1. Rayaldee® - calcifediol
Manufacturer: OPKO Ireland Global Holdings Ltd.
FDA Approval Date: June 21, 2016

2. Rayaldee® - (calcifediol) Objectives
At the end of this presentation participants will be able to:
Appropriately recommend Rayaldee® - (calcifediol)
Effectively educate patients on the purpose, proper use and potential adverse effects of Rayaldee® - (calcifediol)

3. Rayaldee® - (calcifediol) Clinical Application
Indications:
Treatment of secondary hyperparathyroidism in adults with stage 3 and 4 CKD and serum total 25-hydroxyvitamin D levels less than 30ng/mL
Place in therapy:
Can be used instead of low dose oral vitamin D derivatives (calcitriol or doxercalciferol) or ergocalciferol.
Rayaldee [package insert].

4. Rayaldee® - (calcifediol) Clinical Application
Contraindications:
None
Black Box Warnings:
Warnings/ Precautions:
Hypercalcemia
Digitalis toxicity
Adynamic Bone Disease
Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart.
Chronic hypercalcemia can cause vascular calcification and other soft-tissue calcification.
PTH levels suppressed to abnormally low levels can cause adynamic bone disease increasing risk of fractures.
Rayaldee [package insert].

5. Rayaldee® - (calcifediol) Clinical Application
Pregnancy:
Category C: Has been shown to be teratogenic in rabbits when given doses of 8 to 16 times the human dose of 60mcg/day, based on BSA
Lactation:
Caution should be exercised. Limited evidence indicates that calcifediol is poorly excreted in human milk
Rayaldee [package insert].

6. Rayaldee® - (calcifediol) Drug Facts
Pharmacology:
Prohomone of the active form of vitamin D3 (calcitriol)
Calcifediol is converted to calcitriol by cytochrome P450 27B1
Vitamin D responsive pathways result in increased intestinal absorption of calcium and phosphorus
Results in reduced parathyroid hormone synthesis
Rayaldee [package insert].

7. Rayaldee® - (calcifediol) Drug Facts
Pharmacokinetics: A
Steady state: 3 months D
>98% protein bound. Vd = 30L M
CYP27B1: catalyzes; CYP24A1: catabolizes E
T1/2 = 25 days
Vd = 30L and T1/2 = 25 days in pts with stage 3 or 4 CKD following repeated dosing.
Rayaldee [package insert].

8. Rayaldee® - (calcifediol) Drug Interactions
Drug Interactions – Precipitant Drugs:
CYP450 inhibitors
Thiazides: induce hypercalcemia
Cholestyramine: impairs absorption of calcifediol
Phenobarbital: reduces half-life of calcifediol
CYP450 inhibitors: antivirals (atazanavir), antifungals (ketoconazole), and macrolide Abx (clarithromycin).
Rayaldee [package insert].

9. Rayaldee® - (calcifediol) Adverse Effects
Common Adverse Effects: (caldifediol%)[placebo%]
Anemia (4.9)[3.5]
Nasopharyngitis (4.9)[2.8]
Increased Scr (4.9)[1.4]
Serious Adverse Effects: (calcifediol%)[placebo%]
Hypercalcemia (2)[0]
Hyperphosphatemia (0.4)[0]
Rayaldee [package insert].

10. Rayaldee® - (calcifediol) Monitoring Parameters
Efficacy/Toxicity Monitoring:
Serum calcium
Serum phosphorus
Serum 25-hydroxyvitamin D
Intact parathyroid hormone levels
Monitor 3 months after starting therapy or changing dose
Rayaldee [package insert].

11. Rayaldee® - (calcifediol) Prescription Information
Dosing: 30mcg PO once daily at bedtime
Max Dose: 60mcg PO once daily
Increase to 60mcg after 3 months if intact PTH is high. Ensure serum calcium <9.8, serum phosphorus <5.5, 25(OH)D <100 prior to dose escalation.
Cost: Not available
Calcium ( )
Phosphate ( )
Vitamin D (20-50)
Rayaldee [package insert].

12. Rayaldee® - (calcifediol) Clinical Studies Review
Purpose: Determine the safety and efficacy of Rayaldee compared to placebo
Design:
Two identical multicenter, randomized, placebo-controlled, double-blind trials
Dose of calcifediol was 30mcg once daily for first 12 weeks and either 30 or 60mcg once daily for the last 14 weeks (26 weeks total)
Dose was increased to 60mcg at week 13 if plasma intact PTH >70pg/mL, the serum 25(OH)D <65ng/mL, and the serum calcium level was <9.8mg/dL
PTH (10-60)
Rayaldee [package insert].

