Product Monograph - Renagel (Sanofi Genzyme, A Division of Sanofi-Aventis Canada)
INDICATIONS AND CLINICAL USE
Renagel® (sevelamer hydrochloride) is indicated for the control of hyperphosphatemia in patients with ESRD (End Stage Renal Disease) on hemodialysis.
CONTRAINDICATIONS
Renagel® (sevelamer hydrochloride) is contraindicated in the following situations:
C patients with hypophosphatemia
C patients with bowel obstruction
C patients hypersensitive to sevelamer hydrochloride or one of the other ingredients in the product (colloidal silicon dioxide, stearic acid).
WARNINGS
Since Renagel® (sevelamer hydrochloride) expands in water, capsules should not be taken apart prior to administration and should not be chewed. Renagel® tablets should be swallowed intact and should not be crushed, chewed, or broken into pieces.
Patients with renal insufficiency may develop hypocalcemia. As Renagel® does not contain calcium, serum calcium levels should be monitored and elemental calcium should be supplemented whenever considered necessary. In cases of hypocalcemia, patients should be given an evening calcium supplement. Approximately 1000 mg elemental calcium is recommended.
Caution should be exercised to avoid hypophosphatemia, a serum phosphorus of < 0.8 mmol/L (see DOSAGE AND ADMINISTRATION).
The safety and efficacy of Renagel® in ESRD patients who are not on hemodialysis have not been studied.
PRECAUTIONS
General: The safety and efficacy of Renagel® in patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders, or major GI tract surgery have not been established. Caution should be exercised when Renagel® is used in patients with these GI disorders.
Renagel® does not contain calcium or alkali supplementation; serum calcium, bicarbonate, and chloride levels should be monitored.
Serum phosphorus and serum calcium should be monitored every 1 to 3 weeks until the target phosphorus level is reached. The dose of Renagel® (sevelamer hydrochloride) should be adjusted based on serum phosphorus concentration and titrated to a target serum phosphorus of # 1.8 mmol/L.
Use in the Elderly: No special considerations are needed for elderly patients.
Use in Children: The safety and efficacy of Renagel® has not been established in pediatric patients. The minimum age of patients treated with Renagel® in clinical trials was 18 years old.
Use in Obstetrics; Nursing Mothers: The safety of Renagel® has not been established in pregnant or lactating women. In preclinical studies, there was no evidence that Renagel® induced embryolethality, fetotoxicity or teratogenicity at the doses tested (up to 1 g/kg/day in rabbits; up to 4.5 g/kg/day in rats). Renagel® should only be given to pregnant women if the benefits outweigh the risks.
Drug Interactions: Renagel® was studied in human drug-drug interaction studies with digoxin, warfarin, enalapril, metoprolol and iron. Renagel® had no effect on the bioavailability of these medications. However, when administering any other medication where a reduction in the bioavailability of that medication would have a clinically significant effect on safety or efficacy, the physician should consider monitoring blood levels or dosing that medicine apart from Renagel® (at least one hour before or three hours after Renagel®). Patients taking anti-arrhythmic and anti-seizure medications were excluded from the clinical trials. Special precautions should be taken when prescribing Renagel® to patients also taking these medications.
ADVERSE REACTIONS
In clinical trials, Renagel® (sevelamer hydrochloride) was well tolerated. The adverse events presented in the table below were reported on study but not necessarily attributed to Renagel® treatment. The incidences of these events were not dose related.
