NDC 0409-1330 Doxercalciferol

Doxercalciferol

NDC Product Code 0409-1330

NDC CODE: 0409-1330

Proprietary Name: Doxercalciferol What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Doxercalciferol What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is used to treat people with serious kidney disease who have high levels of a certain natural substance (parathyroid hormone-PTH), which your body normally makes. High PTH levels affect the balance of other minerals in your body (calcium and phosphorus) and may result in weak bones. Doxercalciferol is a man-made form of vitamin D. It works by decreasing PTH levels and increasing calcium/phosphorus levels in the body.

NDC Code Structure

  • 0409 - Hospira, Inc.

NDC 0409-1330-01

Package Description: 50 VIAL, MULTI-DOSE in 1 CARTON > 2 mL in 1 VIAL, MULTI-DOSE (0409-1330-11)

NDC Product Information

Doxercalciferol with NDC 0409-1330 is a a human prescription drug product labeled by Hospira, Inc.. The generic name of Doxercalciferol is doxercalciferol. The product's dosage form is injection, solution and is administered via intravenous form.

Labeler Name: Hospira, Inc.

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Doxercalciferol Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • DOXERCALCIFEROL 2 ug/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • ALCOHOL (UNII: 3K9958V90M)
  • POLYSORBATE 20 (UNII: 7T1F30V5YH)
  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • BUTYLATED HYDROXYTOLUENE (UNII: 1P9D0Z171K)
  • SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE (UNII: 70WT22SF4B)
  • SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE (UNII: 593YOG76RN)
  • EDETATE DISODIUM (UNII: 7FLD91C86K)
  • WATER (UNII: 059QF0KO0R)
  • ALCOHOL (UNII: 3K9958V90M)
  • POLYSORBATE 20 (UNII: 7T1F30V5YH)
  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • BUTYLATED HYDROXYTOLUENE (UNII: 1P9D0Z171K)
  • SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE (UNII: 70WT22SF4B)
  • SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE (UNII: 593YOG76RN)
  • EDETATE DISODIUM (UNII: 7FLD91C86K)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.
  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Ergocalciferols - [CS]
  • Vitamin D2 Analog - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Hospira, Inc.
Labeler Code: 0409
FDA Application Number: NDA208614 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 10-24-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Information for Patients

Doxercalciferol Injection

Doxercalciferol Injection is pronounced as (dox'' er kaf sif' er ol)

Why is doxercalciferol injection medication prescribed?
Doxercalciferol injection is used to treat secondary hyperparathyroidism (a condition in which the body produces too much parathyroid hormone [PTH; a natural substance ne...
[Read More]

* Please review the disclaimer below.

Doxercalciferol Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

Doxercalciferol Injection is indicated for the treatment of secondary hyperparathyroidism in adult patients with chronic kidney disease (CKD) on dialysis.

2.1 Prior To Initiation Of Doxercalciferol Injection

  • Ensure serum calcium is not above the upper limit of normal before initiating treatment with Doxercalciferol Injection [see Warnings and Precautions (5.1)].

2.2 Important Administration Instructions For Doxercalciferol Injection

  • Administer Doxercalciferol Injection intravenously as a bolus dose at the end of dialysis.Inspect Doxercalciferol Injection visually prior to administration; the solution should appear clear and colorless. Do not use if the solution is not clear or particles are present.After initial vial use, store opened multiple-dose vial for up to 14 days at room temperature. Discard unused portion of multiple-dose vial after 14 days [see How Supplied/Storage and Handling (16)].

