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Emflaza

Generic Name: Deflazacort
Class: Adrenals
Molecular Formula: C25H31NO6
CAS Number: 13649-88-2

Introduction

Deflazacort is a corticosteroid.1

Uses for Emflaza

Deflazacort has the following uses:

Deflazacort is a corticosteroid indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older.1

Emflaza Dosage and Administration

General

Deflazacort is available in the following dosage form(s) and strength(s):

  • Tablets: 6 mg, 18 mg, 30 mg, and 36 mg.1

  • Oral suspension: 22.75 mg/mL.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • The recommended once-daily dosage is approximately 0.9 mg/kg/day administered orally.1

  • Discontinue gradually when administered for more than a few days.1

Cautions for Emflaza

Contraindications

Hypersensitivity to deflazacort or any of the inactive ingredients in deflazacort.1

Warnings/Precautions

Alterations in Endocrine Function

Corticosteroids, such as deflazacort, can cause serious and life-threatening alterations in endocrine function, especially with chronic use. Monitor patients receiving deflazacort for Cushing’s syndrome, hyperglycemia, and adrenal insufficiency after deflazacort withdrawal. In addition, patients with hypopituitarism, primary adrenal insufficiency or congenital adrenal hyperplasia, altered thyroid function, or pheochromocytoma may be at increased risk for adverse endocrine events.1

Risk of Adrenal Insufficiency Following Corticosteroid Withdrawal

Corticosteroids produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, with the potential for the development of secondary adrenal insufficiency after withdrawal of corticosteroid treatment. Acute adrenal insufficiency can occur if corticosteroids are withdrawn abruptly, and can be fatal. The degree and duration of adrenocortical insufficiency produced is variable among patients and depends on the dose, frequency, and duration of corticosteroid therapy. The risk is reduced by gradually tapering the corticosteroid dose when withdrawing treatment. This insufficiency may persist, however, for months after discontinuation of prolonged therapy; therefore, in any situation of stress occurring during that period of discontinuation, corticosteroid therapy should be reinstituted. For patients already taking corticosteroids during times of stress, the dosage may need to be increased.1

A steroid “withdrawal syndrome”, seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuance of corticosteroids. This syndrome includes symptoms such as anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, and/or weight loss. These effects are thought to be due to the sudden change in corticosteroid concentration rather than to low corticosteroid levels.1

Cushing’s Syndrome

Cushing’s syndrome (hypercortisolism) occurs with prolonged exposure to exogenous corticosteroids, including deflazacort. Symptoms include hypertension, truncal obesity and thinning of the limbs, purple striae, facial rounding, facial plethora, muscle weakness, easy and frequent bruising with thin fragile skin, posterior neck fat deposition, osteopenia, acne, amenorrhea, hirsutism, and psychiatric abnormalities.1

Hyperglycemia

Corticosteroids can increase blood glucose, worsen pre-existing diabetes, predispose those on long-term therapy to diabetes mellitus, and may reduce the effect of anti-diabetic drugs. Monitor blood glucose at regular intervals. For patients with hyperglycemia, anti-diabetic treatment should be initiated or adjusted accordingly.1

Considerations for Use in Patients with Altered Thyroid Function

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate a dose adjustment of the corticosteroid. When concomitant administration of corticosteroids and levothyroxine is required, administration of the corticosteroid should precede the initiation of levothyroxine therapy to reduce the risk of adrenal crisis.1

Pheochromocytoma Crisis

There have been reports of pheochromocytoma crisis, which can be fatal, after administration of systemic corticosteroids. In patients with suspected or identified pheochromocytoma, consider the risk of pheochromocytoma crisis prior to administering corticosteroids.1

Immunosuppression and Increased Risk of Infection

Corticosteroids, including deflazacort, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic. Corticosteroids reduce resistance to new infections, exacerbate existing infections, increase the risk of disseminated infections, increase the risk of reactivation or exacerbation of latent infections, and mask some signs of infection. These infections can be severe, and at times fatal. The degree to which the dose, route, and duration of corticosteroid administration correlates with the specific risks of infection is not well characterized; however, the rate of occurrence of infectious complications increases with increasing doses of corticosteroids.1

