beauty treatment [.001:<55 mg 2 /dL 2 in patients with chronic kidney disease. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition. Since doxercalciferol is a precursor for 1α,25-(OH) 2 D 2 , a potent metabolite of vitamin D 2 , pharmacologic doses of vitamin D and its derivatives should be withheld during doxercalciferol treatment to avoid possible additive effects and hypercalcemia. Oral calcium-based or other non-aluminum-containing phosphate binders and a low phosphate diet should be used to control serum phosphorus levels in patients undergoing dialysis. Uncontrolled serum phosphorus exacerbates secondary hyperparathyroidism and can lessen the effectiveness of doxercalciferol in reducing blood PTH levels. If hypercalcemia occurs after initiating doxercalciferol therapy, the dose of doxercalciferol and/or calcium-containing phosphate binders should be decreased. If hyperphosphatemia occurs after initiating doxercalciferol, the dose of doxercalciferol should be decreased and/or the dose of phosphate binders increased (see dosing recommendations for doxercalciferol under DOSAGE AND ADMINISTRATION ). Magnesium-containing antacids and doxercalciferol should not be used concomitantly in patients on chronic renal dialysis because such use may lead to the development of hypermagnesemia. Serious hypersensitivity reactions, including fatal outcome, have been reported post marketing in patients on hemodialysis following administration of Doxercalciferol Injection. Hypersensitivity reactions include anaphylaxis with symptoms of angioedema (involving face, lips, tongue and airways), hypotension, unresponsiveness, chest discomfort, shortness of breath, and cardiopulmonary arrest. These reactions may occur separately or together. Monitor patients receiving Doxercalciferol Injection upon initiation of treatment for hypersensitivity reactions. Should a hypersensitivity reaction occur, discontinue doxercalciferol, monitor and treat if indicated (see CONTRAINDICATIONS ). Precautions General The principal adverse effects of treatment with Doxercalciferol Injection are hypercalcemia, hyperphosphatemia, and oversuppression of PTH (iPTH less than 150 pg/mL). Prolonged hypercalcemia can lead to calcification of soft tissues, including the heart and arteries, and hyperphosphatemia can exacerbate hyperparathyroidism. Oversuppression of PTH may lead to adynamic bone syndrome. All of these potential adverse effects should be managed by regular patient monitoring and appropriate dosage adjustments. During treatment with doxercalciferol, patients usually require dose titration, as well as adjustment in co-therapy (i.e., dietary phosphate binders) in order to maximize PTH suppression while maintaining serum calcium and phosphorus levels within prescribed ranges. In two open-label, single-arm, multi-centered studies, the incidence of hypercalcemia and hyperphosphatemia increased during therapy with Doxercalciferol Injection (see ADVERSE REACTIONS ). The observed increases during Doxercalciferol treatment underscore the importance of regular safety monitoring of serum calcium and phosphorus levels throughout treatment. Patients with higher pre-treatment serum levels of calcium (> 10.5 mg/dL) or phosphorus (> 6.9 mg/dL) were more likely to experience hypercalcemia or hyperphosphatemia. Therefore, doxercalciferol should not be given to patients with a recent history of hypercalcemia or hyperphosphatemia, or evidence of vitamin D toxicity. Table 3: Incidence Rates of Hypercalcemia and Hyperphosphatemia in Two Phase 3 Studies with Doxercalciferol Injection Study Hypercalcemia (per 100 patient weeks) Hyperphosphatemia (per 100 patient weeks) Washout (Off Treatment) Open-Label (Treatment) Washout (Off Treatment) Open-Label (Treatment) Study C 0.9 0.9 0.9 2.4 Study D 0.3 1 1.2 3.7 Information for the Patient The patient, spouse, or guardian should be informed about adherence to instructions about diet, calcium supplementation, and avoidance of the use of nonprescription drugs without prior approval from the patient s physician. Patients should also be carefully informed about the symptoms of hypercalcemia (see ADVERSE REACTIONS ). Laboratory Tests Serum levels of iPTH, calcium, and phosphorus should be determined prior to initiation of doxercalciferol treatment. During the early phase of