2.3 Dosage Recommendations For Doxercalciferol Injection

  • Initiate Doxercalciferol Injection at a dose of 4 mcg given by bolus intravenous administration three times weekly at the end of dialysis (no more frequently than every other day).Target the maintenance dose of Doxercalciferol Injection to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits.Monitor serum calcium, phosphorus, and intact PTH levels weekly after initiation of therapy or dose adjustment.Titrate the dose of Doxercalciferol Injection based on intact PTH. The dose may be increased at 8-week intervals by 1 mcg to 2 mcg if intact PTH is not lowered by 50% and fails to reach the target range. The maximum dose is 18 mcg weekly. Prior to raising the dose, ensure serum calcium is within normal limits.Suspend or decrease the dose if intact PTH is persistently and abnormally low to reduce the risk of adynamic bone disease [see Warnings and Precautions (5.4)] or if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia [see Warnings and Precautions (5.1)]. If suspended, the drug should be restarted one week later at a dose that is at least 1 mcg lower.

2.4 Drug Interactions That May Require Dosage Adjustments Of Doxercalciferol Injection

  • Increased monitoring of serum calcium and dose adjustment of Doxercalciferol Injection may be necessary when given concomitantly with drugs that may increase the risk of hypercalcemia [see Drug Interactions (7)].Increased monitoring of both serum calcium and intact PTH as well as dose adjustment of Doxercalciferol Injection may be necessary when given concomitantly with cytochrome P450 inhibitors or enzyme inducers [see Drug Interactions (7)].

3 Dosage Forms And Strengths

  • Injection: clear and colorless solution available as follows:4 mcg/2 mL (2 mcg/mL) multiple-dose 2 mL vial10 mcg/5 mL (2 mcg/mL) multiple-dose 5 mL vial

4 Contraindications

  • Doxercalciferol Injection is contraindicated in patients with:Hypercalcemia [see Warnings and Precautions (5.1)]Vitamin D toxicity [see Warnings and Precautions (5.1)]Known hypersensitivity to doxercalciferol or any of the inactive ingredients of Doxercalciferol Injection; serious hypersensitivity reactions including anaphylaxis and angioedema have been reported [see Warnings and Precautions (5.3), Adverse Reactions (6.2)].

5.1 Hypercalcemia

Hypercalcemia may occur during Doxercalciferol Injection treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart [see Warnings and Precautions (5.2)]. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Severe hypercalcemia may require emergency attention.Hypercalcemia may be exacerbated by concomitant administration of high doses of calcium-containing preparations, thiazide diuretics, or other vitamin D compounds [see Drug Interactions (7)]. In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. Patients with a history of hypercalcemia prior to initiating therapy may be at increased risk for development of hypercalcemia with Doxercalciferol Injection. In these circumstances, frequent serum calcium monitoring and Doxercalciferol Injection dose adjustments may be required.When initiating Doxercalciferol Injection or adjusting Doxercalciferol Injection dose, measure serum calcium weekly. Once a maintenance dose has been established, measure serum calcium monthly for 3 months and then every 3 months. If hypercalcemia occurs, reduce the dose or discontinue Doxercalciferol Injection until serum calcium is normal [see Dosage and Administration (2)].Inform patients about the symptoms of elevated calcium (feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss) and instruct them to report new or worsening symptoms when they occur.

5.2 Digitalis Toxicity

Doxercalciferol Injection can cause hypercalcemia [see Warnings and Precautions (5.1)] which increases the risk of digitalis toxicity. In patients using Doxercalciferol Injection concomitantly with digitalis compounds, monitor both serum calcium and patients for signs and symptoms of digitalis toxicity. Increase the frequency of monitoring when initiating or adjusting the dose of Doxercalciferol Injection [see Drug Interactions (7)].

5.3 Serious Hypersensitivity Reactions

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 Injection, monitor and treat if indicated [see Contraindications (4)].

5.4 Adynamic Bone Disease

Adynamic bone disease with subsequent increased risk of fractures may develop if intact PTH levels are suppressed by Doxercalciferol Injection to abnormally low levels. Monitor intact PTH levels to avoid oversuppression and adjust the Doxercalciferol Injection dose, if needed [see Dosage and Administration (2)].

