DOXERCALCIFEROL capsule
For Healthcare Providers >

1. Hypercalcemia:
2. Hypersensitivity:
3. Monitoring:
4. Drug Interactions:
5. 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) [see Warnings and Precautions (5.1)].

Hypersensitivity: ⮝

Inform patients that hypersensitivity reactions can occur with doxercalciferol [see Warnings 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 [see Dosage andAdministration (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 [see Drug Interactions (7)].

Made in India.

Manufactured by:
Cipla Limited
Kurkumbh, Maharashtra, India

Manufactured for:
West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

21072711

Revised April 2019

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)].

Doxercalciferol Capsules

Manufactured by Catalent Pharma Solutions for:
Winthrop U.S.,
a business of sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
A SANOFI COMPANY

HECTOROL Injection

Manufactured by:
Genzyme Corporation
Cambridge, MA 02142

1. Highlights Of Prescribing Information
2. Dosage Forms And Strengths
3. Warnings And Precautions
4. Drug Interactions
5. 1 Indications And Usage
6. 2 Dosage And Administration
7. 3 Dosage Forms And Strengths
8. 4 Contraindications
9. 5 Warnings And Precautions
10. 6 Adverse Reactions
11. 7 Drug Interactions
12. 8 Use In Specific Populations
13. 10 Overdosage
14. 11 Description
15. 12 Clinical Pharmacology
16. 13 Nonclinical Toxicology
17. 14 Clinical Studies
18. 16 How Supplied/storage And Handling
19. Package/label Principal Display Panel
20. 1 Indications And Usage
21. 2 Dosage And Administration
22. 3 Dosage Forms And Strengths
23. 4 Contraindications
24. 5 Warnings And Precautions
25. 6 Adverse Reactions
26. 7 Drug Interactions
27. 8 Use In Specific Populations
28. 10 Overdosage
29. 11 Description
30. 12 Clinical Pharmacology
31. 13 Nonclinical Toxicology
32. 14 Clinical Studies
33. 16 How Supplied/storage And Handling
34. Principal Display Panel - 0.5 Mcg Capsule Bottle Carton
35. Principal Display Panel - 1 Mcg Capsule Bottle Carton
36. Principal Display Panel - 2.5 Mcg Capsule Bottle Carton
37. Principal Display Panel - 0.5 Mcg Capsule
38. Principal Display Panel - 1 Mcg Capsule
39. Principal Display Panel - 2.5 Mcg Capsule
40. Description
41. Clinical Pharmacology
42. Indications And Usage
43. Contraindications
44. Warnings
45. Precautions
46. Adverse Reactions
47. Overdosage
48. Dosage And Administration
49. How Supplied
50. Packaging Information
51. Package/label Display Panel Carton 0.5 Mcg
52. Package/label Display Panel Blister 0.5 Mcg

Highlights Of Prescribing Information ⮝

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

Doxercalciferol capsules, for oral use
HECTOROL (doxercalciferol) injection, for intravenous use
Initial U.S. Approval: 1999

Dosage Forms And Strengths ⮝

• Capsules: 0.5 mcg, 1 mcg, and 2.5 mcg (3)
• Injection: (3)
  • 2 mcg/mL single-dose vial
  • 4 mcg/2 mL (2 mcg/mL) single-dose vial
  • 4 mcg/2 mL (2 mcg/mL) multiple-dose vial

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)

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)
• Cholestyramine: May impair absorption of Doxercalciferol capsules. Administer Doxercalciferol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine. (7)
• Mineral oil or other substances that may affect absorption of fat: May impair absorption of Doxercalciferol capsules. Administer Doxercalciferol capsules at least 1 hour before or 4 to 6 hours after taking substances that may affect absorption.

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 11/2018

1 Indications And Usage  ⮝

Doxercalciferol capsules are indicated for the treatment of secondary hyperparathyroidism in adult patients with Stage 3 or Stage 4 chronic kidney disease (CKD) and adult patients with CKD on dialysis.

2 Dosage And Administration  ⮝

2.1 Prior to Initiation of Doxercalciferol Capsules

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

2.2 Dosage Recommendations for Doxercalciferol Capsules in Patients with Stage 3 or 4 CKD

Initiate doxercalciferol capsules at a dose of 1 mcg orally once daily.

Target the maintenance dose of doxercalciferol 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 at least every two weeks for 3 months after initiation of therapy or dose adjustment, then monthly for 3 months, and every 3 months thereafter.

Titrate the dose of doxercalciferol capsules based on intact PTH. The dose may be increased at 2-week intervals by 0.5 mcg to achieve the desired therapeutic range of intact PTH. The maximum recommended dose of doxercalciferol capsules is 3.5 mcg administered once daily. 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 after one week at a dose that is at least 0.5 mcg lower.

2.3 Dosage Recommendations for Doxercalciferol Capsules in Patients with CKD on Dialysis

Initiate doxercalciferol capsules at a dose of 10 mcg orally administered three times weekly at dialysis (no more frequently than every other day).

Target the maintenance dose of doxercalciferol 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 frequently (e.g., weekly) after initiation of therapy or dose adjustment.

Titrate the dose of doxercalciferol capsules based on intact PTH. The dose may be increased at 8-week intervals by 2.5 mcg to achieve the desired therapeutic range of intact PTH. The maximum recommended dose of doxercalciferol is 20 mcg administered three times weekly at dialysis for a total dose of 60 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 2.5 mcg lower.

2.6 Drug Interactions that May Require Dosage Adjustments of Doxercalciferol

Increased monitoring of serum calcium and dose adjustment of doxercalciferol 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 may be necessary when given concomitantly with cytochrome P450 inhibitors or enzyme inducers [see Drug Interactions (7)].

3 Dosage Forms And Strengths  ⮝

Capsules: soft gelatin, oval capsules with imprinted r available as follows :

0.5 mcg (orange color)

1 mcg (peach color)

2.5 mcg (yellow color)

4 Contraindications  ⮝

Doxercalciferol Capsules 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 capsules or 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 or every 2 weeks for patients with stage 3 or 4 CKD). 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 stage 3 or 4 CKD:

Doxercalciferol capsules have been evaluated in two placebo-controlled, double-blind 24 week studies in patients with Stage 3 or 4 CKD. Patients were treated with doxercalciferol capsules (n=27) or placebo (n=28) [see Clinical Studies (14.1)]. Adverse reactions occurring in the doxercalciferol capsules group at a frequency of 5% or greater and more frequently than in the placebo group are presented in Table 1.

Table 1: Adverse Reactions Occurring in 5% DoxercalciferolCapsule-Treated Patients with CKD on Predialysis and Greater than Placebo in Two Double-Blind Clinical Studies

* Pooled data on adverse reactions from clinical study reports (Studies BCI-CH-115 and BCI-CH-119).
Adverse Reactions*	Doxercalciferol (n=27) %	Placebo (n=28) %
Infection/Bacterial Infection/Viral Infection	30	25
Constipation	26	11
Rhinitis	22	11
Anemia	19	4
Cough	19	4
Dyspnea	19	11
Paresthesia	15	11
Asthenia	15	11
Insomnia	15	4
Hypertonia	11	4
Angina Pectoris	8	0
Dehydration	7	4
Depression	7	0
Dyspepsia	7	4
Edema	7	4
Urinary Tract Infection	7	4
Leukopenia	7	0
Chest pain	7	4
Pruritus	7	4
Sinusitis	7	4

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) [see Clinical Studies (14.2)]. 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

* A patient who reported the same medical term more than once was counted only once for that medical term.
Adverse Reactions*	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

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. 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 and 4 include clinically significant drug interactions with doxercalciferol.

