Duchenne Muscular Dystrophy (DMD)


Emflaza® (deflazacort) is an adrenocortical steroid that is available in both natural and synthetic forms. Its chemical name is (11β,16β)-11,21-bis(acetyloxy)­-2′-methyl-5’H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione, the molecular formula is C25H31NO6, and the molecular weight is 441.518 g/mol. Emflaza is an odorless fine powder that appears white to off-white in color. It is soluble in acetone and methanol and freely soluble in dichloromethane and acetic acid. Emflaza can be administered orally in doses of 6, 18, 30, and 36 mg. For immediate release, an oral suspension is available with a strength of 22.75 mg/mL. Deflazacort is the active ingredient in Emflaza, which also contains inactive ingredients: magnesium stearate, pregelatinized corn starch, colloidal silicon dioxide, magnesium stearate, and lactose monohydrate. Emflaza is indicated for the treatment of patients with Duchenne muscular dystrophy (DMD) aged 5 years or older. The recommended oral dosage of Emflaza is 0.9 mg/kg per day once daily. If tablets are used, round up to the nearest possible dose. Any combination of the 4 Emflaza tablet strengths can be used to achieve this dose. If the oral suspension is used, it is recommended to round up to the nearest tenth of a milliliter (mL). The dosage should be reduced gradually if the medication is to be discontinued and has been administered for more than a few days. It is necessary to follow all precautions and instructions during the administration of Emflaza.1

Emflaza
Deflazacort, also known as Emflaza, is a corticosteroid prodrug used as an agent to manage Duchenne Muscular Dystrophy (DMD).
Credit: PubChem

Safety Information and Adverse Effects

Emflaza is a corticosteroid used to treat patients with DMD. Patients should not take Emflaza if they are allergic to deflazacort or any other of its ingredients. Before they start Emflaza, the dosage needs to be discussed. To prevent withdrawal syndrome and adrenal insufficiency, Emflaza must not be discontinued abruptly or the dose changed before a healthcare provider is consulted. The abrupt discontinuation of a corticosteroid can be fatal becaues it can lead to acute adrenal insufficiency. Patients may also experience steroid withdrawal syndrome. The dose may need to be increased during times of stress. In patients with preexisting diabetes or on long-term treatment for diabetes, hyperglycemia may develop because the effect of antidiabetic drugs is reduced. The blood glucose level needs to be monitored at regular intervals and the antidiabetic treatment adjusted accordingly in such cases. Emflaza increases the risk for infection, which can be severe and even fatal. In addition, salt and water retention associated with Emflaza can lead to an increase in blood pressure and a decrease in calcium and potassium levels. Potassium supplementation and dietary salt restriction may be required. When taken for a long time, Emflaza decreases bone mineral density and increases the risk for osteoporosis, with the possibility of fractures in long bones and vertebrae. Emflaza can slow growth and development in children. It can also cause ocular infections, cataracts, and glaucoma.2  

Get detailed prescribing information on the Emflaza monograph page at MPR.

Drug Properties and Indications

Emflaza, a synthetic glucocorticoid, is converted to an active metabolite by plasma esterases and is well absorbed after oral administration. A 6-mg dose of Emflaza has the same inflammatory potency as 5 mg of prednisolone. In double-blind crossover studies conducted in 160 patients, the potency ratio of Emflaza vs prednisolone was estimated to be 1.28. The elimination plasma half-life of Emflaza is 1.1 to 1.9 hours, and the peak plasma concentration is achieved in 1.5 to 2 hours. Emflaza is 40% protein-bound, 70% is excreted through the kidneys, and 30% is eliminated through fecal excretion. The drug has no affinity for transcortin (corticosteroid-binding globulin). Steroids increase the strength of patients with DMD through their effects on myogenic repair, myoblast proliferation, muscle proteolysis, immunosuppression, and inflammation. Unlike prednisolone, Emflaza improved fiber growth and muscle repair in dystrophic mice by promoting myogenesis. Emflaza has clearly demonstrated its benefits in patients with DMD, preserving muscle strength and decreasing weight gain. Weight gain can affect motor performance.3

Anti-inflammatory Potency and Chemical Structure

Glucocorticoids have anti-inflammatory and immunosuppressive properties related to inhibition of the synthesis of pro-inflammatory cytokines and antagonism of specific leukocyte functions. Deflazacort is characterized by the insertion of a methyl-oxazoline ring in the chemical structure of prednisolone 21-acetate. It is completely absorbed into the intestinal tract, and peak plasma concentration is reached within 1 to 2 hours. Subsequently, deacetylation at position 21 results in formation of the main active metabolite, 21 desacetyl deflazacort, characterized by high binding affinity to tissue glucocorticoid receptors. Emflaza metabolites are eliminated within 24 hours, mainly through the kidneys. Emflaza inhibits the proliferation of mononuclear cells derived from human peripheral blood in studies performed in vitro. It also inhibits the chemiluminescence of human polymorphonuclear leukocytes in vitro, superoxide anion generation, and chemotaxis. Emflaza is an effective inhibitor of the early exudative phase of inflammation according to studies carried out in experimental models. It also inhibits the development of chronic granulomatous inflammation and experimentally induced chronic inflammatory articular disease. Emflaza can increase gluconeogenesis and hepatic glycogen synthesis. The anti-inflammatory potency of Emflaza is 40 times higher than that of hydrocortisone and 10 to 20 times higher than that of prednisolone.4 

Clinical Trials in Patients With Duchenne Muscular Dystrophy

A double-blind, placebo-controlled, randomized, multicenter phase III clinical study of Emflaza in patients with DMD evaluated changes in average muscle strength over 12 weeks on the modified Medical Research Council scale. Patients were graded on an 11-point scale at each study visit to follow disease progression. A total of 196 boys aged 5 to 15 years were then randomized to receive Emflaza at 1.2 mg/kg per day, prednisone at 0.75 mg/kg per day, or placebo for 12 weeks. After 12 weeks, the patients were reassigned to another of the 3 active treatment groups and followed for 52 weeks. Later, they underwent 40 additional weeks of treatment and were assigned to one of 3 treatment groups: (1) deflazacort at 0.9 mg/kg per day, (2) deflazacort at 1.2 mg/kg per day, or (3) prednisone at 0.75 mg/kg per day. Patients were included in the study if they had an alteration in the distribution of dystrophin in muscles or had undergone genetic analysis of the dystrophin gene. They were also included in the study if they had a serum creatinine kinase level at least 10 times the upper limit of normal. Safety evaluations in patients with DMD in the study were conducted via assessments of vital signs, changes in physical examination or laboratory findings, and incidence of adverse effects.5

References

  1. Emflaza (deflazacort). Food and Drug Administration. Revised February 2017. Accessed August 10, 2021.
  2. Indication & important safety information for Emflaza® (deflazacort). PTC Therapeutics. Accessed August 10, 2021.
  3. Joshi N, Rajeshwari K. Deflazacort. J Postgrad Med. 2009;55(4):296-300. doi:10.4103/0022-3859.58942
  4. Parente L. Deflazacort: therapeutic index, relative potency and equivalent doses versus other corticosteroids. BMC Pharmacol Toxicol. 2017;18(1):1. doi:10.1186/s40360-016-0111-8

Bylo M, Farewell R, Coppenrath VA, Yogaratnam D. A review of deflazacort for patients with Duchenne Muscular Dystrophy. Ann Pharmacother. 2020;54(8):788-794. doi:10.1177/1060028019900500

Reviewed by Harshi Dhingra, MD, on 8/12/2021.

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