ERGOCALCIFEROL: 5,505 Adverse Event Reports & Safety Profile

DESCRIPTION Ergocalciferol Capsules, USP are a synthetic calcium regulator for oral administration. Ergocalciferol is a white, colorless crystal, insoluble in water, soluble in organic solvents, and slightly soluble in vegetable oils. It is affected by air and by light. Ergosterol or provitamin D 2 is found in plants and yeast and has no antirachitic activity. There are more than 10 substances belonging to a group of steroid compounds, classified as having vitamin D or antirachitic activity. One USP unit of vitamin D 2 is equivalent to one International Unit (IU), and 1 mcg of vitamin D 2 is equal to 40 USP Units. Each capsule contains Vitamin D (Ergocalciferol) 1.25 mg equivalent to 50,000 USP Units in an edible vegetable oil. Ergocalciferol, also called vitamin D 2 , is 9,10-secoergosta-5,7,10(19), 22-tetraen-3-ol, (3β,5Z,7E,22 E )-; (C 28 H 44 O) with a molecular weight of 396.65, and has the following structural formula: Inactive Ingredients: 2-Ethoxyethanol, FD&C Blue #1, FD&C Yellow #5, Gelatin, Glycerin, Lecithin, Medium chain triglyceride, Purified water, Shellac glaze (modified) IN SD-45, Simethicone, Soybean oil and Titanium dioxide. Vitamin D structure

Indications and Usage Section Ergocalciferol Capsules are indicated for use in the treatment of hypoparathyroidism, refractory rickets, also known as vitamin D resistant rickets, and familial hypophosphatemia.

Dosage and Administration Section DOSAGE AND ADMINISTRATION THE RANGE BETWEEN THERAPEUTIC AND TOXIC DOSES IS NARROW. Vitamin D Resistant Rickets: 12,000 to 500,000 IU units daily. Hypoparathyroidism: 50,000 to 200,000 IU units daily concomitantly with calcium lactate 4 g, six times per day. DOSAGE MUST BE INDIVIDUALIZED UNDER CLOSE MEDICAL SUPERVISION. Calcium intake should be adequate. Blood calcium and phosphorus determinations must be made every 2 weeks or more frequently if necessary. X-rays of the bones should be taken every month until condition is corrected and stabilized.

CONTRAINDICATIONS Ergocalciferol Capsules, USP are contraindicated in patients with hypercalcemia, malabsorption syndrome, abnormal sensitivity to the toxic effects of vitamin D, and hypervitaminosis D.

ADVERSE REACTIONS Hypervitaminosis D is characterized by effects on the following organ system: Renal: Impairment of renal function with polyuria, nocturia, polydipsia, hypercalciuria, reversible azotemia, hypertension, nephrocalcinosis, generalized vascular calcification, or irreversible renal insufficiency which may result in death. CNS: Mental retardation.

Soft

Tissues: Widespread calcification of the soft tissues, including the heart, blood vessels, renal tubules, and lungs. Skeletal: Bone demineralization (osteoporosis) in adults occurs concomitantly. Decline in the average rate of linear growth and increased mineralization of bones in infants and children (dwarfism) vague aches, stiffness, and weakness. Gastrointestinal: Nausea, anorexia, constipation. Metabolic: Mild acidosis, anemia, weight loss. Call your doctor for medical advice about side effects. You may report side effects to Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Warnings and Precautions Hypersensitivity to vitamin D may be one etiologic factor in infants with idiopathic hypercalcemia. In these cases vitamin D must be strictly restricted. Keep out of the reach of children.

General

Vitamin D administration from fortified foods, dietarysupplements, self-administered and prescription drug sources should be evaluated. Therapeutic dosage should be readjusted as soon as there is clinical improvement. Dosage levels must be individualized and great care exercised to prevent serious toxic effects. IN VITAMIN D RESISTANT RICKETS THE RANGE BETWEEN THERAPEUTIC AND TOXIC DOSES IS NARROW. When high therapeutic doses are used progress should be followed with frequent blood calcium determinations. In the treatment of hypoparathyroidism, intravenous calcium, parathyroid hormone, and/or dihydrotachysterol may be required. Maintenance of a normal serum phosphorus level by dietary phosphate restriction and/or administration of aluminum gels as intestinal phosphate binders in those patients with hyperphosphatemia as frequently seen in renal osteodystrophy is essential to prevent metastatic calcification. Adequate dietary calcium is necessary for clinical response to vitamin D therapy. Protect from light.

Drug Interactions

Mineral oil interferes with the absorption of fat-soluble vitamins,including vitamin D preparations. Administration of thiazide diuretics to hypoparathyroid patients who are concurrently being treated with Ergocalciferol Capsules may cause hypercalcemia. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to evaluate the drug's potential in these areas.

