İHALE DÜNYASI
İHALE DÜNYASI
The active ingredient in Renagel Tablets is sevelamer hydrochloride, a polymeric amine that binds phosphate and is meant for oral administration. Sevelamer hydrochloride is poly(allylamine hydrochloride) crosslinked with epichlorohydrin in which forty percent of the amines are protonated. It is known chemically as poly(allylamine- co -N,N'-diallyl-1,3-diamino-2-hydroxypropane) hydrochloride. Sevelamer hydrochloride is hydrophilic, but insoluble in water. The structure is represented in Figure 1 . Figure 1. Chemical Structure of Sevelamer Hydrochloride a, b = number of primary amine groups a + b = 9 c = number of crosslinking groups c = 1 n = fraction of protonated amines n = 0.4 m = large number to indicate extended polymer network The primary amine groups shown in the structure are derived directly from poly(allylamine hydrochloride). The crosslinking groups consist of two secondary amine groups derived from poly(allylamine hydrochloride) and one molecule of epichlorohydrin. Renagel (R) Tablets: Each film-coated tablet of Renagel contains either 800 mg or 400 mg of sevelamer hydrochloride on an anhydrous basis. The inactive ingredients are hypromellose, diacetylated monoglyceride, colloidal silicon dioxide, and stearic acid. The tablet imprint contains iron oxide black ink. Figure 1. Chemical Structure of Sevelamer Hydrochloride
RENAGEL (R) Renagel is a Registered Trademark of Genzyme Corporation. (sevelamer hydrochloride) is indicated for the control of serum phosphorus in patients with chronic kidney disease (CKD) on dialysis. The safety and efficacy of Renagel in CKD patients who are not on dialysis have not been studied. Renagel (R) is a phosphate binder indicated for the control of serum phosphorus in patients with chronic kidney disease on dialysis. ( 1 )
Patients Not Taking a Phosphate Binder . The recommended starting dose of Renagel is 800 to 1600 mg, which can be administered as one or two 800 mg Renagel (R) Tablets or two to four 400 mg Renagel (R) Tablets, with meals based on serum phosphorus level. Table 1 provides recommended starting doses of Renagel for patients not taking a phosphate binder. Table 1. Starting Dose for Dialysis Patients Not Taking a Phosphate Binder Serum Phosphorus Renagel (R) 800 mg Renagel (R) 400 mg > 5.5 and < 7.5 mg/dL 1 tablet three times daily with meals 2 tablets three times daily with meals ? 7.5 and < 9.0 mg/dL 2 tablets three times daily with meals 3 tablets three times daily with meals ? 9.0 mg/dL 2 tablets three times daily with meals 4 tablets three times daily with meals Patients Switching From Calcium Acetate . In a study in 84 CKD patients on hemodialysis, a similar reduction in serum phosphorus was seen with equivalent doses (approximately mg for mg) of Renagel and calcium acetate. Table 2 gives recommended starting doses of Renagel based on a patient's current calcium acetate dose. Table 2. Starting Dose for Dialysis Patients Switching From Calcium Acetate to Renagel Calcium Acetate 667 mg (Tablets per meal) Renagel (R) 800 mg (Tablets per meal) Renagel (R) 400 mg (Tablets per meal) 1 tablet 1 tablet 2 tablets 2 tablets 2 tablets 3 tablets 3 tablets 3 tablets 5 tablets Dose Titration for All Patients Taking Renagel . Dosage should be adjusted based on the serum phosphorus concentration with a goal of lowering serum phosphorus to 5.5 mg/dL or less. The dose may be increased or decreased by one tablet per meal at two week intervals as necessary. Table 3 gives a dose titration guideline. The average dose in a Phase 3 trial designed to lower serum phosphorus to 5.0 mg/dL or less was approximately three Renagel 800 mg tablets per meal. The maximum average daily Renagel dose studied was 13 grams. Table 3. Dose Titration Guideline Serum Phosphorus Renagel (R) Dose >5.5 mg/dL Increase 1 tablet per meal at 2 week intervals 3.5 - 5.5 mg/dL Maintain current dose <3.5 mg/dL Decrease 1 tablet per meal Starting dose is one or two 800 mg or two to four 400 mg tablets three times per day with meals. ( 2 ) Adjust by one tablet per meal in two week intervals as needed to obtain serum phosphorus target 3.5 to 5.5 mg/dL. ( 2 )
Renagel is contraindicated in patients with bowel obstruction. In patients with bowel obstruction. ( 4 )
