DOXERCALCIFEROL injection, solution
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Patient Information ⮝

Hypercalcemia

Advise 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)[seeWarnings and Precautions (5.1)].

Hypersensitivity

Inform patients that hypersensitivity reactions can occur with doxercalciferol[seeWarnings and Precautions (5.3)].

Monitoring

Inform patients that they will need routine monitoring of laboratory parameters such as calcium and intact PTH while receiving doxercalciferol. 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[seeDosage and Administration (2),Drug Interactions (7)].

Drug Interactions

Advise 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 if a new medication is prescribed[seeDrug Interactions (7)].

Manufactured By: ⮝

Amneal Pharmaceuticals Pvt. Ltd.

Parenteral Unit

Ahmedabad 382213, INDIA

Distributed By: ⮝

Amneal PharmaceuticalsLLC

Bridgewater, NJ 08807

Rev. 05-2019-03

1. Highlights Of Prescribing Information
2. Indications And Usage
3. Dosage And Administration
4. Dosage Forms And Strengths
5. Contraindications
6. Warnings And Precautions
7. Adverse Reactions
8. Drug Interactions
9. 1 Indications And Usage
10. 2 Dosage And Administration
11. 3 Dosage Forms And Strengths
12. 4 Contraindications
13. 5 Warnings And Precautions
14. 6 Adverse Reactions
15. 7 Drug Interactions
16. 8 Use In Specific Populations
17. 10 Overdosage
18. 11 Description
19. 12 Clinical Pharmacology
20. 13 Nonclinical Toxicology
21. 14 Clinical Studies
22. 16 How Supplied/storage And Handling
23. Package Label.principal Display Panel
24. Principal Display Panel - 5 Ml Vial Label
25. Principal Display Panel - 5 Ml Vial Carton
26. Principal Display Panel - 2 Ml Vial Label
27. Principal Display Panel - 2 Ml Vial Carton
28. Principal Display Panel
29. Description
30. Clinical Pharmacology
31. Mechanism Of Action
32. Indications And Usage
33. Contraindications
34. Warnings
35. Precautions
36. Adverse Reactions
37. Overdosage
38. Dosage And Administration
39. How Supplied

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use DOXERCALCIFEROL INJECTION safely and effectively. See full prescribing information for DOXERCALCIFEROL INJECTION.

DOXERCALCIFEROL injection, for intravenous use
Initial U.S. Approval: 1999

Indications And Usage ⮝

Doxercalciferol is a synthetic vitamin D2 analog:

• Doxercalciferol injection is indicated for the treatment of secondary hyperparathyroidism in adult patients with CKD on dialysis. (1)

Dosage And Administration ⮝

• Before initiating treatment, ensure serum calcium is not above the upper limit of normal. (2.1)
• Dosage for doxercalciferol injection in patients with CKD on dialysis: Initiate dosing at 4 mcg by bolus intravenous administration three times weekly at the end of dialysis (no more frequently than every other day). Maximum dose is 18 mcg weekly. (2.4)
• Target the maintenance dose of doxercalciferol injection to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits. (2)
• See Full Prescribing Information for dose titration, laboratory monitoring, and important administration instructions. (2)

Dosage Forms And Strengths ⮝

• Injection: 4 mcg/2 mL (2 mcg/mL) multiple-dose vial (3)

Contraindications ⮝

• Hypercalcemia (4)
• Vitamin D toxicity (4)
• Know hypersensitivity to doxercalciferol or any of the inactive ingredients of doxercalciferol injection. (4)

Warnings And Precautions ⮝

• Hypercalcemia: Can occur during treatment with doxercalciferol and can lead to cardiac arrhythmias and seizures. Severe hypercalcemia may require emergency attention. Risk may be increased when used concomitantly with high dose calcium preparations, thiazide diuretics, or vitamin D compounds. Monitor serum calcium prior to initiation and during treatment and adjust dose accordingly. (2, 5.1)
• Digitalis Toxicity: Hypercalcemia increases the risk of digitalis toxicity. In patients using digitalis compounds, monitor serum calcium and patients for signs and symptoms of digitalis toxicity. Increase frequency of monitoring when initiating or adjusting the dose of doxercalciferol. (5.2)
• Serious Hypersensitivity Reactions: Anaphylaxis, with symptoms of angioedema, hypotension, unresponsiveness, chest discomfort, shortness of breath, and cardiopulmonary arrest, has been reported in hemodialysis patients after administration of doxercalciferol. Monitor patients upon treatment initiation for hypersensitivity reactions. Should a reaction occur, discontinue and treat. (5.3)
• Adynamic Bone Disease: May develop and increase risk of fractures if intact PTH levels are suppressed to abnormally low levels. Monitor intact PTH levels to avoid oversuppression and adjust dose if needed. (5.4)