Adverse events reported in $10% of patients for all Renagel® studies (N = 483 patients) is provided in the table below. For these events, in a parallel design study with treatment duration of 52 weeks, adverse events reported for Renagel® tablets (N=99) were similar to those reported for calcium (calcium acetate and calcium carbonate) (N=101).
| Adverse Events in all Renagel® | Trials Adverse Events from a Parallel Design Study of Renagel® vs Calcium (calcium acetate and calcium carbonate) | |
| GTC-49-301 | ||
| System Organ Class Event | Renagel® N = 483 % | Renagel® N = 99 % Calcium N = 101 % |
Gastrointestinal Dis orders Vomiting Nausea Diarrhea Dyspepsia Constipation | 24.4 25.3 21.1 15.7 13.3 | 22.2 21.8 20.2 19.8 19.2 22.8 16.2* 6.9* 8.1 11.9 |
Infections and Infestations Nasopharyngitis Bronchitis Upper Respiratory Tract Infection | 13.9 5.4 7.0 | 14.1 7.9 11.1 12.9 5.1 10.9 |
Musculoskeletal, Connective Tissue and Bone Disorders Pain in Limb Arthralgia Back Pain | 13.7 11.4 6.0 | 13.1 14.9 12.1 17.8 4.0* 17.8* |
Skin Disorders Pruritus | 10.4 | 13.1 9.9 |
Respiratory, Thoracic and Mediastinal Disorders Dyspnea Cough | 15.7 11.6 | 10.1 16.8 7.1 12.9 |
Vascular Disorders Hypertension | 9.3 | 10.1 5.9 |
Nervous System Disorders Headache | 18.4 | 9.1 15.8 |
General Disorders and Site Administration Disorders Mechanical Complication of Implant Pyrexia | 4.3 8.7 | 6.1 10.9 5.1 10.9 |
* Statistically significant
SYMPTOMS AND TREATMENT OF OVERDOSAGE
Since Renagel® (sevalamer hydrochloride) is not absorbed, the risk of systemic toxicity is minimal. Renagel® has been given to healthy volunteers at doses up to 14 grams per day for 8 days with no adverse effects. The maximum average daily dose of Renagel® that has been given to hemodialysis patients is 15.3 grams.
DOSAGE AND ADMINISTRATION
The criteria for initiating Renagel® in patients not using another phosphate binder are outlined below:
| Starting Dose | ||
| Serum Phosphorus | Renagel® Tablets 800 mg | Renagel® Tablets 400 mg or Renagel® Capsules 403 mg |
| > 1.8 and < 2.4 mmol/L | 3 tablets per day (2.4 grams) | 6 tablets or capsules per day (2.4 grams) |
| $ 2.4 and < 2.9 mmol/L | 6 tablets per day (4.8 grams) | 9 tablets or capsules per day (3.6 grams) |
| $ 2.9 mmol/L | 6 tablets per day (4.8 grams) | 12 tablets or capsules per day (4.8 grams) |
When switching from calcium-based phosphate binders to Renagel®, an equivalent starting dose on a mg/weight basis of Renagel® should be prescribed.
Dosage adjustments, when necessary should be recommended every 1 to 3 weeks by increasing one tablet or capsule per meal (3 per day) until the target serum phosphorus levels are met.
The total daily dose should be divided according to meal portions during the day.
The tablets or capsules should not be bitten, chewed or broken apart prior to dosing.
Renagel® should be taken immediately prior to or with meals. If a dose is forgotten, it should be skipped.
Average Maintenance Dose: The average final dose, in the chronic phase of a 52 week Phase 3 clinical trial designed to lower serum phosphorous to 1.6 mmol/L or less was approximately 7.1 grams, (approximately nine 800 mg tablets per day equivalent to three 800 mg tablets per meal). The maximum average daily Renagel® dose studied was 15.3 grams.
When administering any other medication where a reduction in the bioavailability of that medication would have a clinically significant effect on safety or efficacy, the physician should consider monitoring blood levels or dosing that medicine apart from Renagel® (at least one hour before or three hours after Renagel®).
PHARMACEUTICAL INFORMATION
Drug Substance
Common Name: Sevelamer hydrochloride (USAN)
Chemical Name:
- 1. poly(allylamine-co-N,N’-diallyl-1,3-diamino-2-hydroxypropane) hydrochloride (CAS)
- 2. Oxirane, (chloromethyl)-, polymer with 2-propen-1-amine, hydrochloride (CAS)
- 3. 2-Propen-1-amine, polymer with (chloromethyl) oxirane, hydrochloride (CAS)
- 4. Allylamine polymer with 1-chloro-2,3-epoxypropane, hydrochloride (IUPAC)
Structural Formula:
Where: 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.