Table 3: Clinically Significant Drug Interactions with Doxercalciferol Injection and Doxercalciferol Capsules

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.

Table 4: Clinically Significant Drug Interactions with Doxercalciferol Capsules

Cholestyramine
Clinical Impact	Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins. Therefore, it may impair intestinal absorption of doxercalciferol capsules.
Intervention	Administer doxercalciferol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine.
Mineral Oil or other Substances that May Affect Absorption of Fat
Clinical Impact	The use of mineral oil or other substances that may affect absorption of fat may influence the absorption and availability of doxercalciferol.
Intervention	Administer doxercalciferol capsules at least 1 hour before or 4 to 6 hours after taking mineral oil or other substances that may affect absorption of fat.

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 andPrecautions (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, the active ingredient in Doxercalciferol Capsules, 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 a white to off-white powder with a calculated molecular weight of 412.65 and a molecular formula of C28H44O2. It is soluble in N,N-dimethylformamide, sparingly soluble in methanol, slightly soluble in acetonitrile and practically insoluble in water. Chemically, doxercalciferol is (1 ,3 ,5Z,7E,22E)-9,10-Seco-ergosta-5,7,10(19),22-tetraene-1,3-diol and has the following structural formula:

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

Doxercalciferol Capsules are soft gelatin capsules containing 0.5 mcg, 1 mcg, or 2.5 mcg doxercalciferol for oral use. Each capsule also contains butylated hydroxyanisole (BHA), dehydrated alcohol, and medium chain triglyceride. The capsule shells contain D&C Yellow No. 10 (0.5 mcg and 2.5 mcg), FD&C Yellow No. 6 (1 mcg only), FD&C Red No. 40 (0.5 mcg only), gelatin, glycerin, Opacode Black, purified water, and titanium dioxide. Opacode Black contains ammonium hydroxide, iron oxide black, isopropyl alcohol, N-butyl alcohol, propylene glycol, and shellac.

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 and at 11 to 12 hours following capsule doses.

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  ⮝

14.1 Clinical Studies of Doxercalciferol Capsules in Patients with Stage 3 or 4 CKD

The safety and effectiveness of doxercalciferol capsules were evaluated in two clinical studies in 55 patients with Stage 3 or 4 CKD. Eighty-two percent of the patients were male, the average age was 65 years, 51% were Caucasian, 40% African-American, and the average serum intact PTH level at baseline was 195 pg/mL. While levels of 25-(OH) vitamin D were not evaluated at baseline, retrospective assessments of stored serum revealed that the mean SD serum 25-(OH) vitamin D was 19 8 ng/mL (range: <5 to 54 ng/mL) in the study population.

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, one group received doxercalciferol capsules and the other placebo during the double-blind period of 24 weeks. The initial dose of doxercalciferol capsules was 1 mcg per day. The dosage of doxercalciferol capsules was adjusted as necessary by the investigator to reduce intact PTH levels to a target of 30% below postwashout baseline. The maximum dosage was limited to 3.5 mcg per day. If at any time during the trial intact PTH fell below 15 pg/mL, doxercalciferol capsules were immediately suspended and restarted at a lower dosage the following week.

Decreases in the mean plasma intact PTH from baseline values were calculated using as baseline the average of the last 2 values obtained during the 8-week washout phase. In analyses of pooled data from the two studies, intact PTH levels decreased from baseline by an average of 101 pg/mL in the doxercalciferol capsules group and by 4 pg/mL in the placebo group (p<0.001). Twenty (74%) of 27 subjects in the doxercalciferol capsules group achieved mean plasma intact PTH suppression of 30% from baseline for the last four weeks of treatment, whereas two (7%) of the 28 subjects treated with placebo achieved this level of intact PTH suppression.

14.2 Clinical Studies of Doxercalciferol Capsules in Patients with CKD on Dialysis

The safety and effectiveness of doxercalciferol capsules were evaluated in two double-blind, placebo-controlled, multicenter clinical studies (Study A and Study B) in a total of 138 patients with CKD on hemodialysis. Patients in Study A were an average age of 52 years (range: 22 to 75), were 55% male, and were 58% African-American, 31% Caucasian, and 11% Hispanic, and had been on hemodialysis for an average of 53 months. Patients in Study B were an average of 52 years (range: 27 to 75), were 45% male, and 99% African-American, and 1% Caucasian, and had been on hemodialysis for an average of 56 months. 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. The initial dose of doxercalciferol capsules during the open-label phase was 10 mcg after each dialysis session (3 times weekly) for a total of 30 mcg per week. The dosage of doxercalciferol was adjusted as necessary by the investigator to achieve intact PTH levels within 150 pg/mL to 300 pg/mL. The maximum dosage was limited to 20 mcg after each dialysis session (60 mcg/week). If at any time during the trial intact PTH fell below 150 pg/mL, doxercalciferol was immediately suspended and restarted at a lower dosage the following week. Mean weekly doses during the 16-week open-label period ranged from 15 mcg to 29 mcg in Study A and from 19 mcg to 28 mcg in Study B.

One hundred and six (77%) of the 138 patients who were treated with doxercalciferol capsules during the 16-week open-label phase achieved intact PTH levels 300 pg/mL. Ninety-four (68%) of these patients exhibited plasma intact PTH levels 300 pg/mL on at least 3 occasions. Eighty-seven (63%) patients had plasma intact PTH levels <150 pg/mL on at least one occasion during the open-label phase of 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 phase and are displayed in Table 5.

Table 5: Intact PTH Summary Data for Patients with CKD on Dialysis Receiving Doxercalciferol Capsules in Studies A and B

* All subjects; last value carried to discontinuation. NA = not applicable
		Intact PTH (pg/mL)
		means SD (n)* p-value vs Baseline p-value vs Placebo
		DoxercalciferolCapsules	Placebo
Study A	Baseline	797.2 443.8 (30) NA 0.97	847.1 765.5 (32) - -
	Week 16 (open-label)	384.3 397.8 (24) <0.001 0.72	526.5 872.2 (29) <0.001
	Week 24 (double-blind)	404.4 262.9 (21) <0.001 0.008	672.6 356.9 (24) 0.70
Study B	Baseline	973.9 567.0 (41) NA 0.81	990.4 488.3 (35) - -
	Week 16 (open-label)	476.1 444.5 (37) <0.001 0.91	485.9 443.4 (32) <0.001
	Week 24 (double-blind)	459.8 443.0 (35) <0.001 <0.001	871.9 623.6 (30) <0.065

Doxercalciferol capsules treatment resulted in a statistically significant reduction from baseline in mean intact PTH levels during the 16-week open-label treatment period in more than 94% of the 138 treated patients. During the double-blind period (weeks 17 to 24), the reduction in mean intact PTH levels was maintained in the doxercalciferol capsules treatment group compared to a return to near baseline in the placebo group.

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

* Values were carried forward for the two patients on study for 10 weeks Treatment intact PTH minus baseline intact PTH Wilcoxon one-sample test
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

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  ⮝

Doxercalciferol Capsules are supplied as a clear, oily solution encapsulated in oval shaped, soft gelatin capsules. The 0.5 mcg capsules are orange, opaque with "r" imprinted in black ink along one side of the capsule. The 1 mcg capsules are light peach, opaque with "r" imprinted in black ink along one side of the capsule. The 2.5 mcg capsules are yellow, opaque with "r" imprinted in black ink along one side of the capsule.