Adverse Reactions ⮝

The most common adverse reactions in patients with CKD on dialysis (incidence > 5%) were headache, malaise, edema, nausea/vomiting, dyspnea, dizziness, pruritus, and bradycardia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

• Cytochrome P450 inhibitors: Formation of the active doxercalciferol moiety may be hindered and may necessitate dosage adjustment. Monitor intact PTH and serum calcium concentrations closely. (7)
• Enzyme inducers: Formation of the active doxercalciferol moiety may be affected and may necessitate dosage adjustment. Monitor intact PTH and serum calcium concentrations closely. (7)
• Magnesium-containing products: Combined use may cause hypermagnesemia. Monitor serum magnesium concentrations more frequently and adjust dose as needed. (7)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 5/2019

1 Indications And Usage ⮝

• Doxercalciferol injection is indicated for the treatment of secondary hyperparathyroidism in adult patients with CKD on dialysis.

2 Dosage And Administration ⮝

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)].

2.4 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 3 days at 2 to 8 C (36 to 46 F). Discard unused portion of multiple-dose vial after 3 days [see How Supplied/Storage and Handling (16)].

2.5 Dosage Recommendations for Doxercalciferol Injection in Patients with CKD on Dialysis

• 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.

2.6 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: Sterile, clear, colorless aqueous solution available as 4 mcg/2 mL (2 mcg/mL) multiple-dose vial.

4 Contraindications ⮝

Doxercalciferol 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 Warnings And Precautions ⮝

5.1 Hypercalcemia

Hypercalcemia may occur during doxercalciferol 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. In these circumstances, frequent serum calcium monitoring and doxercalciferol dose adjustments may be required.

When initiating doxercalciferol or adjusting doxercalciferol dose, measure serum calcium frequently (weekly in patients with CKD on dialysis). 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 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 can cause hypercalcemia [see Warnings and Precautions (5.1)] which increases the risk of digitalis toxicity. In patients using doxercalciferol 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 [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 upon initiation of treatment for hypersensitivity reactions. Should a hypersensitivity reaction occur, discontinue doxercalciferol, 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 to abnormally low levels. Monitor intact PTH levels to avoid oversuppression and adjust the doxercalciferol 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.

Doxercalciferol Capsules

Adverse reactions in patients with CKD on dialysis

Doxercalciferol capsules have been 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 capsule groups at a frequency of 2% or greater, and more frequently than in the placebo group are presented in Table 2.

Table 2: Adverse Reactions Occurring in 2% Doxercalciferol Capsule-Treated Patients with CKD on Dialysis and Greater than Placebo in Two Double-Blind Clinical Studies

Adverse Reaction*	Doxercalciferol (n=61) %	Placebo (n=61) %
Edema	34	21
Malaise	28	20
Headache	28	18
Nausea/Vomiting	21	20
Dizziness	12	10
Dyspnea	12	7
Pruritus	8	7
Bradycardia	7	5
Anorexia	5	3
Dyspepsia	5	2
Arthralgia	5	0
Weight increase	5	0
Abscess	3	0
Sleep disorder	3	0
* A patient who reported the same medical term more than once was counted only once for that medical term.

Doxercalciferol Injection

Adverse reactions in patients with CKD on hemodialysis

Doxercalciferol injection has been studied in 70 patients with CKD on hemodialysis in two 12-week, open-label, single-arm, multicenter studies [see Clinical Studies (14.3)]. The incidence of hypercalcemia and hyperphosphatemia increased during therapy with doxercalciferol injection. Patients with higher pretreatment 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 2.

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 ⮝

Tables 3 include clinically significant drug interactions with doxercalciferol injection.