Molecular Weight: (C3H7N•nHCl)812z(C9H18N2O•nHCl)94z where z = a large number. The equivalent molecular weight, which corresponds to 1.0 allylamine unit, 0.094 hydroxypropyl units and 0.40 HCl, is 77.1 grams/mole.
Description: Sevelamer hydrochloride is a cross linked poly(allylamine hydrochloride) polymer. The cross linking agent is epichlorohydrin (1-chloro,2,3-epoxypropane). A portion of the amine is present as the hydrochloride salt; the finished polymer is 40% amine hydrochloride and 60% free amine.
Physical Form: White to off-white powder.
Melting Point: Indistinct melting point. Starts to decompose at >180°C. Solubilities: Insoluble in all tested aqueous and organic solvents.
Crystallinity: Amorphous with no crystalline structure.
pH Values: A 1% slurry in 0.01 KCl results in a pH between 7.5-8.5.
Hygroscopicity: Sevelamer hydrochloride is hygroscopic.
Composition
Renagel® Tablets: Sevelamer hydrochloride; hydroxypropyl methylcellulose; diacetylated monoglyceride; colloidal silicon dioxide; and stearic acid. The tablet imprint contains iron oxide black ink.
Renagel® Capsules: Sevelamer hydrochloride; colloidal silicon dioxide; stearic acid; titanium dioxide, E171; indigo carmine ink, E132; shellac and propylene glycol.
Stability and Storage Recommendations
Store at controlled room temperature 15°C to 30°C. Protect from moisture.
AVAILABILITY OF DOSAGE FORMS
Renagel® 800 mg Tablets are supplied as capsule shaped, film-coated tablets, imprinted with “RENAGEL 800,” containing 800 mg of sevelamer hydrochloride. Renagel® 800 mg Tablets are available in bottles of 180 tablets.
Renagel® 400 mg Tablets are supplied as capsule shaped, film-coated tablets, imprinted with “RENAGEL 400,” containing 400 mg of sevelamer hydrochloride. Renagel® 400 mg Tablets are available in bottles of 360 tablets.
Renagel® Capsules are suppled as white, opaque, hard gelatin capsules, containing 403 mg of sevelamer hydrochoride, axially imprinted with G403. Renagel® Capsules are available in bottles of 200 capsules.
PHARMACOLOGY
The following column contains summary tables summarizing major findings from the pharmacology and toxicology studies.
| Primary Therapeutic Activity: Listing of studies and summary of pharmacological effects | |||||||
| Subject | In vitro Binding to Phosphate | Effects on Faecal Phosphorus Excretion | Effects of Renagel® and Calcium Carbonate on Faecal Phosphorus Excretion | Pilot Study: Model of Renal Secondary Hyperparathyroidism & Hyperphosphatemia | Effects on Mass Balance of Phosphorus Excretion in Normal Rats Fed a High Phosphorus Diet | Effect on Urinary Phosphorus Excretion | Effects on Bile Acid Mass Excretion in Fat Fed Hamsters |
| Duration | N/A | 5 days | 5 days | 49 days | 7 days | 4 days | 2 days |
| Species/ Strain | N/A | Wistar Rat | Wistar Rat | Sprague-Dawley Rat | Sprague-Dawley Rat | Sprague-Dawley Rat | Hamster |
| N | N/A | 6 M cross-over | 6 M cross-over | 16 M | 12 F cross-over | 12 F | 28 F |
