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CLINICAL PHARMACOLOGY Action And Clinical Pharmacology Mechanism Of Action There is evidence that calcitriol (1,25-(OH)2 D3) is the biologically active form of vitamin D responsible, in part, for maintaining calcium and phosphorous homeostasis. Calcitriol stimulates the intestinal transport of calcium. The active transport of calcium occurs primarily in the duodenum. Although the exact mechanism by which this occurs is uncertain, most evidence suggests that calcitriol enhances calcium movement across the brush border into the intestinal cells. Evidence further suggests that a specific calcium-binding protein, which is stimulated by calcitriol, acts to augment the entry of calcium into the cell. In addition, calcitriol may exert a nuclear effect by directing the synthesis of messenger RNA which in turn stimulates the synthesis of new proteins which are thought to be involved in the calcium transport process. Bone is the second tissue at which calcitriol acts to mobilize calcium for circulation. Whether calcitriol can directly stimulate bone mineralization or whether it leads to mineralization by increasing the levels of calcium and phosphate in the extracellular fluid surrounding bone remains unclear. Cytosolic receptor proteins for calcitriol in bone cells have been isolated. In acutely uremic rats, calcitriol has been shown to stimulate intestinal calcium absorption. In bone, calcitriol, in conjunction with parathyroid hormone, stimulates resorption of calcium; and in the kidney, calcitriol increases the tubular reabsorption of calcium. Calcitriol stimulates bone resorption which serves to mobilize calcium for the circulation, when an intestinal credit of calcium is absent. This effect is related to the role of vitamin D in maintaining the homeostasis of calcium and phosphorous in plasma. In addition, calcitriol may interact directly with osteoblasts. The mechanism whereby calcitriol acts on the kidney and parathyroid gland remains unclear. Evidence suggests that calcitriol may enhance renal tubular calcium reabsorption. Recent studies in parathyroidectomized animals suggest that calcitriol has a direct proximal tubular action in regulating the secretion of PTH by the parathyroid gland. Evidence suggests that calcitriol may affect the secretion of PTH through a direct action on the parathyroid gland and may be involved in the regulation of PTH synthesis and/or its secretion. Pharmacodynamics Calcitriol is the active form of vitamin D3 (cholecalciferol). The natural or endogenous supply of vitamin D in man mainly depends on ultraviolet light for conversion of 7-dehydrocholesterol to vitamin D3 in the skin. Vitamin D3 must be metabolically activated in the liver and the kidney before it is fully active on its target tissues. The initial transformation is catalyzed by a vitamin D3-25-hydroxylase enzyme present in the liver, and the product of this reaction is 25-hydroxyvitamin D3 (calcifediol). The latter undergoes hydroxylation in the mitochondria of kidney tissue, and this reaction is activated by the renal 25-hydroxyvitamin D3-1-alpha-hydroxylase to produce 1,25-dihydroxyvitamin D3 (calcitriol), the active form of vitamin D3. The known sites of action of calcitriol are intestine and bone, but additional evidence suggests that it also acts on the kidney and the parathyroid gland. Calcitriol is the most active known form of vitamin D3 in stimulating intestinal calcium transport. Pharmacokinetics Absorption Not applicable as CALCIJEX® is an injectable drug. Distribution Calcitriol, when administered by bolus injection, is rapidly available in the blood stream. Vitamin D metabolites are known to be transported in blood, bound to specific alpha2 globulins. The pharmacologic activity of an administered dose of calcitriol is about 3 to 5 days. Metabolism Two metabolic pathways for calcitriol have been identified: conversion to 1,24,25-(OH)3D3 and to calcitroic acid. Clinical Trials Study Demographics And Trial Design Table 2: Summary of Patient Demographics for Clinical Trials in Management of Hypocalcemia in Patients Undergoing Chronic Renal Dialysis Study # Trial Design Dosage, Route of Administration and Duration Study Subjects (N=Number) Mean Age (Range) Gender (%M/F) Race (%B/C) CP5691 Unblinded, multi-dose, three-period study Initial dose: 0.25-1.0 mcg 3 times weekly post-dialysis Dose increases: weekly increments of 0.25 to 0.50 mcg Maximum dose: 1.75-4.0 mcg 3 times weekly post-dialysis No comparator: each patient served as his/her own control Intravenous Period 1: pre-treatment (3 weeks)1 Period 2: treatment (4-8 weeks)2 Period 3: post-treatment (3 weeks)1 20 48.3 years (21-67) Gender: 55/45 Race: 75/25 1: No vitamin D therapy. 