6 Adverse Reactions

  • The following adverse reactions are discussed in greater detail in another section of the label:Hypercalcemia [see Warnings and Precautions (5.1)]Serious Hypersensitivity Reactions [see Warnings and Precautions (5.3)]Adynamic Bone Disease [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of Doxercalciferol Injection has been established from adequate and well-controlled studies of doxercalciferol capsules and from studies of another doxercalciferol injection product (doxercalciferol injection) [see Clinical Studies (14)]. Below is a display of the adverse reactions of doxercalciferol capsules and doxercalciferol injection from these studies.Doxercalciferol capsules for oral use were evaluated in two placebo-controlled, double-blind studies in patients with CKD on hemodialysis. Patients were treated with doxercalciferol capsules (n=61) or placebo (n=61). After randomization to two groups, eligible patients underwent an 8-week washout period during which no vitamin D derivatives were administered to either group. Subsequently, all patients received doxercalciferol capsules in an open-label fashion for 16 weeks followed by a double-blind period of 8 weeks during which patients received either doxercalciferol capsules or placebo. Adverse reactions occurring in the doxercalciferol capsules groups at a frequency of 2% or greater, and more frequently than in the placebo group are presented in Table 1.Table 1: Adverse Reactions Occurring in ≥2% of Doxercalciferol Capsules-Treated Patients with CKD on Dialysis and Greater than Placebo in Two Double-Blind Clinical StudiesAdverse ReactionA patient who reported the same medical term more than once was counted only once for that medical term.Doxercalciferol (n=61)%Placebo (n=61)%Edema3421Malaise2820Headache2818Nausea/Vomiting2120Dizziness1210Dyspnea127Pruritus87Bradycardia75Anorexia53Dyspepsia52Arthralgia50Weight increase50Abscess30Sleep disorder30Doxercalciferol injection was studied in 70 patients with CKD on hemodialysis in two 12-week, open-label, single-arm, multi-center studies [see Clinical Studies (14)]. The incidence of hypercalcemia and hyperphosphatemia increased during therapy with doxercalciferol injection. 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.There was no placebo group included in the studies of doxercalciferol injection. Adverse reactions in patients with CKD on hemodialysis receiving Doxercalciferol Injection are expected to be similar to those reported in placebo-controlled studies of doxercalciferol capsules presented in Table 1.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Doxercalciferol Injection. 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.

7 Drug Interactions

Table 2 includes clinically significant drug interactions with doxercalciferol.Table 2: Clinically Significant Drug Interactions with DoxercalciferolDrugs that May Increase the risk of HypercalcemiaClinical ImpactConcomitant administration of high doses of calcium-containing preparations or other vitamin D compounds may increase the risk of hypercalcemia. Thiazide diuretics are known to induce hypercalcemia by reducing excretion of calcium in the urine.ExamplesCalcium-containing products, other vitamin D compounds or thiazide diureticsInterventionMonitor serum calcium concentrations more frequently and adjust Doxercalciferol Injection dose as needed [see Warnings and Precautions (5.1)].Digitalis CompoundsClinical ImpactDoxercalciferol can cause hypercalcemia which can potentiate the risk of digitalis toxicity.InterventionMonitor patients for signs and symptoms of digitalis toxicity and increase frequency of serum calcium monitoring when initiating or adjusting the dose of Doxercalciferol Injection in patients receiving digitalis compounds [see Warnings and Precautions (5.2)].Cytochrome P450 InhibitorsClinical ImpactDoxercalciferol is activated by CYP 27 in the liver. Cytochrome P450 inhibitors may inhibit the 25-hydroxylation of doxercalciferol and thus reduce the formation of active doxercalciferol moiety [see Clinical Pharmacology (12.3)].ExamplesKetoconazole and erythromycinInterventionIf a patient initiates or discontinues therapy with a cytochrome P450 inhibitor, dose adjustment of Doxercalciferol Injection may be necessary. Monitor intact PTH and serum calcium concentrations closely.Enzyme InducersClinical ImpactDoxercalciferol is activated by CYP 27 in the liver. Enzyme inducers may affect the 25-hydroxylation of doxercalciferol [see Clinical Pharmacology (12.3)].ExamplesGlutethimide and phenobarbitalInterventionIf a patient initiates or discontinues therapy with an enzyme inducer, dose adjustment of Doxercalciferol Injection may be necessary. Monitor intact PTH and serum calcium concentrations closely.Magnesium-containing ProductsClinical ImpactConcomitant administration of Doxercalciferol Injection and high doses of magnesium-containing products may increase the risk of hypermagnesemia.ExamplesMagnesium-containing products such as antacidsInterventionAvoid use of magnesium-containing products and Doxercalciferol Injection.