treatment (i.e., first 12 weeks), serum iPTH, calcium, and phosphorus levels should be determined weekly. For dialysis patients in general, serum or plasma iPTH and serum calcium, phosphorus, and alkaline phosphatase should be determined periodically. Drug Interactions Specific drug interaction studies have not been conducted. Magnesium-containing antacids and doxercalciferol should not be used concomitantly because such use may lead to the development of hypermagnesemia (see WARNINGS ). Although not examined specifically, enzyme inducers (such as glutethimide and phenobarbital) may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments. Cytochrome P450 inhibitors (such as ketoconazole and erythromycin) may inhibit the 25-hydroxylation of doxercalciferol. Hence, formation of the active doxercalciferol moiety may be hindered. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate the carcinogenic potential of doxercalciferol have not been conducted. No evidence of genetic toxicity was observed in an in vitro bacterial mutagenicity assay (Ames test) or a mouse lymphoma gene mutation assay. Doxercalciferol caused structural chromatid and chromosome aberrations in an in vitro human lymphocyte clastogenicity assay with metabolic activation. However, doxercalciferol was negative in an in vivo mouse micronucleus clastogenicity assay. Doxercalciferol had no effect on male or female fertility in rats at oral doses up to 2.5 mcg/kg/day (approximately 3 times the maximum recommended human oral dose of 60 mcg/wk based on mcg/m 2 body surface area). Use in Pregnancy Pregnancy Category B Reproduction studies in rats and rabbits, at doses up to 20 mcg/kg/day and 0.1 mcg/kg/day (approximately 25 times and less than the maximum recommended human oral dose of 60 mcg/week based on mcg/m 2 body surface area, respectively) have revealed no teratogenic or fetotoxic effects due to doxercalciferol. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether doxercalciferol is excreted in human milk. Because other vitamin D derivatives are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from doxercalciferol, 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. Pediatric Use Safety and efficacy of doxercalciferol in pediatric patients have not been established. Geriatric Use Of the 70 patients treated with Doxercalciferol Injection in the two Phase 3 clinical studies, 12 patients were 65 years or over. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients. Hepatic Insufficiency Studies examining the influence of hepatic insufficiency on the metabolism of doxercalciferol were inconclusive. Since patients with hepatic insufficiency may not metabolize doxercalciferol appropriately, the drug should be used with caution in patients with impaired hepatic function. More frequent monitoring of iPTH, calcium, and phosphorus levels should be done in such individuals. Adverse Reactions Doxercalciferol Injection has been evaluated for safety in 70 patients with chronic renal disease on hemodialysis (who had been previously treated with oral doxercalciferol) from two 12-week, open-label, single-arm, multi-centered studies. (Dosage titrated to achieve target plasma iPTH levels, see CLINICAL PHARMACOLOGY/ Clinical Studies ). Because there was no placebo group included in the studies of Doxercalciferol Injection, Table 4 provides the adverse event incidence rates from placebo-controlled studies of oral doxercalciferol. Table 4: Adverse Events Reported by 2% of Doxercalciferol Treated Patients and More Frequently Than Placebo During the Double-blind Phase of Two Clinical Studies Adverse Event Doxercalciferol (n=61) % Placebo (n=61) % Body as a Whole Abscess 3.3 0 Headache 27.9 18 Malaise 27.9 19.7 Cardiovascular System Bradycardia 6.6 4.9 Digestive System Anorexia 4.9 3.3 Constipation 3.3 3.3 Dyspepsia 4.9 1.6 Nausea/Vomiting 21.3 19.7 Musculo-Skeletal System Arthralgia 4.9 0 Metabolic and Nutritional Edema 34.4 21.3 Weight increase 4.9 0 Nervous System Dizziness 11.5 9.8 Sleep disorder 3.3 0 Respiratory System Dyspnea 11.5 6.6 Skin Pruritus 8.2 6.6 A patient who reported the same medical term more than once was counted only once for that medical term. Potential adverse effects of doxercalciferol are, in general, similar to those encountered with excessive vitamin D intake. The