2.1 Assessments Prior to First Dose of EMFLAZA

Administer all immunizations according to immunization guidelines prior to starting EMFLAZA. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting EMFLAZA [see Warnings and Precautions (5.8)].

2.2 Dosing Information

The recommended oral dosage of EMFLAZA is approximately 0.9 mg/kg/day once daily.  If tablets are used, round up to the nearest possible dose.  Any combination of the four EMFLAZA tablet strengths can be used to achieve this dose.  If the oral suspension is used, round up to the nearest tenth of a milliliter (mL).

2.3 Discontinuation

Dosage of EMFLAZA must be decreased gradually if the drug has been administered for more than a few days [see Warnings and Precautions (5.1)].

2.4 Important Preparation and Administration Instructions

EMFLAZA Tablets and Oral Suspension can be taken with or without food. Do not administer EMFLAZA with grapefruit juice [see Drug Interactions (7.1)]

EMFLAZA Tablets
EMFLAZA Tablets can be administered whole or crushed and taken immediately after mixing with applesauce.

EMFLAZA Oral Suspension
Shake EMFLAZA Oral Suspension well before administration.

Use only the oral dispenser provided with the product.  After withdrawing the appropriate dose into the oral dispenser, slowly add the EMFLAZA Oral Suspension into 3 to 4 ounces of juice (except grapefruit juice) or milk and mix well. The dose should then be administered immediately.

Discard any unused EMFLAZA Oral Suspension remaining after 1 month of first opening the bottle.

2.5 Dosage Modification for Use with CYP3A4 Inhibitors and Inducers

CYP3A4 Inhibitors
Give one third of the recommended dosage when EMFLAZA is administered with moderate or strong CYP3A4 inhibitors.  For example, a 36 mg per day dose would be reduced to a 12 mg per day dose when used with moderate or strong CYP3A4 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

CYP3A4 Inducers
Avoid use with moderate or strong CYP3A4 inducers with EMFLAZA [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

5.1 Alterations in Endocrine Function

Corticosteroids, such as EMFLAZA, can cause serious and life-threatening alterations in endocrine function, especially with chronic use.  Monitor patients receiving EMFLAZA for Cushing’s syndrome, hyperglycemia, and adrenal insufficiency after EMFLAZA 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.

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.

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.

Cushing’s Syndrome
Cushing’s syndrome (hypercortisolism) occurs with prolonged exposure to exogenous corticosteroids, including EMFLAZA.  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.

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.

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 corticosteroid should precede the initiation of levothyroxine therapy to reduce the risk of adrenal crisis.

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.

5.2 Immunosuppression and Increased Risk of Infection

Corticosteroids, including EMFLAZA, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can:

• Reduce resistance to new infections
• Exacerbate existing infections
• Increase the risk of disseminated infections
• Increase the risk of reactivation or exacerbation of latent infections
• Mask some signs of infections

Corticosteroid-associated infections can be mild but can be severe, and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages.

Monitor for the development of infection and consider EMFLAZA withdrawal or dosage reduction as needed.

Tuberculosis

If EMFLAZA is used to treat a condition in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation. During prolonged EMFLAZA therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis.

Varicella Zoster and Measles Viral Infections

Varicella and measles can have a serious or even fatal course in non-immune patients taking corticosteroids, including EMFLAZA. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles.

• If an EMFLAZA-treated patient is exposed to varicella, prophylaxis with varicella zoster immunoglobulin may be indicated. If varicella develops, treatment with antiviral agents may be considered.
• If an EMFLAZA-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated.

Hepatitis B Virus Reactivation

Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including EMFLAZA. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection.

Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with EMFLAZA. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy.

Fungal Infections

Corticosteroids, including EMFLAZA, may exacerbate systemic fungal infections; therefore, avoid EMFLAZA use in the presence of such infections unless EMFLAZA is needed to control drug reactions. For patients on chronic EMFLAZA therapy who develop systemic fungal infections, EMFLAZA withdrawal or dose reduction is recommended.

Amebiasis

Corticosteroids, including EMFLAZA, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating EMFLAZA in patients who have spent time in the tropics or patients with unexplained diarrhea.

Strongyloides Infestation

Corticosteroids, including EMFLAZA, should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, 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.

Cerebral Malaria

Avoid corticosteroids, including EMFLAZA, in patients with cerebral malaria.

