RAYALDEE Extended-release capsule Ref.[49873] Active ingredients: Calcidiol

5.1 Hypercalcemia

Hypercalcemia may occur during RAYALDEE treatment [see Adverse Reactions (6.1)]. 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. In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. In these circumstances, frequent serum calcium monitoring and RAYALDEE dose adjustments may be required. Patients with a history of hypercalcemia prior to initiating therapy with RAYALDEE should be monitored more frequently for possible hypercalcemia during therapy.

Patients should be informed about the symptoms of elevated serum calcium, which include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, and weight loss.

5.2 Digitalis Toxicity

Hypercalcemia of any cause, including RAYALDEE [see Warnings and Precautions (5.1)], increases the risk of digitalis toxicity. In patients using RAYALDEE concomitantly with digitalis compounds, monitor both serum calcium and patients for signs and symptoms of digitalis toxicity and increase the frequency of monitoring when initiating or adjusting the dose of RAYALDEE [see Dosage and Administration (2)].

5.3 Adynamic Bone Disease

Adynamic bone disease with subsequent increased risk of fractures may develop if intact PTH levels are suppressed by RAYALDEE to abnormally low levels. Monitor intact PTH levels and adjust RAYALDEE dose, if needed [see Dosage and Administration (2.2)].

The following important adverse reactions are discussed in greater detail in other sections of the label:

• Hypercalcemia [see Warnings and Precautions (5.1)]
• Adynamic Bone Disease [see Warnings and Precautions (5.3)]

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

The data in Table 1 are derived from two pivotal studies described below [see Clinical Studies (14)]. These data reflect exposure of 285 subjects to RAYALDEE 30 or 60 mcg daily for up to 6 months (mean 24 weeks, range 1 to 31 weeks). The mean age of the study population was 66 years old (range 25-85 years). Half of the subjects were male, 65% were White, and 32% were African-American or Black. At baseline, subjects had secondary hyperparathyroidism, stage 3 (52%) or 4 (48%) chronic kidney disease without macroalbuminuria and serum total 25-hydroxyvitamin D levels less than 30 ng/mL. The most common causes of chronic kidney disease were diabetes and hypertension and the mean estimated GFR at baseline was 31 mL/min/1.73m². At baseline, mean plasma intact PTH was 148 pg/mL, mean serum calcium was 9.2 mg/dL, mean serum phosphorus was 3.7 mg/dL and mean serum 25-hydroxyvitamin D was 20 ng/mL.

Table 1 shows common adverse reactions associated with the use of RAYALDEE in the pooled placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on RAYALDEE than on placebo, and occurred in at least 1.4% of patients treated with RAYALDEE.

Table 1. Common Adverse Reactions in Placebo-controlled Trials Reported in ≥1.4% of RAYALDEE-Treated Subjects:

Increase in Serum Calcium

Patients randomized to RAYALDEE experienced a greater mean (SE) increase in serum calcium (P<0.001) than patients randomized to placebo [i.e., 0.2 (0.02) mg/dL on RAYALDEE versus 0.1 (0.03) mg/dL on placebo from baseline to trial end]. Six subjects (2%) in the RAYALDEE treatment group and no subjects (0%) in the placebo group required dose reductions for protocol-defined hypercalcemia (two consecutive serum calcium values greater than 10.3 mg/dL). A total of 4.2% of RAYALDEE treated subjects and 2.1% of placebo treated subjects experienced at least one elevation in serum calcium above the upper limit of normal (10.5 mg/dL).

Increase in Serum Phosphorus

Patients randomized to RAYALDEE experienced a greater mean (SE) increase in serum phosphorus than patients randomized to placebo [i.e., 0.2 (0.03) mg/dL on RAYALDEE versus 0.1 (0.04) mg/dL on placebo from baseline to trial end]. One subject (0.4%) in the RAYALDEE treatment group met protocol-defined hyperphosphatemia (two consecutive serum phosphorus values greater than 5.5 mg/dL deemed to be study drug related) compared to no subjects in the placebo group. A total of 45% of RAYALDEE treated subjects and 44% of placebo treated subjects experienced at least one elevation in serum phosphorus above the upper limit of normal (4.5 mg/dL).