| Dosage | N/A | 0, 11.7% w/w | 0, 11.7% w/w | 0, 5, 7.5, 10% w/w | 0, 8, 12% w/w | 0, 0.5, 1.0, 3.0, 9.0% w/w | 0, 0.2, 0.4, 0.6% w/w |
| Route/For m | N/A | Oral in diet | Oral in diet | Oral in diet | Oral in diet | Oral in diet | Oral in diet |
| Results | Renagel® exhibits theoretical binding capacity required to meet therapeutic objectives. | 90% 8 in faecal phosphorus excretion vs cellulose. 34.23 ± 5.67 mg/g vs 17.97 ± 2.09 mg/g. | 77% 8 in faecal phosphorus excretion vs cellulose & 23% 8 vs calcium carbonate. 27.43 ± 2.42 mg/g vs 15.45 ± 3.79 mg/g vs 19.08 mg/g. | Renagel® suppresses PTH elevation in partially nephrectomized rats. The diff in PTH levels in control and Renagel® rats was significant (p < 0.05) on days 40 & 49. | Ratio of faecal to in urinary phosphorus excretion 8 significantly (p < 0.05). | Renagel® produced a dose-dependent 9 urinary phosphorus excretion. (56.6, 65.6, 87.6, 96.4% 9 in urinary phosphorus respectively). | Renagel® produced a dose-dependent 8 in bile acid mass excretion. |
| Pre-Clinical Pharmacokinetics Studies: Listing of studies and summary of pharmacological effects | |||||||||
| Subject | Degradatio n in GI Contents | Disposition and Excretion of Cross- Linked Polymer Hydrogel (CPH) [14C]Renagel® in Rats | Absorption and Distribution after a Single Oral dose of [14C]Renagel® | Excretion after a Single Oral dose of [14C]Renagel® | Excretion after a Single Oral dose of [3H]Renagel® | Absorption, Distribution and Excretion after a Single Oral dose of [3H]Renagel® | Absorption, Distribution and Excretion | Open Balance Study of 14C-Polyallylami ne Renagel® | Absorption, Distribution and Excretion of Radioactivity of a Single Dose of [3H]-Labeled Renagel® With and Without Renagel® Pretreatment via Feed for One Month |
| Duration | 2 days | 1 day | 1 day | 1 day | 1 day | 1 day | 1 day | 1 day | 29 days |
| Species/ Strain | In vitro | Sprague-Dawley | Sprague-Dawley | Sprague-Dawley | Sprague-Dawley Rat | Beagle/LRE Dog | Rat/Dog | Beagle Dog | Sprague-Dawley Rat |
| N | N/A | Rat 27 male | Rat 15 male | Rat 15 male | 18 male | 6 male | 1 male each | 6 male | 12 male |
| Dosage | N/A | 0.10 g/kg | 0.25 g/kg | 0.25 g/kg | 0.25 g/kg | 0.25 g/kg | 0.25 g/kg | 0.20 g/kg | 6.0 g/kg and 0.25 g/kg |
| Route | N/A | Oral, gavage | Oral, gavage | Oral, gavage | Oral, gavage | Oral , capsule | Oral | Oral, capsule | Oral, gavage |
| Results | No significant decompositi on occurred in GI contents. | Faeces 94.7%; Blood and urine 0.00%. See next table for more details. | None detected in blood, <0.005% in tissue. | Faeces 102.98%; urine 0.06%; Expired air 0.08%. See next table for more details. | Faeces 108.07%; Urine 0.04%; Expired air 0.01%. See next table for more details. | Faeces 93.62%; Urine 0.03%; Blood 0.00%. See next table for more details. | Rat: Excreted in faeces. Dog: Excreted in faeces, none detected in blood. | Faeces 97.33%; Blood 0.00%; Urine 0.06%. See next table for more details. | Single dose: Faeces 97.60%; Blood 0.01%; Urine 0.05%. After 1 month: Faeces 104.65%; Blood 0.01%; Urine 0.05%. See next table for more |