0054-0338-19 0.5 mcg, orange capsules, bottle of 50

0054-0388-19 1 mcg, light peach capsules, bottle of 50

0054-0339-19 2.5 mcg, yellow capsules, bottle of 50

Storage

Store at 25 C (77 F), with excursions permitted between 15 to 30 C (59 to 86 F). [See USP Controlled Room Temperature.]

Package/label Principal Display Panel  ⮝

Doxercalciferol Capsules, 2.5 mcg

NDC 0054-0339-19

Rx only

DOXERCALCIFEROL doxercalciferol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0054-0338 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXERCALCIFEROL (UNII: 3DIZ9LF5Y9) (DOXERCALCIFEROL - UNII:3DIZ9LF5Y9) DOXERCALCIFEROL 0.5 ug

Inactive Ingredients Ingredient Name Strength BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C RED NO. 40 (UNII: WZB9127XOA) GLYCERIN (UNII: PDC6A3C0OX) ISOPROPYL ALCOHOL (UNII: ND2M416302) MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) WATER (UNII: 059QF0KO0R) SHELLAC (UNII: 46N107B71O) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) ALCOHOL (UNII: 3K9958V90M) AMMONIA (UNII: 5138Q19F1X) FERROSOFERRIC OXIDE (UNII: XM0M87F357) GELATIN, UNSPECIFIED (UNII: 2G86QN327L)

Product Characteristics Color ORANGE Score no score Shape OVAL Size 9mm Flavor Imprint Code r Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0054-0338-19 50 in 1 BOTTLE; Type 0: Not a Combination Product 02/18/2014

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA091433 02/18/2014

DOXERCALCIFEROL doxercalciferol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0054-0388 Route of Administration ORAL

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

Inactive Ingredients Ingredient Name Strength AMMONIA (UNII: 5138Q19F1X) BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) ALCOHOL (UNII: 3K9958V90M) GLYCERIN (UNII: PDC6A3C0OX) FERROSOFERRIC OXIDE (UNII: XM0M87F357) ISOPROPYL ALCOHOL (UNII: ND2M416302) MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) WATER (UNII: 059QF0KO0R) SHELLAC (UNII: 46N107B71O) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FD&C YELLOW NO. 6 (UNII: H77VEI93A8) GELATIN, UNSPECIFIED (UNII: 2G86QN327L)

Product Characteristics Color PINK Score no score Shape OVAL Size 9mm Flavor Imprint Code r Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0054-0388-19 50 in 1 BOTTLE; Type 0: Not a Combination Product 02/18/2014

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA091433 02/18/2014

DOXERCALCIFEROL doxercalciferol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0054-0339 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXERCALCIFEROL (UNII: 3DIZ9LF5Y9) (DOXERCALCIFEROL - UNII:3DIZ9LF5Y9) DOXERCALCIFEROL 2.5 ug

Inactive Ingredients Ingredient Name Strength AMMONIA (UNII: 5138Q19F1X) BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) ALCOHOL (UNII: 3K9958V90M) GLYCERIN (UNII: PDC6A3C0OX) FERROSOFERRIC OXIDE (UNII: XM0M87F357) ISOPROPYL ALCOHOL (UNII: ND2M416302) MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) WATER (UNII: 059QF0KO0R) SHELLAC (UNII: 46N107B71O) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) GELATIN, UNSPECIFIED (UNII: 2G86QN327L)

Product Characteristics Color YELLOW Score no score Shape OVAL Size 9mm Flavor Imprint Code r Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0054-0339-19 50 in 1 BOTTLE; Type 0: Not a Combination Product 02/18/2014

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA091433 02/18/2014

Labeler - West-Ward Pharmaceuticals Corp. (080189610)

Establishment
Name	Address	ID/FEI	Business Operations
Cipla		917066446	MANUFACTURE(0054-0388, 0054-0338, 0054-0339)

Establishment
Name	Address	ID/FEI	Business Operations
Polymed Therapeutics, Inc.		528197487	API MANUFACTURE(0054-0388, 0054-0338, 0054-0339)

Establishment
Name	Address	ID/FEI	Business Operations
Sai Life Sciences Limited		675977617	API MANUFACTURE(0054-0338, 0054-0388, 0054-0339)

Revised: 4/2019 Document Id: d0bb4ab0-12bd-4ac6-8063-ef52a70cba49 34391-3 Set id: 1bb3ce2f-c77a-436f-980f-a02668f99fed Version: 6 Effective Time: 20190425 West-Ward Pharmaceuticals Corp.

1 Indications And Usage ⮝

• Doxercalciferol capsules are indicated for the treatment of secondary hyperparathyroidism in adult patients with Stage 3 or Stage 4 chronic kidney disease (CKD) and adult patients with CKD on dialysis.
• HECTOROL 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 Capsules or Injection

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

2.2 Dosage Recommendations for Doxercalciferol Capsules in Patients with Stage 3 or 4 CKD

• Initiate doxercalciferol capsules at a dose of 1 mcg orally once daily.
• Target the maintenance dose of doxercalciferol 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 at least every two weeks for 3 months after initiation of therapy or dose adjustment, then monthly for 3 months, and every 3 months thereafter.
• Titrate the dose of Doxercalciferol capsules based on intact PTH. The dose may be increased at 2-week intervals by 0.5 mcg to achieve the desired therapeutic range of intact PTH. The maximum recommended dose of Doxercalciferol capsules is 3.5 mcg administered once daily. 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 after one week at a dose that is at least 0.5 mcg lower.

2.3 Dosage Recommendations for Doxercalciferol Capsules in Patients with CKD on Dialysis

• Initiate Doxercalciferol capsules at a dose of 10 mcg orally administered three times weekly at dialysis (no more frequently than every other day).
• Target the maintenance dose of doxercalciferol 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 frequently (e.g., weekly) after initiation of therapy or dose adjustment.
• Titrate the dose of Doxercalciferol capsules based on intact PTH. The dose may be increased at 8-week intervals by 2.5 mcg to achieve the desired therapeutic range of intact PTH. The maximum recommended dose of doxercalciferol is 20 mcg administered three times weekly at dialysis for a total dose of 60 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 2.5 mcg lower.

2.4 Important Administration Instructions for HECTOROL Injection

• Administer HECTOROL injection intravenously as a bolus dose at the end of dialysis.
• Inspect HECTOROL 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:
  • discard unused portion of the single-dose vial;
  • store opened multiple-dose vial for up to 3 days at 2 C to 8 C (36 F 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 HECTOROL Injection in Patients with CKD on Dialysis

• Initiate HECTOROL 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 HECTOROL 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 HECTOROL 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

• Increased monitoring of serum calcium and dose adjustment of doxercalciferol 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 may be necessary when given concomitantly with cytochrome P450 inhibitors or enzyme inducers [see Drug Interactions (7)].

3 Dosage Forms And Strengths ⮝

Capsules: soft gelatin, oval capsules with imprinted "g" available as follows:

• 0.5 mcg (salmon color)
• 1 mcg (peach color)
• 2.5 mcg (butter-yellow color)

Injection: clear and colorless solution available as follows:

• 2 mcg/mL single-dose vial
• 4 mcg/2 mL (2 mcg/mL) single-dose vial
• 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 capsules or HECTOROL 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 or every 2 weeks for patients with stage 3 or 4 CKD). 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 HECTOROL 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 stage 3 or 4 CKD

Doxercalciferol capsules have been evaluated in two placebo-controlled, double-blind 24 week studies in patients with Stage 3 or 4 CKD. Patients were treated with Doxercalciferol capsules (n=27) or placebo (n=28) [see Clinical Studies (14.1)]. Adverse reactions occurring in the Doxercalciferol capsules group at a frequency of 5% or greater and more frequently than in the placebo group are presented in Table 1.