Monitor for the development of infection and consider withdrawal of corticosteroids or reduction of the dose of corticosteroids as needed. 1

Varicella Zoster and Measles Viral Infections

Chickenpox caused by varicella zoster virus and measles can have a serious or even fatal course in non-immune children or adults on corticosteroids, including deflazacort. In children or adults who have not had these diseases, particular care should be taken to avoid exposure. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with immune globulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.1

Hepatitis B Virus Reactivation

Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers undergoing treatment with immunosuppressive drugs including corticosteroids. Reactivation can also occur in patients who appear to have resolved hepatitis B infection.1

Fungal Infections

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections. For patients on corticosteroids who develop systemic fungal infections, withdrawal of corticosteroids or reduction of the dose of corticosteroids is recommended.1

Amebiasis

Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics, or any patient with unexplained diarrhea.1

Strongyloides Infestation

In patients with known or suspected Strongyloides (threadworm) infestation, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. For patients on corticosteroids who develop known or suspected Strongyloides (threadworm) infestation, withdrawal of corticosteroids or reduction of the dose of corticosteroids is recommended.1

Alterations in Cardiovascular/Renal Function

Corticosteroids, including deflazacort, can cause elevation of blood pressure, salt, and water retention, and increased excretion of potassium and calcium. Monitor blood pressure and assess for signs and symptoms of volume overload. Monitor serum potassium levels. Dietary salt restriction and potassium supplementation may be necessary. Deflazacort should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.1

Literature reports suggest an association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with deflazacort should be used with great caution in these patients.1

Gastrointestinal Perforation

There is an increased risk of gastrointestinal perforation during corticosteroid use in patients with certain gastrointestinal disorders such as active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and non-specific ulcerative colitis. Signs of gastrointestinal perforation, such as peritoneal irritation, may be masked in patients receiving corticosteroids.1

Avoid corticosteroids if there is a probability of impending perforation, abscess, or other pyogenic infections; diverticulitis; fresh intestinal anastomoses; or active or latent peptic ulcer.1

Behavioral and Mood Disturbances

Potentially severe psychiatric adverse reactions may occur with systemic corticosteroids, including deflazacort. Symptoms typically emerge within a few days or weeks of starting treatment and may be dose-related. These reactions may improve after either dose reduction or withdrawal, although pharmacologic treatment may be necessary. Psychiatric adverse reactions usually involve hypomanic or manic symptoms (e.g., euphoria, insomnia, mood swings) during treatment and depressive episodes after discontinuation of treatment. Inform patients or caregivers of the potential for behavioral and mood changes and encourage them to seek medical attention if psychiatric symptoms develop, especially if depressed mood or suicidal ideation is suspected.1

Effects on Bones

Decreased Bone Mineral Density

Corticosteroids, including deflazacort, decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of bone loss at any age. Bone loss can predispose patients to vertebral and long bone fractures. Consider a patient’s risk of osteoporosis before initiating corticosteroid therapy. Monitor bone mineral density in patients on long-term treatment with deflazacort.1

Avascular Necrosis

Corticosteroids, including deflazacort, may cause avascular necrosis.1

Ophthalmic Effects

Use of corticosteroids, including deflazacort, may produce posterior subcapsular cataracts. Corticosteroids may also cause glaucoma with possible damage to the optic nerves, and may increase the risk of secondary ocular infections caused by bacteria, fungi, or viruses. Corticosteroids are not recommended for patients with active ocular herpes simplex. 1

Intraocular pressure may become elevated in some patients taking corticosteroids. If treatment with deflazacort is continued for more than 6 weeks, monitor intraocular pressure.1

Vaccination

Administration of live or live attenuated vaccines is not recommended in patients receiving immunosuppressive doses of corticosteroids, including deflazacort. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines.1

Killed or inactivated vaccines may be administered during corticosteroid therapy; however, the response to such vaccines cannot be predicted.1

Patients on corticosteroid therapy, including deflazacort, may exhibit a diminished response to toxoids and live or inactivated vaccines because of inhibition of antibody response.1

