Doxercalciferol

DOXERCALCIFEROL- doxercalciferol injection, solution
Akorn, Inc.

1 INDICATIONS AND USAGE

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

2 DOSAGE AND ADMINISTRATION

2.1 Prior to Initiation of Doxercalciferol Injection

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

2.4 Important Administration Instructions for Doxercalciferol Injection

  • Administer doxercalciferol injection intravenously as a bolus dose at the end of dialysis.
  • Inspect doxercalciferol injection visually prior to administration; the solution should appear clear and colorless. Do not use if the solution is not clear or particles are present.
  • After initial vial use:
    • discard unused portion of the single-dose vial [see How Supplied/Storage and Handling (16)].

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

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

2.6 Drug Interactions that May Require Dosage Adjustments of Doxercalciferol Injection

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

3 DOSAGE FORMS AND STRENGTHS

Injection: Sterile, clear and colorless aqueous solution available as follows:

  • 2 mcg/mL single-dose vial
  • 4 mcg/2 mL (2 mcg/mL) single-dose vial

4 CONTRAINDICATIONS

Doxercalciferol is contraindicated in patients with:

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

5 WARNINGS AND PRECAUTIONS

5.1 Hypercalcemia

Hypercalcemia may occur during doxercalciferol treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart [see Warnings and Precautions (5.2)]. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Severe hypercalcemia may require emergency attention.

Hypercalcemia may be exacerbated by concomitant administration of high doses of calcium-containing preparations, thiazide diuretics, or other vitamin D compounds [see Drug Interactions (7)]. In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. Patients with a history of hypercalcemia prior to initiating therapy may be at increased risk for development of hypercalcemia with doxercalciferol. In these circumstances, frequent serum calcium monitoring and doxercalciferol dose adjustments may be required.

When initiating doxercalciferol or adjusting doxercalciferol dose, measure serum calcium frequently (weekly in patients with CKD on dialysis). Once a maintenance dose has been established, measure serum calcium monthly for 3 months and then every 3 months. If hypercalcemia occurs, reduce the dose or discontinue doxercalciferol until serum calcium is normal [see Dosage and Administration (2)].

Inform patients about the symptoms of elevated calcium (feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss) and instruct them to report new or worsening symptoms when they occur.

5.2 Digitalis Toxicity

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

5.3 Serious Hypersensitivity Reactions

Serious hypersensitivity reactions, including fatal outcome, have been reported post marketing in patients on hemodialysis following administration of doxercalciferol injection. Hypersensitivity reactions include anaphylaxis with symptoms of angioedema (involving face, lips, tongue and airways), hypotension, unresponsiveness, chest discomfort, shortness of breath, and cardiopulmonary arrest. These reactions may occur separately or together.

Monitor patients receiving doxercalciferol upon initiation of treatment for hypersensitivity reactions. Should a hypersensitivity reaction occur, discontinue doxercalciferol, monitor and treat if indicated [see Contraindications (4)].

5.4 Adynamic Bone Disease

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

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in another section of the label:

  • Hypercalcemia [see Warnings and Precautions (5.1)]
  • Serious Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
  • Adynamic Bone Disease [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Doxercalciferol Capsules

Adverse reactions in patients with CKD on dialysis

Doxercalciferol capsules have been evaluated in two placebo-controlled, double-blind studies in patients with CKD on hemodialysis. Patients were treated with doxercalciferol capsules (n=61) or placebo (n=61). After randomization to two groups, eligible patients underwent an 8-week washout period during which no vitamin D derivatives were administered to either group. Subsequently, all patients received doxercalciferol capsules in an open-label fashion for 16 weeks followed by a double-blind period of 8 weeks during which patients received either doxercalciferol capsules or placebo. Adverse reactions occurring in the doxercalciferol capsule groups at a frequency of 2% or greater, and more frequently than in the placebo group are presented in Table 2.

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

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

Adverse Reaction* Doxercalciferol (n=61)
%
Placebo (n=61)
%
Edema 34 21
Malaise 28 20
Headache 28 18
Nausea/Vomiting 21 20
Dizziness 12 10
Dyspnea 12 7
Pruritus 8 7
Bradycardia 7 5
Anorexia 5 3
Dyspepsia 5 2
Arthralgia 5 0
Weight increase 5 0
Abscess 3 0
Sleep disorder 3 0

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.

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