Table 1: Adverse Reactions Occurring in 5% Doxercalciferol Capsule-Treated Patients with CKD on Predialysis and Greater than Placebo in Two Double-Blind Clinical Studies

Adverse Reaction*	Doxercalciferol (n=27) %	Placebo (n=28) %
* Pooled data on adverse reactions from clinical study reports (Studies BCI-CH-115 and BCI-CH-119).
Infection/bacterial infection/viral infection	30	25
Constipation	26	11
Rhinitis	22	11
Anemia	19	4
Cough	19	4
Dyspnea	19	11
Paresthesia	15	11
Asthenia	15	11
Insomnia	15	4
Hypertonia	11	4
Angina pectoris	8	0
Dehydration	7	4
Depression	7	0
Dyspepsia	7	4
Edema	7	4
Urinary tract infection	7	4
Leukopenia	7	0
Chest pain	7	4
Pruritus	7	4
Sinusitis	7	4

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) [see Clinical Studies (14.2)]. 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) %
* A patient who reported the same medical term more than once was counted only once for that medical term.
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

HECTOROL Injection

Adverse reactions in patients with CKD on hemodialysis

HECTOROL 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 HECTOROL 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 HECTOROL injection. Adverse reactions in patients with CKD on hemodialysis receiving HECTOROL 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. 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 HECTOROL 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 and 4 include clinically significant drug interactions with doxercalciferol.

Table 3: Clinically Significant Drug Interactions with HECTOROL Injection and Doxercalciferol Capsules

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.

Table 4: Clinically Significant Drug Interactions with Doxercalciferol Capsules

Cholestyramine
Clinical Impact	Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins. Therefore, it may impair intestinal absorption of Doxercalciferol capsules.
Intervention	Administer Doxercalciferol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine.
Mineral Oil or other Substances that May Affect Absorption of Fat
Clinical Impact	The use of mineral oil or other substances that may affect absorption of fat may influence the absorption and availability of doxercalciferol.
Intervention	Administer Doxercalciferol capsules at least 1 hour before or 4 to 6 hours after taking mineral oil or other substances that may affect absorption of fat.

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% 4% and 15% 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 HECTOROL 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 capsule 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 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:

Capsules

Doxercalciferol capsules are soft gelatin capsules containing 0.5 mcg, 1 mcg, or 2.5 mcg doxercalciferol for oral use. Each capsule also contains butylated hydroxyanisole (BHA), ethanol, and fractionated triglyceride of coconut oil. The capsule shells contain gelatin, glycerin, and titanium dioxide. In addition, the 0.5 mcg capsule shells contain yellow iron oxide and FD&C Red No. 40, the 1 mcg capsule shells contain FD&C Yellow No. 6, and the 2.5 mcg capsule shells contain yellow iron oxide.

Injection

HECTOROL injection 1 mL single-dose vials contain 2 mcg/mL of doxercalciferol. HECTOROL injection 2 mL single-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: butylated hydroxytoluene (0.02 mg); disodium edetate (1.1 mg); ethanol, 100% (0.05 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).

HECTOROL injection 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: 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 HECTOROL and at 11 to 12 hours following capsule doses.

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 ⮝

14.1 Clinical Studies of Doxercalciferol Capsules in Patients with Stage 3 or 4 CKD

The safety and effectiveness of Doxercalciferol capsules were evaluated in two clinical studies in 55 patients with Stage 3 or 4 CKD. Eighty-two percent of the patients were male, the average age was 65 years, 51% were Caucasian, 40% African-American, and the average serum intact PTH level at baseline was 195 pg/mL. While levels of 25-(OH) vitamin D were not evaluated at baseline, retrospective assessments of stored serum revealed that the mean SD serum 25-(OH) vitamin D was 19 8 ng/mL (range: <5 to 54 ng/mL) in the study population.

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, one group received Doxercalciferol capsules and the other placebo during the double-blind period of 24 weeks. The initial dose of Doxercalciferol capsules was 1 mcg per day. The dosage of Doxercalciferol capsules was adjusted as necessary by the investigator to reduce intact PTH levels to a target of 30% below postwashout baseline. The maximum dosage was limited to 3.5 mcg per day. If at any time during the trial intact PTH fell below 15 pg/mL, Doxercalciferol capsules were immediately suspended and restarted at a lower dosage the following week.

Decreases in the mean plasma intact PTH from baseline values were calculated using as baseline the average of the last 2 values obtained during the 8-week washout phase. In analyses of pooled data from the two studies, intact PTH levels decreased from baseline by an average of 101 pg/mL in the Doxercalciferol capsules group and by 4 pg/mL in the placebo group (p<0.001). Twenty (74%) of 27 subjects in the Doxercalciferol capsules group achieved mean plasma intact PTH suppression of 30% from baseline for the last four weeks of treatment, whereas two (7%) of the 28 subjects treated with placebo achieved this level of intact PTH suppression.

14.2 Clinical Studies of Doxercalciferol Capsules in Patients with CKD on Dialysis

The safety and effectiveness of Doxercalciferol capsules were evaluated in two double-blind, placebo-controlled, multicenter clinical studies (Study A and Study B) in a total of 138 patients with CKD on hemodialysis. Patients in Study A were an average age of 52 years (range: 22 to 75), were 55% male, and were 58% African-American, 31% Caucasian, and 11% Hispanic, and had been on hemodialysis for an average of 53 months. Patients in Study B were an average of 52 years (range: 27 to 75), were 45% male, and 99% African-American, and 1% Caucasian, and had been on hemodialysis for an average of 56 months. 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. The initial dose of Doxercalciferol capsules during the open-label phase was 10 mcg after each dialysis session (3 times weekly) for a total of 30 mcg per week. The dosage of doxercalciferol was adjusted as necessary by the investigator to achieve intact PTH levels within 150 pg/mL to 300 pg/mL. The maximum dosage was limited to 20 mcg after each dialysis session (60 mcg/week). If at any time during the trial intact PTH fell below 150 pg/mL, doxercalciferol was immediately suspended and restarted at a lower dosage the following week. Mean weekly doses during the 16-week open-label period ranged from 15 mcg to 29 mcg in Study A and from 19 mcg to 28 mcg in Study B.

One hundred and six (77%) of the 138 patients who were treated with Doxercalciferol capsules during the 16-week open-label phase achieved intact PTH levels 300 pg/mL. Ninety-four (68%) of these patients exhibited plasma intact PTH levels 300 pg/mL on at least 3 occasions. Eighty-seven (63%) patients had plasma intact PTH levels <150 pg/mL on at least one occasion during the open-label phase of 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 phase and are displayed in Table 5.

