Deflazacort

1 INDICATIONS AND USAGE Deflazacort oral suspension is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older. Additional pediatric use information is approved for PTC Therapeutics, Inc.'s Emflaza™ (deflazacort) oral suspension. However, due to PTC Therapeutics, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information . Deflazacort oral suspension is a corticosteroid indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older ( 1 )

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.

2 DOSAGE AND ADMINISTRATION The recommended once-daily dosage is approximately 0.9 mg/kg/day administered orally ( 2.2 ) Discontinue gradually when administered for more than a few days ( 2.3 ) 2.1 Assessments Prior to First Dose of Deflazacort Oral Suspension Administer all immunizations according to immunization guidelines prior to starting deflazacort oral suspension. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting deflazacort oral suspension [see Warnings and Precautions (5.8) ]. 2.2 Dosing Information The recommended oral dosage of deflazacort oral suspension is approximately 0.9 mg/kg/day once daily. If the oral suspension is used, round up to the nearest tenth of a milliliter (mL). 2.3 Discontinuation Dosage of deflazacort oral suspension 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 Deflazacort oral suspension can be taken with or without food. Do not administer deflazacort oral suspension with grapefruit juice [see Drug Interactions (7.1) ]. Shake deflazacort 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 deflazacort 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 deflazacort 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 deflazacort oral suspension 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 deflazacort oral suspension [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections: Alterations in Endocrine Function [see Warnings and Precautions (5.1) ] Immunosuppression and Increased Risk of Infection [see Warnings and Precautions (5.2) ] Alterations in Cardiovascular/Renal Function [see Warnings and Precautions (5.3) ] Gastrointestinal Perforation [see Warnings and Precautions (5.4) ] Behavioral and Mood Disturbances [see Warnings and Precautions (5.5) ] Effects on Bones [see Warnings and Precautions (5.6) ] Ophthalmic Effects [see Warnings and Precautions (5.7 )] Immunizations [see Warnings and Precautions (5.8) ] Serious Skin Rashes [see Warnings and Precautions (5.9) ] Effects on Growth and Development [see Warnings and Precautions (5.10) ] Myopathy [see Warnings and Precautions (5.11) ] Kaposi's Sarcoma [see Warnings and Precautions (5.12) ] Risk of Serious Adverse Reactions in Infants because of Benzyl Alcohol Preservative [see Warnings and Precautions (5.13) ] Thromboembolic Events [see Warnings and Precautions (5.14) ] Anaphylaxis [see Warnings and Precautions (5.15) ] The most common adverse reactions (≥10% for deflazacort and greater than placebo) are Cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, and nasopharyngitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Table 1: Adverse Reactions that Occurred in ≥ 5% of Deflazacort-Treated Patients and Occurred More Frequently than in Placebo Patients with DMD (Study 1) Adverse Reaction Deflazacort 0.9 mg/kg/d (N=51) % at 12 weeks Placebo (N=50) % at 12 weeks 1 Cushingoid appearance 33 12 Weight increased 20 6 Increased appetite 14 2 Upper respiratory tract infection 12 10 Cough 12 6 Pollakiuria 12 2 Nasopharyngitis 10 6 Hirsutism 10 2 Central obesity 10 4 Erythema 8 6 Irritability 8 4 Rhinorrhea 8 0 Abdominal discomfort 6 2 1 At 12 weeks placebo patients were re-randomized to receive either deflazacort or an active comparator. 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%), ski

5 WARNINGS AND PRECAUTIONS Alterations in Endocrine Function : Hypothalamic-pituitary-adrenal axis suppression, Cushing's syndrome, and hyperglycemia can occur; Monitor patients for these conditions with chronic use of deflazacort ( 2.3 , 5.1 ) Immunosuppression and Increased Risk of Infection: Increased risk of new, exacerbation, dissemination, or reactivation of latent infections, which can be severe and at times fatal; Signs and symptoms of infection may be masked ( 5.2 ) Alterations in Cardiovascular/Renal Function : Monitor for elevated blood pressure and sodium, and for decreased potassium levels ( 5.3 ) Gastrointestinal Perforation: Increased risk in patients with certain GI disorders; Signs and symptoms may be masked ( 5.4 ) Behavioral and Mood Disturbances: May include euphoria, insomnia, mood swings, personality changes, severe depression, and psychosis ( 5.5 ) Effects on Bones: Monitor for decreases in bone mineral density with chronic use of deflazacort ( 5.6 ) Ophthalmic Effects: May include cataracts, infections, and glaucoma; Monitor intraocular pressure if deflazacort is continued for more than 6 weeks ( 5.7 ) Vaccination: Do not administer live or live attenuated vaccines to patients receiving immunosuppressive doses of corticosteroids. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting deflazacort ( 5.8 ) Serious Skin Rashes: Discontinue at the first sign of rash, unless the rash is clearly not drug related ( 5.9 ) 5.1 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. 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 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. Hyperglycemia Corticosteroids can increase blood glucose, worsen pre-existing diabetes, predispose those on long-term therapy to diabetes mellitus,

4 CONTRAINDICATIONS Deflazacort oral suspension is contraindicated in patients with known hypersensitivity to deflazacort or to any of the inactive ingredients. Instances of hypersensitivity, including anaphylaxis, have occurred in patients receiving corticosteroid therapy [see Warnings and Precautions (5.15) and Adverse Reactions (6.2) ] . Hypersensitivity to deflazacort or any of the inactive ingredients in deflazacort oral suspension ( 4 )

10 OVERDOSAGE Treatment of acute overdosage is by immediate gastric lavage or emesis followed by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of deflazacort may be reduced temporarily, or alternate day treatment may be introduced.