2: CALCIJEX® administered 3 times weekly, post-hemodialysis; 2 to 6 weeks of dose adjustment followed by 2 weeks at optimal dose. Definitions: B/C = Black / Caucasion; M/F = Male / Female. Study Results The safety and efficacy of CALCIJEX® (calcitriol injection) in the management of hypocalcemia in patients undergoing maintenance hemodialysis for chronic renal disease were investigated in Study 1. Twenty patients received calcitriol; doses were titrated for each patient based upon serum total calcium response. The primary parameter for determining efficacy was serum total calcium. Serum levels of ionized calcium, phosphorus, magnesium, and alkaline phosphatase were also measured to determine the effect, if any, of calcitriol on these parameters. A significant increase (p < 0.001) in serum total calcium (CaT) of 1.7 ± 0.2 mcg/dL was observed during the last two weeks of treatment compared with the last week of the pre-treatment period, where CaT decreased by 1.2 ± 0.2 mcg/dL (p < 0.001). Mean serum C-terminal parathyroid hormone (PTH) levels decreased to 50% of pre-treatment values during Period 2 and returned to pre-treatment levels by the end of Period 3. Detailed Pharmacology In human studies, calcitriol is rapidly absorbed from the intestine. Vitamin D metabolites are known to be transported in blood, bound to a specific alpha2 globulin. A vitamin D-resistant state may exist in uremic patients because of the failure of the kidney to adequately convert precursors to the active compound, calcitriol. Recent reports have indicated that vitamin D analogues may cause a deterioration of renal function in chronic renal failure patients who are not on renal dialysis. Calcitriol administered intravenously or intraperitonealy was found to be a simple and effective means to suppress secondary hyperparathyroidism in patients undergoing hemodialysis or ambulatory peritoneal dialysis. Toxicology Acute Toxicity The acute toxicity of calcitriol administered by a variety of routes was studied in mice and rats. The lethal dosages are shown in Table 3. Table 3: Acute Toxicity of CALCIJEX® in Mice and Rats Median Lethal Dosages Species Route LD50 mcg/kg Mice intraperitoneal 1900 oral 1350 subcutaneous 145 Rat subcutaneous 66 Definition: LD50 = Lethal dose that killed 50% of the animals. The primary signs of toxicity included decreased lacrimation, ataxia, body temperature decrease and somnolence. Subacute Toxicity Rat Neonatal rats (15/sex/dose) were administered calcitriol once daily for 14 to 16 days at oral doses of 0, 0.06, 0.19 and 0.64 mcg/kg/day. Five controls, four low-dose, two mid-dose, and fifteen high-dose pups died during the two-week treatment period. Some of the deaths were attributed to dosing accidents, but more than half of the deaths in the high-dose group were drug-related. An additional 6 high-dose pups died during a 7-week “recovery” period. Drug-related deaths resulted from metastatic calcification alone or in combination with the stress imposed by weaning. Many high-dose pups were considerably smaller than pups in the other groups, exhibited subcutaneous white patches on head and lower jaw and developed splayed limbs, and had higher serum calcium levels than controls. Gross and histologic changes reflective of metastatic calcification were seen in a number of organs including kidney and heart. Nephrocalcinosis was the most consistent histologic lesion noted. No significant signs of toxicity were noted in low-dose pups examined soon after final treatment, but 3 of 8 low-dose animals examined after the 7-week “recovery” period exhibited a minimal degree of renal calcification. The observed effects, were deemed to be entirely attributable to the induction of hypercalcemia in previously normocalcemic animals. Neonatal rats (15/sex/dose) were treated intramuscularly once daily for 14 to 16 consecutive days with calcitriol at doses of 0, 0.13, 0.38 and 1.28 mcg/kg/day. The majority of the animals were killed following the last treatment, but a number of pups were maintained on a 7-week “recovery” period. One control, one mid-dose and two high-dose pups died during the two-week treatment period; six additional mid-dose and seven additional high-dose pups died during the “recovery” period. Drug-related deaths resulted from metastatic calcification or renal tubular necrosis. Subcutaneous white patches on the head and splayed limbs were observed at the high-dose, 1.28 mcg/kg/day. Mean body weights of males in all groups were significantly less than the control mean. Serum calcium levels were elevated in all animals receiving calcitriol. Gross pathologic changes included white streaks of spots on the liver, heart and diaphragm. Metastatic calcification was the principal treatment-related histologic lesion found in all treatment groups. Nephrocalcinosis, gastric mineralization and calcium deposition in heart, aorta and respiratory system were consistently seen. Residual calcium deposits tended to be less severe in the tissues of the recovery animals. Rats (10/sex/dose) were injected intramuscularly with calcitriol at dosage levels of 0, 0.03, 0.13 and 0.64 mcg/kg/day for 14 days. Dosage groups consisted of 10 males and 10 females. There were six deaths at 0.64 mcg/kg/day during the study. Apparent signs of toxicity observed at 0.13 and 0.64 mcg/kg/day included labored breathing, reduced motor activity, corneal opacities, decreased defecation and elevated serum calcium levels. Elevation in blood urea