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Calcifediol

Rayaldee

0.03MG capsule, extended releaseVereinigte StaatenIm HandelZugelassen am 17. Juni 2016

Inhalt auf Englisch

Anwendungsgebiete

RAYALDEE is a vitamin D 3 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 Use RAYALDEE 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. RAYALDEE is a vitamin D 3 analog indicated for the treatment of secondary hyperparathyroidism in adults with stage 3 or 4 chronic kidney disease and serum total 25-hydroxyvitamin D levels less than 30 ng/mL.

( 1 ) Limitations of Use: RAYALDEE is not indicated in patients with stage 5 chronic kidney disease or end-stage renal disease on dialysis. ( 1 )

Gegenanzeigen

None. None ( 4 )

Warnhinweise und Vorsichtsmaßnahmen

Hypercalcemia: Excessive administration of vitamin D compounds, including RAYALDEE, can cause hypercalcemia and hypercalciuria. Severe hypercalcemia due to substantial overdosage of vitamin D and its metabolites may require emergency attention. Patients should be informed about the symptoms of elevated calcium. ( 5.1 )
Digitalis 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 )
Adynamic Bone Disease: Monitor for abnormally low levels of intact PTH levels when using RAYALDEE, and adjust dose if needed. ( 2.2 , 5.3 )

5.1Hypercalcemia

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.

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Calcifediol

Rayaldee

0.03MG capsule, extended releaseVereinigte StaatenIm HandelZugelassen am 17. Juni 2016

Inhalt auf Englisch

Im Register öffnenFrag Osler dazu

Anwendungsgebiete

( 1 ) Limitations of Use: RAYALDEE is not indicated in patients with stage 5 chronic kidney disease or end-stage renal disease on dialysis. ( 1 )

Gegenanzeigen

None. None ( 4 )

Warnhinweise und Vorsichtsmaßnahmen

Hypercalcemia: Excessive administration of vitamin D compounds, including RAYALDEE, can cause hypercalcemia and hypercalciuria. Severe hypercalcemia due to substantial overdosage of vitamin D and its metabolites may require emergency attention. Patients should be informed about the symptoms of elevated calcium. ( 5.1 )
Digitalis 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 )
Adynamic Bone Disease: Monitor for abnormally low levels of intact PTH levels when using RAYALDEE, and adjust dose if needed. ( 2.2 , 5.3 )

5.1Hypercalcemia

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Wechselwirkungen

Co-administration of cytochrome P450 inhibitors, such as ketoconazole, may alter serum levels of calcifediol. ( 7.1 )
Co-administration of thiazides may cause hypercalcemia. ( 7.2 )
Cholestyramine may impair the absorption of calcifediol. ( 7.3 )
The half-life of calcifediol is reduced by drugs stimulating microsomal hydroxylation, such as phenobarbital or other anticonvulsants. ( 7.4 )

7.1CYP3A 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.

7.2Thiazides

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 ) ].

7.3Cholestyramine

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.

7.4Other 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.

Schwangerschaft und Stillzeit

8.1Pregnancy 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 ≥8 times the human dose of 60 mcg/day, based on body surface area (mg/m 2 ), during the period of organogenesis.

No adverse developmental effects were observed in rats given up to 10 times the human dose, based on body surface area (mg/m 2 ), 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 10 and 16 times, respectively, a human dose of 60 mcg/day, based on body surface area (mg/m 2 ). 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 8 and 16 times the human dose of 60 mcg/day, respectively, based on body surface area (mg/m 2 ).

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.

Nebenwirkungen

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 ) ] 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.

6.1Clinical 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 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/1.73m 2 .

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

1.4Increase 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).

Rayaldee

Anwendungsgebiete

Gegenanzeigen

Warnhinweise und Vorsichtsmaßnahmen

5.1Hypercalcemia

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Rayaldee

Anwendungsgebiete

Gegenanzeigen

Warnhinweise und Vorsichtsmaßnahmen

5.1Hypercalcemia

Zwei Arzneimittel in einer Frage?

5.2Digitalis Toxicity Hypercalcemia

5.3Adynamic Bone Disease

Wechselwirkungen

7.1CYP3A Inhibitors Cytochrome

7.2Thiazides

7.3Cholestyramine

7.4Other Agents Phenobarbital

Schwangerschaft und Stillzeit

8.1Pregnancy Risk Summary

Nebenwirkungen

6.1Clinical Trial Experience

1.4Increase in Serum Calcium

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