ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following important adverse reactions are discussed in greater detail in other sections of the label: oHypercalcemia [see Warnings and Precautions (5.1)]oAdynamic Bone Disease [see Warnings and Precautions (5.3)]. oHypercalcemia [see Warnings and Precautions (5.1)]. oAdynamic Bone Disease [see Warnings and Precautions (5.3)]. The most common adverse reactions (>=3% and more frequent than placebo) were anemia, nasopharyngitis, increased blood creatinine, dyspnea, cough, congestive heart failure and constipation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact OPKO Pharmaceuticals, LLC at 1-844-729-2539 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trial Experience 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 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 months (mean 24 weeks, range 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 (52%) or (48%) chronic kidney disease without macroalbuminuria and serum total 25-hydroxyvitamin 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 was 20 ng/mL. Table 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 SubjectsAdverse ReactionPlacebo N=144RAYALDEEN=285%%Anemia3.54.9Nasopharyngitis2.84.9Blood creatinine increased1.44.9Dyspnea2.84.2Cough2.13.5Cardiac failure congestive0.73.5Constipation2.83.2Bronchitis0.72.8Hyperkalemia0.72.5Osteoarthritis0.72.1Hyperuricemia0.71.8Contusion0.01.8Pneumonia0.71.4Chronic obstructive pulmonary disease 0.01.4Increase in Serum CalciumPatients randomized to RAYALDEE experienced 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). 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 PhosphorusPatients randomized to RAYALDEE experienced 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. 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. oTell patients to take RAYALDEE at bedtime and to swallow the capsules whole.oInform patients if they miss dose, to take RAYALDEE at the next scheduled time. Do not take an extra dose to make up for the missed dose.oInform patients that they will need routine monitoring of laboratory parameters such as calcium, iPTH and total 25-hydroxyvitamin while taking RAYALDEE.oAdvise patients to contact health care provider if they develop symptoms of elevated calcium (e.g., feeling tired, having difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination or weight loss).oAdvise patients to inform their physician of all use of medications, including prescription and nonprescription drugs, supplements and herbal preparations, and of any changes in medical condition. Patients should also be advised to inform their physicians, when receiving newly prescribed medication, that they are taking RAYALDEE.oInform lactating women about the need to monitor infants exposed to RAYALDEE through breast milk for signs of hypercalcemia to include seizures, vomiting, constipation and weight loss [see Use in Specific Populations (8.2)].RAYALDEE(R) is registered trademark of EirGen Pharma Ltd.Patent: https://www.opko.com/what-we-do/our-research/patentsManufactured for:OPKO Pharmaceuticals, LLC4400 Biscayne Blvd.Miami FL 33137 USA(C) 2021 OPKO Pharmaceuticals, LLC. All rights reserved.. oTell patients to take RAYALDEE at bedtime and to swallow the capsules whole.. oInform patients if they miss dose, to take RAYALDEE at the next scheduled time. Do not take an extra dose to make up for the missed dose.. oInform patients that they will need routine monitoring of laboratory parameters such as calcium, iPTH and total 25-hydroxyvitamin while taking RAYALDEE.. oAdvise patients to contact health care provider if they develop symptoms of elevated calcium (e.g., feeling tired, having difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination or weight loss).. oAdvise patients to inform their physician of all use of medications, including prescription and nonprescription drugs, supplements and herbal preparations, and of any changes in medical condition. Patients should also be advised to inform their physicians, when receiving newly prescribed medication, that they are taking RAYALDEE.. oInform lactating women about the need to monitor infants exposed to RAYALDEE through breast milk for signs of hypercalcemia to include seizures, vomiting, constipation and weight loss [see Use in Specific Populations (8.2)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Calcifediol (25-hydroxyvitamin D3) is prohormone of the active form of vitamin D3, calcitriol (1,25-dihydroxyvitamin D3). Calcifediol is converted to calcitriol by cytochrome P450 27B1 (CYP27B1), also called 1-alpha hydroxylase, primarily in the kidney. Calcitriol binds to the vitamin receptor in target tissues and activates vitamin responsive pathways that result in increased intestinal absorption of calcium and phosphorus and reduced parathyroid hormone synthesis. 