Table 3: Clinically Significant Drug Interactions with Doxercalciferol Injection

Drugs that May Increase the Risk of Hypercalcemia
Clinical Impact	Concomitant 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.
Examples	Calcium-containing products, other vitamin D compounds or thiazide diuretics
Intervention	Monitor serum calcium concentrations more frequently and adjust doxercalciferol dose as needed [see Warnings and Precautions (5.1)].
Digitalis Compounds
Clinical Impact	Doxercalciferol can cause hypercalcemia which can potentiate the risk of digitalis toxicity.
Intervention	Monitor patients for signs and symptoms of digitalis toxicity and increase frequency of serum calcium monitoring when initiating or adjusting the dose of doxercalciferol in patients receiving digitalis compounds [see Warnings and Precautions (5.2)].
Cytochrome P450 Inhibitors
Clinical Impact	Doxercalciferol 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)].
Examples	Ketoconazole and erythromycin
Intervention	If a patient initiates or discontinues therapy with a cytochrome P450 inhibitor, dose adjustment of doxercalciferol may be necessary. Monitor intact PTH and serum calcium concentrations closely.
Enzyme Inducers
Clinical Impact	Doxercalciferol is activated by CYP 27 in the liver. Enzyme inducers may affect the 25-hydroxylation of doxercalciferol [see Clinical Pharmacology (12.3)].
Examples	Glutethimide and phenobarbital
Intervention	If a patient initiates or discontinues therapy with an enzyme inducer, dose adjustment of doxercalciferol may be necessary. Monitor intact PTH and serum calcium concentrations closely.
Magnesium-containing Products
Clinical Impact	Concomitant administration of doxercalciferol and high doses of magnesium-containing products may increase the risk of hypermagnesemia.
Examples	Magnesium-containing products such as antacids
Intervention	Avoid use of magnesium-containing products and doxercalciferol in patients on chronic renal dialysis.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Risk Summary

The limited available data with doxercalciferol 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% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Chronic kidney disease in pregnancy increases the risk for maternal hypertension and preeclampsia, miscarriage, preterm delivery polyhydramnios, stillbirth, and low-birth-weight infants.

Data

Animal data

There 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.

8.2 Lactation

Risk Summary

There 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 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 and any potential adverse effects on the breastfed child from doxercalciferol or from the underlying maternal condition.

Clinical Considerations

Infants 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.

8.4 Pediatric Use

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

8.5 Geriatric Use

Clinical studies of doxercalciferol 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 appropriately. More frequent monitoring of intact PTH, calcium, and phosphorus levels should be done in patients with hepatic impairment.

10 Overdosage ⮝

Overdosage of doxercalciferol 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 administration. Serum calcium levels should be measured until normal. Based on similarities between doxercalciferol and its active metabolite, 1 ,25-(OH)2D2, it is expected that doxercalciferol is not removed from the blood by dialysis.

11 Description ⮝

Doxercalciferol injection contains doxercalciferol, which is a synthetic vitamin D2 analog. Doxercalciferol undergoes metabolic activation in vivo to form 1 ,25-dihydroxyvitamin D2 (1 ,25-(OH)2D2), a naturally occurring, biologically active form of vitamin D2.

Doxercalciferol, USP is a colorless crystalline compound with a calculated molecular weight of 412.66 and a molecular formula of C28H44O2. It is soluble in oils and organic solvents, but is relatively insoluble in water. Chemically, doxercalciferol is (1 ,3 ,5Z,7E,22E)-9,10-secoergosta-5,7,10(19),22-tetraene-1,3-diol. The structural formula is:

Doxercalciferol injection 2 mL multiple-dose vials contain 4 mcg/2 mL (2 mcg/mL) of doxercalciferol, USP. Each milliliter (mL) of solution contains 2 mcg doxercalciferol, USP and the following inactive ingredients: butylated hydroxytoluene (0.02 mg); disodium edetate (1.1 mg); ethanol, 100% (0.075 mL); polysorbate 20 (10 mg); sodium chloride (1.5 mg); sodium phosphate dibasic, heptahydrate (14.4 mg); and sodium phosphate monobasic, monohydrate (1.8 mg).

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

Doxercalciferol is a synthetic vitamin D2 analog that requires metabolic activation to form the active 1 ,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.

12.3 Pharmacokinetics

Absorption

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

Elimination

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

Metabolism

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

Specific Populations

Patients with renal impairment

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

13 Nonclinical Toxicology ⮝

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 ⮝

14.3 Clinical Studies of Doxercalciferol Injection in Patients with CKD on Dialysis

The safety and effectiveness of doxercalciferol injection were evaluated in two open-label, single-arm, multicenter 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 (Study A and Study B) 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 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 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 6.