5.3 Alterations in Cardiovascular/Renal Function

Corticosteroids, including EMFLAZA, 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.  EMFLAZA should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.

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

5.4 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.

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.

5.5 Behavioral and Mood Disturbances

Potentially severe psychiatric adverse reactions may occur with systemic corticosteroids, including EMFLAZA.  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.

5.6 Effects on Bones

Decreased Bone Mineral Density
Corticosteroids, including EMFLAZA, 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 EMFLAZA.

Avascular Necrosis
Corticosteroids, including EMFLAZA, may cause avascular necrosis.

5.7 Ophthalmic Effects

Use of corticosteroids, including EMFLAZA, 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.

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

5.8 Immunizations

Administer all immunizations according to immunization guidelines prior to starting EMFLAZA. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting EMFLAZA. Patients on EMFLAZA may receive concurrent vaccinations, except for live-attenuated or live vaccines.

5.9 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.

5.10 Effects on Growth and Development

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

5.11 Myopathy

Patients receiving corticosteroids, including EMFLAZA, 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.

5.12 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 of Kaposi’s sarcoma.

5.13 Risk of Serious Adverse Reactions in Infants because of Benzyl Alcohol Preservative

EMFLAZA Oral Suspension contains benzyl alcohol and is not approved for use in pediatric patients less than 2 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, including EMFLAZA.  The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.
When prescribing EMFLAZA Oral Suspension, consider the combined daily metabolic load of benzyl alcohol from all sources, including EMFLAZA Oral Suspension (EMFLAZA Oral Suspension contains 10.45 mg of benzyl alcohol per mL; EMFLAZA Tablets do not contain benzyl alcohol) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. At the recommended dose of 0.9 mg/kg/day of EMFLAZA Oral Suspension, patients would receive approximately 0.4 mg/kg/day of benzyl alcohol [see Use in Specific Populations (8.4)].

5.14 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 EMFLAZA with caution in patients who have or may be predisposed to thromboembolic disorders.

5.15 Anaphylaxis

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

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In Study 1 [see Clinical Studies (14)], the adverse reactions that were associated with deflazacort treatment discontinuation, in decreasing order of frequency, were weight increased, obesity, cataract, and sleep disorder.

Most Common Adverse Reactions in Clinical Studies
Table 1 lists the adverse reactions that occurred in ≥ 5% of patients in the 0.9 mg/kg/day deflazacort-treated group and that occurred more frequently than in placebo patients in Study 1, which included patients with DMD between the ages of 5 and 15 years.

Common adverse reactions (≥ 5% of deflazacort-treated patients) that occurred over 52 weeks of exposure to deflazacort 0.9 mg/kg/day in Study 1 and at a higher rate than deflazacort 0.9 mg/kg/day in the 12-week placebo-controlled phase of the trial include Cushingoid appearance (60%), hirsutism (35%), weight increased (28%), erythema (28%), central obesity (25%), abdominal pain/abdominal pain upper (18% combined), pollakiuria (15%), constipation (10%), irritability (10%), abnormal behavior (9%), pyrexia (9%), back pain (7%), rash (7%), contusion (6%), nausea (6%), psychomotor hyperactivity (6%), epistaxis (6%), and skin striae (6%).

Study 1 also evaluated a higher dosage of deflazacort (1.2 mg/kg/day).  Compared with the 0.9 mg/kg/day dosage, deflazacort 1.2 mg/kg/day over 52 weeks was associated with a higher incidence of certain adverse reactions, including Cushingoid appearance (69%), erythema (49%), hirsutism (37%), headache (34%), weight increased (32%), constipation (15%), abdominal pain upper (14%), skin striae (11%), acne (11%), and abdominal discomfort (8%).  As there was no additional benefit with the 1.2 mg/kg/day dose of deflazacort, use of EMFLAZA 1.2 mg/kg/day is not recommended for the treatment of DMD [see Dosage and Administration (2.2)].

In an additional clinical study of two years duration with extended follow-up (Study 2), many of the same adverse reactions were observed.  In addition, musculoskeletal events associated with long-term steroid use were also observed, including muscle weakness, tendon disorder, and osteopenia.

Less Common Adverse Reactions Observed in Clinical Studies
Other adverse reactions (≥ 1% frequency in any deflazacort treatment group and greater than placebo) that were observed during the 12-week placebo-controlled phase of Study 1 are shown below.