12.2 Pharmacodynamics. In repeat-dose clinical studies with RAYALDEE, increased levels of serum total 25-hydroxyvitamin were associated with corresponding increases in serum total 1,25-dihydroxyvitamin concentrations and reductions in circulating plasma intact PTH observed within the first two weeks of RAYALDEE treatment [see Clinical Studies (14)]. 12.3 Pharmacokinetics. AbsorptionNo food effect study was conducted with 30 mcg and 60 mcg doses of RAYALDEE. However, food effect study with supratherapeutic dose of 450 mcg in healthy subjects showed an approximately 5-fold increase in maximum serum calcifediol concentration (C max) and 3.5-fold increase in AUC0-t when RAYALDEE was administered with 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 insufficiency. Steady-state levels of serum total 25-hydroxyvitamin are reached after approximately months [see Clinical Studies (14)]. DistributionCalcifediol is extensively bound to plasma proteins (>98%). The mean apparent volume of distribution is 8.8 in healthy subjects following single oral dose of RAYALDEE, and 30.1 in subjects with stage or chronic kidney disease following repeated dosing.EliminationThe mean elimination half-life of calcifediol is approximately 11 days in healthy individuals following single dose of RAYALDEE, and approximately 25 days in patients with stage or stage 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. Specific PopulationsAge, Gender and RaceBased on population pharmacokinetic analysis, age, gender and race had no meaningful impact on steady-state concentrations of calcifediol following RAYALDEE administration. Hepatic ImpairmentThe pharmacokinetics of RAYALDEE have not been investigated in patients with hepatic impairment.Renal ImpairmentBased on the population pharmacokinetics analysis, there was no meaningful difference in calcifediol steady-state concentrations following repeated RAYALDEE administration in patients with stage or stage chronic kidney disease.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy and safety of RAYALDEE were evaluated in two identical multicenter, randomized, placebo-controlled, double-blind trials in patients with secondary hyperparathyroidism, stage or chronic kidney disease and serum total 25-hydroxyvitamin levels between 10 and 30 ng/mL. Subjects were stratified by chronic kidney disease stage and randomized in 2:1 ratio to receive RAYALDEE or matching placebo at bedtime over 26 weeks. The dose of RAYALDEE was 30 mcg once daily for the first 12 weeks and either 30 or 60 mcg once daily for the last 14 weeks. The dose was increased to 60 mcg at the start of week 13 if the plasma intact PTH level was greater than 70 pg/mL, the serum 25-hydroxyvitamin level was less than 65 ng/mL and the serum calcium level was less than 9.8 mg/dL.A total of 213 subjects were randomized in one trial (72 received placebo and 141 received RAYALDEE), and 216 subjects were randomized in the second trial (72 received placebo and 144 received RAYALDEE). The subjects mean age was 66 years (range 25-85), 50% were male, 65% White, 32% African-American or Black and 3% Other. At baseline, subjects had secondary hyperparathyroidism, and stage (52%) or stage (48%) chronic kidney disease without macroalbuminuria. The most common causes of chronic kidney disease were diabetes and hypertension and the mean estimated GFR was 31 mL/min/1.73m2. Mean baseline intact PTH was 130 pg/mL for subjects with stage disease (n=222) and 166 pg/mL for subjects with stage disease (n=207). Mean serum calcium was 9.2 mg/dL, mean serum phosphorus was 3.7 mg/dL and mean serum 25-hydroxyvitamin was 20 ng/mL. Of the 429 subjects randomized, 354 (83%) completed the studies.The primary analysis compared the proportion of individuals who experienced an at least 30% reduction in plasma intact PTH from baseline to end of trial (average of weeks 20, 22, 24 and 26). larger proportion of patients randomized to RAYALDEE experienced an at least 30% reduction in plasma intact PTH from baseline compared to placebo in both trials [33% versus 8% in the first trial (P<0.001) and 34% versus 7% in the second trial (P<0.001)]. description of mean (SE) percent change in plasma intact PTH from baseline across study visits in the two trials combined is shown in Figure 1. Serum total 25-hydroxyvitamin levels increased to at least 30 ng/mL in 80% and 83% of subjects treated with RAYALDEE vs. 3% and 7% of subjects treated with placebo (P<0.001) in the two studies, respectively. Average steady-state 25-hydroxyvitamin levels were 50 and 56 ng/mL for subjects receiving 30 mcg daily, and 69 and 67 ng/mL for subjects receiving 60 mcg daily, in the first and second studies, respectively. Figure 1. Mean (+-SE) Percent Change from Baseline in Plasma Intact PTH in the Per Protocol Populations (Pooled Data from Two Phase Studies)The Per Protocol (PP) population consisted of all subjects with at least intact PTH values in the calculated baseline and efficacy assessment period (EAP) values and who did not have major protocol deviation during the treatment period of the study. The PP population comprised 83% of randomized subjects.. Figure 1.