13. Rayaldee® - (calcifediol) Clinical Studies Review
Included: Patients with secondary hyperparathyroidism, stage 3 or 4 chronic kidney disease, and serum total 25(OH)D levels between 10 and 30ng/mL
N = 213 (72 placebo, 141 calcifediol); 216 (72 placebo, 144 calcifediol)
Mean age = 66y
65% white, 32% AA, 3% other
CKD: Stage 3 (52%) and Stage 4 (48%)
PTH: Stage 3 (130pg/mL); Stage 4 (166pg/mL)
Calcium (9.2mg/dL), Phosphorus (3.7mg/dL), 25(OH)D (20ng/mL)
Rayaldee [package insert].

14. Rayaldee® - (calcifediol) Clinical Studies Review
Primary Outcome: At least a 30% reduction in plasma intact PTH from baseline to end of trial
Trial 1: calcifediol (30%) vs placebo (8%), (P<0.001)
Trial 2: calcifediol (34%) vs placebo (7%), (P<0.001)
Rayaldee [package insert].

15. Rayaldee® - (calcifediol) Clinical Studies Review
Figure 1. Mean (+SE) Percent Change From Baseline in Plasma Intact PTH in the Per Protocol Populations (Pooled Data from Two Phase 3 Studies).
Rayaldee [package insert].

16. Rayaldee® - (calcifediol) Clinical Studies Review
Secondary Outcome: Serum total 25(OH)D levels increased to at least 30ng/mL
Calcifediol: 80% and 83%
Placebo: 3% and 7%
(P<0.001)
Average steady state 25(OH)D levels
30mcg dose: 50ng/mL and 56ng/mL
60mcg dose: 69ng/mL and 67ng/mL
Vitamin D (20-50)
Rayaldee [package insert].

17. Rayaldee® - (calcifediol) Summary
Indicated for treatment of secondary hyperparathyroidism in stage 3 or 4 CKD with serum total 25(OH)D <30
Warnings include: Hypercalcemia, Digitalis Toxicity, and Adynamic Bone Disease

18. Rayaldee® - (calcifediol) Summary
Initial Dose:
30mcg PO once daily at bedtime
If intact PTH is high after 3 months;
Increase dose to 60mcg
Ensure serum calcium <9.8, phosphorus <5.5, 25(OH)D <100 prior to dose increase
Can be used instead of low dose oral vitamin D derivatives (calcitriol or doxercalciferol) or ergocalciferol
Prevalence of the Stages of CKD:
Stage 3 CKD – Prevalence: 18.7 million - % w/ low VitD (71%) - % w/ SHPT (40%)
Stage 4 CKD – Prevalence: 1.4 million - % w/ low VitD (83%) - % w/ SHPT (82%)
Stage 5 CKD – Prevalence: 0.5 million - % w/ low VitD (97%) - % w/ SHPT (95%)
Comparison to VitD (cholecalciferol/ergocalciferol) OTC, ergocalciferol Rx, calcitriol, and doxercalciferol:
Rayaldee (calcifediol): 25D (significant inc), Ca (no change), iPTH (significant dec)
VitD (chole/ergo) OTC: 25D (minor inc), Ca (no change), iPTH (minor dec)
Drisdol (ergo) Rx: 25D (minor inc), Ca (no change), iPTH (minor dec)
Rocaltrol (calcitriol): 25D (dec), Ca (inc), iPTH (significant dec)
Hectorol (doxer); 25D (dec), Ca (inc), iPTH (significant dec)
Ergocalciferol study: Prospective, nonrandomized observational analysis. Dosed based on 25(OH)D levels (>25 then units daily, units x4wks then 1200 IU daily, < units x4wks then monthly x3mo then 1200 IU/daily) These were adjusted every 3 months. Median 13% dec in PTH in stage 3 CKD and 2% dec in PTH in stage 4 CKD (not stat sig). Data collected for a year (June 2004-June 2005).
Calcitriol study: Pts w/ stage 3 and 4 CKD w/ PTH >120pg/mL. Dose 0.25ug/dL. Dose adjustments allowed to reach 40%-60% suppression below baseline. Took 12 weeks to reach 40% reduction in PTH. At 24wks mean PTH was suppressed 46%. Mean final dose was 0.5ug/dL. Ca and Phos increased significantly but returned to baseline 1 week after drug withdrawal.
Doxercalciferol study: Dose 1.5ug/day and increased by 1ug/day if PTH did not dec by 30% on subsequent visit. 18 week study. Mean iPTH dec by 30% in 83% of subjects and 50% in 72% of subjects. Mean serum Ca, Phos, and Ca-Phos values did not differ significantly from baseline values.

19. Rayaldee® - (calcifediol) References
kage_insert.pdf
Rayaldee® [package insert]. OPKO; 2016.