nitrogen (BUN) and decreases in total serum protein and potassium, body weight and food consumption were noted at 0.64 mcg/kg/day. Microscopic lesions found included calcification of the myocardial fibers, arteriosclerosis of the coronary and aortic arteries, nephrolithiasis, calcification of the stomach and the large intestine and thymus hypoplasia. The only histopathological change observed at 0.03 and 0.13 mcg/kg/day was an increase in phagocytosis by the large cortical cells of the thymus. The thymus hypoplasia was considered to be attributable to a high degree of stress consequent upon debilitation and possibly severe electrolyte changes. Corneal opacities observed were not considered by the authors to be drug-related. The maximum tolerated dosage was 0.03 mcg/kg/day in this study. Immature rats (10/sex/dose) were administered calcitriol once daily for a minimum of six weeks beginning on postnatal Day 15. At doses of 0, 0.02, 0.06 and 0.20 mcg/kg/day, no evidence of toxicity attributable to calcitriol administration was noted. The “no-effect” level was determined to be 0.20 mcg/kg/day in these animals. Dog Dogs (3/sex/dose) were injected intramuscularly with calcitriol at dosage levels of 0, 0.02, 0.06 and 0.21 mcg/kg/day for 14 days. There were no deaths in the study. Thinness, dehydration, decreased activity, ocular discharge, decreased body weight and food consumption were observed at 0.06 and 0.21 mcg/kg/day. Significantly elevated serum calcium levels were noted at the two higher dosage levels (0.06 and 0.21 mcg/kg/day). Calcium deposition was not evident in the tissues at any dosage level. Therefore, a dosage of 0.02 mcg/kg/day was considered to be the maximum-tolerated dose in this study. Mutagenicity And Carcinogenicity There was no evidence of mutagenicity as studied by the Ames Method. Concentrations as high as 1000 mcg were found to be non mutagenic to Salmonella strain. Long-term studies in animals have not been performed to evaluate the carcinogenic potential of calcitriol. Reproduction And Teratology Fertility and General Reproductive Performance Calcitriol was administered orally to male rats for 60 days prior to mating and to female rats (24/dosage) from 14 days prior to mating until sacrifice of the females either on gestation Day 13 or on lactation day 21. Dosages tested were 0, 0.002, 0.08 and 0.30 mcg/kg/day. No adverse effects on either fertility or neonatal development were noted. All F0 generation animals survived. It was concluded that under the conditions of this study there were no adverse effects observed on either reproductive parameters or the pups themselves at dosages as great as 0.30 mcg/kg/day of calcitriol. Teratology Calcitriol was orally administered to pregnant rats (20/dosage) from gestation Day 7 to gestation Day 15. Dosages tested were 0 (control), 0.02, 0.08 and 0.30 mcg/kg/day. Numbers of fetuses, implantation sites and resorption sites were counted. Fetuses were weighed and examined for external abnormalities. One-third of the fetuses in each litter were examined for visceral abnormalities, two-thirds of the fetuses in each litter were prepared for skeletal evaluation. Maternal weight gain was significantly reduced in dams receiving 0.3 mcg/kg/day. No biologically significant adverse effects on rat embryonic or fetal development were observed at any of the tested dosages. There was no evidence that calcitriol was teratogenic in rats. Calcitriol was orally administered to pregnant rabbits from gestation Day 7 to gestation Day 18. Dosages tested were 0, 0.02, 0.08 and 0.30 mcg/kg/day for 31, 16, 15 and 16 rabbits respectively. Numbers of live or dead pups, resorption sites, corpora lutea and implantation sites were recorded. Fetuses were examined for external abnormalities, dissected to check for visceral abnormalities and prepared for skeletal evaluation. Marked weight loss occurred among high-dose dams; 3 high-dose animals died (2 clearly as a result of hypervitaminosis D). The mean litter size was reduced and the resorption frequency was increased among high-dose dams. Although not statistically significant, these changes were considered to be biologically significant by the authors. The percentage of viable pups that survived 24 hours of incubation was significantly decreased at the highest dose. The average fetal body weight was slightly reduced at this dosage as well. While the overall incidence of external, visceral and skeletal anomalies was comparable among all groups, one entire litter in each of the 0.08 and 0.30 mcg/kg groups exhibited multiple external malformations. These malformations included open eyelids, microphthalmia, cleft palate, reduced long bones, gnarled paws, pes caves, shortened ribs and sternebral defects in 9 mid-dose fetuses and open eyelids, reduced long bones and shortened ribs in 6 high-dose fetuses. The authors concluded that while the low incidence of litters involved, the lack of clear dose-response and the lack of statistical significance made it uncertain that these abnormalities were related to calcitriol administration, this possibility could not be