early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia include: Early Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, metallic taste, and anorexia. Late Polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated blood urea nitrogen (BUN), albuminuria, hypercholesterolemia, elevated serum aspartate transaminase (AST) and alanine transaminase (ALT), ectopic calcification, hypertension, cardiac arrhythmias, sensory disturbances, dehydration, apathy, arrested growth, urinary tract infections, and, rarely, overt psychosis. Postmarketing Experience 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. Hypersensitivity reactions, including fatal outcome, have been reported in patients on hemodialysis following administration of Doxercalciferol Injection. Hypersensitivity reactions include anaphylaxis with symptoms of angioedema (involving face, lips, tongue and airways), hypotension, unresponsiveness, chest discomfort, shortness of breath, cardiopulmonary arrest, pruritus and skin burning sensation (see WARNINGS ). These reactions may occur separately or together. To report SUSPECTED ADVERSE REACTIONS, contact Amneal Biosciences at 1-855-266-3251 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Overdosage Administration of doxercalciferol to patients in excess doses can cause hypercalcemia, hypercalciuria, hyperphosphatemia, and over-suppression of PTH secretion leading in certain cases to adynamic bone disease. High intake of calcium and phosphate concomitant with doxercalciferol may lead to similar abnormalities. High levels of calcium in the dialysate bath may contribute to hypercalcemia. Treatment of Hypercalcemia and Overdosage General treatment of hypercalcemia (greater than 1 mg/dL above the upper limit of the normal range) consists of immediate suspension of doxercalciferol therapy, institution of a low calcium diet, and withdrawal of calcium supplements. Serum calcium levels should be determined at least weekly until normocalcemia ensues. Hypercalcemia usually resolves in 2 to 7 days. When serum calcium levels have returned to within normal limits, doxercalciferol therapy may be reinstituted at a dose that is at least 1 mcg lower than prior therapy. Serum calcium levels should be obtained weekly after all dosage changes and during subsequent dosage titration. Persistent or markedly elevated serum calcium levels may be corrected by dialysis against a reduced calcium or calcium-free dialysate. Treatment of Accidental Overdosage of Doxercalciferol The treatment of acute accidental overdosage of doxercalciferol should consist of general supportive measures. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and institution of a low calcium diet are also indicated in accidental overdosage. If persistent and markedly elevated serum calcium levels occur, treatment with standard medical care should be followed, as needed. Based on similarities between doxercalciferol and its active metabolite, 1α,25-(OH) 2 D 2 , it is expected that doxercalciferol is not removed from the blood by dialysis. Doxercalciferol Injection Dosage and Administration Adult Administration: For intravenous use only. The optimal dose of Doxercalciferol Injection must be carefully determined for each patient. The recommended initial dose of Doxercalciferol Injection is 4 mcg administered intravenously as a bolus dose three times weekly at the end of dialysis (approximately every other day). The initial dose should be adjusted, as needed, in order to lower blood iPTH into the range of 150 to 300 pg/mL. The dose may be increased at 8-week intervals by 1 to 2 mcg if iPTH is not lowered by 50% and fails to reach the target range. Dosages higher than 18 mcg weekly have not been studied. Drug administration should be suspended if iPTH falls below 100 pg/mL and restarted one week later at a dose that is at least 1 mcg lower than the last administered dose. During titration, iPTH, serum calcium, and serum phosphorus levels should be obtained weekly. If hypercalcemia, hyperphosphatemia, or a serum calcium times phosphorus product greater than 55 mg 2 /dL 2 is noted, the dose of Doxercalciferol Injection should be decreased or suspended and/or the dose of phosphate binders should be appropriately adjusted. If suspended, the drug should be restarted at a dose that is 1 mcg lower. Dosing must be individualized