JAYTHARI

1 INDICATIONS AND USAGE JAYTHARI is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 years of age and older. JAYTHARI 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 JAYTHARI Administer all immunizations according to immunization guidelines prior to starting JAYTHARI. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting JAYTHARI [see Warnings and Precautions ( 5.8 )]. 2.2 Dosing Information The recommended oral dosage JAYTHARI 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 JAYTHARI strengths can be used to achieve this dose. 2.3 Discontinuation Dosage of JAYTHARI 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 JAYTHARI Tablets can be taken with or without food. Do not administer JAYTHARI with grapefruit juice [see Drug Interactions ( 7.1 )]. JAYTHARI 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 JAYTHARI 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 JAYTHARI [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )].

3 DOSAGE FORMS AND STRENGTHS 6 mg: White to off white, round, biconvex tablets, with "49" debossed on one side 18 mg: White to off white, round, biconvex tablets, with "50" debossed on one side 30 mg: White to off white, oblong, biconvex tablets, with "51" debossed on one side 36 mg: White to off white, oblong, biconvex tablets, with "52" debossed on one side Tablets: 6 mg, 18 mg, 30 mg, and 36 mg ( 3 )

4 CONTRAINDICATIONS JAYTHARI 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 JAYTHARI ( 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 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 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/k …

7 DRUG INTERACTIONS Moderate or strong CYP3A4 inhibitors: Give one third of the recommended dosage of JAYTHARI ( 7.1 ) Avoid use of moderate or strong CYP3A4 inducers with JAYTHARI, 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 JAYTHARI when moderate or strong CYP3A4 inhibitors (e.g., clarithromycin, fluconazole, diltiazem, verapamil, grapefruit juice) are used concomitantly with JAYTHARI [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 JAYTHARI [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . 7.2 Neuromuscular Blockers Patients receiving corticosteroids, including JAYTHARI, 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 JAYTHARI, 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 JAYTHARI, 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 JAYTHARI and any potential adverse effects on the breastfed infant from JAYTHARI. 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 2 years of age and older. Use of deflazacort 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 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. Juvenile Animal Toxicity Data Oral administration of deflazacort (0, 0.1, 0.3, and 1 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 JAYTHARI (0.9 mg/kg/day). 8.5 Geriatric Use DMD is largely a di …

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 JAYTHARI 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 structural formula is: Deflazacort is a white to pale yellow crystalline powder and has a molecular weight of 441.5. Deflazacort is freely soluble in acetic acid and dichloromethane and sparingly soluble in methanol and acetone. JAYTHARI tablets for oral administration is available as an immediate-release tablet in strengths of 6, 18, 30 and 36 mg. Each tablet contains deflazacort and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, and pregelatinized starch. Image

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 JAYTHARI may be reduced temporarily, or alternate day treatment may be introduced.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied JAYTHARI 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 JAYTHARI 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