Pharmacology Update

Prednisone Delayed-Release Tablets (RAYOS®)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

THE FDA HAS APPROVED A NEW FORMULATION OF PREDNISONE for the treatment rheumatoid arthritis and other conditions in which an anti-inflammatory or immuosuppressive agent is indicated. This delayed-release (DR) formulation is designed to target the circadian rhythm of proinflammatory cytokines such as interleukin 6. The new product is marketed by Horizon Pharma, Inc. as RAYOS®.

Indications

Prednisone DR is indicated as an anti-inflammatory or immunosuppressive agent for diseases of various organ systems as well as endocrine or neoplastic conditions.1

Dosage

Prednisone DR is dosed once daily and the dose should be individualized based on disease severity and response. The timing of the dose should be based on the pharmacokinetics of the DR formulation and the disease being treated.1 For example, rheumatoid arthritis subjects were dosed at 10 p.m. in clinical trials.1,2 Prednisone DR should be taken whole and with food. Patients on immediate release formulation of prednisone or other glucocorticoids can be switched to prednisone DR at equivalent doses based on relative potency.1

Prednisone DR is available as 1 mg, 2 mg, and 5 mg tablets.

Potential Advantages

For patients with rheumatoid arthritis, prednisone DR at 10 p.m. appears to be more effective than prednisone dosed in the morning in terms of reduction of morning stiffness.3

Potential Disadvantages

The long-term effect of this formulation is not currently known. Prednisone DR carries the same risks of short-acting prednisone, including hypertension, edema, elevated blood sugar, and muscle atrophy, etc.

Comments

Morning stiffness in patients with rheumatoid arthritis is believed to be due to inadequate endogenous production of adrenal cortisol to suppress the proinflammatory cytokines. Both endogenous cortisol synthesis and cytokine levels follow circadian rhythmicity.4 The objective of prednisone DR is to augment endogenous cortisol and suppress these proinflammatory cytokines. To time the administration of prednisone according to the circadian rhythm, it would need to be given at 2 a.m. Prednisone DR is designed to provide peak levels at 2 a.m. when taken at 10 p.m.

The efficacy of prednisone DR in rheumatoid arthritis was studied in one placebo-controlled, randomized, 12-week trial (CAPRA-2).1,2 Subjects were 18 years of age or older, had active disease based on the criteria of the American College of Rheumatology (ACR), had received non-biologic DMARD therapy for at least 6 months with inadequate response, and were not currently on corticosteroid therapy. Subjects were randomized at a 2:1 ratio to prednisone DR at 10 p.m. (n = 231) or placebo (n = 119). The primary endpoint was ACR response criteria 20, 50, and 70. A secondary endpoint was change in duration of morning stiffness between baseline and week 12. At week 12, ACR 20 was 47% vs 29% for placebo (difference [95% CI] of 17% [7.2, 27.6]). Values for ACR50 and ACR70 vs placebo were 22% vs 10%, and 7% vs 3%, respectively. Both differences in ACR20 and ACR50 were statistically significant. There was a greater median reduction from baseline in morning stiffness (55% vs 35%, P < 0.002).2 This represented a change from 127 minutes to 46 minutes for prednisone and 139 minutes to 79 minutes for placebo. Stiffness occurred later in the day but was of lesser severity. When prednisone DR was compared to morning administration of immediate-release prednisone (CAPRA-1), there was a mean reduction in duration of morning stiffness of 22.7% vs 0.4%, P = 0.045.3 Interleukin 6 levels were significantly reduced with DR, but no clinically relevant differences were observed with joint disease activity score (DAS28), pain intensity, C-reactive protein, erythrocyte sedimentation rate, or osteocalcin. In a 9-month open-label extension of the same study, subjects initially randomized to IR prednisone were switched to prednisone DR and achieved similar reduction in morning stiffness at 6 months and maintained for 12 months as those who stayed on the DR formulation.5 The efficacy of prednisone DR to IR prednisone has not been compared when given at the same time. However, in a small study (n = 60) the bedtime dose of prednisolone may provide improved morning stiffness in patients clinically stable with morning dosing.6

Clinical Implications

Prednisone DR provides a novel approach to treating the morning stiffness of rheumatoid arthritis. It remains to be determined whether this formulation is significantly better than IR prednisone administered at bedtime.

References

1. RAYOS Prescribing Information. Deerfield, IL: Horizon Pharma, Inc.; July 2012.

2. Buttgereit F, et al. Low-dose prednisone chronotherapy for rheumatoid arthritis: A randomised clinical trial (CAPRA-2). Ann Rheum Dis 2012; May 5. [Epub ahead of print.]

3. Buttgereit F, et al. Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): A double-blind, randomised controlled trial. Lancet 2008;371:205-214.

4. Cutolo M. Curr Opin Rheumatol 2012;24:312-318.

5. Buttgereit F, et al. Targeting pathophysiological rhythms: Prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis. Ann Rheum Dis 2010; 69:1275-1280.

6. Bagher OM, et al. Bedtime single-dose prednisolone in clinically stable rheumatoid arthritis patients. ISRN Pharmacol 2012;2012:637204.