DESCRIPTION SECTION.

11 DESCRIPTION. Calcifediol, USP, the active ingredient in RAYALDEE, is synthetically manufactured as calcifediol monohydrate. Calcifediol is also known as calcidiol, 25-hydroxycholecalciferol or 25-hydroxyvitamin D3.Calcifediol monohydrate is white crystalline powder, has calculated molecular weight of 418.65 and is soluble in alcohol and fatty oils but practically insoluble in water. Chemically, calcifediol monohydrate is (3,5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-3,25-diol monohydrate and its structural formula is:RAYALDEE is formulated as extended-release capsules containing 30 mcg of calcifediol. Each capsule contains the following excipients: mineral oil, monoglycerides and diglycerides, paraffin, hypromellose, lauroyl polyoxylglycerides, dehydrated alcohol and butylated hydroxytoluene. The capsule shells contain modified starch, carrageenan, sodium phosphate, dibasic, sorbitol sorbitan solution, FD&C Blue 1, titanium dioxide and purified water. Medium chain triglyceride (fractionated coconut) oil is used as lubricant during manufacture, and trace amounts may be present in the final formulation.. calcifediol Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oThe initial dose of RAYALDEE is 30 mcg administered orally once daily at bedtime. Serum calcium should be below 9.8 mg/dL before initiating treatment. (2)oMonitor serum calcium, phosphorus, 25-hydroxyvitamin and intact parathyroid hormone (PTH) months after starting therapy or changing dose. (2.2, 5.3)oIncrease the dose to 60 mcg once daily after months if intact PTH is above the treatment goal. Ensure serum calcium is below 9.8 mg/dL, phosphorus is below 5.5 mg/dL and 25-hydroxyvitamin is below 100 ng/mL before increasing the dose. (2.2)oSuspend dosing if intact PTH is persistently abnormally low, serum calcium is consistently above the normal range or serum 25-hydroxyvitamin is consistently above 100 ng/mL. (2.2). oThe initial dose of RAYALDEE is 30 mcg administered orally once daily at bedtime. Serum calcium should be below 9.8 mg/dL before initiating treatment. (2). oMonitor serum calcium, phosphorus, 25-hydroxyvitamin and intact parathyroid hormone (PTH) months after starting therapy or changing dose. (2.2, 5.3). oIncrease the dose to 60 mcg once daily after months if intact PTH is above the treatment goal. Ensure serum calcium is below 9.8 mg/dL, phosphorus is below 5.5 mg/dL and 25-hydroxyvitamin is below 100 ng/mL before increasing the dose. (2.2). oSuspend dosing if intact PTH is persistently abnormally low, serum calcium is consistently above the normal range or serum 25-hydroxyvitamin is consistently above 100 ng/mL. (2.2). 2.1 Important Dosage and Administration Information oEnsure serum calcium is below 9.8 mg/dL before initiating treatment [see Warnings and Precautions (5.1)].oInstruct patients to swallow RAYALDEE capsules whole. oInstruct patients to skip missed dose and to resume taking the medicine at the next regularly scheduled time. Do not administer an extra dose.. oEnsure serum calcium is below 9.8 mg/dL before initiating treatment [see Warnings and Precautions (5.1)].. oInstruct patients to swallow RAYALDEE capsules whole. oInstruct patients to skip missed dose and to resume taking the medicine at the next regularly scheduled time. Do not administer an extra dose.. 2.2 Starting Dose and Dose Titration oThe initial dose of RAYALDEE is 30 mcg administered orally once daily at bedtime. oThe maintenance dose of RAYALDEE should target serum total 25-hydroxyvitamin levels between 30 and 100 ng/mL, intact parathyroid hormone (PTH) levels within the desired therapeutic range, serum calcium (corrected for low albumin) within the normal range and serum phosphorus below 5.5 mg/dL. oMonitor serum calcium, serum phosphorus, serum total 25-hydroxyvitamin and intact PTH levels at minimum of months after initiation of therapy or dose adjustment, and subsequently at least every to 12 months. oIncrease the dose to 60 mcg orally once daily at bedtime after approximately months, if intact PTH remains above the desired therapeutic range. Prior to raising the dose, ensure serum calcium is below 9.8 mg/dL, serum