Eye Disorders: Lacrimation increased

Gastrointestinal Disorders: Dyspepsia, nausea, gastrointestinal disorder

General Disorders and Administration Site Conditions: Thirst

Infections: Hordeolum, impetigo, influenza, otitis externa, pharyngitis, tooth abscess, urinary tract infection, viral infection

Injury, Poisoning and Procedural Complications: Back injury, contusion, face injury, fibula fracture, greenstick fracture, heat exhaustion

Investigations: Glucose urine present, heart rate irregular

Musculoskeletal and Connective Tissue Disorders: Back pain, muscle spasms, myalgia, neck mass, neck pain, pain in extremity

Nervous System Disorders: Dizziness, psychomotor hyperactivity

Psychiatric Disorders: Affect lability, aggression, depression, emotional disorder, middle insomnia, mood altered, mood swings, sleep disorder

Renal and Urinary Disorders: Chromaturia, dysuria, hypertonic bladder

Reproductive System and Breast Disorders: Testicular pain

Respiratory, Thoracic, and Mediastinal Disorders: Hypoventilation, rhinorrhea

Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis acneiform

Vascular Disorders: Hot flush

6.2 Postmarketing Experience

The following adverse reactions have been reported during post-approval use of deflazacort worldwide or during post-approval use of other corticosteroids.  These reactions are reported voluntarily from a population of uncertain size; therefore, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Leukocytosis

Cardiac Disorder: Heart failure

Eye Disorders: Chorioretinopathy, corneal or scleral thinning

Gastrointestinal Disorders: Acute pancreatitis (especially in children), hemorrhage, peptic ulceration, perforation of peptic ulcer

General Disorders and Administration Site Conditions: Edema, impaired healing

Immune System Disorders: Hypersensitivity including anaphylaxis

Metabolism and Nutrition Disorders: Impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy, negative protein and calcium balance, potassium loss and hypokalemic alkalosis when co-administered with beta 2-agonist and xanthines

Musculoskeletal and Connective Tissue Disorders: Avascular necrosis, muscle wasting, negative nitrogen balance, tendonitis and tendon rupture when co-administered with quinolones, vertebral and long bone fractures

Nervous System Disorders: Aggravation of epilepsy, increased intra-cranial pressure with papilledema in children (pseudotumor cerebri) usually after treatment withdrawal, vertigo

Psychiatric Disorders: Anxiety, cognitive dysfunction including confusion and amnesia, delusions, hallucinations, mania, suicidal thoughts

Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis

Vascular Disorders: Thromboembolism, in particular in patients with underlying conditions associated with increased thrombotic tendency, benign intracranial hypertension

7.1 CYP3A4 Inhibitors and Inducers

Moderate or Strong CYP3A4 Inhibitors
The active metabolite of deflazacort, 21-desDFZ, is a substrate of CYP3A4 [see Clinical Pharmacology (12.3)].  Co-administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.  Therefore, give one third the recommended dosage of EMFLAZA when moderate or strong CYP3A4 inhibitors (e.g., clarithromycin, fluconazole, diltiazem, verapamil, grapefruit juice) are used concomitantly with EMFLAZA [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

Moderate or Strong CYP3A4 Inducers
Co-administration of deflazacort with rifampin, a strong CYP3A4 inducer, significantly decreased the exposure of 21-desDFZ.  Avoid concomitant use of strong (e.g., efavirenz) or moderate (e.g., carbamazepine, phenytoin) CYP3A4 inducers with EMFLAZA [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

7.2 Neuromuscular Blockers

Patients receiving corticosteroids, including EMFLAZA, and concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium) may be at increased risk of developing an acute myopathy [see Warnings and Precautions (5.11)].

8.1 Pregnancy

Risk Summary
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 EMFLAZA in pregnant women to inform drug-associated risks.

Corticosteroids, including EMFLAZA, 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 EMFLAZA, 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 (see Data).  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.

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.

Data
Human Data
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.

8.2 Lactation

Risk Summary
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 EMFLAZA and any potential adverse effects on the breastfed infant from EMFLAZA.  There are no data on the effects on milk production.

8.4 Pediatric Use

The safety and effectiveness of EMFLAZA for the treatment of DMD have been established in patients 2 years of age and older.  Use of EMFLAZA in pediatric patients is supported by a multicenter, randomized, double-blind, placebo- and active-controlled study in 196 males 5 to 15 years of age [see Clinical Studies (14)]. Use of EMFLAZA in patients 2 years to less than 5 years of age is supported by the findings of efficacy and safety in patients 5 years and older with DMD.