and based on iPTH levels with monitoring of serum calcium and serum phosphorus levels. Table 5 presents a suggested approach in dose titration. Table 5: Initial Dosing iPTH Level Doxercalciferol Injection Dose >400 pg/mL 4 mcg three times per week at the end of dialysis, or approximately every other day Dose Titration iPTH Level Doxercalciferol Injection Dose Decrease by <50% and above 300 pg/mL Increase by 1 to 2 mcg at eight-week intervals as necessary Decrease by> 50% and above 300 pg/mL Maintain 150 to 300 pg/mL Maintain <100 pg/mL Suspend for one week, then resume at a dose that is at least 1 mcg lower How is Doxercalciferol Injection Supplied Single-Dose Vial Doxercalciferol Injection is supplied in single-dose amber glass vials containing 4 mcg doxercalciferol in 2 mL of solution or 2 mcg in 1 mL of solution. The closure consists of a fluorocarbon-coated chlorobutyl stopper, with an aluminum seal and either a yellow (4 mcg/2 mL) or purple (2 mcg/mL) plastic flip off cap. Discard unused portion of single-dose vial. 2 mcg/mL, 1 mL 1 mL, single-dose vial: NDC 70121-1393-1 50 single-dose vials in a carton: NDC 70121-1393-5 2 mcg/mL, 2 mL 2 mL, single-dose vial: NDC 70121-1392-1 50 single-dose vials in a carton: NDC 70121-1392-5 STORAGE Single-Dose Vial Store at 20 to 25 C (68 to 77 F); excursions permitted between 15 to 30 C (59 to 86 F) [see USP Controlled Room Temperature]. Protect from light. Manufactured by: Amneal Pharmaceuticals Pvt. Ltd., Parenteral Unit Plot No. 15, PHARMEZ Special Economic Zone, Sarkhej-Bavla N.H. No. 8A, Vil.: Matoda, Tal.: Sanand, Ahmedabad, Gujarat 382213, INDIA Distributed by: Amneal Biosciences Bridgewater, NJ 08807 Rev. 12-2016-00 PRINCIPAL DISPLAY PANEL DOXERCALCIFEROL Doxercalciferol Injection, solution Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:70121-1393 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXERCALCIFEROL (DOXERCALCIFEROL) DOXERCALCIFEROL 2 ug in 1 mL Inactive Ingredients Ingredient Name Strength ALCOHOL POLYSORBATE 20 SODIUM CHLORIDE BUTYLATED HYDROXYTOLUENE SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE EDETATE DISODIUM Packaging # Item Code Package Description 1 NDC:70121-1393-5 50 VIAL, SINGLE-DOSE in 1 CARTON 1 NDC:70121-1393-1 1 mL in 1 VIAL, SINGLE-DOSE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA208974 05/24/2017 DOXERCALCIFEROL Doxercalciferol Injection, solution Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:70121-1392 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXERCALCIFEROL (DOXERCALCIFEROL) DOXERCALCIFEROL 4 ug in 2 mL Inactive Ingredients Ingredient Name Strength ALCOHOL POLYSORBATE 20 SODIUM CHLORIDE BUTYLATED HYDROXYTOLUENE SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE EDETATE DISODIUM Packaging # Item Code Package Description 1 NDC:70121-1392-5 50 VIAL, SINGLE-DOSE in 1 CARTON 1 NDC:70121-1392-1 2 mL in 1 VIAL, SINGLE-DOSE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA208974 05/24/2017 Labeler - Amneal Biosciences (079785595) Revised: 05/2017 Amneal Biosciences Next Interactions Print this page Add to My Med List More about doxercalciferol Side Effects During Pregnancy Dosage Information Drug Images Drug Interactions Support Group Pricing & Coupons En Español 0 Reviews Add your own review/rating Drug class: vitamins Consumer resources Doxercalciferol Doxercalciferol Capsules Doxercalciferol Injection Professional resources Doxercalciferol (AHFS Monograph) Doxercalciferol Capsules (FDA) Doxercalciferol (Wolters Kluwer) Other brands: Hectorol Related treatment guides Secondary Hyperparathyroidism> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only B Pregnancy Category No proven risk in humans N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Manufacturers Roxane Laboratories, Inc. Sandoz Inc. Prasco Laboratories Hikma Pharmaceuticals PLC More... Drug Class Vitamins Related Drugs vitamins cholecalciferol , cyanocobalamin , folic acid , ergocalciferol , Vitamin D3 , biotin Secondary Hyperparathyroidism Sensipar , Zemplar , cinacalcet , paricalcitol , Hectorol , doxercalciferol , More... Doxercalciferol Rating No Reviews - Be the first! 8.0 /10 No Reviews - Be the first! 8.0 Rate it! Doxercalciferol Images Doxercalciferol systemic 0.5 mcg (r ) View all images} } personalize
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