phosphorus is below 5.5 mg/dL and serum total 25-hydroxyvitamin is below 100 ng/mL.oSuspend dosing if intact PTH is persistently and abnormally low to reduce the risk of adynamic bone disease [see Warnings and Precautions (5.3)], if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia [see Warnings and Precautions (5.1)], or if serum total 25-hydroxyvitamin is consistently above 100 ng/mL. Restart at reduced dose after these laboratory values have normalized.. oThe initial dose of RAYALDEE is 30 mcg administered orally once daily at bedtime. oThe maintenance dose of RAYALDEE should target serum total 25-hydroxyvitamin levels between 30 and 100 ng/mL, intact parathyroid hormone (PTH) levels within the desired therapeutic range, serum calcium (corrected for low albumin) within the normal range and serum phosphorus below 5.5 mg/dL. oMonitor serum calcium, serum phosphorus, serum total 25-hydroxyvitamin and intact PTH levels at minimum of months after initiation of therapy or dose adjustment, and subsequently at least every to 12 months. oIncrease the dose to 60 mcg orally once daily at bedtime after approximately months, if intact PTH remains above the desired therapeutic range. Prior to raising the dose, ensure serum calcium is below 9.8 mg/dL, serum phosphorus is below 5.5 mg/dL and serum total 25-hydroxyvitamin is below 100 ng/mL.. oSuspend dosing if intact PTH is persistently and abnormally low to reduce the risk of adynamic bone disease [see Warnings and Precautions (5.3)], if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia [see Warnings and Precautions (5.1)], or if serum total 25-hydroxyvitamin is consistently above 100 ng/mL. Restart at reduced dose after these laboratory values have normalized.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oCo-administration of cytochrome P450 inhibitors, such as ketoconazole, may alter serum levels of calcifediol. (7.1)oCo-administration of thiazides may cause hypercalcemia. (7.2)oCholestyramine may impair the absorption of calcifediol. (7.3)oThe half-life of calcifediol is reduced by drugs stimulating microsomal hydroxylation, such as phenobarbital or other anticonvulsants. (7.4). oCo-administration of cytochrome P450 inhibitors, such as ketoconazole, may alter serum levels of calcifediol. (7.1). oCo-administration of thiazides may cause hypercalcemia. (7.2). oCholestyramine may impair the absorption of calcifediol. (7.3). oThe half-life of calcifediol is reduced by drugs stimulating microsomal hydroxylation, such as phenobarbital or other anticonvulsants. (7.4). 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 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 patient initiates or discontinues therapy with 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 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 patient initiates or discontinues therapy with phenobarbital or other anticonvulsants.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionNo food effect study was conducted with 30 mcg and 60 mcg doses of RAYALDEE. However, food effect study with supratherapeutic dose of 450 mcg in healthy subjects showed an approximately 5-fold increase in maximum serum calcifediol concentration (C max) and 3.5-fold increase in AUC0-t when RAYALDEE was administered with 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 insufficiency. Steady-state levels of serum total 25-hydroxyvitamin are reached after approximately months [see Clinical Studies (14)]. DistributionCalcifediol is extensively bound to plasma proteins (>98%). The mean apparent volume of distribution is 8.8 in healthy subjects following single oral dose of RAYALDEE, and 30.1 in subjects with stage or chronic kidney disease following repeated dosing.EliminationThe mean elimination half-life of calcifediol is approximately 11 days in healthy individuals following single dose of RAYALDEE, and approximately 25 days in patients with stage or stage 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. Specific PopulationsAge, Gender and RaceBased on population pharmacokinetic analysis, age, gender and race had no meaningful impact on steady-state concentrations of calcifediol following RAYALDEE administration. Hepatic ImpairmentThe pharmacokinetics of RAYALDEE have not been investigated in patients with hepatic impairment.Renal ImpairmentBased on the population pharmacokinetics analysis, there was no meaningful difference in calcifediol steady-state concentrations following repeated RAYALDEE administration in patients with stage or stage chronic kidney disease.