Table 6: Intact PTH Summary Data for Patients with CKD on Dialysis Receiving Doxercalciferol Injection in Studies C and D

Intact PTH Level	Study 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)
Median	562	648	634
On-treatment (Week 12*)
Mean (SE)	406 (63)	426 (60)	418 (43)
Median	311	292	292
Change from Baseline
Mean (SE)	-292 (55)	-336 (41)	-318 (33)
Median	-274	-315	-304
P-value	0.004	0.001	<0.001
* Values were carried forward for the two patients on study for 10 weeks Treatment intact PTH minus baseline intact PTH Wilcoxon one-sample test

Doxercalciferol 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 ⮝

How Supplied

Doxercalciferol Injection is a sterile, clear, colorless aqueous solution for intravenous injection supplied in multi-dose amber glass vials containing 4 mcg doxercalciferol in 2 mL of solution. The closure consists of a fluorocarbon-coated chlorobutyl stopper, with an aluminum seal and a red plastic flip-off cap.

It is available as follows:

4 mcg/ 2 mL (2 mcg/mL)

2 mL, Multi-dose Vial: NDC 70121-1408-1

50 Multi-dose Vials in a Carton: NDC 70121-1408-5

Storage and Handling

Store unopened multi-dose vials 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].

Store opened multi-dose vials at 2 to 8 C (36 to 46 F). Discard 3 days after opening.

Protect from light. Store unopened vial in original carton.

Package Label.principal Display Panel ⮝

Doxercalciferol Injection, 4 mcg/2 mL

2 mL Multi-dose Vial Label

NDC 68180-718-01

Doxercalciferol Injection, 4 mcg/2 mL

Carton Label- 2 mL Multi-dose Vials in Package of 50

NDC 68180-718-52

DOXERCALCIFEROL doxercalciferol injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68180-718 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXERCALCIFEROL (UNII: 3DIZ9LF5Y9) (DOXERCALCIFEROL - UNII:3DIZ9LF5Y9) DOXERCALCIFEROL 4 ug in 2 mL

Inactive Ingredients Ingredient Name Strength ALCOHOL (UNII: 3K9958V90M) 0.15 mL in 2 mL BUTYLATED HYDROXYTOLUENE (UNII: 1P9D0Z171K) 0.04 mg in 2 mL EDETATE DISODIUM (UNII: 7FLD91C86K) 2.2 mg in 2 mL POLYSORBATE 20 (UNII: 7T1F30V5YH) 20 mg in 2 mL SODIUM CHLORIDE (UNII: 451W47IQ8X) 3 mg in 2 mL SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE (UNII: 70WT22SF4B) 28.8 mg in 2 mL SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE (UNII: 593YOG76RN) 3.6 mg in 2 mL

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68180-718-52 50 in 1 CARTON 08/15/2019 1 NDC:68180-718-01 2 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product 2 NDC:68180-718-12 10 in 1 CARTON 08/15/2019 2 NDC:68180-718-01 2 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA210801 08/15/2019

Labeler - Lupin Pharmaceuticals, Inc. (089153071)

Registrant - LUPIN LIMITED (675923163)

Establishment
Name	Address	ID/FEI	Business Operations
Gland Pharma Limited		918601238	MANUFACTURE(68180-718) , PACK(68180-718)

Revised: 7/2019 Document Id: 3e975b2c-5319-42ca-aa47-99a40a5086ba 34391-3 Set id: b00fcf3f-c576-4121-b305-05bcbdd3525e Version: 5 Effective Time: 20190711 Lupin Pharmaceuticals, Inc.

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5 mL Multi-Dose Vial
Rx only

Doxercalciferol
Injection
10 mcg/5 mL (2 mcg/mL)

For Intravenous Use Only

Dist. by Hospira, Inc.
Lake Forest, IL 60045 USA

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50 x 5 mL Multi-Dose Vials
Rx only
NDC 0409-1331-01

Doxercalciferol Injection
10 mcg/5 mL (2 mcg/mL)

For Intravenous Use Only
Store unopened vial in original carton;
discard vial 14 days after opening

Hospira

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NDC 0409-1330-11
Rx only
2 mL Multi-Dose Vial

Doxercalciferol
Injection
4 mcg/2 mL (2 mcg/mL)

For Intravenous Use Only

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50 x 2 mL Multi-Dose Vials
Rx only
NDC 0409-1330-01

Doxercalciferol Injection
4 mcg/2 mL (2 mcg/mL)

For Intravenous Use Only
Store unopened vial in original carton;
discard vial 14 days after opening