Table 5: Intact PTH Summary Data for Patients with CKD on Dialysis Receiving Doxercalciferol Capsules in Studies A and B

		Intact PTH (pg/mL)
		means SD (n)* p-value vs Baseline p-value vs Placebo
		Doxercalciferol Capsules	Placebo
NA = not applicable
* All subjects; last value carried to discontinuation.
Study A	Baseline	797.2 443.8 (30) NA 0.97	847.1 765.5 (32)
	Week 16 (open-label)	384.3 397.8 (24) <0.001 0.72	526.5 872.2 (29) <0.001
	Week 24 (double-blind)	404.4 262.9 (21) <0.001 0.008	672.6 356.9 (24) 0.70
Study B	Baseline	973.9 567.0 (41) NA 0.81	990.4 488.3 (35)
	Week 16 (open-label)	476.1 444.5 (37) <0.001 0.91	485.9 443.4 (32) <0.001
	Week 24 (double-blind)	459.8 443.0 (35) <0.001 <0.001	871.9 623.6 (30) <0.065

Doxercalciferol capsules treatment resulted in a statistically significant reduction from baseline in mean intact PTH levels during the 16-week open-label treatment period in more than 94% of the 138 treated patients. During the double-blind period (weeks 17 to 24), the reduction in mean intact PTH levels was maintained in the Doxercalciferol capsules treatment group compared to a return to near baseline in the placebo group.

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

The safety and effectiveness of HECTOROL 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 HECTOROL Injection in an open-label fashion for 12 weeks following an 8-week washout (control) period. Dosing of HECTOROL 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 HECTOROL 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, HECTOROL 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 HECTOROL 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 HECTOROL Injection in Studies C and D

Intact PTH Level	Study C (n=28)	Study D (n=42)	Combined Protocols (n=70)
* Values were carried forward for the two patients on study for 10 weeks Treatment intact PTH minus baseline intact PTH Wilcoxon one-sample test
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

HECTOROL 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 capsules are oval, soft gelatin capsules supplied as follows.

Strength	Capsule Color	Imprint Code	Package size	NDC
0.5 mcg	salmon	g	bottle of 50 capsules	0955-1720-50
1 mcg	peach	g	bottle of 50 capsules	0955-1721-50
2.5 mcg	butter-yellow	g	bottle of 50 capsules	0955-1722-50

HECTOROL injection is a clear, colorless solution supplied in 2 mL amber glass vials as follows.

Total Strength per Total Volume	Strength per mL	Flip-off Cap Color	Vial Count per Carton Total Vial Volume and Vial Type	Carton NDC	Vial NDC
2 mcg/mL	2 mcg/mL	Green	50 1 mL single-dose vials	58468-0126-1	58468-0126-0
4 mcg/2 mL	2 mcg/mL	Yellow	50 2 mL single-dose vials	58468-0123-1	58468-0123-0
4 mcg/2 mL	2 mcg/mL	Orange	50 2 mL multiple-dose vials	58468-0127-1	58468-0127-0

Storage and Handling

Dosage Form	Storage temperature	Excursions permitted to	In-use storage
* Protect from light. Store unopened vial in original carton.
Capsule	25 C (77 F)	15 C to 30 C (59 F to 86 F) [see USP controlled room temperature]
Single-dose vial*	25 C (77 F)	15 C to 30 C (59 F to 86 F) [see USP controlled room temperature]	Discard unused portion
Multiple-dose vial*	25 C (77 F)	15 C to 30 C (59 F to 86 F) [see USP controlled room temperature]	2 C to 8 C (36 F to 46 F), Discard 3 days after opening

Principal Display Panel - 0.5 Mcg Capsule Bottle Carton ⮝

NDC 0955-1720-50
Rx ONLY

Winthrop
A SANOFI COMPANY

Doxercalciferol
Capsules

0.5 mcg

50 Capsules

SANOFI

Principal Display Panel - 1 Mcg Capsule Bottle Carton ⮝

NDC 0955-1721-50
Rx ONLY

Winthrop
A SANOFI COMPANY

Doxercalciferol
Capsules

1 mcg

50 Capsules

SANOFI

Principal Display Panel - 2.5 Mcg Capsule Bottle Carton ⮝

NDC 0955-1722-50
Rx ONLY

Winthrop
A SANOFI COMPANY

Doxercalciferol
Capsules

2.5 mcg

50 Capsules

SANOFI

DOXERCALCIFEROL doxercalciferol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0955-1720 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXERCALCIFEROL (UNII: 3DIZ9LF5Y9) (DOXERCALCIFEROL - UNII:3DIZ9LF5Y9) DOXERCALCIFEROL 0.5 ug

Inactive Ingredients Ingredient Name Strength MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U) ALCOHOL (UNII: 3K9958V90M) BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT) FD&C RED NO. 40 (UNII: WZB9127XOA)

Product Characteristics Color PINK (salmon) Score no score Shape OVAL Size 6mm Flavor Imprint Code g Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0955-1720-50 1 in 1 CARTON 04/17/2017 1 50 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA020862 04/17/2017

DOXERCALCIFEROL doxercalciferol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0955-1721 Route of Administration ORAL

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

Inactive Ingredients Ingredient Name Strength MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U) ALCOHOL (UNII: 3K9958V90M) BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FD&C YELLOW NO. 6 (UNII: H77VEI93A8)

Product Characteristics Color PINK (peach) Score no score Shape OVAL Size 6mm Flavor Imprint Code g Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0955-1721-50 1 in 1 CARTON 04/17/2017 1 50 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA020862 04/17/2017

DOXERCALCIFEROL doxercalciferol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0955-1722 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXERCALCIFEROL (UNII: 3DIZ9LF5Y9) (DOXERCALCIFEROL - UNII:3DIZ9LF5Y9) DOXERCALCIFEROL 2.5 ug

Inactive Ingredients Ingredient Name Strength MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U) ALCOHOL (UNII: 3K9958V90M) BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color YELLOW (butter yellow) Score no score Shape OVAL Size 6mm Flavor Imprint Code g Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0955-1722-50 1 in 1 CARTON 04/17/2017 1 50 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA020862 04/17/2017

Labeler - Winthrop U.S. (824676584)

Establishment
Name	Address	ID/FEI	Business Operations
Catalent Pharma Solutions, LLC		051762268	MANUFACTURE(0955-1720, 0955-1721, 0955-1722)

Establishment
Name	Address	ID/FEI	Business Operations
AndersonBrecon Inc.		053217022	LABEL(0955-1720, 0955-1721, 0955-1722) , PACK(0955-1720, 0955-1721, 0955-1722)

Establishment
Name	Address	ID/FEI	Business Operations
Assia Chemical Industries Ltd. - Teva Tech Site		514678507	ANALYSIS(0955-1720, 0955-1721, 0955-1722) , API MANUFACTURE(0955-1720, 0955-1721, 0955-1722)

Establishment
Name	Address	ID/FEI	Business Operations
Genzyme Ireland Limited		985127419	ANALYSIS(0955-1720, 0955-1721, 0955-1722)

Revised: 10/2019 Document Id: 35597cf9-a441-45b2-950b-c28397240106 34391-3 Set id: bd60e285-6559-4ca7-93ce-006a8e000bd1 Version: 9 Effective Time: 20191010 Winthrop U.S.