discounted. Perinatal and Postnatal Studies Calcitriol was orally administered to pregnant rats (20/dosage) from gestation Day 15 through Day 21 of lactation. Dosages tested were 0, 0.02, 0.08 and 0.30 mcg/kg/day. Hypercalcemia and hypophosphatemia were noted in dams receiving 0.08 and 0.30 mcg/kg/day. Serum sampled from pups on postnatal Day 21 was hypercalcemic in both the mid- and high-dose groups. Aside from this no adverse effects on reproduction or pup growth and survival were observed at the tested dosages. Special Studies Vein-irritation Study Calcitriol was given intravenously into an ear vein in rabbits at doses of 5 mcg/kg which is ten times the proposed maximum dosage. Calcitriol was found not to be irritating to veins. REFERENCES 1. Andress DL, Norric KC, Coburn JW, Slatopolsky EA, Sherrard DJ. Intravenous calcitriol in the treatment of refractory osteitis fibrosa of chronic renal failure. N Engl J Med 1989;321:274-279. 2. Attie MF. Treatment of hypercalcemia. Endocrinol Metabol Clin N America, 1989;18(3):807-828. 3. Avioli LV, Hadda JG. Vitamin D current concepts. Metabolism 1973;22:507. 4. Brickman AS, Hartenbower DL, Norman AW, Coburn JW. Actions of 1alphahydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on mineral metabolism in man. Am J Clin Nutr 1977;30:1064-1069. 5. Brickman AS, et al. Biological action of 1,25-dihydroxy-vitamin D3 in the rachitic dog. Endocrinology 1973;92:728-734. 6. Cannella G, Bonucci E, Rolla D, Ballanti P, Moriero E, De Grandi R, Augeri C, Claudiani F, Di Maio G. Evidence of healing of secondary hyperparathyroidism in chronically hemodialyzed uremic patients treated with long-term intravenous calcitriol. Kidney, Intern 1994;46:1124-1132. 7. Christiansen C, Rodbro P, Naestoft J, Christensen MS. A possible direct effect of 24,25-dihydroxycholecalciferol on the parathyroid gland in patients with chronic renal failure. Clin Endocrinol (OXF) 1981;15:237-242. 8. Coburn JW, Hartenbower DL, Brickman AS. Advances in vitamin D metabolism as they pertain to chronic renal disease. Am J Clin Nutr 1976;29:1283-1299. 9. Coburn JW, Hartenbower DL, Norman AW. Metabolism and action of the hormone vitamin D. Its relation to diseases of calcium homeostasis. West J Med 1974;121:22-44. 10. Davies M, Hill LF, Taylor CM, Stanbury SW. 1,25-dihydroxycholecalciferol in hypoparathyroidism. Lancet 1977;55-59. 11. Delmez JA, Dougan CS, Gearing BK, Rothstein M, Windus DW, Rapp N, Slatopolsky E. The effects of intraperitoneal calcitriol on calcium and parathyroid hormone. Kidney Int 1987;31:795-799. 12. Eisman JA, Hamstra AJ, Kream BE, DeLuca HF. 1,25-dihydroxy-vitamin D in biological fluids: a simplified and sensitive assay. Science 1976;193:1021-1023. 13. Fisher JA, Biswanger U. 1,25-dihydroxycholecalciferol in ialysed patients with clinically asymptomatic renal osteodystrophy: a controlled study. Cont Nephrol 1980;18:82-91. 14. Haussler MR, Norman AW. Chromosomal receptor for a vitamin D metabolite. Proc Natl Acad Sci (USA) 1969;62:155-162. 15. Healy MD, Malluche HH, Goldstein SA, Riner FR, Massry SG. Effects of long term therapy with calcitriol in patients with moderate renal failure. Arch Intern Med 1980;140:1030-1033. 16. Massry SG. Current status of the use of 1,25-dihydroxyvitamin in the management of renal osteodystrophy. Kidney Int 1980;18:409-418. 17. Mawer BE, Backhause J, Davies M, Hill LF. Metabolic fate of administered 1,25-dihydroxycholecalciferol in controls and in patients with hypoparathyroidism. Lancet 1976;1203-1206. 18. McLain RM, Langhoff L, Hoar RM. Reproductive studies with 1alpha,25-dihydroxyvitamin D3 (calcitriol) in rats and rabbits. Toxicol Appl Pharmacol 1980;52:89-98. 19. Midgett RJ, Spielvogel AM, Coburn JW, Norman AW. Studies on calciferol metabolism VI. The renal production of the biologically active form of vitamin D, 1,25-dihydroxycholecalciferol; species, tissue and subcellular distribution. J Clin Endocrinol Metab 1973;36:1153-1161. 20. Ponchon G, DeLuca HF. The role of the liver in the metabolism of vitamin D. J Clin Invest 1969;48:1273-1279. 21. Ponchon G. Kennan AL, DeLuca HF. “Activation” of vitamin D by the liver. J Clin Invest 1969;48:2032-2037. 22. Prior JC, Cameron EC, Ballon HS, Lirenman DS, Moriarity MV, Price JDS. Experience with 1,25-dihydroxycholecalciferol therapy in undergoing hemodialysis patients with progressive vitamin D2 treated osteodystrophy. Am J Med 1979;67:583-589. 23. Silverberg DS, Bettcher KB, Dossetor JB, Overton TR, Holick MF, DeLuca HF. Effects of 1,25-dihydroxycholecalciferol in renal osteodystrophy. Can Med Assoc J 1975;112: 190-195. 24. Sinha TK, DeLuca HF, Bell HN. Evidence for a defect in the formation of 1,25-dihydroxyvitamin D in pseudohypoparathyroidism. Metatolism 1977;26:731-738. 25. Slatopolsky E, Weerts C, Thielan J, Horst R, Harter H, Martin KJ. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients. J Clin Invest 1984;74:2136-2143. 26. Smith JE, Goodman DS. The turnover and transport of vitamin D and of a polar metabolite with the properties of 25-hydroxycholecalciferol in human plasma. J Clin Invest 1971;50:2159-2167. 