Hospira

DOXERCALCIFEROL doxercalciferol injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0409-1331 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXERCALCIFEROL (UNII: 3DIZ9LF5Y9) (DOXERCALCIFEROL - UNII:3DIZ9LF5Y9) DOXERCALCIFEROL 2 ug in 1 mL

Inactive Ingredients Ingredient Name Strength ALCOHOL (UNII: 3K9958V90M) 0.078 mL in 1 mL POLYSORBATE 20 (UNII: 7T1F30V5YH) 10 mg in 1 mL SODIUM CHLORIDE (UNII: 451W47IQ8X) 1.5 mg in 1 mL BUTYLATED HYDROXYTOLUENE (UNII: 1P9D0Z171K) 0.02 mg in 1 mL SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE (UNII: 70WT22SF4B) 14.4 mg in 1 mL SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE (UNII: 593YOG76RN) 1.8 mg in 1 mL EDETATE DISODIUM (UNII: 7FLD91C86K) 1.1 mg in 1 mL WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0409-1331-01 50 in 1 CARTON 10/24/2019 10/24/2019 1 NDC:0409-1331-11 5 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA208614 10/24/2019 10/24/2019

DOXERCALCIFEROL doxercalciferol injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0409-1330 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXERCALCIFEROL (UNII: 3DIZ9LF5Y9) (DOXERCALCIFEROL - UNII:3DIZ9LF5Y9) DOXERCALCIFEROL 2 ug in 1 mL

Inactive Ingredients Ingredient Name Strength ALCOHOL (UNII: 3K9958V90M) 0.078 mL in 1 mL POLYSORBATE 20 (UNII: 7T1F30V5YH) 10 mg in 1 mL SODIUM CHLORIDE (UNII: 451W47IQ8X) 1.5 mg in 1 mL BUTYLATED HYDROXYTOLUENE (UNII: 1P9D0Z171K) 0.02 mg in 1 mL SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE (UNII: 70WT22SF4B) 14.4 mg in 1 mL SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE (UNII: 593YOG76RN) 1.8 mg in 1 mL EDETATE DISODIUM (UNII: 7FLD91C86K) 1.1 mg in 1 mL WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0409-1330-01 50 in 1 CARTON 10/24/2019 1 NDC:0409-1330-11 2 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA208614 10/24/2019

Labeler - Hospira, Inc. (141588017)

Establishment
Name	Address	ID/FEI	Business Operations
Hospira, Inc.		030606222	ANALYSIS(0409-1330, 0409-1331) , LABEL(0409-1330, 0409-1331) , MANUFACTURE(0409-1330, 0409-1331) , PACK(0409-1330, 0409-1331)

Establishment
Name	Address	ID/FEI	Business Operations
Pfizer Healthcare India Private Limited		650490118	ANALYSIS(0409-1330, 0409-1331)

Revised: 10/2019 Document Id: f1c1c084-f5fa-4742-9748-dc8d5c87130d 34391-3 Set id: df65e54b-d134-4b64-ade1-b86cc12bc5eb Version: 3 Effective Time: 20191024 Hospira, Inc.

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NDC 70121-1408-1

Doxercalciferol Injection, 4 mcg/2 mL

Rx Only

Vial Label

Amneal Pharmaceuticals LLC

NDC 70121-1408-5

Doxercalciferol Injection, 4 mcg/2 mL

Rx Only

Carton Label

Amneal Pharmaceuticals LLC

DOXERCALCIFEROL doxercalciferol injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70121-1408 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXERCALCIFEROL (UNII: 3DIZ9LF5Y9) (DOXERCALCIFEROL - UNII:3DIZ9LF5Y9) DOXERCALCIFEROL 4 ug in 2 mL

Inactive Ingredients Ingredient Name Strength 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)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:70121-1408-5 50 in 1 CARTON 05/24/2017 1 NDC:70121-1408-1 2 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA208975 05/24/2017

Labeler - Amneal Pharmaceuticals LLC (827748190)

Revised: 5/2019 Document Id: d2692796-ae99-4cc5-aa99-7cd4ee20f6b8 34391-3 Set id: fa7e4294-0f59-492d-bd4f-d06a6c2d522c Version: 4 Effective Time: 20190505 Amneal Pharmaceuticals LLC

Description  ⮝

Doxercalciferol, the active ingredient in Doxercalciferol Injection, is a synthetic vitamin D2 analog that undergoes metabolic activation in vivo to form 1 ,25-dihydroxyvitamin D2 (1 ,25-(OH)2D2), a naturally occurring, biologically active form of vitamin D2. Doxercalciferol is available as a sterile, clear, colorless aqueous solution for intravenous injection. Doxercalciferol Injection is supplied in a stoppered 2 mL amber glass vial containing either 4 mcg/2 mL or 2 mcg/mL. Each vial includes an aluminum seal and gray (4 mcg/2 mL) or aqua (2 mcg/mL) flip-off cap. Each milliliter (mL) of solution contains doxercalciferol, 2 mcg; alcohol 5% (v/v); 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.