| details. |
| Total Recovery of Radioactivity from Rats and Dogs Administered Radiolabelled-Renagel® | |||||||
| Duration | Single dose | Single dose | Single dose | 28 days | Single dose | Single dose | Single dose |
| Species/Strain | Sprague-Dawley Rat | Beagle Dog | Sprague-Dawley Rat | Sprague-Dawley Rat | Beagle Dog | Sprague-Dawley Rat | |
| N | 6 + 21 | 6 | 6 | 6 + 3 | 15 | 6 | 18 |
| Dosage | 100 mg/kg | 200 mg/kg | 250 mg/kg | 6 g/kg/d x 28d, then 250 mg/kg test | 250 mg/kg | 250 mg/kg | 250 mg/kg |
| Route of Admin | Oral gavage | Oral capsule | Oral gavage | Oral gavage | Oral capsule | Oral gavage | |
| Results | Fraction of Dose (%) | ||||||
| Faeces | 94.7 ± 5.4 | 97.33 ± 2.18 | 97.60 ± 6.22 | 104.65 ± 2.97 | 102.98 ± 4.47 | 93.62 ± 2.35 | 108.07 ± 3.32 |
| GI Content | 0.00 ± 0.00 | 0.07 ± 0.07 | 0.11 ± 0.23 | 0.01 ± 0.01 | 0.01 ± 0.01 | 0.27 ± 0.27 | 0.01 ± 0.00 |
| GI Tissue | 0.00 ± 0.00 | 0.05 ± 0.09 | 0.00 ± 0.00 | 0.00 ± 0.00 | 0.00 ± 0.00 | 0.00 ± 0.00 | 0.01 ± 0.01 |
| Liver | 0.00 ± 0.00 | 0.02 ± 0.04 | 0.00 ± 0.00 | 0.00 ± 0.00 | Not Done | 0.00 ± 0.00 | Not Done |
| Kidney | 0.00 ± 0.00 | 0.00 ± 0.00 | 0.00 ± 0.00 | 0.00 ± 0.00 | Not Done | 0.00 ± 0.00 | Not Done |
| Skeletal Muscle | Not Done | Not Done | 0.05 ± 0.01 | 0.05 ± 0.01 | Not Done | 0.00 ± 0.00 | Not Done |
| Urine | 0.00 ± 0.00 | 0.06 ± 0.08 | 0.05 ± 0.00 | 0.05 ± 0.01 | 0.06 ± 0.01 | 0.03 ± 0.02 | 0.04 ± 0.00 |
| Blood | 0.00 ± 0.00 | 0.00 ± 0.00 | 0.01 ± 0.00 | 0.01 ± 0.00 | Not Done | 0.00 ± 0.00 | Not Done |
| Cage Wash | 0.00 ± 0.00 | Not Done | 0.00 ± 0.00 | 0.00 ± 0.00 | Not Done | 0.00 ± 0.00 | Not Done |
| Expired Air | Not Done | Not Done | Not Done | Not Done | 0.08 ± 0.01 | Not Done | 0.01 ± 0.00 |
| Carcass | Not Done | Not Done | Not Done | Not Done | 0.00 ± 0.00 | Not Done | 0.20 ± 0.03 |
Pre-Clinical Drug Interaction Studies: Listing of studies and brief summary of results
| Subject | Effect on the Oral Bioavailability of 125I-L-Thyroxine, 3H-Digoxin, 3H-Estrone, and 3H-Propranolol | Effect on the Oral Bioavailability of 3H-Tetracycline, 3H-Verapamil, 3H-Quinidine, 3H-Valproic Acid, Dihydroxy Vitamin D3 and 14C-Warfarin |
| Duration | 1 day | 1 day |
| Species/ Strain | Beagle Dog | Beagle Dog |
| N | 8 male | 8 male |
| Dosage | 0.10 g/kg | 0.10 g/kg |
| Route/ Form | Oral, capsule | Oral, capsule |
| Results | No effect on Cmax or AUC for estrone, propranolol, digoxin, or thyroxine. Increased tmax for estrone and propranolol. See next table for detailed results. | No effect on Cmax, tmax, or AUC for tetracycline, verapamil, quinidine, valproic acid, dihydroxy vitamin D3 or warfarin. See next table for detailed results. |
| Beagle Dog Drug Interaction Study Results | |||
| Test Article /Vehicle | Total Radioactivity | ||
| t max(hours) | Cmax (:g eq/mL) | AUC0-48 (:g eq.h/mL) | |