27. Teiltebaum SL, Bergfield MA, Freitag J, Hruska KA, Slatopolsky E. Do parathyroid hormone and 1,25-dihydroxyvitamin D modulate bone formation in uremia? J Clin Endocrinol Metab 1980;51(2):247-251. 28. Tougaard L, Sorensen E, Brochner-Mortensen J, Christensen MB, Rodbro P, Sorensen AWS. Controlled trial of 1-hydroxycholecalciferol in chronic renal failure. Lancet 1976;1:1044-1047. 29. Trachtman H, Gauthier B. Parenteral calcitriol for treatment of severe renal osteodystrophy in children with chronic renal insufficiency. J Pediatr 1987;110:966-970. 30. Tsai HC, Norman AW. Studies on calciferol metabolism VIII. Evidence for a cytoplasmic receptor for 1,25-dihydroxy-vitamin D3 in the intestinal mucosa. J Biol Chem 1973;248:5967-5975. 31. Tsai HC, Wong RG, Norman AW. Studies on calciferol metabolism IV. Subcellular localization of 1,25-dihydroxy-vitamin D3 in intestinal mucosa and correlation with increased calcium transport. J Biol Chem 1972;247:5511-5519. 32. Velentzas C, Oreopoulos DG, Pierratos A, Meema HE, Rabinovitch S, Meindock-Hudsan H, Murray TM, Ogilvie R, Katirzoglou A. Treatment of renal osteodystrophy with 1,25-dihydroxycholecalciferol. Can Med Assoc J 1981;124:577-583. 33. Weber JC, Pons U, Kodicek E. The localization of 1,25-dihydroxycholecalciferol in bone cell nuclei of rechitic chicks. Biochem J 1971;125:147-153. 34. Winterborn MH, Mace PJ, Heath DA, White RHR. Impairment of renal function in patients on 1-hydroxycholecalciferol. Lancet 1978;2:150-151. 35. Wong RG, Norman AW, Reddy CR, Coburn JW. Biological effects of 1,25-dihydroxycholecalciferol (a highly active vitamin D metabolite) in acutely uremic rats. J Clin Invest 1972;51:1287-1291.

CALCIJEX® (calcitriol) Injection DESCRIPTION Drug Substance Proper name: calcitriol Chemical name: (5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-1α,3β,25-triol Molecular formula and molecular mass: C27H44O3 416.64 Structural formula: Physicochemical properties: Calcitriol is a white crystalline powder, slightly soluble in methanol, ethanol, ethyl acetate and relatively insoluble in water. The melting point is 111to 115°C.

INDICATIONS Indications And Clinical Use CALCIJEX® (calcitriol injection) is indicated for: the management of hypocalcemia in patients undergoing chronic renal dialysis. It has been also shown to significantly reduce elevated parathyroid hormone levels (PTH) in many of these patients. Reduction of PTH has been shown to result in an improvement in renal osteodystrophy. Geriatrics ( ≥ 65 Years of Age) Clinical studies of CALCIJEX® did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Pediatrics ( < 18 Years of Age) Safety and efficacy of CALCIJEX® have not been established in the pediatric population. DOSAGE AND ADMINISTRATION Dosing Considerations CALCIJEX® is for intravenous injection only. The optimal dose of CALCIJEX® (calcitriol injection) must be carefully determined for each patient. The effectiveness of CALCIJEX® therapy is predicated on the assumption that each patient is receiving an adequate daily intake of calcium. The recommended daily allowance for calcium in adults is in the order of 1 g. To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in appropriate dietary measures. However, because of improved calcium absorption from the gastrointestinal tract, some patients may be maintained on a lower calcium intake or no supplementation at all. Recommended Dose And Dosage Adjustment The recommended initial dose of CALCIJEX® is 0.5 mcg (0.01 mcg/kg) administered three times weekly, every other day. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease state is not observed, the dose may be increased by 0.25 to 0.50 mcg at two to four week intervals. During this titration period, serum calcium and phosphorous levels should be obtained at least twice weekly. If hypercalcemia or a serum calcium times phosphate product greater than 70 is noted, the drug should be immediately discontinued until these parameters normalize. The CALCIJEX® dose should then be reinitiated at a lower dose. Doses may need to be reduced as the PTH levels decrease and commensurate with PTH, serum calcium and phosphorous levels. Most patients undergoing hemodialysis respond to doses between 0.5 and 3 mcg (0.01 to 0.05 mcg/kg) three times per week. Administration CALCIJEX® can be administered as a bolus dose intravenously through the catheter at the end of hemodialysis. HOW SUPPLIED Storage And Stability Store between 15 and 25°C; however, brief exposure up to 40°C does not adversely affect the product. Protect from light. Special Handling Instructions Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Discard unused portion. Dosage Forms, Composition And Packaging CALCIJEX® (calcitriol injection) is a sterile, isotonic, clear, aqueous solution for intravenous injection and is supplied in 1 mL ampoules available in 2 strengths: 1 mcg or 2 mcg of calcitriol. Listing Of Non-Medicinal Ingredients Each 1 mL ampoule contains 1 or 2 mcg calcitriol, anhydrous dibasic sodium phosphate (buffer), edetate disodium, monobasic sodium phosphate monohydrate (buffer), polysorbate 20, sodium ascorbate and sodium chloride. The pH of the solution is approximately 7. It does not contain a preservative. AbbVie Corporation., 8401 Trans-Canada Highway, St-Laurent, Qc H4S 1Z1 Revised: Aug 2015