Doxercalciferol is a colorless crystalline compound with a calculated molecular weight of 412.66 and a molecular formula of C28H44O2. It is soluble in oils and organic solvents, but is relatively insoluble in water. Chemically, doxercalciferol is (1 ,3 ,5Z,7E,22E)-9,10-secoergosta-5,7,10(19),22-tetraene-1,3-diol and has the structural formula presented in Figure 1.

Figure 1: Chemical Structure of Doxercalciferol

Other names frequently used for doxercalciferol are 1 -hydroxyvitamin D2, 1 -OH-D2, and 1 -hydroxyergocalciferol.

Clinical Pharmacology  ⮝

Vitamin D levels in humans depend on two sources: (1) exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol in the skin to vitamin D3 (cholecalciferol) and (2) dietary intake of either vitamin D2 (ergocalciferol) or vitamin D3. Vitamin D2 and vitamin D3 must be metabolically activated in the liver and kidney before becoming fully active on target tissues. The initial step in the activation process is the introduction of a hydroxyl group in the side chain at C-25 by the hepatic enzyme, CYP 27 (a vitamin D-25-hydroxylase). The products of this reaction are 25-(OH)D2 and 25-(OH)D3, respectively. Further hydroxylation of these metabolites occurs in the mitochondria of kidney tissue, catalyzed by renal 25-hydroxyvitamin D-1- -hydroxylase to produce 1 ,25-(OH)2D2, the primary biologically active form of vitamin D2, and 1 ,25-(OH)2D3 (calcitriol), the biologically active form of vitamin D3.

Mechanism Of Action  ⮝

Calcitriol (1 ,25-(OH)2D3) and 1 ,25-(OH)2D2 regulate blood calcium at levels required for essential body functions. Specifically, the biologically active vitamin D metabolites control the intestinal absorption of dietary calcium, the tubular reabsorption of calcium by the kidney and, in conjunction with parathyroid hormone (PTH), the mobilization of calcium from the skeleton. They act directly on bone cells (osteoblasts) to stimulate skeletal growth, and on the parathyroid glands to suppress PTH synthesis and secretion. These functions are mediated by the interaction of these biologically active metabolites with specific receptor proteins in the various target tissues. In uremic patients, deficient production of biologically active vitamin D metabolites (due to lack of or insufficient 25-hydroxyvitamin D-1-alpha-hydroxylase activity) leads to secondary hyperparathyroidism, which contributes to the development of metabolic bone disease in patients with renal failure.

Pharmacokinetics and Metabolism

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

Peak blood levels of 1 ,25-(OH)2D2 are reached at 8 +/- 5.9 hours (mean +/- SD) after a single intravenous dose of 5 mcg of doxercalciferol. The mean elimination half-life of 1 ,25-(OH)2D2 after an oral dose is approximately 32 to 37 hours with a range of up to 96 hours. The mean elimination half-life in patients with end stage renal disease (ESRD) and in healthy volunteers appears to be similar following an oral dose. Hemodialysis causes a temporary increase in 1 ,25-(OH)2D2 mean concentrations presumably due to volume contraction. 1 ,25-(OH)2D2 is not removed from blood during hemodialysis.

Clinical Studies

The safety and effectiveness of doxercalciferol injection were evaluated in two open-label, single-arm, multi-centered clinical studies (Study C and Study D) in a total of 70 patients with chronic kidney disease on hemodialysis (Stage 5 CKD). 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 (Study A and Study B) 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 in an attempt to achieve iPTH levels within a targeted range of 150 to 300 pg/mL. The dosage was increased by 2 mcg per dialysis session after 8 weeks of treatment if the iPTH 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 trial iPTH fell below 150 pg/mL, doxercalciferol injection was immediately suspended and restarted at a lower dosage the following week.