Other

Risk SummaryThe limited available data with Doxercalciferol Injection in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with chronic kidney disease in pregnancy [see Clinical Considerations]. In reproduction studies in rats and rabbits administered doxercalciferol during organogenesis at up to 20 mcg/kg/day and 0.1 mcg/kg/day, respectively (approximately 25 times (rats) and less than (rabbits) the maximum recommended human oral dose of 60 mcg/week based on mcg/m2 body surface area), no adverse developmental effects were observed [see Data].The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal riskChronic kidney disease in pregnancy increases the risk for maternal hypertension and preeclampsia, miscarriage, preterm delivery polyhydramnios, still birth, and low-birth-weight infants.

Data

Animal DataThere were no adverse effects on fetal development when doxercalciferol was administered at doses up to 20 mcg/kg/day in pregnant rats or doses up to 0.1 mcg/kg/day in pregnant rabbits during the period of organogenesis.

Risk SummaryThere is no information available on the presence of doxercalciferol in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Infants exposed to Doxercalciferol Injection through breast milk should be monitored for signs and symptoms of hypercalcemia [see Clinical Considerations].The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Doxercalciferol Injection and any potential adverse effects on the breastfed child from Doxercalciferol Injection or from the underlying maternal condition.

Clinical ConsiderationsInfants exposed to Doxercalciferol Injection through breast milk should be monitored for signs and symptoms of hypercalcemia, including seizures, vomiting, constipation and weight loss. Monitoring of serum calcium in the infant should be considered.

AbsorptionIn healthy volunteers, peak blood levels of 1α,25-(OH)2D2, the major metabolite of doxercalciferol, are attained at 8 hours after a single intravenous dose of doxercalciferol.

EliminationThe mean elimination half-life of 1α,25-(OH)2D2 after an oral dose is approximately 32 to 37 hours with a range of up to 96 hours.

MetabolismDoxercalciferol is activated by CYP 27 in the liver to form 1α,25-(OH)2D2 (major metabolite) and 1α,24-dihydroxyvitamin D2 (minor metabolite). Activation of doxercalciferol does not require the involvement of the kidneys.

Specific Populations

Patients with renal impairmentThe mean elimination half-life of 1α,25-(OH)2D2 in patients with end-stage renal disease (ESRD) and in healthy volunteers appears to be similar following an oral dose. Doxercalciferol Injection is not approved for oral use.Hemodialysis causes a temporary increase in 1α,25-(OH)2D2 mean concentrations, presumably due to volume contraction. 1α,25-(OH)2D2 is not removed from blood during hemodialysis.

HypercalcemiaAdvise patients to contact a health care provider if they develop symptoms of elevated calcium (e.g. feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss) [see Warnings and Precautions (5.1)].

HypersensitivityInform patients that hypersensitivity reactions can occur with Doxercalciferol Injection [see Warnings and Precautions (5.3)].

MonitoringInform patients that they will need routine monitoring of laboratory parameters such as calcium and intact PTH while receiving Doxercalciferol Injection. Inform patients that more frequent monitoring is necessary during the initiation of therapy, following dose changes or when potentially interacting medications are started or discontinued [see Dosage and Administration (2), Drug Interactions (7)].