Principal Display Panel - 0.5 Mcg Capsule ⮝

Rising NDC 64980-228-50
Doxercalciferol
Capsules
0.5 mcg
Rx ONLY
50 Capsules

Principal Display Panel - 1 Mcg Capsule ⮝

Rising NDC 64980-229-50
Doxercalciferol
Capsules
1 mcg
Rx ONLY
50 Capsules

Principal Display Panel - 2.5 Mcg Capsule ⮝

Rising NDC 64980-230-50
Doxercalciferol
Capsules
2.5 mcg
Rx ONLY
50 Capsules

DOXERCALCIFEROL doxercalciferol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:64980-228 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Doxercalciferol (UNII: 3DIZ9LF5Y9) (Doxercalciferol - UNII:3DIZ9LF5Y9) Doxercalciferol 0.5 ug

Inactive Ingredients Ingredient Name Strength MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U) ALCOHOL (UNII: 3K9958V90M) BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT) FD&C RED NO. 40 (UNII: WZB9127XOA)

Product Characteristics Color PINK (salmon) Score no score Shape OVAL Size 6mm Flavor Imprint Code g Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:64980-228-50 1 in 1 CARTON 09/09/2016 1 50 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA201518 09/09/2016

DOXERCALCIFEROL doxercalciferol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:64980-229 Route of Administration ORAL

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

Inactive Ingredients Ingredient Name Strength MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U) ALCOHOL (UNII: 3K9958V90M) BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FD&C YELLOW NO. 6 (UNII: H77VEI93A8)

Product Characteristics Color PINK (peach) Score no score Shape OVAL Size 6mm Flavor Imprint Code g Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:64980-229-50 1 in 1 CARTON 09/09/2016 1 50 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA201518 09/09/2016

DOXERCALCIFEROL doxercalciferol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:64980-230 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Doxercalciferol (UNII: 3DIZ9LF5Y9) (Doxercalciferol - UNII:3DIZ9LF5Y9) Doxercalciferol 2.5 ug

Inactive Ingredients Ingredient Name Strength MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U) ALCOHOL (UNII: 3K9958V90M) BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics Color YELLOW (butter yellow) Score no score Shape OVAL Size 6mm Flavor Imprint Code g Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:64980-230-50 1 in 1 CARTON 09/09/2016 1 50 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA201518 09/09/2016

Labeler - Rising Pharmaceuticals, Inc. (041241766)

Establishment
Name	Address	ID/FEI	Business Operations
Catalent Pharma Solutions LLC		051762268	MANUFACTURE(64980-228, 64980-229, 64980-230)

Revised: 12/2017 Document Id: 4774de14-3235-45ff-8d0c-44cb224800cf 34391-3 Set id: a43afaad-1862-4885-9b47-ddc2302160a3 Version: 2 Effective Time: 20171210 Rising Pharmaceuticals, Inc.

Description ⮝

Doxercalciferol, the active ingredient in Doxercalciferol Capsules, is a synthetic vitamin D 2 analog that undergoes metabolic activation in vivo to form 1 ,25-dihydroxyvitamin D 2 (1 ,25-(OH) 2D 2), a naturally occurring, biologically active form of vitamin D 2. Doxercalciferol Capsules are available as a soft gelatin capsule containing 0.5 mcg or 2.5 mcg doxercalciferol. Each capsule also contains butylated hydroxyanisole (BHA), dehydrated alcohol, and medium chain triglyceride. The capsule shells contain D&C Yellow No. 10 (0.5 mcg and 2.5 mcg), FD&C Yellow No. 6 (1 mcg only), FD&C Red No. 40 (0.5 mcg only), gelatin, glycerin, Opacode Black, purified water, and titanium dioxide. Opacode Black contains ammonium hydroxide, iron oxide black, isopropyl alcohol, N-butyl alcohol, propylene glycol, and shellac.

Doxercalciferol is a colorless crystalline compound with a calculated molecular weight of 412.66 and a molecular formula of C 28H 44O 2. 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 following structural formula:

Other names frequently used for doxercalciferol are 1 -hydroxyvitamin D 2, 1 -OH-D 2, 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 D 3 (cholecalciferol) and (2) dietary intake of either vitamin D 2 (ergocalciferol) or vitamin D 3. Vitamin D 2 and vitamin D 3 must be metabolically activated in the liver and the 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 ( vitamin D-25-hydroxylase). The products of this reaction are 25-(OH)D 2 and 25-(OH)D 3, 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) 2D 2, the primary biologically active form of vitamin D 2, and 1 ,25-(OH) 2D 3 (calcitriol), the biologically active form of vitamin D 3.

Mechanism of Action
Calcitriol (1 ,25-(OH) 2D 3) and 1 ,25-(OH) 2D 2 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 patients with chronic kidney disease (CKD), 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.

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

In healthy volunteers, peak blood levels of 1 ,25-(OH) 2D 2, the major metabolite of doxercalciferol, are attained at 11 to 12 hours after repeated oral doses of 5 to 15 mcg of doxercalciferol and the mean elimination half-life of 1 ,25-(OH) 2D 2 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) on dialysis appears to be similar. Hemodialysis causes a temporary increase in 1 ,25-(OH) 2D 2 mean concentrations, presumably due to volume contraction. 1 ,25-(OH) 2D 2 is not removed from blood during hemodialysis.

Clinical Studies
Dialysis: The safety and effectiveness of doxercalciferol was evaluated in two double-blind, placebo-controlled, multi-centered clinical studies (Study A and Study B) in a total of 138 patients with chronic kidney disease on hemodialysis (Stage 5 CKD). Patients in Study A were an average age of 52 years (range: 22 to 75), were 55% male, and were 58% African-American, 31% Caucasian, and 11% Hispanic, and had been on hemodialysis for an average of 53 months. Patients in Study B were an average of 52 years (range: 27 to 75), were 45% male, and 99% African-American, and 1% Caucasian, and had been on hemodialysis for an average of 56 months. 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 in an open-label fashion for 16 weeks followed by a double-blind period of 8 weeks during which patients received either doxercalciferol or placebo. The initial dose of doxercalciferol during the open-label phase was 10 micrograms after each dialysis session (3 times weekly) for a total of 30 mcg per week. The dosage of doxercalciferol was adjusted as necessary by the investigator in an attempt to achieve intact parathyroid hormone (iPTH) levels within a targeted range of 150 to 300 pg/mL. The maximum dosage was limited to 20 mcg after each dialysis session (60 mcg/week). If at any time during the trial iPTH fell below 150 pg/mL, doxercalciferol was immediately suspended and restarted at a lower dosage the following week.

Results: One hundred and six of the 138 patients who were treated with doxercalciferol during the 16-week open-label phase achieved iPTH levels 300 pg/mL. Ninety-four of these patients exhibited plasma iPTH levels 300 pg/mL on at least 3 occasions. Eighty-seven patients had plasma iPTH levels <150 pg/mL on at least one occasion during the open-label phase of study participation.

Mean weekly doses during the 16-week open-label period in Study A ranged from 14.8 mcg to 28.7 mcg. In Study B, the mean weekly doses during the 16-week open-label period ranged from 19.2 mcg to 28 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 phase and are displayed in Table 1 below.

Table 1: iPTH Summary Data for Dialysis Patients Receiving Doxercalciferol

* all subjects; last value carried to discontinuation
		iPTH (pg/mL)
		means s.d. (n*)
		p Value v. Baseline
		p Value v. Placebo
		Doxercalciferol	Placebo
Study A	Baseline	797.2 443.8 (30)	847.1 765.5 (32)
		n.a.
		0.97
	Week 16	384.3 397.8 (24)	526.5 872.2 (29)
	(open-label)	<0.001	<0.001
		0.72
	Week 24	404.4 262.9 (21)	672.6 356.9 (24)
	(double-blind)	<0.001	0.7
		0.008
Study B	Baseline	973.9 567 (41)	990.4 488.3 (35)
		n.a.
		0.81
	Week 16	476.1 444.5 (37)	485.9 443.4 (32)
	(open-label)	<0.001	<0.001
		0.91
	Week 24	459.8 443 (35)	871.9 623.6 (30)
	(double-blind)	<0.001	<0.065
		<0.001

In both studies, iPTH levels increased progressively and significantly in 65.9% of the patients during the 8-week washout (control) period during which no vitamin D derivatives were administered. In contrast, doxercalciferol treatment resulted in a statistically significant reduction from baseline in mean iPTH levels during the 16-week open-label treatment period in more than 93.5% of the 138 treated patients. During the double-blind period (weeks 17 to 24), the reduction in mean iPTH levels was maintained in the doxercalciferol treatment group compared to a return to near baseline in the placebo group.