Pregnancy Pregnancy

Category C Animal reproduction studies have shown fetal abnormalities in several species associated with hypervitaminosis D. These are similar to the supravalvular aortic stenosis syndrome described in infants by Black in England (1963). This syndrome was characterized by supravalvular aortic stenosis, elfin facies, and mental retardation. For the protection of the fetus, therefore, the use of vitamin D in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved. The safety in excess of 400 IU of vitamin D daily during pregnancy has not been established.

Nursing Mothers

Caution should be exercised when Ergocalciferol Capsules are administered to a nursing woman. In a mother given large doses of vitamin D, 25-hydroxycholecalciferol appeared in the milk and caused hypercalcemia in her child. Monitoring of the infant's serum calcium concentration is required in that case (Goldberg, 1972).

Pediatric Use

Pediatric doses must be individualized (see DOSAGE AND ADMINISTRATION).

Geriatric Use

Clinical studies of Ergocalciferol Capsules 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. A few published reports have suggested that the absorption of orally administered vitamin D may be attenuated in elderly compared to younger, individuals. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

PRECAUTIONS General Vitamin D administration from fortified foods, dietary supplements, self-administered and prescription drug sources should be evaluated. Therapeutic dosage should be readjusted as soon as there is clinical improvement. Dosage levels must be individualized and great care exercised to prevent serious toxic effects. IN VITAMIN D RESISTANT RICKETS THE RANGE BETWEEN THERAPEUTIC AND TOXIC DOSES IS NARROW. When high therapeutic doses are used progress should be followed with frequent blood calcium determinations. In the treatment of hypoparathyroidism, intravenous calcium, parathyroid hormone, and/or dihydrotachysterol may be required. Maintenance of a normal serum phosphorus level by dietary phosphate restriction and/or administration of aluminum gels as intestinal phosphate binders in those patients with hyperphosphatemia as frequently seen in renal osteodystrophy is essential to prevent metastatic calcification. Adequate dietary calcium is necessary for clinical response to vitamin D therapy. This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Protect from light.

Drug Interactions

Mineral oil interferes with the absorption of fat-soluble vitamins, including vitamin D preparations. Administration of thiazide diuretics to hypoparathyroid patients who are concurrently being treated with Ergocalciferol Capsules, USP may cause hypercalcemia. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to evaluate the drug's potential in these areas.

Pregnancy

Category C Animal reproduction studies have shown fetal abnormalities in several species associated with hypervitaminosis D. These are similar to the supravalvular aortic stenosis syndrome described in infants by Black in England (1963). This syndrome was characterized by supravalvular aortic stenosis, elfin facies, and mental retardation. For the protection of the fetus, therefore, the use of vitamin D in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved. The safety in excess of 400 USP Units of vitamin D daily during pregnancy has not been established.

Nursing Mothers

Caution should be exercised when Ergocalciferol Capsules, USP are administered to a nursing woman. In a mother given large doses of vitamin D, 25-hydroxycholecalciferol appeared in the milk and caused hypercalcemia in her child. Monitoring of the infant's serum calcium concentration is required in that case (Goldberg, 1972).

Pediatric Use

Pediatric doses must be individualized (see DOSAGE AND ADMINISTRATION ).

Geriatric Use

Clinical studies of Ergocalciferol Capsules, USP 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. A few published reports have suggested that the absorption of orally administered vitamin D may be attenuated in elderly compared to younger, individuals. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Drug Interactions Mineral oil interferes with the absorption of fat-soluble vitamins, including vitamin D preparations. Administration of thiazide diuretics to hypoparathyroid patients who are concurrently being treated with ergocalciferol may cause hypercalcemia. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to evaluate the drug's potential in these areas.

Pregnancy

Category C Animal reproduction studies have shown fetal abnormalities in several species associated with hypervitaminosis D. These are similar to the supravalvular aortic stenosis syndrome described in infants by Black in England (1963). This syndrome was characterized by supravalvular aortic stenosis, elfin facies, and mental retardation. For the protection of the fetus, therefore, the use of vitamin D in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved. The safety in excess of 400 USP units of vitamin D daily during pregnancy has not been established.

Nursing Mothers

Caution should be exercised when ergocalciferol is administered to a nursing woman. In a mother given large doses of vitamin D, 25-hydroxycholecalciferol appeared in the milk and caused hypercalcemia in her child. Monitoring of the infant’s serum calcium concentration is required in that case (Goldberg, 1972).

Pediatric Use

Pediatric doses must be individualized (see DOSAGE AND ADMINISTRATION ).

Geriatric Use

Clinical studies of ergocalciferol 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. A few published reports have suggested that the absorption of orally administered vitamin D may be attenuated in elderly compared to younger individuals. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.