Deflazacort Oral Suspension

1 INDICATIONS AND USAGE Deflazacort oral suspension is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 years of age and older. Deflazacort oral suspension is a corticosteroid indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 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 )] . Deflazacort Oral Suspension 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 )] .

3 DOSAGE FORMS AND STRENGTHS Oral Suspension 22.75 mg/mL: White to off white homogeneous suspension Oral Suspension: 22.75 mg/mL ( 3)

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 )

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 oral suspension 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 Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 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 ( …

7 DRUG INTERACTIONS Moderate or strong CYP3A4 inhibitors: Give one third of the recommended dosage of deflazacort oral suspension ( 7.1 ) Avoid use of moderate or strong CYP3A4 inducers with deflazacort oral suspension, as they may reduce efficacy ( 7.1 ) 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 oral suspension when moderate or strong CYP3A4 inhibitors (e.g., clarithromycin, fluconazole, diltiazem, verapamil, grapefruit juice) are used concomitantly with deflazacort oral suspension [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 oral suspension [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . 7.2 Neuromuscular Blockers Patients receiving corticosteroids, including deflazacort oral suspension, 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 USE IN SPECIFIC POPULATIONS 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 deflazacort oral suspension in pregnant women to inform drug-associated risks. Corticosteroids, including deflazacort oral suspension, 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 oral suspension, 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 deflazacort oral suspension and any potential adverse effects on the breastfed infant from deflazacort oral suspension. There are no data on the effects on milk production. 8.4 Pediatric Use The safety and effectiveness of deflazacort oral suspension for the treatment of DMD have been established in patients 2 years of age and older. Use of deflazacort oral suspension 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 deflazacort oral suspension 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. Deflazacort 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). Add …

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.

11 DESCRIPTION The active ingredient in deflazacort oral suspension is deflazacort (a corticosteroid). Corticosteroids are adrenocortical steroids, both naturally occurring and synthetic. The molecular formula for deflazacort is C 25 H 31 NO 6 . The chemical name for deflazacort is (11β,16β)-21-(acetyloxy)-11-hydroxy-2'-methyl-5'H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione, and the structure is: Deflazacort is a white or almost white crystalline powder and has a molecular weight of 441.52. Deflazacort is soluble in dichloromethane and chloroform, slightly soluble in ethanol and ethyl acetate, almost insoluble in water. Deflazacort oral suspension for oral administration is available as an immediate-release oral suspension in a strength of 22.75 mg/mL. The oral suspension contains deflazacort and the following inactive ingredients: benzyl alcohol, glacial acetic acid, magnesium aluminum silicate, noncrystallizing sorbitol solution, polysorbate 80, purified water, sodium carboxymethylcellulose, and sodium hydroxide. deflazacort-oral-suspension-1

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 oral suspension may be reduced temporarily, or alternate day treatment may be introduced.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Deflazacort Oral Suspension 22.75 mg/mL is a white to off white homogeneous suspension. Supplied as 13 mL in a 30 mL bottle packaged with one bottle adapter and two 1 mL oral dispensers. NDC 70710-2007-3 16.2 Storage and Handling Store at 20oC to 25oC (68oF to 77oF); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Discard any unused deflazacort oral suspension remaining after 1 month of first opening the bottle.

16.1 How Supplied Deflazacort Oral Suspension 22.75 mg/mL is a white to off white homogeneous suspension. Supplied as 13 mL in a 30 mL bottle packaged with one bottle adapter and two 1 mL oral dispensers. NDC 70710-2007-3