In the clinical trials, the values for iPTH varied widely from patient to patient and from week to week for individual patients. Table 2 shows the numbers of patients within each group who achieved and maintained iPTH levels below 300 pg/mL during the open-label and double-blind phases. Seventy-four of 138 patients (53.6%) had plasma iPTH levels within the target range (150 to 300 pg/mL) during Weeks 14 to 16.

Table 2: Number of Times iPTH 300 pg/mL

		1		2		3
		Doxercalciferol	Placebo	Doxercalciferol	Placebo	Doxercalciferol	Placebo
Study A	Weeks 1-16	2/30	2/32	0/30	0/32	22/30	23/32
	(open-label)
	Weeks 17-24	0/24	9/29	3/24	1/29	17/24	5/29
	(double-blind)
Study B	Weeks 1-16	2/41	4/35	1/41	0/35	29/41	21/35
	(open-label)
	Weeks 17-24	2/37	6/32	1/37	4/32	26/37	4/32
	(double-blind)

During the 8-week double-blind phase, more patients achieved and maintained the target range of values for iPTH with doxercalciferol than with placebo.

Pre-Dialysis: The safety and effectiveness of doxercalciferol were evaluated in two clinical studies in 55 patients with Stage 3 or Stage 4 chronic kidney disease. Eighty-two percent of the patients were male, the average age was 64.6 years, 51% were Caucasian, 40% African-American, and the average serum iPTH level at baseline was 194.6 pg/mL. While levels of 25-(OH) vitamin D were not evaluated at baseline, retrospective assessments of stored serum revealed that the mean SD serum 25-(OH) vitamin D was 18.5 8.1 ng/mL (range: <5 to 54 ng/mL) in the study population.

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, one group received doxercalciferol and the other placebo during a double-blind period of 24 weeks. The initial dose of doxercalciferol was 1 mcg per day. The dosage of doxercalciferol was adjusted as necessary by the investigator in order to reduce intact parathyroid hormone (iPTH) levels to a target of 30% below post-washout baseline. The maximum dosage was limited to 3.5 mcg per day. If at any time during the trial iPTH fell below 15 pg/mL, doxercalciferol was immediately suspended and restarted at a lower dosage the following week.

Results: Decreases in the mean plasma iPTH from baseline values were calculated using as baseline the average of the last 2 values obtained during the 8-week washout phase. In analyses of pooled data from the two studies, iPTH levels decreased from baseline by an average of 101.4 pg/mL in the doxercalciferol group and by 4.4 pg/mL in the placebo group (p<0.001). Greater reductions of iPTH with doxercalciferol compared to placebo were observed in each study. Twenty (74%) of 27 subjects in the doxercalciferol group achieved mean plasma iPTH suppression of 30% from baseline for the last four weeks of treatment, whereas two (7%) of the 28 subjects treated with placebo achieved this level of iPTH suppression. In the doxercalciferol-treated patients, the reductions in plasma iPTH were associated with a reduction in serum bone-specific alkaline phosphatase.

Indications And Usage ⮝

Doxercalciferol is a synthetic vitamin D2 analog:

• Doxercalciferol capsules are indicated for the treatment of secondary hyperparathyroidism in adult patients with Stage 3 or Stage 4 chronic kidney disease (CKD) and adult patients with CKD on dialysis. (1)
• HECTOROL injection is indicated for the treatment of secondary hyperparathyroidism in adult patients with CKD on dialysis. (1)

Contraindications ⮝

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

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 mg 2/dL 2 in patients with chronic kidney disease. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.

Since doxercalciferol is a precursor for 1 ,25-(OH) 2D 2, a potent metabolite of vitamin D 2, pharmacologic doses of vitamin D and its derivatives should be withheld during doxercalciferol treatment to avoid possible additive effects and hypercalcemia.

Oral calcium-based or other non-aluminum-containing phosphate binders and a low phosphate diet should be used to control serum phosphorus levels in patients with chronic kidney disease. Uncontrolled serum phosphorus exacerbates secondary hyperparathyroidism and can lessen the effectiveness of doxercalciferol in reducing blood PTH levels. If hypercalcemia occurs after initiating doxercalciferol therapy, the dose of doxercalciferol and/or calcium-containing phosphate binders should be decreased. If hyperphosphatemia occurs after initiating doxercalciferol therapy, the dose of doxercalciferol should be decreased and/or the dose of phosphate binders increased. (See dosing recommendations for doxercalciferol under DOSAGE AND ADMINISTRATION section.)

Magnesium-containing antacids and doxercalciferol should not be used concomitantly in patients on chronic renal dialysis because such use may lead to the development of hypermagnesemia.

Precautions ⮝

General
Active vitamin D sterols should not be used as initial treatment of nutritional vitamin D deficiency (as defined by low 25-hydroxy vitamin D). Patients should be checked and treated for nutritional vitamin D deficiency prior to initiating treatment with doxercalciferol.

The principal adverse effects of treatment with doxercalciferol are hypercalcemia, hyperphosphatemia, hypercalciuria, 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. Hypercalciuria can accelerate the onset of renal failure through nephrocalcinosis. Oversuppression of PTH may lead to adynamic bone syndrome. All of these potential adverse effects should be managed by regular patient monitoring and appropriate dosage adjustments. During treatment with doxercalciferol, patients usually require dose titration, as well as adjustment in co-therapy (i.e., dietary phosphate binders) in order to maximize PTH suppression while maintaining serum calcium and phosphorus within prescribed ranges.

Dialysis: In four adequate and well-controlled studies, the incidence of hypercalcemia and hyperphosphatemia increased during therapy with doxercalciferol. The observed increases during doxercalciferol treatment, although occurring at a low rate, underscore the importance of regular safety monitoring of serum calcium and phosphorus levels throughout treatment. Patients with higher pre-treatment serum levels of calcium (>10.5 mg/dL) or phosphorus (>6.9 mg/dL) were more likely to experience hypercalcemia or hyperphosphatemia. Therefore, doxercalciferol should not be given to patients with a recent history of hypercalcemia or hyperphosphatemia, or evidence of vitamin D toxicity.

Pre-Dialysis: In two clinical studies, the incidences of hypercalcemia and hyperphosphatemia during therapy with doxercalciferol were similar to placebo therapy, and no episodes of hypercalciuria were observed. The baseline median 25-(OH) vitamin D levels of patients enrolled in these studies was 17.2 ng/mL. Ninety-three percent of patients had 25-(OH) vitamin D levels less than 30 ng/mL; 26% had 25-(OH) vitamin D levels 20 to <30 ng/mL; 58% had levels >10 to <20 ng/mL; 7% had levels >5 to <10 ng/mL; and 2% had levels <5 ng/mL. The incidences of hypercalcemia, hyperphosphatemia, and hypercalciuria in patients treated with doxercalciferol for hyperparathyroidism related to pre-dialysis renal insufficiency has not been fully studied when 25-OH vitamin D levels are greater than or equal to 30 ng/mL.

Information for Patients
The patient, spouse, or guardian should be informed about compliance with dosage instructions, adherence to instructions about diet, calcium supplementation, and avoidance of the use of nonprescription drugs without prior approval from their physician. Patients should also be carefully informed about the symptoms of hypercalcemia (see ADVERSE REACTIONS section).