Drug InteractionsAdvise patients to inform their physician of all medications, including prescription and nonprescription drugs, and supplements they are taking. Advise patients to also inform their physician that they are receiving Doxercalciferol Injection if a new medication is prescribed [see Drug Interactions (7)].

This product's label may have been updated. For the current prescribing information, please visit www.pfizer.com.Distributed by Hospira, Inc., Lake Forest, IL 60045 USALAB-0887-3.0

8.4 Pediatric Use

Safety and efficacy of Doxercalciferol Injection in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of doxercalciferol injection did not include sufficient numbers of patients 65 years or over to determine whether they respond differently from younger subjects. 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 or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

Patients with hepatic impairment may not metabolize Doxercalciferol Injection appropriately. More frequent monitoring of intact PTH, calcium, and phosphorus levels should be done in patients with hepatic impairment.

10 Overdosage

Overdosage of Doxercalciferol Injection may lead to hypercalcemia, hypercalciuria, and hyperphosphatemia [see Warnings and Precautions (5.1)]. The treatment of acute overdosage should consist of supportive measures and discontinuation of Doxercalciferol Injection administration. Serum calcium levels should be measured until normal.Based on similarities between Doxercalciferol Injection and its active metabolite, 1α,25-(OH)2D2, it is expected that doxercalciferol is not removed from the blood by dialysis.

11 Description

Doxercalciferol is a synthetic vitamin D2 analog. Doxercalciferol undergoes metabolic activation in vivo to form 1α,25-dihydroxyvitamin D2 (1α,25-(OH)2D2), a naturally occurring, biologically active form of vitamin D2.Doxercalciferol is a colorless crystalline compound with a calculated molecular weight of 412.65 and a molecular formula of C28H44O2. It is soluble in oils and organic solvents, but is relatively insoluble in water. Chemically, doxercalciferol is (1α,3β,5Z,7E,22E)-9,10-secoergosta-5,7,10(19),22-tetraene-1,3-diol. The structural formula is:Doxercalciferol Injection is a sterile, clear, and colorless solution.The 2 mL multiple-dose vials contain 4 mcg/2 mL (2 mcg/mL) of doxercalciferol. Each milliliter (mL) of solution contains 2 mcg doxercalciferol and the following inactive ingredients: ethanol, 96% (0.078 mL); polysorbate 20 (10 mg); sodium chloride (1.5 mg); butylated hydroxytoluene (0.02 mg); sodium phosphate dibasic, heptahydrate (14.4 mg); sodium phosphate monobasic, monohydrate (1.8 mg); and disodium edetate (1.1 mg).The 5 mL multiple-dose vials contain 10 mcg/5 mL (2 mcg/mL) of doxercalciferol. Each milliliter (mL) of solution contains 2 mcg doxercalciferol and the following inactive ingredients: ethanol, 96% (0.078 mL); polysorbate 20 (10 mg); sodium chloride (1.5 mg); butylated hydroxytoluene (0.02 mg); sodium phosphate dibasic, heptahydrate (14.4 mg); sodium phosphate monobasic, monohydrate (1.8 mg); and disodium edetate (1.1 mg).

12.1 Mechanism Of Action

Doxercalciferol is a synthetic vitamin D2 analog that requires metabolic activation to form the active 1α,25-(OH)2D2 metabolite, which binds to the vitamin D receptor (VDR) to result in the selective activation of vitamin D responsive pathways. Vitamin D and doxercalciferol have been shown to reduce PTH levels by inhibiting PTH synthesis and secretion.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a 104-week carcinogenicity study in rats, there was an increased incidence of benign and malignant adrenal pheochromocytomas in both males and females at oral doses of 0.04, 0.13, and 0.39 mcg/kg/day (less than the maximum recommended human oral dose of 60 mcg/week based on mcg/m2 body surface area). This increased incidence of pheochromocytomas in rats may be due to altered calcium homeostasis by doxercalciferol. 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/week based on mcg/m2 body surface area).

