Deflazacort

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.

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 )

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%), 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 deflazacort 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, impetig

7 DRUG INTERACTIONS Moderate or strong CYP3A4 inhibitors: Give one third of the recommended dosage of deflazacort ( 7.1 ) Avoid use of moderate or strong CYP3A4 inducers with deflazacort, as they may reduce efficacy ( 7.1) 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 . 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 deflazacort when moderate or strong CYP3A4 inhibitors (e.g., clarithromycin, fluconazole, diltiazem, verapamil, grapefruit juice) are used concomitantly with deflazacort [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 deflazacort [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . 7.2 Neuromuscular Blockers Patients receiving corticosteroids, including deflazacort, 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) ] .