Excessive administration of RAYALDEE can cause hypercalciuria, hypercalcemia, hyperphosphatemia, or oversuppression of intact PTH. Common symptoms of vitamin D overdosage may include constipation, decreased appetite, dehydration, fatigue, irritability, muscle weakness, or vomiting.
Treatment of acute accidental overdosage with RAYALDEE should consist of general supportive measures. If the overdosage is discovered within a short time, induce emesis or perform gastric lavage to prevent further absorption. Obtain serial serum and urine calcium measurements, and assess any electrocardiographic abnormalities due to hypercalcemia. Discontinue supplemental calcium. Treat with standard medical care if persistent and markedly elevated serum calcium levels occur.
Calcifediol is not significantly removed by dialysis.
None.
The following important adverse reactions are discussed in greater detail in other sections of the label:
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. 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 25hydroxyvitamin 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
| Adverse Reaction | Placebo N=144 % |
RAYALDEE N=285 % |
| Anemia | 3.5 | 4.9 |
| Nasopharyngitis | 2.8 | 4.9 |
| Blood creatinine increased | 1.4 | 4.9 |
| Dyspnea | 2.8 | 4.2 |
| Cough | 2.1 | 3.5 |
| Cardiac failure congestive | 0.7 | 3.5 |
| Constipation | 2.8 | 3.2 |
| Bronchitis | 0.7 | 2.8 |
| Hyperkalemia | 0.7 | 2.5 |
| Osteoarthritis | 0.7 | 2.1 |
| Hyperuricemia | 0.7 | 1.8 |
| Contusion | 0.0 | 1.8 |
| Pneumonia | 0.7 | 1.4 |
| Chronic obstructive pulmonary disease | 0.0 | 1.4 |
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 1 elevation in serum calcium above the upper limit of normal (10.5 mg/dL).
Increase In Serum PhosphorusPatients 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 >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).
RAYALDEE is a vitamin D3 analog indicated for the treatment of secondary hyperparathyroidism in adult patients with stage 3 or 4 chronic kidney disease and serum total 25-hydroxyvitamin D levels less than 30 ng/mL.
Limitations Of UseRAYALDEE is not indicated for the treatment of secondary hyperparathyroidism in patients with stage 5 chronic kidney disease or in patients with end-stage renal disease on dialysis.
In repeat-dose clinical studies with RAYALDEE, increased levels of serum total 25hydroxyvitamin D were associated with corresponding increases in serum total 1,25-dihydroxyvitamin D concentrations and reductions in circulating plasma intact PTH observed within the first two weeks of RAYALDEE treatment.
No food effect study was conducted with 30 mcg and 60 mcg doses of RAYALDEE. However, a food effect study with a supratherapeutic dose of 450 mcg in healthy subjects showed an approximately 5-fold increase in maximum serum calcifediol concentration (Cmax) and a 3.5-fold increase in AUC0-t when RAYALDEE was administered with a high fat, high calorie meal compared to fasting.
Exposure to calcifediol increased proportionally over the dose range of 30 to 90 mcg following repeated daily administration of RAYALDEE at bedtime to subjects with secondary hyperparathyroidism, chronic kidney disease and vitamin D insufficiency. Steady-state levels of serum total 25-hydroxyvitamin D are reached after approximately 3 months.
DistributionCalcifediol is extensively bound to plasma proteins (>98%). The mean apparent volume of distribution is 8.8 L in healthy subjects following a single oral dose of RAYALDEE, and 30.1 L in subjects with stage 3 or 4 chronic kidney disease following repeated dosing.
EliminationThe mean elimination half-life of calcifediol is approximately 11 days in healthy individuals following a single dose of RAYALDEE, and approximately 25 days in patients with stage 3 or stage 4 chronic kidney disease following repeated once daily dosing.
MetabolismProduction of calcitriol from calcifediol is catalyzed by the 1-alpha-hydroxylase enzyme, CYP27B1, located in the kidney and other tissues. CYP24A1, located in all vitamin D-responsive tissues, catabolizes both calcifediol and calcitriol to inactive metabolites.