Serious Skin Rashes

Toxic epidermal necrolysis has been reported with the use of deflazacort with symptoms beginning within 8 weeks of starting treatment. Discontinue at the first sign of rash, unless the rash is clearly not drug related.1

Effects on Growth and Development

Long-term use of corticosteroids, including deflazacort, can have negative effects on growth and development in children.1

Myopathy

Patients receiving corticosteroids, including deflazacort, and concomitant therapy with neuromuscular blocking agents (e.g., pancuronium) or patients with disorders of neuromuscular transmission (e.g., myasthenia gravis) may be at increased risk of developing acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.1

Kaposi’s Sarcoma

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.1

Risk of Serious Adverse Reactions in Infants Because of Benzyl Alcohol Preservative

Deflazacort oral suspension contains benzyl alcohol and is not approved for use in pediatric patients less than 5 years of age. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (deflazacort oral suspension contains 10.45 mg of benzyl alcohol per mL; deflazacort tablets do not contain benzyl alcohol).1

Thromboembolic Events

Observational studies have shown an increased risk of thromboembolism (including venous thromboembolism), particularly with higher cumulative doses of corticosteroids. It is unclear if risk differs by daily dose or duration of use. Use deflazacort with caution in patients who have or may be predisposed to thromboembolic disorders.1

Anaphylaxis

Rare instances of anaphylaxis have occurred in patients receiving corticosteroid therapy, including deflazacort.1

Specific Populations

Pregnancy

Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. There are no adequate and well-controlled studies with deflazacort in pregnant women to inform drug-associated risks.1

Corticosteroids, including deflazacort, readily cross the placenta. Adverse developmental outcomes, including orofacial clefts (cleft lip, with or without cleft palate) and intrauterine growth restriction, and decreased birth weight, have been reported with maternal use of corticosteroids, including deflazacort, during pregnancy. Some epidemiologic studies report an increased risk of orofacial clefts from about 1 per 1000 infants to 3 to 5 per 1000 infants; however, a risk for orofacial clefts has not been observed in all studies. Intrauterine growth restriction and decreased birth weight appear to be dose-related; however, the underlying maternal condition may also contribute to these risks. The estimated background risk of major birth defects and miscarriage for the indicated populations 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. 1

Animal reproduction studies have not been conducted with deflazacort. Animal reproduction studies conducted with other corticosteroids in pregnant mice, rats, hamsters, and rabbits using clinically relevant doses have shown an increased incidence of cleft palate. An increase in embryofetal death, intrauterine growth retardation, and constriction of the ductus arteriosus were observed in some animal species. 1

Multiple cohort and case-controlled studies in humans suggest that maternal corticosteroid use during the first trimester increases the rate of cleft lip, with or without cleft palate, from about 1/1000 infants to 3–5/1000 infants. Two prospective case-controlled studies showed decreased birth weight in infants exposed to maternal corticosteroids in utero.1

Lactation

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for deflazacort and any potential adverse effects on the breastfed infant from deflazacort. There are no data on the effects on milk production.1

Pediatric Use

The safety and effectiveness of deflazacort for the treatment of DMD have been established in patients 5 years of age and older. Use of deflazacort in pediatric patients is supported by a multicenter, randomized, double-blind, placebo- and active-controlled study in 196 males.1

Safety and effectiveness of deflazacort have not been established in pediatric patients less than 5 years of age.1

Deflazacort oral suspension contains benzyl alcohol and is not approved for use in pediatric patients less than 5 years of age. Serious adverse reactions including fatal reactions and “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (deflazacort oral suspension contains 10.45 mg of benzyl alcohol per mL; deflazacort tablets do not contain benzyl alcohol).1

Oral administration of deflazacort (0, 0.1, 0.3, and 1.0 mg/kg/day) to juvenile rats from postnatal day 21 to 80 resulted in decreased body weight gain and adverse effects on skeletal development (including decreased cellularity of growth plate and altered bone distribution) and on lymphoid tissue (decreased cellularity). A no-effect dose was not identified. In addition, neurological and neurobehavioral abnormalities were observed at the mid and/or high dose. Plasma 21-desDFZ exposure (AUC) at the lowest dose tested (0.1 mg/kg/day) was lower than that in humans at the recommended human dose of deflazacort (0.9 mg/kg/day).1