PATIENT INFORMATION CALCIJEX® (calcitriol) injection ABOUT THIS MEDICATION What the medication is used for: The management of hypocalcemia (low calcium levels) in patients undergoing chronic renal dialysis. What it does: CALCIJEX® helps to regulate calcium levels in the blood. When it should not be used: You should not use CALCIJEX® if you: are allergic to calcitriol, or vitamin D or its analogues and derivatives, or any of the non-medicinal ingredients in CALCIJEX® have high calcium levels (hypercalcemia) have high vitamin D levels (vitamin D toxicity). What the medicinal ingredient is: calcitriol What the important non-medicinal ingredients are: Anhydrous dibasic sodium phosphate, edentate disodium, monobasic sodium phosphate monohydrate, polysorbate 20, sodium ascorbate, sodium chloride. What dosage forms it comes in: CALCIJEX® is supplied in 1 mL ampoules containing 1 mcg or 2 mcg of calcitriol. WARNINGS AND PRECAUTIONS BEFORE you use CALCIJEX® talk to your doctor or pharmacist if: you are allergic to vitamin D or to any ingredient of CALCIJEX® you are on digitalis you are pregnant or nursing you are taking other vitamin D product or its derivatives. The safety and effectiveness of CALCIJEX® in children under 18 years of age have not been established. INTERACTIONS WITH THIS MEDICATION Drugs that may interact with CALCIJEX® include: digitalis anti-seizure medications (e.g., diphenylhydantoin and barbiturates) antacids containing magnesium corticosteroids thiazide diuretics (e.g., hydrochlorothiazide) PROPER USE OF THIS MEDICATION The effectiveness of CALCIJEX® therapy is based on the assumption that each patient is receiving an adequate daily intake of calcium. To ensure that each patient receives an adequate daily intake of calcium, the physician may either prescribe a calcium supplement or instruct the patient in appropriate dietary measures. Usual dose: The dose will be decided by your doctor and be given through a catheter three times per week at the end of hemodialysis. You should also take your prescribed daily dose of calcium and follow the instructions on diet and supplement intake. Overdose: If you think you have been given more CALCIJEX® than you should have, talk to your doctor or nurse or contact a poison control center. SIDE EFFECTS AND WHAT TO DO ABOUT THEM The most common side effect of CALCIJEX® is hypercalcemia (high calcium levels). Early symptoms (within first few months of use of drug) of hypercalcemia and vitamin D toxicity include: weakness, headache, feeling sleepy, nausea, irregular heart beat, excessive thirst, vomiting, dry mouth, constipation, abdominal pain, loss of appetite, discomfort or unpleasant sensation in the upper abdomen, muscle pain, bone pain, and metallic taste. Late symptoms (with continued [chronic] use of drug): too much protein in your urine, loss of appetite, feeling indifferent or lack of emotion, abnormal heart beat, swelling or infection near your eyelid, decreased sex drive, loss of water/not enough water in your body, abnormal changes in bone and muscle development, deposit of calcium salt in tissues, excessive nitrogen in your urine, elevated liver function tests, high cholesterol, high blood pressure, feeling too hot, too much calcium in your kidneys, needing to urinate at night, inflammation of the pancreas, sensitivity to light, excessive thirst, increased need to urinate, itching, loss of contact with reality, runny nose, changes in sensation such as pain, touch, pressure and temperature sensation, urinary tract infections, and weight loss. If these side effects do not go away or if you experience other side effects which are not listed above, talk to your doctor right away. SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Symptom/effect Talk with your doctor or pharmacist Stop taking drug and call your doctor or pharmacist Only if severe In all cases Common elevated blood calcium allergic reactions such as: - hives - difficulty breathing - rapid drop in blood pressure dehydration such as: - lightheadedness - dizziness - weakness - dry mouth - increased thirst - decreased production of urine This is not a complete list of side effects. For any unexpected effects while taking CALCIJEX®, contact your doctor or pharmacist. HOW TO STORE IT Store between 15 and 25°C. Protect from light. REPORTING SUSPECTED SIDE EFFECTS You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways: Report on line at: www.healthcanada.gc.ca/medeffect Call toll-free at 1-866-234-2345 Complete a Canada Vigilance Reporting Form and: Fax toll-free to 1-866-678-6789 Mail to: Canada Vigilance Program Health Canada Postal Locator 0701D Ottawa, ON K1A 0K9 Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffectTM Canada Web site at http://www.healthcanada.gc.ca/medeffect NOTE: Should you require information related to the management of side effects, contact your health professional. The Canada Vigilance Program does not provide medical advice.