ExcretionExcretion of calcifediol occurs primarily through the biliary fecal route.
RAYALDEE 30 mcg extended-release capsules are blue oval soft capsules labeled with “O” in white ink.
Storage And HandlingRAYALDEE is supplied as 30 mcg calcifediol in blue, oval extended-release capsules, imprinted O:
Bottles of 30 [NDC 70301-1001-1]
Bottles of 60 [NDC 70301-1001-2]
Store at 20-25®C (68-77®F); excursions permitted to 15-30®C (59-86®F).
Manufactured for: OPKO Pharmaceuticals, LLC 4400 Biscayne Blvd Miami FL 33137. Revised Mar 2016
Included as part of the PRECAUTIONS section.
PRECAUTIONS HypercalcemiaHypercalcemia may occur during RAYALDEE treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart. 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.
Digitalis ToxicityHypercalcemia of any cause, including RAYALDEE , 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.
Adynamic Bone DiseaseAdynamic 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.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityNo neoplastic changes attributable to calcifediol were observed at subcutaneous doses of 3, 10 and 33 mcg/kg/day in a 26-week rasH2 transgenic mouse study.
In vitro or in vivo mutagenicity studies have not been performed with RAYALDEE. No genotoxic or mutagenic effects have been reported with calcifediol.
Calcifediol has not been shown to have significant effects on fertility in rats.
Use In Specific Populations Teratogenic EffectsPregnancy Category C: Calcifediol has been shown to be teratogenic in rabbits when given in doses of 8 to 16 times the human dose of 60 mcg/day, based on body surface area. There are no adequate and well-controlled studies in pregnant women. RAYALDEE should be used during pregnancy only if the potential benefit justifies potential risk to the fetus.
When calcifediol was given orally to bred rabbits on the 6th through the 18th day of gestation, gross visceral and skeletal examination of pups indicated that the compound was teratogenic at doses of 25 and 50 mcg/kg/day. A dose of 5 mcg/kg/day was not teratogenic. In a similar study in rats, calcifediol was not teratogenic at doses up to and including 60 mcg/kg/day.
Labor And DeliveryThe effect of this drug on the mother and fetus during labor and delivery is not known.
Nursing MothersLimited available evidence indicates that calcifediol is poorly excreted in human milk. Caution should be exercised when RAYALDEE is administered to a nursing woman.
Pediatric UseThe safety and efficacy of RAYALDEE have not been established in pediatric patients.
Geriatric UseOf 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.
Renal ImpairmentNo 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.
The following important adverse reactions are discussed in greater detail in other sections of the label:
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. 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 25hydroxyvitamin 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
| Adverse Reaction | Placebo N=144 % |
RAYALDEE N=285 % |
| Anemia | 3.5 | 4.9 |
| Nasopharyngitis | 2.8 | 4.9 |
| Blood creatinine increased | 1.4 | 4.9 |
| Dyspnea | 2.8 | 4.2 |
| Cough | 2.1 | 3.5 |
| Cardiac failure congestive | 0.7 | 3.5 |
| Constipation | 2.8 | 3.2 |
| Bronchitis | 0.7 | 2.8 |
| Hyperkalemia | 0.7 | 2.5 |
| Osteoarthritis | 0.7 | 2.1 |
| Hyperuricemia | 0.7 | 1.8 |
| Contusion | 0.0 | 1.8 |
| Pneumonia | 0.7 | 1.4 |
| Chronic obstructive pulmonary disease | 0.0 | 1.4 |
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 1 elevation in serum calcium above the upper limit of normal (10.5 mg/dL).
Increase In Serum PhosphorusPatients 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 >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).
DRUG INTERACTIONS CYP3A InhibitorsCytochrome 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 25hydroxyvitamin D, intact PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.
ThiazidesThiazides 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.
CholestyramineCholestyramine 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.
Other AgentsPhenobarbital 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.
