Vitamin D Analog (Oral) Step Therapy Program

STEP THERAPY POLICY

POLICY: Vitamin D Analog (Oral) Step Therapy Program

APPROVAL DATE: 08/07/2019

DRUGS AFFECTED: • Hectorol® (doxercalciferol capsules – Genzyme; generics)  Rayaldee® (calcifediol extended-release capsule – OPKO)  Rocaltrol® (calcitriol capsules and oral solution – Validus; generics)  Zemplar® (paricalcitol capsules – Abbvie; generics)

OVERVIEW Vitamin D analogs are therapeutic options for the reduction of elevated parathyroid hormone (PTH) levels in patients with chronic kidney disease (CKD) who have secondary hyperparathyroidism (SHPT).1 SHPT is a common complication of CKD, affecting nearly all of the more than 400,000 patients receiving dialysis (CKD Stage 5D classification) in the US.2,3 It may also affect CKD patients not yet on dialysis.2,3 SHPT is associated with increased PTH levels and alterations in calcium and phosphorus levels.2 These alterations can then lead to bone disease, bone pain and fractures, and vascular and soft tissue calcifications which may lead to cardiovascular (CV) morbidity and mortality.

Exogenous calcitriol is a synthetic vitamin D analog, which is active in the regulation of the absorption of calcium from the gastrointestinal (GI) tract and its utilization in the body.4,7 Doxercalciferol is a synthetic vitamin D2 analog which undergoes metabolic activation in vivo to form 1α,25-(OH)2D2, a 5 naturally occurring biologically active form of vitamin D2. Paricalcitol is a synthetically manufactured analog of calcitriol.6 Rayaldee is a synthetically manufactured prohormone of calcitriol, calcifediol, which is also known as calcidiol.7 Calcifediol/calcidiol is converted to calcitriol in the kidney; calcitriol then binds to vitamin D receptors (VDRs) in the target tissues. Among the vitamin D analogs, it appears that calcitriol and paricalcitol have a similar high-affinity binding of these VDRs, while doxercalciferol lacks this high-affinity binding.1

The oral activated vitamin D analogs are indicated for the management of SHPT in pre-dialysis patients.4-7 All of the oral vitamin D analogs, except Rayaldee, are also indicated for SHPT in patients receiving dialysis. Oral calcitriol is additionally indicated in the management of hypocalcemia and its clinical manifestations in patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism. Of note, Rayaldee is the only oral vitamin D analog not indicated for use in patients with end-stage renal disease (ESRD) receiving dialysis. Doxercalciferol and Rayaldee are only indicated for use in adults. Paricalcitol is indicated for use in pediatric patients ≥ 10 years of age. The safety and effectiveness of oral calcitriol in pediatric patients undergoing dialysis have not been established. Oral calcitriol can be used in pediatric predialysis patients; the prescribing information does not specify the age range. Dosing guidelines have not been established for pediatric patients < 1 year of age with hypoparathyroidism or for pediatric patients < 6 years of age with pseudohypoparathyroidism

Oral Vitamin D Analogs Comparative Data An analysis of select clinical studies for these agents summarized some of the safety and efficacy data from non-comparative studies of the oral vitamin D analogs in patients with CKD Stage 3 and 4; results are reported in Table 3.1 This analysis was published prior to the approval of Rayaldee. In pivotal studies, 33% to 34% of patients receiving Rayaldee achieved a ≥ 30% reduction in intact PTH levels from baseline (measured based on an average intact PTH level between Weeks 20 and 26).7 Mean

Vitamin D Analog (Oral) Step Therapy Program Page 2 reduction in intact parathyroid hormone (iPTH) from baseline to Week 26 was approximately 20%. Additionally, 4.2% of patients experienced a ≥ 1 mg/dL elevation in serum calcium above the upper limit of normal. Of note, there were differences in the study design and patient populations included in these trials (e.g., mean baseline PTH levels were higher in the doxercalciferol and paricalcitol studies than the Rayaldee studies), therefore, comparing the efficacy of the oral vitamin D analogs using this non- comparative data is not advised.

Table 1. Select Safety and Efficacy Results for the Oral Vitamin D Analogs.1 Drug/Study Change in PTH Levels Rate of Change in Urine Duration Mean Reduction > 30% Reduction Hypercalcemia Calcium Calcitriol (52 weeks) 25% - 64% +139% (P < 0.01) Doxercalciferol (24 weeks) 46% 74% 4% +42% (P < 0.01) Paricalcitol (24 weeks) 42% 91% 2% +6% (P = NS) PTH – parathyroid hormone.

Rayaldee pivotal studies reported changes in bone markers.7 Reductions in bone-specific alkaline phosphatase (BSAP), c-terminal telopeptide-1, and procallagen-1 amino-terminal propetide were observed with higher serum 25-hydroxyvitamin D levels. In the oral paricalcitol clinical studies, reductions in BSAP were also observed.6 Bone marker levels were not reported in the oral doxercalciferol prescribing information, although it was noted that reductions in plasma PTH levels were associated with a reduction in serum BSAP.5

POLICY STATEMENT A step therapy program has been developed to encourage the use of generic calcitriol (capsules or oral solution) product prior to the use of product prior to the use of Hectorol (brand and generic), Rayaldee, Rocaltrol capsules (brand), Rocaltrol oral solution (brand), or Zemplar (brand and generic). If the step therapy rule is not met, coverage will be determined by prior authorization criteria.

Automation: Patients with a history of at least one Step 1 product within the 130-day look-back period are excluded from step therapy.

Step 1: calcitriol capsules, calcitriol oral solution

Step 2: Hectorol capsules (brand and generic), Rayaldee capsules, Rocaltrol capsules (brand), Rocaltrol oral solution (brand), Zemplar capsules (brand and generic)

CRITERIA

1. If the patient has tried one Step 1 product, approve a Step 2 product.

2. If the patient has tried intravenous (IV) calcitriol injection, approve a Step 2 product.

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REFERENCES 1. Andress DL. Vitamin D treatment in chronic kidney disease. Semin Dial. 2005;18(4):315-321. 2. Kidney Disease Improving Global Outcomes (KDIGO). KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease – mineral and bone disorder (CKD-MBD). Kid Int Supp. 2017;7:1-59. 3. Kidney disease statistics for the United States. National Institute of Diabetes and Digestive and Kidney Diseases Website. Available at: https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease. Created December 2016. Accessed on August 2, 2019. 4. Rocaltrol® capsules and oral solution [prescribing information]. Parsippany, NJ: Validus Pharmaceuticals, LLC; May 2018. 5. Hectorol® capsules [prescribing information]. Cambridge, MA: Genzyme Corporation; November 2018. 6. Zemplar® capsules [prescribing information]. North Chicago, IL: Abbvie Inc.; February 2018. 7. Rayaldee® extended-release capsules [prescribing information]. Miami, FL: OPKO Pharmaceuticals LLC; June 2016.