia.

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