Safety and effectiveness in pediatric patients below the age of 2 years have not been established.

EMFLAZA Oral Suspension contains benzyl alcohol and is not approved for use in pediatric patients less than 2 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.

When prescribing EMFLAZA Oral Suspension consider the combined daily metabolic load of benzyl alcohol from all sources including EMFLAZA Oral Suspension (EMFLAZA Oral Suspension contains 10.45 mg of benzyl alcohol per mL; EMFLAZA Tablets do not contain benzyl alcohol) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. At the recommended dose of 0.9 mg/kg/day of EMFLAZA Oral Suspension, patients would receive approximately 0.4 mg/kg/day of benzyl alcohol [see Warnings and Precautions (5.13)].

Juvenile Animal Toxicity Data
Oral administration of deflazacort (0, 0.1, 0.3, and 1.0 mg/kg/day) to juvenile rats from postnatal day (PND) 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 EMFLAZA (0.9 mg/kg/day).

8.5 Geriatric Use

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

8.6 Renal Impairment

No dose adjustment is required in patients with mild, moderate or severe renal impairment [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3)].  There is no clinical experience in patients with severe hepatic impairment, and a dosing recommendation cannot be provided for patients with severe hepatic impairment.

12.1 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.

12.3 Pharmacokinetics

Absorption
After oral administration in the fasted state, the median Tmax with deflazacort tablets or suspension is about 1 hour (range 0.25 to 2 hours).

Food Effect: Co-administration of deflazacort tablets with a high-fat meal reduced Cmax by about 30% and delayed Tmax by one hour, relative to administration under fasting conditions, but there was no effect on the overall systemic absorption as measured by AUC.  The bioavailability of deflazacort tablets was similar to that of the oral suspension.  The administration of deflazacort with food or crushed in applesauce did not affect the absorption and bioavailability of deflazacort.

Distribution
The protein binding of the active metabolite of deflazacort is about 40%.

Elimination
Metabolism
Deflazacort is rapidly converted to the active metabolite 21-desDFZ by esterases after oral administration.  21-desDFZ is further metabolized by CYP3A4 to several other inactive metabolites, including 6β-hydroxy-21-desacetyl deflazacort.

Excretion
Urinary excretion is the predominant route of deflazacort elimination (about 68% of the dose), and the elimination is almost completed by 24 hours post dose.  21-desDFZ accounts for 18% of the eliminated drug in the urine.

Specific Populations
Pediatric Patients
The Cmax values (Geometric mean, %CV) of 21-desDFZ in children (ages 4-11, N=16) and adolescents (ages 12-16, N=8) was 206 ng/mL (95.6%) and 381 ng/mL (37.7%), respectively, on Day 1 after administration of 0.9 mg/kg deflazacort.  The AUCinf (Geometric mean, %CV) of 21-desDFZ in children (ages 4-11, N=16) and adolescents (ages 12-16, N=8) was 400 ng•h/mL (87.5%) and 655 ng•h/mL (58.1%) on Day 1 after administration of 0.9 mg/kg deflazacort.

Male and Female Patients
There are no differences in the pharmacokinetics of 21-desDFZ between males and females.

Racial or Ethnic Groups
There are no differences in the pharmacokinetics of 21-desDFZ between Caucasians and non-Caucasians.

Patients with Renal Impairment
In a study (N=16) comparing subjects with end stage renal disease (creatinine clearance less than 15 mL/min) with healthy matched controls, 21-desDFZ exposure was similar between the groups.

Patients with Hepatic Impairment
In a study (N=16) comparing subjects with moderate hepatic impairment (Child-Pugh Class B) with healthy matched controls, 21-desDFZ exposure was similar between the groups.  There is no experience in patients with severe hepatic impairment.

Drug Interaction Studies

In Vivo Assessment of Drug Interactions

Compared to administration of deflazacort alone, administration of deflazacort following multiple doses of a strong CYP3A4 and Pgp inhibitor (clarithromycin) resulted in markedly higher Cmax, AUClast, and AUCinf values of 21-desDFZ.  Geometric mean exposure (Cmax, AUClast, and AUCinf) of 21-desDFZ ranged from 2.3-fold to 3.4-fold higher following administration of clarithromycin [see Dosage and Administration (2.5)].