Patients' total combined elemental calcium intake (dietary and phosphate binder) should not exceed 2 g daily.

Laboratory Tests
Serum or plasma iPTH and serum calcium, phosphorus, and alkaline phosphatase should be determined periodically. In the early phase of treatment for dialysis patients, iPTH, serum calcium, and serum phosphorus should be determined prior to initiation of doxercalciferol treatment and weekly thereafter. For pre-dialysis patients, serum levels of calcium and phosphorus and plasma levels of iPTH should be monitored at least every two weeks for 3 months after initiation of doxercalciferol therapy or following dose-adjustments in doxercalciferol therapy, then monthly for 3 months, and every 3 months thereafter.

Drug Interactions
Specific drug interaction studies have not been conducted. Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; therefore, it may impair intestinal absorption of doxercalciferol. Magnesium-containing antacids and doxercalciferol should not be used concomitantly because such use may lead to the development of hypermagnesemia (see WARNINGS). The use of mineral oil or other substances that may affect absorption of fat may influence the absorption and availability of doxercalciferol. Although not examined specifically, enzyme inducers (such as glutethimide and phenobarbital) may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments. Cytochrome P450 inhibitors (such as ketoconazole and erythromycin) may inhibit the 25-hydroxylation of doxercalciferol. Hence, formation of the active doxercalciferol moiety may be hindered.

Carcinogenesis, Mutagenesis, Impairment of Fertility
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 ( 1 times the human exposure in pre-dialysis patients with a maximum recommended dose of 3.5 mcg/day or 24.5 mcg/week). 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 dose of 60 mcg/week based on mcg/m 2 body surface area).

Use in Pregnancy
Pregnancy Category B: Reproduction studies in rats and rabbits, at doses up to 20 mcg/kg/day and 0.1 mcg/kg/day (approximately 25 times and less than the maximum recommended human dose of 60 mcg/week based on mcg/m 2 body surface area, respectively) have revealed no teratogenic or fetotoxic effects due to doxercalciferol. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers
It is not known whether doxercalciferol is excreted in human milk. Because other vitamin D derivatives are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from doxercalciferol, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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

Geriatric Use

Of the 138 patients treated with doxercalciferol capsules in two Phase 3 clinical studies, 30 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
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 ⮝

The most common adverse reactions in patients with Stage 3 or 4 CKD (incidence >5%) were infection, urinary tract infection, chest pain, angina pectoris, constipation, dyspepsia, anemia, leucopenia, dehydration, edema, depression, hypertonia, insomnia, asthenia, paresthesia, cough increased, dyspnea, pruritus, sinusitis, and rhinitis. (6.1)

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 Genzyme Corporation at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Overdosage ⮝

Administration of doxercalciferol to patients in excess doses can cause hypercalcemia, hypercalciuria, hyperphosphatemia, and 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 in dialysis patients; >10.7 mg/dL in pre-dialysis patients) 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 lower (at least 2.5 mcg in dialysis patients and 0.5 mcg in pre-dialysis patients) than prior therapy. In dialysis patients, serum calcium levels should be obtained weekly after all dosage changes and during subsequent dosage titration. Persistent or markedly elevated serum calcium levels may be corrected by dialysis against a reduced calcium or calcium-free dialysate.

Treatment of Accidental Overdosage of Doxercalciferol
The treatment of acute accidental overdosage of doxercalciferol should consist of general supportive measures. If drug ingestion is discovered within a relatively short time (10 minutes), induction of emesis or gastric lavage may be of benefit in preventing further absorption. If drug ingestion is discovered later than 10 minutes post-ingestion, the administration of mineral oil may promote its fecal elimination. 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) 2D 2, it is expected that doxercalciferol is not removed from the blood by dialysis.

Dosage And Administration ⮝

• Before initiating treatment, ensure serum calcium is not above the upper limit of normal. (2.1)
• Dosage for doxercalciferol capsules in patients with:
  • Stage 3 or 4 CKD: Initiate dosing at 1 mcg orally once daily. Maximum dose is 3.5 mcg once daily. (2.2)
  • CKD on dialysis: Initiate dosing at 10 mcg orally three times weekly at dialysis (no more frequently than every other day). Maximum dose is 20 mcg three times weekly for a total of 60 mcg weekly. (2.3)
• Dosage for HECTOROL 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 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)

How Supplied ⮝

Doxercalciferol Capsules are supplied as a clear, oily solution encapsulated in oval shaped, soft gelatin capsules. The 0.5 mcg capsules are orange, opaque with "r" imprinted in black ink along one side of the capsule.
Unit dose packages of 30 (5 x 6) NDC 68084-872-25

Storage
Store at 25 C (77 F); excursions permitted to 15 to 30 C (59 to 86 F). [See USP Controlled Room Temperature.]

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

Made in India.

Packaging Information ⮝

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from West-Ward Pharmaceuticals Corp. as follows:
(0.5 mcg / 30 UD) NDC 68084-872-25 packaged from NDC 0054-0338

Distributed by:
American Health Packaging
Columbus, OH 43217

8287225/0617OS

Package/label Display Panel Carton 0.5 Mcg ⮝

NDC 68084- 872-25

Doxercalciferol
Capsules

0.5 mcg

30 Capsules (5 x 6) Rx Only

Each Capsule Contains:
Doxercalciferol.............................................0.5 mcg

Usual Dosage: See package insert for full
prescribing information.

Store at 20 to 25 C (68 to 77 F); excursions
permitted between 15 to 30 C (59 to 86 F) [see
USP Controlled Room Temperature].

Keep this and all drugs out of reach of
children.

FOR YOUR PROTECTION: Do not use if blister is
torn or broken.

The drug product contained in this package is from
NDC # 0054-0338, West-Ward
Pharmaceuticals Corp.

Distributed by:
American Health Packaging
Columbus, Ohio 43217

087225
0287225/0619OS

Package/label Display Panel Blister 0.5 Mcg ⮝

Doxercalciferol
Capsule

0.5 mcg

DOXERCALCIFEROL doxercalciferol capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68084-872(NDC:0054-0338) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DOXERCALCIFEROL (UNII: 3DIZ9LF5Y9) (DOXERCALCIFEROL - UNII:3DIZ9LF5Y9) DOXERCALCIFEROL 0.5 ug

Inactive Ingredients Ingredient Name Strength BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) ALCOHOL (UNII: 3K9958V90M) MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9H2L21V7U) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C RED NO. 40 (UNII: WZB9127XOA) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) GLYCERIN (UNII: PDC6A3C0OX) WATER (UNII: 059QF0KO0R) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) AMMONIA (UNII: 5138Q19F1X) FERROSOFERRIC OXIDE (UNII: XM0M87F357) ISOPROPYL ALCOHOL (UNII: ND2M416302) BUTYL ALCOHOL (UNII: 8PJ61P6TS3) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) SHELLAC (UNII: 46N107B71O)

Product Characteristics Color orange Score no score Shape OVAL Size 9mm Flavor Imprint Code r Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68084-872-25 30 in 1 BOX, UNIT-DOSE 11/03/2015 1 NDC:68084-872-95 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA091433 11/03/2015

Labeler - American Health Packaging (929561009)

Establishment
Name	Address	ID/FEI	Business Operations
American Health Packaging		929561009	repack(68084-872)

Revised: 6/2019 Document Id: 8b4a549a-33ed-0f96-e053-2995a90afe25 34391-3 Set id: 3a0919fa-3ff5-43d9-bf37-2da671c34bf2 Version: 4 Effective Time: 20190614 American Health Packaging