Results:

Fifty-two of the 70 patients who were treated with doxercalciferol injection achieved iPTH levels 300 pg/mL. Forty-one of these patients exhibited plasma iPTH levels 300 pg/mL on at least 3 occasions. Thirty-six patients had plasma iPTH levels < 150 pg/mL on at least one occasion during study participation.

Mean weekly doses in Study C ranged from 8.9 mcg to 12.5 mcg. In Study D, the mean weekly doses ranged from 9.1 mcg to 11.6 mcg.

Decreases in plasma iPTH 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 the table below. Plasma iPTH levels were measured weekly during the 12-week study.

Table 1: iPTH Summary Data for Patients Receiving Doxercalciferol Injection

*Values were carried forward for the two patients on study for 10 weeks
**Treatment iPTH minus baseline iPTH
***Wilcoxon one-sample test
iPTH Level	Study 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)
Median	562	648	634
On-treatment (Week 12 * )
Mean (SE)	406 (63)	426 (60)	418 (43)
Median	311	292	292
Change from Baseline **
Mean (SE)	-292 (55)	-336 (41)	-318 (33)
Median	-274	-315	-304
P-value ***	0.004	0.001	<0.001

In both studies, iPTH levels increased progressively and significantly in 62.9% of patients during the 8-week washout (control) period during which no vitamin D derivatives were administered. In contrast, doxercalciferol injection treatment resulted in a clinically significant reduction (at least 30%) from baseline in mean iPTH levels during the 12-week open-label treatment period in more than 92% of the 70 treated patients.

Table 2 shows the numbers of patients who achieved iPTH levels below 300 pg/mL on one, two, or three or more non-consecutive occasions during the 12-week treatment period. Thirty-seven of 70 patients (53%) had plasma iPTH levels within the targeted range (150 to 300 pg/mL) during Weeks 10 to 12.

Table 2: Number of times iPTH 300 pg/mL

	1	2	3
Study C	3/28	0/28	16/28
Study D	4/42	4/42	25/42

Indications And Usage  ⮝

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

Contraindications  ⮝

Doxercalciferol Injection should not be given to patients with a tendency towards hypercalcemia or current evidence of vitamin D toxicity.

Doxercalciferol Injection is contraindicated in patients with previous hypersensitivity to doxercalciferol or any of its ingredients (see WARNINGS and ADVERSE REACTIONS).

Warnings  ⮝

Overdosage of any form of vitamin D, including doxercalciferol is dangerous (see OVERDOSAGE). Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention. Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the action of digitalis drugs. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. The serum calcium times serum phosphorus (Ca X P) product should be maintained at <55 mg2/dL2 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 1 ,25-(OH)2D2, a potent metabolite of vitamin D2, pharmacologic doses of vitamin D and its derivatives should be withheld during doxercalciferol injection 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 injection in reducing blood PTH levels. If hypercalcemia occurs after initiating doxercalciferol injection therapy, the dose of doxercalciferol injection and/or calcium-containing phosphate binders should be decreased. If hyperphosphatemia occurs after initiating doxercalciferol injection, the dose of doxercalciferol injection should be decreased and/or the dose of phosphate binders increased. (See dosing recommendations for doxercalciferol injection under DOSAGE AND ADMINISTRATION).

Magnesium-containing antacids and doxercalciferol injection 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 injection, 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 injection, 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 injection 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	1.0	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 injection 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. Magnesiumcontaining antacids and doxercalciferol injection 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 injection and may necessitate dosage adjustments. Cytochrome P450 inhibitors (such as ketoconazole and erythromycin) may inhibit the 25-hydroxylation of doxercalciferol injection. Hence, formation of the active doxercalciferol injection 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/m2 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/m2 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

A patient who reported the same medical term more than once was counted only once for that medical term.
Adverse Event	Doxercalciferol Injection (n=61) %	Placebo (n=61) %
Body as a Whole
Abscess	3.3	0.0
Headache	27.9	18.0
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	0.0
Metabolic and Nutritional
Edema	34.4	21.3
Weight increase	4.9	0.0
Nervous System
Dizziness	11.5	9.8
Sleep disorder	3.3	0.0
Respiratory System
Dyspnea	11.5	6.6
Skin
Pruritus	8.2	6.6

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.

Overdosage  ⮝

Administration of doxercalciferol to patients in excess doses can cause hypercalcemia, hypercalciuria, hyperphosphatemia, and oversuppression 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 Injection

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, 1 ,25-(OH)2D2, it is expected that doxercalciferol is not removed from the blood by dialysis.