3H-digoxin /80% ethanol 3H-digoxin and Renagel® | 3.1 ± 2.2a 2.6 ± 2.1b | 3.905 ± 3.3847 3.089 ± 2.0827b | 39.3 ± 15.12 37.4 ± 16.88b |
3H-estrone /anhydrous ethanol 3H-estrone and Renagel® | 1.3 ± 1.2 5.0 ± 4.2 | 21.681 ± 9.4670 22.823 ± 14.5855 | 187.4 ± 90.33 270.6 ± 144.04 |
3H-propranolol /anhydrous ethanol 3H-propranolol and Renagel® | 2.8 ± 3.8 4.2 ± 2.8b | 1.159 ± 0.1833 1.066 ± 0.2779b | 20.5 ± 2.19 21.2 ± 2.01b |
125I-L-thyroxine /anhydrous ethanol 125I-L-thyroxine and Renagel® | 7.9 ± 4.1 8.6 ± 3.4b | 5.570 ± 1.6367 5.154 ± 1.0673b | 136.9 ± 28.57 139.3 ± 24.65b |
3H-tetracycline /deionized water 3H-tetracycline and Renagel® | 1.2 ± 0.5 1.6 ± 1.1 | 1.534 ± 0.626 1.490 ± 0.750 | 30.8 ± 12.9 25.7 ± 13.1 |
3H-verapamil /anhydrous ethanol 3H-verapamil and Renagel® | 7.5 ± 7.7 5.0 ± 3.8 | 3.979 ± 0.801 4.060 ± 0.785 | 161.0 ± 24.9 164.1 ± 28.7 |
3H-quinidine /anhydrous ethanol 3H-quinidine and Renagel® | 2.1 ± 0.8 3.4 ± 2.4 | 5.135 ± 1.932 4.552 ± 2.183 | 56.3 ± 26.1 53.5 ± 26.3 |
3H-valproic acid /ethanol:water (4:1 v/v) 3H-valproic and Renagel® | 2.0 ± 2.5 2.4 ± 3.9 | 27.04 ± 12.48 27.62 ± 11.96 | 433.8 ± 64.7 429.0 ± 75.6 |
Dihydroxy vitamin D3 /anhydrous ethanol Dihydroxy vitamin D3 and Renagel® | 3.4 ± 2.2 2.9 ± 1.2 | 240.9 ± 125.9 180.5 ± 30.9 | 3289 ± 390 3064 ± 396 |
14C-warfarin /anhydrous ethanol 14C-warfarin and Renagel® | 6.9 ± 3.9 7.9 ± 3.2 | 1.938 ± 0.279 2.024 ± 0.259 | 45.4 ± 3.9 45.4 ± 3.3 |
a = mean ± SD, N = 8; b = mean ± SD, N = 7
TOXICOLOGY
| Pre-Clinical Toxicology: Listing of Repeat-Dose studies and summary of toxicology effects CONTINUED ON NEXT PAGE | ||||||
| Duration | 28 days | 1 month | 28 days | 12 weeks | 90 days | 13 & 26 weeks |
| Species/Strai n | Hsd:SD Rat | Slc Rat | Crl:CD Rat | SD Rat | Hsd:SD Rat | Hsd:SD Rat |
| N | 80 (10F, 10 M/grp) | 150 (15F, 15M/grp) | 80 (10F, 10M/grp) | 32 (4F, 4M/grp) | 150 (15F, 15M/grp) | 160 (20F, 20M/grp) |
| Dosage | 1.0, 4.5, 10.0 g/kg; 10.0 g/kg cellulose | 0.03, 1.0, 3.0, 10.0 g/kg; 10.0 g/kg cellulose | 1.0, 4.5, 10.0 g/kg; 10.0 g/kg cellulose | Range-finding study 0.6, 2.0, 6.0 - 7.0 g/kg; 6.0 g/kg cellulose | 1.0, 2.0, 4.5, 10.0 g/kg; 10.0 g/kg/d cellulose | 0.6, 3.0, 6.0 g/kg; 6.0 g/kg/d cellulose |
| Route/Form | Oral, diet | Oral, diet | Oral, diet | Oral, diet | Oral, diet | Oral, diet |
| Results | NOAEL = 1g/kg. In the high dose male: anaemia, 9 vitamins D & E and haemorrhagic syndrome was observed. | NOAEL = 1g/kg. In the high dose male and female: anaemia, 8 GPT, alkaline phosphatase and 9 total protein, P, K, and vitamin E were observed. | NOAEL = 1g/kg. High dose male: anaemia, prolonged coagulation times; 9 food consumption, body weight gains,9 in vitamins D, E & K were observed. 8M in 10 g/kg grp found dead or moribund sacrificed | 8 food consumption were observed in the high dose male. | The NOAEL was 4.5g/kg. In the high dose, 9 in vitamins D & E and organ weight change in spleen, liver, kidney and heart were observed. 3M in 10/g/kg grp were found dead or | In the mid and high-dose groups there was a 9 in vitamins D & E. Minimal submucosal gastric edema with no histopathological damage observed in all groups. |