Geriatric Use

DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with deflazacort.1

Renal Impairment

No dose adjustment is required in patients with mild, moderate, or severe renal impairment.1

Hepatic Impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment, and a dosing recommendation cannot be provided for patients with severe hepatic impairment. 1

Common Adverse Effects

The most common adverse reactions (≥10% for deflazacort and greater than placebo) are cushingoid appearance, increased weight, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, and nasopharyngitis.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Moderate or strong CYP3A4 inhibitors: Give one-third of the recommended dosage of deflazacort.1

  • Avoid use of moderate or strong CYP3A4 inducers with deflazacort, as they may reduce efficacy.1

Actions

Mechanism of Action

Deflazacort is a corticosteroid prodrug, whose active metabolite, 21-desDFZ, acts through the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects. The precise mechanism by which deflazacort exerts its therapeutic effects in patients with DMD is unknown.1

Advice to Patients

    Administration
  • Warn patients and/or caregivers to not stop taking deflazacort abruptly or without first checking with their healthcare providers as there may be a need for gradual dose reduction to decrease the risk of adrenal insufficiency.1

  • Deflazacort may be taken with or without food.1

  • Deflazacort tablets may be taken whole or crushed and taken immediately after mixing with applesauce. 1

  • Deflazacort oral suspension must be shaken well prior to measuring out each dose with the enclosed oral dispenser.1

  • The deflazacort oral suspension dose may be placed in 3–4 ounces of juice or milk, mixed thoroughly, and immediately administered. Do not take with grapefruit juice.1

  • Discard any unused deflazacort oral suspension remaining after 1 month of first opening the bottle.1

    Increased Risk of Infection
  • Tell patients and/or caregivers to inform their healthcare provider if the patient has had recent or ongoing infections or if they have recently received a vaccine. Medical advice should be sought immediately if the patient develops fever or other signs of infection. Patients and/or caregivers should be made aware that some infections can potentially be severe and fatal.1

  • Warn patients who are on corticosteroids to avoid exposure to chickenpox or measles and to alert their healthcare provider immediately if they are exposed.1

    Alterations in Cardiovascular/Renal Function
  • Inform patients and/or caregivers that deflazacort can cause an increase in blood pressure and water retention. If this occurs, dietary salt restriction and potassium supplementation may be needed.1

    Behavioral and Mood Disturbances
  • Advise patients and/or caregivers about the potential for severe behavioral and mood changes with deflazacort and encourage them to seek medical attention if psychiatric symptoms develop.1

    Decreases in Bone Mineral Density
  • Advise patients and/or caregivers about the risk of osteoporosis with prolonged use of deflazacort, which can predispose the patient to vertebral and long bone fractures.1

    Ophthalmic Effects
  • Inform patients and/or caregivers that deflazacort may cause cataracts or glaucoma and advise monitoring if corticosteroid therapy is continued for more than 6 weeks.1

    Vaccination
  • Advise patients and/or caregivers that the administration of live or live attenuated vaccines are not recommended. Inform them that killed or inactivated vaccines may be administered, but the responses cannot be predicted.1

    Serious Skin Rashes
  • Instruct patients and/or caregivers to seek medical attention at the first sign of a rash.1

    Drug Interactions
  • Certain medications can cause an interaction with deflazacort. Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines (such as insulin, aspirin or other NSAIDS), dietary supplements, and herbal products. Inform patients and/or caregivers that alternate therapy, dosage adjustment, and/or special test(s) may be needed during the treatment.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Deflazacort

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

6 mg

Emflaza

Marathon

18 mg

Emflaza

Marathon

30 mg

Emflaza

Marathon

36 mg

Emflaza

Marathon

Suspension

22.75 mg /1 mL

Emflaza

Marathon

AHFS Drug Information. © Copyright 2017, Selected Revisions March 8, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Marathon Pharmaceuticals, LLC. EMFLAZA (deflazacort) ORAL prescribing information. 2017 Feb.

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