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary. There are no human data with calcifediol use in pregnant women to identify 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 DataCalcifediol was given orally to pregnant rats and rabbits during the period of organogenesis (in rats, from gestation day [GD] to 15; in rabbits, from GD 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, 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 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.

RISKS.

Risk Summary. There are no human data with calcifediol use in pregnant women to identify 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oLactation: Monitor infants exposed to RAYALDEE through breast milk for seizures, vomiting, constipation and weight loss. (8.2). oLactation: Monitor infants exposed to RAYALDEE through breast milk for seizures, vomiting, constipation and weight loss. (8.2). 8.1 Pregnancy Risk Summary. There are no human data with calcifediol use in pregnant women to identify 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 DataCalcifediol was given orally to pregnant rats and rabbits during the period of organogenesis (in rats, from gestation day [GD] to 15; in rabbits, from GD 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, 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 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.. 8.2 Lactation 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 mothers 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.. 8.4 Pediatric Use. The safety and efficacy of RAYALDEE have not been established in pediatric patients.. 8.5 Geriatric Use. Of the total number of subjects in phase 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.. 8.6 Renal Impairment No difference in efficacy was observed between patients with stage chronic kidney disease or those with stage 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 or stage chronic kidney disease and patients with end-stage renal disease on dialysis have not been established [see Indications and Usage (1)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oHypercalcemia: Excessive administration of vitamin compounds, including RAYALDEE, can cause hypercalcemia and hypercalciuria. Severe hypercalcemia due to substantial overdosage of vitamin and its metabolites may require emergency attention. Patients should be informed about the symptoms of elevated calcium. (5.1)oDigitalis toxicity: Potentiated by hypercalcemia of any cause. Monitor serum calcium and signs and symptoms of digitalis toxicity more frequently when initiating or adjusting the dose of RAYALDEE. (5.2)oAdynamic Bone Disease: Monitor for abnormally low levels of intact PTH levels when using RAYALDEE, and adjust dose if needed. (2.2, 5.3). oHypercalcemia: Excessive administration of vitamin compounds, including RAYALDEE, can cause hypercalcemia and hypercalciuria. Severe hypercalcemia due to substantial overdosage of vitamin and its metabolites may require emergency attention. Patients should be informed about the symptoms of elevated calcium. (5.1). oDigitalis toxicity: Potentiated by hypercalcemia of any cause. Monitor serum calcium and signs and symptoms of digitalis toxicity more frequently when initiating or adjusting the dose of RAYALDEE. (5.2). oAdynamic Bone Disease: Monitor for abnormally low levels of intact PTH levels when using RAYALDEE, and adjust dose if needed. (2.2, 5.3). 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 compounds. In addition, high intake of calcium and phosphate concomitantly with vitamin compounds may lead to hypercalciuria and hyperphosphatemia. In these circumstances, frequent serum calcium monitoring and RAYALDEE dose adjustments may be required. Patients with 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)].