| Pre-Clinical Toxicology: Listing of Repeat-Dose studies and summary of toxicology effects CONTINUED ON NEXT PAGE | ||||||
prior to study termination. Effects probably due to vitamins D & K deficiency. 4.5 & 10 g/kg males: physeal dysplasia femur. 10 g/kg males physeal dysplasia sternebrae. Both consistent with early changes seen in vitamin D deficiency. | moribund sacrificed prior to study termination probably as a result of vitamin K deficiency. | |||||
| Pre-Clinical Toxicology: Listing of Repeat-Dose studies and summary of toxicology effects CONTINUED FROM PREVIOUS PAGE | |||||
| Duration | 28 days | 28 days | 1 month | 13 weeks | 1 year |
| Species/Strai n | Dog | Beagle Dog | Dog | Beagle Dog | Beagle Dog |
| N | 16 (4F/grp) | 32 (4F, 4M/grp) | 36 (6F, 6M/grp) | 32 (4F, 4M/grp) | 40 (6F, 6M/grp + 4F, 4M) |
| Dosage | 1.2, 4.0, 12.0 g/kg; 12 g/kg/d cellulose | 0, 0.2, 1.0, 2.0 g/kg | 0, 0.6, 2.0 g/kg | 0.2, 1.0, 2.0 g/kg | 0, 0.2, 0.60, 2.0 g/kg |
| Route/Form | Oral, diet | Oral, capsule | Oral, capsule | Oral, capsule | Oral, capsule |
| Results | Serum calcium was decreased in the high-dose. Serum chloride was increased in the mid and high-dose. | In the high-dose decreases in vitamins D, E and iron were observed. In the mid and high-dose, decreases in urinary urobilinogen were seen. Dose related decrease in triglycerides and cholesterol. | The NOAEL was 0.6 g/kg. In the high-dose male and female, there was a decrease in total cholesterol, free cholesterol, phospholipid and serum vitamin E and an increase in water consumption and urinary calcium and chloride. | In the high-dose, decreases in cholesterol/triglyceride concentrations and decreases in serum vitamins D & E and increases in urinary calcium and chloride were observed. | The NOAEL was 0.6 g/kg. Renagel® produced no dose limiting toxicity at doses up to 2 g/kg/d. In the high-dose, there was a decrease in cholesterol, phospholipids, triglycerides, vitamins D, E and folic acid. Relative kidney weights were increased in the high dose. |
| Pre-Clinical Toxicology: Listing of Genotoxicity studies and summary of results | ||||
| Subject | Salmonella typhimurium Reverse Mutation Assay | Reverse Mutation Test | In Vitro Mammalian Cytogenetic Test | Micronucleus Cytogenetic Assay in the Mouse |
| Duration | N/A | N/A | N/A | 2 days |
| Species/Strai n | Ames Test | Bacterial Reverse Mutation Test | Chromosome Aberration | Mouse |
| N | N/A | N/A | N/A | 5 female, 5 male |
| Dosage | 5 mg/mL | 5 mg/plate | 5 mg/mL | 572, 1144, 2286 mg/kg/d |
| Route/Form | N/A | N/A | N/A | Intraperitoneal |