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 mg2/dL2 is noted, the dose of doxercalciferol 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 Supplied  ⮝

Doxercalciferol Injection is supplied in single-use 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 gray (4 mcg/2 mL) or aqua (2 mcg/mL) plastic flip-off cap.

NDC 17478-987-01 1 mL (2 mcg/mL) single-dose vial
NDC 17478-987-11 1 mL (2 mcg/mL) vials in packages of 10
NDC 17478-987-21 1 mL (2 mcg/mL) vials in packages of 25
NDC 17478-988-02 2 mL (4 mcg/2 mL) single-dose vial
NDC 17478-988-12 2 mL (4 mcg/2 mL) vials in packages of 10
NDC 17478-988-22 2 mL (4 mcg/2 mL) vials in packages of 25

Storage: Store at 20 to 25 C (68 to 77 F) [see USP controlled room temperature].

Protect from light.

Discard unused portion.

Rx only
AKORN

Manufactured by: Akorn, Inc.
Lake Forest, IL 60045

DX00N Rev. 01/19

Principal Display Panel Text for Container Label:

NDC 17478-987-01

Doxercalciferol

Injection

2 mcg/mL

For Intravenous Use Only

Contains: Alcohol 5% (v/v)

Principal Display Panel Text for Carton Label:

NDC 17478-987-11

Doxercalciferol Injection

2 mcg/mL

For Intravenous Use Only

Contains Alcohol 5% (v/v)

10 x 1 mL Single-dose Vials

Rx only Akorn Logo

DOXERCALCIFEROL doxercalciferol injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:17478-988 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Doxercalciferol (UNII: 3DIZ9LF5Y9) (Doxercalciferol - UNII:3DIZ9LF5Y9) Doxercalciferol 4 ug in 2 mL

Inactive Ingredients Ingredient Name Strength Alcohol (UNII: 3K9958V90M) Sodium Phosphate, Dibasic, Heptahydrate (UNII: 70WT22SF4B) Polysorbate 20 (UNII: 7T1F30V5YH) Sodium Phosphate, Monobasic, Monohydrate (UNII: 593YOG76RN) Sodium Chloride (UNII: 451W47IQ8X) Edetate Disodium (UNII: 7FLD91C86K) Butylated Hydroxytoluene (UNII: 1P9D0Z171K)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:17478-988-12 10 in 1 CARTON 05/08/2015 1 NDC:17478-988-02 2 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product 2 NDC:17478-988-22 25 in 1 CARTON 05/08/2015 2 NDC:17478-988-02 2 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203929 05/08/2015

DOXERCALCIFEROL doxercalciferol injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:17478-987 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Doxercalciferol (UNII: 3DIZ9LF5Y9) (Doxercalciferol - UNII:3DIZ9LF5Y9) Doxercalciferol 2 ug in 1 mL

Inactive Ingredients Ingredient Name Strength Alcohol (UNII: 3K9958V90M) Sodium Phosphate, Dibasic, Heptahydrate (UNII: 70WT22SF4B) Polysorbate 20 (UNII: 7T1F30V5YH) Sodium Phosphate, Monobasic, Monohydrate (UNII: 593YOG76RN) Sodium Chloride (UNII: 451W47IQ8X) Edetate Disodium (UNII: 7FLD91C86K) Butylated Hydroxytoluene (UNII: 1P9D0Z171K)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:17478-987-11 10 in 1 CARTON 05/08/2015 1 NDC:17478-987-01 1 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product 2 NDC:17478-987-21 25 in 1 CARTON 05/08/2015 2 NDC:17478-987-01 1 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203929 05/08/2015

Labeler - Akorn, Inc. (062649876)

Establishment
Name	Address	ID/FEI	Business Operations
Akorn, Inc		063434679	PACK(17478-988, 17478-987) , LABEL(17478-988, 17478-987)

Establishment
Name	Address	ID/FEI	Business Operations
Akorn, Inc.		155135783	MANUFACTURE(17478-988, 17478-987) , ANALYSIS(17478-988, 17478-987) , STERILIZE(17478-988, 17478-987)

Revised: 1/2019 Document Id: 76b40268-c6d1-4ac6-8bfb-1c95cffc54d8 34391-3 Set id: b552eae1-840b-425f-b279-787cfeb9645d Version: 6 Effective Time: 20190130 Akorn, Inc.