Compared to administration of deflazacort alone, administration of deflazacort following multiple doses of a strong CYP3A4 inducer (rifampicin) resulted in markedly lower Cmax, AUClast, and AUCinf values of 21-desDFZ.  Geometric mean exposures (Cmax, AUClast, and AUCinf) of 21-desDFZ were approximately 95% lower following administration of rifampin [see Drug Interactions (7.1)].

6β-Hydroxy-21-desacetyl deflazacort, a secondary and inactive metabolite, is not expected to cause any clinically meaningful interactions with the CYP enzymes or transporters.

In Vitro Assessment of Drug Interactions

Drug-Metabolizing Enzyme Inhibition
21-desDFZ at clinically relevant concentrations did not inhibit CYP1A2, 2C9, 2C19, 3A4, UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and exhibited weak and not likely clinically meaningful inhibition for 2B6, 2C8, 2D6, and 3A4, UGT1A3 and UGT2B15.

6β-Hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly inhibit CYP2C19, 3A4 1A2, 2B6, 2C8, 2C9, or 2D6.

Drug-Metabolizing Enzyme Induction
21-desDFZ and 6β-hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly induce CYP1A2, 2B6, or 3A4.

Transporters
Both deflazacort and 21-desDFZ are substrates of Pgp.  21-desDFZ is not a substrate for BCRP.  Neither deflazacort nor 21-desDFZ inhibited Pgp or BCRP in vitro.  21-desDFZ was not a substrate for SLC transporters OATP1B1 or OATP1B3, and did not inhibit SLC transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.

6β-Hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly inhibit BCRP, OAT1, OAT3, Pgp, OATP1B1, OATP1B3 MATE1, MATE2-K, OCT1, OCT2, or BSEP transporters.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
In a published 2-year carcinogenicity study in rats, oral administration of deflazacort (0, 0.03, 0.06, 0.12, 0.25, 0.50, or 1.0 mg/kg/day) resulted in bone tumors (osteosarcoma and osteoma) of the head at 0.25 mg/kg/day, the highest evaluable dose.  Doses higher than 0.25 mg/kg/day could not be evaluated for tumors because of a marked decrease in survival.

In a 6-month carcinogenicity study in transgenic (Tg.RasH2) mice, oral administration of deflazacort (0, 2, 5, or 20 mg/kg/day in males; 0, 0.5, 2, or 5 mg/kg/day in females) resulted in an increase in stomach tumors (adenoma) at the highest dose tested in males and females.

Mutagenesis
Deflazacort and 21-desDFZ were negative in in vitro (bacterial reverse mutation and human lymphocyte chromosomal aberration) assays and deflazacort was negative in an in vivo (rat micronucleus) assay.

Impairment of Fertility
Fertility studies in animals were not conducted with deflazacort.  No effects on the male reproductive system were observed following oral administration of deflazacort to monkeys (0, 1.0, 3.0, or 6.0 mg/kg/day) for 39 weeks or rats (0, 0.05, 0.15, or 0.5 mg/kg/day) for 26 weeks.  Plasma 21-desDFZ exposures (AUC) at the highest doses tested in monkey and rat were 4 and 2 times, respectively, that in humans at the recommended human dose of EMFLAZA (0.9 mg/kg/day).

16.1 How Supplied

EMFLAZA Tablets

• 6 mg are white, round with “6” debossed on one side.  They are supplied as follows:
  NDC 52856-501-01      Bottle of 100 tablets
  
  
• 18 mg are white, round with “18” debossed on one side.  They are supplied as follows:
  NDC 52856-502-03      Bottle of 30 tablets
  
  
• 30 mg are white, oval with “30” debossed on one side.  They are supplied as follows:
  NDC 52856-503-03      Bottle of 30 tablets
  
  
• 36 mg are white, oval with “36” debossed on one side.  They are supplied as follows:
  NDC 52856-504-03      Bottle of 30 tablets

EMFLAZA Oral Suspension

• 22.75 mg/mL is a whitish colored suspension. Supplied as 13 mL in a 30 mL bottle packaged with one bottle adapter and two 1 mL oral dispensers.
  NDC 52856-505-22

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F).  Excursion permitted between 15°C to 30°C (59°F to 86°F).  See USP controlled room temperature.

Discard any unused EMFLAZA Oral Suspension remaining after 1 month of first opening the bottle.