| Results | Renagel® produced same mean # of revertants as the negative control in all strains ± metabolic activation. Renagel® was found non- mutagenic. | No antibacterial activity was observed. Renagel® was found non-mutagenic. | Renagel® was found to be weakly positive for the induction of structural chromosome aberration and negative for the induction of numerical chromosome aberration. | Renagel® was negative in the mice micronucleus assay. |
| Pre-Clinical Toxicology: Listing of Reproductive Toxicity studies and results | ||||
| Subject | Fertility | Teratology | Range-Finding Teratology | Teratology |
| Duration | Males: -4 weeks through mating. Females: -2 weeks to Day 7 Gestation | Days 6-17 of gestation | Days 7-19 of gestation | Days 6-18 of gestation |
| Species/Strain | Rat | Rat | Rabbit | Rabbit |
| N | 200 (20F, 20M/grp) | 125 (25F/grp) | 25 (5F/grp) | 117* (22F/grp, + 29F) |
| Dosage | 0, 0.5, 1.5, 4.5 g/kg; 4.5 g/kg/d cellulose | 0, 0.5, 1.5, 4.5 g/kg; 4.5 g/kg/d cellulose | 0, 0.15, 0.5, 1.5 g/kg | 0, 0.1, 0.5, 1.0 g/kg; *29F in 1.0 g/kg grp |
| Route/Form | Oral, diet | Oral, diet | Oral, gavage | Oral, gavage |
| Results | Male and female fertility and | No maternal toxicity. No | There were no treatment- | No maternal toxicity. No |
| embryonic development NOAEL > 4.5g/kg . | evidence of embryolethality or teratogenicity. Increase incidence of minor fetal skeletal abnormalities due to transitory changes in ossification rates; not indicative of fetotoxicity. | related changes. | evidence of embryolethality, fetotoxicity or teratogenicity. NOAEL > 1.0g/kg. |
| Pre-Clinical Toxicology: Listing of Carcinogenicity studies and results | ||
| Subject | Carcinogenicity | Carcinogenicity |
| Duration | 104 weeks | 104 weeks |
| Species/Strain | CD-1 Mouse | Charles River Sprague-Dawley CD Rats |
| N | 100 (50F, 50M/grp) | 100 (50F, 50M/grp) |
| Dosage | 0, 5000, 20000, 50000 ppm | 0, 0.3, 1.0, and 3.0 g/kg/day |
| Route/Form | Orally (diet) | Orally (diet) |
| Results | Mortality, survival time and clinical observations were similar in all treatment groups. Decreased body weights in high dose male and female mice were observed through most of study. Increased incidence of lymphomas in high dose females when compared to one of two concurrent control groups. No significant difference from the other control group. Dose is approximately 60X multiple of maximum projected human dose. Findings are of questionable biological significance and no significance to human use of the drug. No other significant treatment-related findings. | Mortality, survival time, and clinical observations were similar across groups. Decreased body weights, vitamin D and vitamin E levels, increased hemoglobin, hematocrit, red blood cells, and plasma and urine calcium observed in high dose males. Renal findings were transitional cell hyperplasia, increased transitional epithelial mineralization, pelvic inflammatory cell infiltrate, and pelvic hemorrhage in high dose males. High dose females showed increased incidence of pelvic hemorrhage. No other significant treatment-related histological findings. |
REFERENCES
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