7.1 CYP3A Inhibitors

Cytochrome P450 inhibitors, such as ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1), and may alter serum levels of calcifediol. Dose adjustment of RAYALDEE may be required, and serum 25-hydroxyvitamin D, intact PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.

7.2 Thiazides

Thiazides are known to induce hypercalcemia by reducing excretion of calcium in the urine.

Concomitant administration of thiazides with RAYALDEE may cause hypercalcemia. Patients may require more frequent serum calcium monitoring in this setting [see Warnings and Precautions (5.1)].

7.3 Cholestyramine

Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins and may impair the absorption of calcifediol, the active ingredient in RAYALDEE. Dose adjustment of RAYALDEE may be required, and serum total 25-hydroxyvitamin D, intact PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with cholestyramine.

7.4 Other Agents

Phenobarbital or other anticonvulsants or other compounds that stimulate microsomal hydroxylation reduce the half-life of calcifediol, the active ingredient in RAYALDEE. Dose adjustment of RAYALDEE may be required, and serum total 25-hydroxyvitamin D, intact PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with phenobarbital or other anticonvulsants.

Risk Summary

There are no human data with calcifediol use in pregnant women 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 animal reproduction studies, calcifediol increased skeletal and soft tissue malformation when rabbits were given once daily oral doses representing ≥6 times the human dose of 60 mcg/day, based on body surface area (mg/m²), during the period of organogenesis. No adverse developmental effects were observed in rats given up to 15 times the human dose, based on body surface area (mg/m²), during organogenesis.

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 maternal risk for hypertension, miscarriage, preterm labor, and preeclampsia. Chronic kidney disease increases the fetal risk for intrauterine growth restriction (IUGR), prematurity, polyhydramnios, still birth, and low birth weight.

Data

Animal Data

Calcifediol was given orally to pregnant rats and rabbits during the period of organogenesis (in rats, from gestation day [GD] 6 to 15; in rabbits, from GD 6 to 18). Rats were given 0, 12, 40, 60 mcg/kg/day; and rabbits were given 0, 5, 25, 50 mcg/kg/day, representing up to 15 and 13 times, respectively, a human dose of 60 mcg/kg, based on body surface area (mg/m²).

In rats, no adverse developmental effects were observed at calcifediol doses up to 60 mcg/kg/day. In rabbits, increased incidences of domed skull, enlarged atrium of the heart, and dilatation of pulmonary artery, were observed at doses of 25 and 50 mcg/kg/day (representing 6 and 13 times the human dose of 60 mcg/day, respectively, based on body surface area (mg/m²). Rats were given calcifediol during the pre/postnatal period (GD 15 to weaning). No adverse effects on gestation, parturition, lactation or survival of offspring were observed at calcifediol doses up to 60 mcg/kg/day.

Risk Summary

There is no information available on the presence of calcifediol in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Infants potentially exposed to calcifediol 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 RAYALDEE and any potential adverse effects on the breastfed child from RAYALDEE or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to calcifediol through breast milk for signs and symptoms of hypercalcemia, including seizures, vomiting, constipation and weight loss. Consider monitoring of serum calcium in the infant.

The safety and efficacy of RAYALDEE have not been established in pediatric patients.

Of the total number of subjects in phase 3 placebo-controlled clinical studies of RAYALDEE, 63% were ≥65 years of age and 22% were ≥75 years of age. No overall differences in the safety or efficacy of RAYALDEE were observed between subjects older than 65 years and younger subjects.

No difference in efficacy was observed between patients with stage 3 chronic kidney disease or those with stage 4 disease in subgroup analysis. Safety outcomes were similar in these subgroups. The safety and efficacy of RAYALDEE in the treatment of secondary hyperparathyroidism in patients with stage 2 or stage 5 chronic kidney disease and patients with end-stage renal disease on dialysis have not been established [see Indications and Usage (1)].