SIDE EFFECTS Adverse Drug Reaction Overview The following adverse reactions have been reported in association with CALCIJEX® (calcitriol injection) treatment. The most frequently reported adverse effect is hypercalcemia (35% approximately after the 4th week of treatment). The less frequently reported adverse effects were headache, nausea, vomiting, constipation, abdominal cramp, pruritis, conjunctivitis, agitation, extremity pain, apprehension, polyuria, insomnia, elevated serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamic pyruvic transaminase (SGPT), elevated alkaline phosphatase, hypercalciuria, hypermagnesemia, hyperphosphatemia, elevated lymphocytes, elevated hematocrit, elevated neutrophils, and elevated hemoglobin. The adverse effects of CALCIJEX® are, in general, similar to those encountered with excessive vitamin D intake. The early and late signs and symptoms associated with vitamin D intoxication and hypercalcemia are: Early Asthenia, headache, somnolence, nausea, cardiac arrhythmias, excessive thirst, vomiting, dry mouth, constipation, myalgia, bone pain, dysgeusia, decreased appetite, abdominal pain, and dyspepsia. Late Polyuria, polydipsia, decreased appetite, weight decreased, nocturia, conjunctival deposit, pancreatitis, photophobia, rhinorrhoea, pruritus, hyperthermia, libido decreased, blood urea increased, albuminuria, hypercholesterolemia, aspartate aminotransferase increased, alanine aminotransferase increased, calcinosis, hypertension, cardiac arrhythmias, muscular weakness, paresthesia, dehydration, apathy, urinary tract infections, and rarely, overt psychosis. Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. CALCIJEX® was studied in 20 patients undergoing maintenance hemodialysis for chronic renal disease (see Clinical Trials, Study CP5691). This open-label study had no comparator; each patient served as his/her own control. Patients received CALCIJEX® three times weekly, post-dialysis over a treatment period of 4 to 8 weeks. Doses were titrated for each patient based upon serum total calcium response. Abnormal Hematologic And Clinical Chemistry Findings The most frequently reported adverse effect is hypercalcemia (35% approximately after the 4th week of treatment). Post-Market Adverse Drug Reactions Hypersensitivity reactions have been commonly reported in Post-Market Clinical Trials at a frequency of 2.3%. Rare postmarketing reports of anaphylaxis have also been received. Occasional mild pain and localized redness at the injection site have been observed. The adverse drug reactions occurring in patients receiving CALCIJEX® in seven Post Market Clinical Studies are summarized for a total of 485 subjects randomized to CALCIJEX® (Table 1). Table 1: Summary of ADRs Occurring in Patients Receiving Calcitriol in CALCIJEX® Post Market Clinical Trials System Organ Class Very Common Common Uncommon Not Known Infections and Infestations Urinary tract infection Immune System Disorders Hypersensitivity* Metabolism and Nutrition Disorders Decreased appetite Dehydration Polydipsia Hypercholesterolemia Psychiatric Disorders Libido decreased Apathy Psychosis Nervous System Disorders Headache Somnolence Paresthesia Dysgeusia Eye Disorders Conjuctival deposit Photophobia Cardiac Disorders Cardiac arrhythmia Vascular Disorders Hypertension Respiratory, Thoracic and Mediastinal Disorders Rhinorrhoea Gastrointestinal Disorders Nausea Vomiting Constipation Abdominal pain Dyspepsia Pancreatitis Dry mouth Skin and Subcutaneous Tissue Disorders Pruritus Musculoskeletal and Connective Tissue Disorders Myalgia Bone pain Muscular weakness Renal and Urinary Disorders Polyuria Nocturia Albuminuria General Disorders and Administration Site Conditions Pain Injection site pain Asthenia Injection site reaction Calcinosis Hyperthermia Investigations Weight decreased Aspartate aminotransferase increased Blood urea increased Alanine aminotransferase increased *Anaphylaxis has not been observed in clinical trials. DRUG INTERACTIONS Drug-Drug Interactions The drugs listed in Table 1 are based on potential interactions due to the expected magnitude and seriousness of the interaction. Table 1: Established or Potential Drug-Drug Interaction Proper name Ref Effect Clinical comment Anticonvulsants (e.g. diphenylhydantoin and barbiturates) T ↑ calcitriol elimination and ↓ calcitriol effect Patients under concurrent treatment with such agents may require slightly higher doses of calcitriol. Corticosteroids T May counteract the effects of vitamin D analogs May worsen bone disease and demineralization. Digitalis T Possible increase of digitalis toxicity Hypercalcemia in patients on digitalis may precipitate cardiac arrhythmias. Magnesium-containing preparations (e.g. antacids) T ↑ intestinal absorption of magnesium Magnesium-containing antacids and calcitriol should not be used concomitantly, since such use may lead to the development of hypermagnesemia. Thiazide diuretics T ↑risk of hypercalcemia Thiazide diuretics act on the distal tubule and inhibit reabsorption of sodium and potassium. This in turn stimulates the reabsorption of calcium, therefore, an increase in calcium level. Legend: T = Theoretical Drug-Food Interactions Interactions with food have not been established. Drug-Herb Interactions Interactions with herbal products have not been established. Drug-Laboratory Interactions Interactions with laboratory tests have not been established.