The most common reasons for discontinuing treatment were gastrointestinal adverse reactions. ( 6.1 ) In a parallel design study, of 12 weeks duration, treatment emergent adverse reactions to Renagel Tablets in peritoneal dialysis patients included dyspepsia (12%), peritonitis (8%), diarrhea (5%), nausea (5%), constipation (4%), pruritus (4%), abdominal distension (3%), vomiting (3%), fatigue (3%), anorexia (3%), and arthralgia (3%). ( 6.1 ) Similar reactions at similar rates occurred in hemodialysis and peritoneal dialysis patients. ( 6.1 ) Cases of fecal impaction and, less commonly, ileus, bowel obstruction, and bowel perforation have been reported. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-847-0069 and or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a parallel design study of sevelamer hydrochloride with treatment duration of 52 weeks, adverse reactions reported for sevelamer hydrochloride (n=99) were similar to those reported for the active-control group (n=101). Overall adverse reactions among those treated with sevelamer hydrochloride occurring in > 5% of patients included: vomiting (22%), nausea (20%), diarrhea (19%), dyspepsia (16%), abdominal pain (9%), flatulence (8%) and constipation (8%). A total of 27 patients treated with sevelamer and 10 patients treated with comparator withdrew from the study due to adverse reactions. Based on studies of 8-52 weeks, the most common reason for withdrawal from Renagel was gastrointestinal adverse reactions (3-16%). In one hundred and forty-three peritoneal dialysis patients studied for 12 weeks most adverse reactions were similar to adverse reactions observed in hemodialysis patients. The most frequently occurring treatment emergent serious adverse reaction was peritonitis (8 reactions in 8 patients [8%] in the sevelamer group and 2 reactions in 2 patients [4%] on active-control). Thirteen patients (14%) in the sevelamer group and 9 patients (20%) in the active-control group discontinued, mostly for gastrointestinal adverse reactions. Patients on peritoneal dialysis should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of sevelamer hydrochloride (Renagel (R) ): pruritus, rash, abdominal pain, fecal impaction and uncommon cases of ileus, intestinal obstruction, and intestinal perforation. Appropriate medical management should be given to patients who develop constipation or have worsening of existing constipation to avoid severe complications. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.
Serious cases of dysphagia, bowel obstruction, and perforation have been associated with sevelamer use, some requiring hospitalization and surgery. ( 5.1 ) 5.1 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 Renagel clinical studies. 5.2 Monitor Serum Chemistries Bicarbonate and chloride levels should be monitored. 5.3 Monitor for Reduced Vitamins D, E, K (clotting factors) and Folic Acid Levels In preclinical studies in rats and dogs, sevelamer hydrochloride 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 ng/mL to 34 ± 22 ng/mL (p<0.01) with sevelamer hydrochloride treatment. Most (approximately 75%) patients in sevelamer hydrochloride clinical trials received vitamin supplements, which is typical of patients on dialysis.
Renagel has been studied in human drug-drug interaction studies with ciprofloxacin, digoxin, warfarin, enalapril, metoprolol and iron. Decreases the bioavailability of ciprofloxacin by approximately 50%. ( 7.1 ) In normal volunteer studies, sevelamer hydrochloride did not alter the pharmacokinetics of a single dose of digoxin, warfarin, enalapril, metoprolol, and iron. ( 7 ) When administering an oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, the drug should be administered at least one hour before or three hours after Renagel, or the physician should consider monitoring blood levels of the drug. ( 7.7 ) 7.1 Ciprofloxacin In a study of 15 healthy subjects, a co-administered single dose of 7 Renagel capsules (approximately 2.8 g) decreased the bioavailability of ciprofloxacin by approximately 50%. 7.2 Digoxin In 19 healthy subjects receiving 6 Renagel capsules three times a day with meals for 2 days, Renagel did not alter the pharmacokinetics of a single dose of digoxin. 7.3 Warfarin In 14 healthy subjects receiving 6 Renagel capsules three times a day with meals for 2 days, Renagel did not alter the pharmacokinetics of a single dose of warfarin. 7.4 Enalapril In 28 healthy subjects a single dose of 6 Renagel capsules did not alter the pharmacokinetics of a single dose of enalapril. 7.5 Metoprolol In 31 healthy subjects a single dose of 6 Renagel capsules did not alter the pharmacokinetics of a single dose of metoprolol. 7.6 Iron In 23 healthy subjects, a single dose of 7 Renagel capsules did not alter the absorption of a single oral dose of iron as 200 mg exsiccated ferrous sulfate tablet. 7.7 Other Concomitant Drug Therapy There are no empirical data on avoiding drug interactions between Renagel (R) and most concomitant drugs. During postmarketing experience, very rare cases of increased thyroid stimulating hormone (TSH) levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Closer monitoring of TSH levels is therefore recommended in patients receiving both medications. When administering an oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, the drug should be administered at least one hour before or three hours after Renagel, or the physician should consider monitoring blood levels of the drug. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials. Special precautions should be taken when prescribing Renagel to patients also taking these medications.