14 Clinical Studies

The safety and efficacy of Doxercalciferol Injection have been established based on adult studies of doxercalciferol injection in patients with CKD on hemodialysis. Below is a display of the results of these studies of doxercalciferol injection.The safety and effectiveness of doxercalciferol injection was evaluated in two open-label, single-arm, multi-center clinical studies (Study C and Study D) in a total of 70 patients with CKD on hemodialysis. Patients in Study C were an average age of 54 years (range: 23 to 73), were 50% male, and were 61% African-American, 25% Caucasian, and 14% Hispanic, and had been on hemodialysis for an average of 65 months. Patients in Study D were an average age of 51 years (range: 28 to 76), were 48% male, and 100% African-American and had been on hemodialysis for an average of 61 months. This group of 70 of the 138 patients who had been treated with doxercalciferol capsules in prior clinical studies received doxercalciferol injection in an open-label fashion for 12 weeks following an 8-week washout (control) period. Dosing of doxercalciferol injection was initiated at the rate of 4 mcg administered at the end of each dialysis session (3 times weekly) for a total of 12 mcg per week. The dosage of doxercalciferol injection was adjusted to achieve intact PTH levels (measured weekly) within a targeted range of 150 pg/mL to 300 pg/mL. The dosage was increased by 2 mcg per dialysis session after 8 weeks of treatment if the intact PTH levels remained above 300 pg/mL and were greater than 50% of baseline levels. The maximum dosage was limited to 18 mcg per week. If at any time during the study intact PTH fell below 150 pg/mL, doxercalciferol injection was immediately suspended and restarted at a lower dosage the following week. Mean weekly doses ranged from 9 mcg to 13 mcg in Study C and ranged from 9 mcg to 12 mcg in Study D.Fifty-two (74%) of the 70 patients who were treated with doxercalciferol injection achieved intact PTH levels ≤300 pg/mL. Forty-one (59%) of these patients exhibited plasma intact PTH levels ≤300 pg/mL on at least 3 occasions. Thirty-six (51%) patients had plasma intact PTH levels <150 pg/mL on at least one occasion during study participation. Decreases in plasma intact PTH from baseline values were calculated using as baseline the average of the last 3 values obtained during the 8-week washout period and are displayed in Table 3.Table 3: Intact PTH Summary Data for Patients with CKD on Dialysis Receiving Doxercalciferol Injection in Studies C and DIntact PTH LevelStudy C(n=28)Study D(n=42)Combined Protocols(n=70)Baseline (Mean of Weeks -2, -1, and 0)Mean (SE)698 (60)762 (65)736 (46)Median562648634On-treatment (Week 12Values were carried forward for the two patients on study for 10 weeks)Mean (SE)406 (63)426 (60)418 (43)Median311292292Change from BaselineTreatment intact PTH minus baseline intact PTHMean (SE)-292 (55)-336 (41)-318 (33)Median-274-315-304P-valueWilcoxon one-sample test0.0040.001<0.001Doxercalciferol injection treatment resulted in at least 30% reduction from baseline in mean intact PTH levels during the 12-week open-label treatment period in more than 92% of the 70 treated patients.

16 How Supplied/Storage And Handling

Doxercalciferol Injection is a clear, colorless solution in multiple-dose amber glass vials supplied as follows:Total Strength per Total VolumeStrength per mLFlip-off Cap ColorVial Count per Carton × Total Vial Volume and Vial TypeCarton NDC4 mcg/2 mL2 mcg/mLOrange50 × 2 mL multiple-dose vials0409-1330-0110 mcg/5 mL2 mcg/mLGray50 × 5 mL multiple-dose vials0409-1331-01

Storage And Handling

StorageStore multiple-dose vials at 20°C to 25°C (68°F to 77°F) [see USP controlled room temperature].Protect from light. Store unopened vial in original carton. Discard vial 14 days after opening.

* Please review the disclaimer below.