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS General Since CALCIJEX® (calcitriol injection) is a potent cholecalciferol derivative with profound effects on intestinal absorption of dietary calcium and inorganic phosphate, vitamin D and its derivatives should be withheld during treatment to avoid possible additive effects and hypercalcemia. Therapy with CALCIJEX® should only be considered when adequate laboratory facilities for monitoring of blood and urine chemistries are available. Overdosage of any form of vitamin D is dangerous. During treatment with CALCIJEX®, progressive hypercalcemia either due to hyper-responsiveness or overdosage may become so severe as to require emergency treatment (see OVERDOSAGE). Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis, and calcifications of the cornea or other soft tissues. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition. During treatment with calcitriol, the serum total calcium times serum inorganic phosphate product (Ca x P) should not exceed 70 mg2/dL2. Dialysate calcium level of 7 mg % or above in addition to excessive dietary calcium supplements may lead to frequent episodes of hypercalcemia. To control serum phosphorus levels and dietary phosphate absorption in patients undergoing dialysis, a non-aluminum phosphate-binding compound should be used. Magnesium-containing antacids may contribute towards hypermagnesemia in patients on chronic renal dialysis and should be avoided during therapy with calcitriol (see DRUG INTERACTIONS). Patient Selection and Follow-up: Patients with renal osteodystrophy and hypocalcemia, poorly managed by conventional vitamin D therapy, are likely to respond to CALCIJEX®. The desired therapeutic margin of calcitriol is narrow; therefore, the optimal daily dose must be carefully determined for each patient by dose titration to obtain satisfactory response in the biochemical parameters and clinical manifestations (see DOSAGE AND ADMINISTRATION). Excessive dosage of calcitriol induces hypercalcemia and hypercalciuria; therefore, early in treatment during dosage adjustment, serum calcium and phosphorus should be determined at least twice weekly. A fall in serum alkaline phosphatase values may indicate impending hypercalcemia. Should hypercalcemia develop, the drug should be discontinued immediately until the serum calcium level has normalized. This may take several days to a week. CALCIJEX® should be used with extreme caution in patients on digitalis. Hypercalcemia in such patients may precipitate cardiac arrhythmias (see DRUG INTERACTIONS). Carcinogenesis And Mutagenesis See Toxicology, Mutagenicity and Carcinogenicity. Special Populations Pregnant Women Calcitriol has been reported to be teratogenic in rabbits when given orally in doses 4 and 15 times the dose recommended for human use. All 15 fetuses in 3 litters at these doses showed external and skeletal abnormalities. However, none of the other 23 litters (156 fetuses) showed significant abnormalities compared with controls. Teratology studies in rats at doses up to 0.45 mcg/kg showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. CALCIJEX® should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus. Nursing Women It is not known whether calcitriol is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from calcitriol, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatrics ( < 18 Years of Age) Safety and efficacy of CALCIJEX® in pediatric patients younger than eighteen years of age have not been established. Geriatrics ( ≥ 65 Years of Age) Clinical studies of CALCIJEX® did not include sufficient numbers of subjects aged 65 years 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 dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Monitoring And Laboratory Tests Serum calcium, inorganic phosphorous, magnesium, alkaline phosphatase as well as 24-hour urinary calcium and phosphorous should be determined periodically during maintenance therapy with CALCIJEX®. During the initial phase of the medication, serum calcium and phosphorous should be determined more frequently (at least twice weekly). Periodic ophthalmological examinations and radiological evaluation of suspected anatomical regions for early detection of ectopic classifications are advisable. Adynamic bone disease may develop if PTH levels are suppressed to abnormal levels. If a biopsy is not being done for other (diagnostic) reasons, PTH levels may be used to indicate the rate of bone turnover. In patients treated with CALCIJEX®, if PTH levels fall below the recommended target range (1.5 to 3 times the upper limit of normal), the calcitriol dose should be reduced or therapy should be discontinued. Discontinuation of CALCIJEX® therapy may result in rebound effect; therefore, appropriate titration downward to a maintenance dose is recommended.