HECTOROL Capsule / Solution for injection Ref.[10031] Active ingredients: Doxercalciferol

5.1 Hypercalcemia

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

When initiating HECTOROL or adjusting HECTOROL 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 HECTOROL 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

HECTOROL can cause hypercalcemia [see Warnings and Precautions (5.1)] which increases the risk of digitalis toxicity. In patients using HECTOROL 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 HECTOROL [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 HECTOROL upon initiation of treatment for hypersensitivity reactions. Should a hypersensitivity reaction occur, discontinue HECTOROL, 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 HECTOROL to abnormally low levels. Monitor intact PTH levels to avoid oversuppression and adjust the HECTOROL dose, if needed [see Dosage and Administration (2)].

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)]

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.

HECTOROL Capsules

Adverse reactions in patients with stage 3 or 4 CKD

HECTOROL 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 HECTOROL capsules (n=27) or placebo (n=28) [see Clinical Studies (14.1)]. Adverse reactions occurring in the HECTOROL 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% HECTOROL Capsule-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 in patients with CKD on dialysis

HECTOROL capsules have been evaluated in two placebo-controlled, double-blind studies in patients with CKD on hemodialysis. Patients were treated with HECTOROL 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 HECTOROL capsules in an open-label fashion for 16 weeks followed by a double-blind period of 8 weeks during which patients received either HECTOROL capsules or placebo. Adverse reactions occurring in the HECTOROL 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% HECTOROL Capsule-Treated Patients with CKD on Dialysis and Greater than Placebo in Two Double-Blind Clinical Studies:

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 HECTOROL capsules presented in Table 2.

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

Tables 3 and 4 include clinically significant drug interactions with HECTOROL.

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

Table 4. Clinically Significant Drug Interactions with HECTOROL Capsules:

Risk Summary

The limited available data with HECTOROL 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.

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 HECTOROL 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 HECTOROL and any potential adverse effects on the breastfed child from HECTOROL 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.

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

Clinical studies of HECTOROL 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.

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