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. 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.
Doxercalciferol Injection is contraindicated in patients with: Hypercalcemia [see Warnings and Precautions (5.1)] Vitamin D toxicity [see Warnings and Precautions (5.1)] Known hypersensitivity to doxercalciferol or any of the inactive ingredients of Doxercalciferol Injection; serious hypersensitivity reactions including anaphylaxis and angioedema have been reported [see Warnings and Precautions (5.3), Adverse Reactions (6.2)].
- Hypercalcemia ( 4 )
- Vitamin D toxicity ( 4 )
- Know hypersensitivity to doxercalciferol or any of the inactive ingredients of Doxercalciferol Injection ( 4 )
AND PRECAUTIONS Hypercalcemia: Can occur during treatment with Doxercalciferol Injection 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 Injection. (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 Injection. 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)
5.1 Hypercalcemia Hypercalcemia may occur during Doxercalciferol Injection treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> . In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. Patients with a history of hypercalcemia prior to initiating therapy may be at increased risk for development of hypercalcemia with Doxercalciferol Injection. In these circumstances, frequent serum calcium monitoring and Doxercalciferol Injection dose adjustments may be required. When initiating Doxercalciferol Injection or adjusting Doxercalciferol Injection dose, measure serum calcium 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 Injection until serum calcium is normal <span class="opacity-50 text-xs">[see Dosage and Administration (2) ]</span> . Inform patients about the symptoms of elevated calcium (feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss) and instruct them to report new or worsening symptoms when they occur.
5.2 Digitalis Toxicity Doxercalciferol Injection can cause hypercalcemia <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> which increases the risk of digitalis toxicity. In patients using Doxercalciferol Injection concomitantly with digitalis compounds, monitor both serum calcium and patients for signs and symptoms of digitalis toxicity. Increase the frequency of monitoring when initiating or adjusting the dose of Doxercalciferol Injection <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> .
5.3 Serious Hypersensitivity Reactions Serious hypersensitivity reactions, including fatal outcome, have been reported post marketing in patients on hemodialysis following administration of Doxercalciferol Injection. Hypersensitivity reactions include anaphylaxis with symptoms of angioedema (involving face, lips, tongue and airways), hypotension, unresponsiveness, chest discomfort, shortness of breath, and cardiopulmonary arrest. These reactions may occur separately or together. Monitor patients receiving Doxercalciferol Injection upon initiation of treatment for hypersensitivity reactions. Should a hypersensitivity reaction occur, discontinue Doxercalciferol Injection, monitor and treat if indicated <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .
5.4 Adynamic Bone Disease Adynamic bone disease with subsequent increased risk of fractures may develop if intact PTH levels are suppressed by Doxercalciferol Injection to abnormally low levels. Monitor intact PTH levels to avoid oversuppression and adjust the Doxercalciferol Injection dose, if needed <span class="opacity-50 text-xs">[see Dosage and Administration (2) ]</span> .
5.1 Hypercalcemia Hypercalcemia may occur during Doxercalciferol Injection treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> . In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. Patients with a history of hypercalcemia prior to initiating therapy may be at increased risk for development of hypercalcemia with Doxercalciferol Injection. In these circumstances, frequent serum calcium monitoring and Doxercalciferol Injection dose adjustments may be required. When initiating Doxercalciferol Injection or adjusting Doxercalciferol Injection dose, measure serum calcium 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 Injection until serum calcium is normal <span class="opacity-50 text-xs">[see Dosage and Administration (2) ]</span> . Inform patients about the symptoms of elevated calcium (feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss) and instruct them to report new or worsening symptoms when they occur.
5.2 Digitalis Toxicity Doxercalciferol Injection can cause hypercalcemia <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> which increases the risk of digitalis toxicity. In patients using Doxercalciferol Injection concomitantly with digitalis compounds, monitor both serum calcium and patients for signs and symptoms of digitalis toxicity. Increase the frequency of monitoring when initiating or adjusting the dose of Doxercalciferol Injection <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> .
5.3 Serious Hypersensitivity Reactions Serious hypersensitivity reactions, including fatal outcome, have been reported post marketing in patients on hemodialysis following administration of Doxercalciferol Injection. Hypersensitivity reactions include anaphylaxis with symptoms of angioedema (involving face, lips, tongue and airways), hypotension, unresponsiveness, chest discomfort, shortness of breath, and cardiopulmonary arrest. These reactions may occur separately or together. Monitor patients receiving Doxercalciferol Injection upon initiation of treatment for hypersensitivity reactions. Should a hypersensitivity reaction occur, discontinue Doxercalciferol Injection, monitor and treat if indicated <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .
5.4 Adynamic Bone Disease Adynamic bone disease with subsequent increased risk of fractures may develop if intact PTH levels are suppressed by Doxercalciferol Injection to abnormally low levels. Monitor intact PTH levels to avoid oversuppression and adjust the Doxercalciferol Injection dose, if needed <span class="opacity-50 text-xs">[see Dosage and Administration (2) ]</span> .