Deflazacort

RECENT MAJOR CHANGES Warnings and Precautions Immunosuppression and Increased Risk of Infection (5.2) 6/2024

1 INDICATIONS AND USAGE Deflazacort tablets are 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) tablets. However, due to PTC Therapeutics, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. Deflazacort tablets are 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 Tablets Administer all immunizations according to immunization guidelines prior to starting deflazacort tablets. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting deflazacort tablets [see Warnings and Precautions ( 5.8 )]. 2.2 Dosing Information The recommended oral dosage of deflazacort tablets are approximately 0.9 mg/kg/day once daily. If tablets are used, round up to the nearest possible dose. Any combination of the four deflazacort tablets strengths can be used to achieve this dose. 2.3 Discontinuation Dosage of deflazacort tablets 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 tablets can be taken with or without food. Do not administer deflazacort tablets with grapefruit juice [see Drug Interactions ( 7.1 )]. Deflazacort tablets can be administered whole or crushed and taken immediately after mixing with applesauce. 2.5 Dosage Modification for Use with CYP3A4 Inhibitors and Inducers CYP3A4 Inhibitors Give one third of the recommended dosage when deflazacort tablets are 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 tablets [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )].

3 DOSAGE FORMS AND STRENGTHS Deflazacort Tablets, 6 mg are white to off-white, round, uncoated tablet debossed with ‘J6’ on one side and plain on other side. Deflazacort Tablets, 18 mg are white to off-white, round, uncoated tablet debossed with ‘AC91’ on one side and plain on other side. Deflazacort Tablets, 30 mg are white to off-white, oval, uncoated tablet debossed with ‘AC92’ on one side and plain on other side. Deflazacort Tablets, 36 mg are white to off white, oval, uncoated tablet debossed with ‘AC93’ on one side and plain on other side. Tablets: 6 mg, 18 mg, 30 mg and 36 mg. ( 3 )

4 CONTRAINDICATIONS Deflazacort tablets are 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 tablets ( 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 )] 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 AvKARE at 1-855-361-3993;email drugsaftey@avkare.com 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 At 12 weeks placebo patients were re-randomized to receive either deflazacort or an active comparator. 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 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 …

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 EmflazaTM (deflazacort) tablets. 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 )] .

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 in pregnant women to inform drug-associated risks. 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 1,000 infants to 3 to 5 per 1,000 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% to 4% and 15% to 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 1/1,000 infants to 3 to 5/1,000 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 and any potential adverse effects on the breastfed infant from deflazacort. There are no data on the effects on milk production. 8.4 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 tablets 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) ] . Safety and effectiveness in pediatric patients below the age of 2 years have not been established. 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 deflazacort (0.9 mg/kg/day). Additional pediatric use information is approved for PTC Therapeutics, Inc.'s EmflazaTM (deflazacort) tablets. However, due to PTC Therapeutics, Inc.'s marketing exclusivity r …

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 tablet 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 to off-white crystalline powder and has a molecular weight of 441.52 g/mol. Deflazacort is freely soluble in methylene chloride and in chloroform, soluble in methanol and in acetone, practically insoluble in water and in light petroleum (petroleum ether). Deflazacort tablets for oral administration is available as an immediate-release tablet in strengths of 6 mg, 18 mg, 30 mg and 36 mg. Each tablet contains deflazacort and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pre-gelatinized corn starch. 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 may be reduced temporarily, or alternate day treatment may be introduced.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Deflazacort Tablets 6 mg are white to off white, round, biconvex tablets, with "49" debossed on one side. They are supplied as follows: NDC in bottle of 100 Tablets with child-resistant closure 18 mg are white to off white, round, biconvex tablets, with "50" debossed on one side. They are supplied as follows: NDC in bottle of 30 Tablets with child-resistant closure 30 mg are white to off white, oblong, biconvex tablets, with "51" debossed on one side. They are supplied as follows: NDC in bottle of 30 Tablets with child-resistant closure 36 mg are white to off white, oblong, biconvex tablets, with "52" debossed on one side. They are supplied as follows: NDC in bottle of 30 Tablets with child-resistant closure 16.2 Storage and Handling Store at 20o to 25oC (68o to 77oF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

16.1 How Supplied Deflazacort Tablets 6 mg are white to off white, round, biconvex tablets, with "49" debossed on one side. They are supplied as follows: NDC in bottle of 100 Tablets with child-resistant closure 18 mg are white to off white, round, biconvex tablets, with "50" debossed on one side. They are supplied as follows: NDC in bottle of 30 Tablets with child-resistant closure 30 mg are white to off white, oblong, biconvex tablets, with "51" debossed on one side. They are supplied as follows: NDC in bottle of 30 Tablets with child-resistant closure 36 mg are white to off white, oblong, biconvex tablets, with "52" debossed on one side. They are supplied as follows: NDC in bottle of 30 Tablets with child-resistant closure