Deflazacort Oral Suspension

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 Tris Pharma, Inc. at 1-732-940-0358 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 oral suspension 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, impetigo, influenza, otitis externa, pharyngitis, tooth abscess, urinary tract infection, viral infection Injury, Poisoning and Procedural Complications: Back injury, contusion, face injury, fibula fracture, greenstick fracture, heat exhaustion Investigations: Glucose urine present, heart rate irregular Musculoskeletal and Connective Tissue Disorders: Back pain, muscle spasms, myalgia, neck mass, neck pain, pain in extremity Nervous System Disorders: Dizziness, psychomotor hyperactivity Psychiatric Disorders: Affect lability, aggression, depression, emotional disorder, middle insomnia, mood altered, mood swings, sleep disorder Renal and Urinary Disorders: Chromaturia, dysuria, hypertonic bladder Reproductive System and Breast Disorders: Testicular pain Respiratory, Thoracic, and Mediastinal Disorders: Hypoventilation, rhinorrhea Skin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis acneiform Vascular Disorders: Hot flush 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of deflazacort worldwide or during post-approval use of other corticosteroids. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Leukocytosis Cardiac Disorder: Heart failure Eye Disorders: Chorioretinopathy, corneal or scleral thinning Gastrointestinal Disorders: Acute pancreatitis (especially in children), hemorrhage, peptic ulceration, perforation of peptic ulcer General Disorders and Administration Site Conditions: Edema, impaired healing Immune System Disorders: Hypersensitivity including anaphylaxis Metabolism and Nutrition Disorders: Impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy, negative protein and calcium balance, potassium loss and hypokalemic alkalosis when co-administered with beta 2-agonist and xanthines Musculoskeletal and Connective Tissue Disorders: Avascular necrosis, muscle wasting, negative nitrogen balance, tendonitis and tendon rupture when co-administered with quinolones, vertebral and long bone fractures Nervous System Disorders: Aggravation of epilepsy, increased intra-cranial pressure with papilledema in children (pseudotumor cerebri) usually after treatment withdrawal, vertigo Psychiatric Disorders: Anxiety, cognitive dysfunction including confusion and amnesia, delusions, hallucinations, mania, suicidal thoughts Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis Vascular Disorders: Thromboembolism, in particular in patients with underlying conditions associated with increased thrombotic tendency, benign intracranial hypertension

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 )

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[17,16α-d]oxazole-3,20-dione, and the structure is: Deflazacort is a white to off white fine powder and has a molecular weight of 441.52. Deflazacort is freely soluble in acetic acid and dichloromethane and soluble in methanol and acetone. 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, Polysorbate 80, Purified Water, Sodium Carboxymethyl cellulose, Sorbitol Solution. Tris Chemdraw Structure

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 )] .

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.

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 )] .

12 CLINICAL PHARMACOLOGY 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. 12.3 Pharmacokinetics Absorption After oral administration in the fasted state, the median T max with deflazacort suspension is about 1 hour (range 0.25 to 2 hours). Food Effect: Co-administration of deflazacort tablets with a high-fat meal reduced C max by about 30% and delayed T max by one hour, relative to administration under fasting conditions, but there was no effect on the overall systemic absorption as measured by AUC. The bioavailability of deflazacort tablets was similar to that of the oral suspension. The administration of deflazacort with food or crushed in applesauce did not affect the absorption and bioavailability of deflazacort. Distribution The protein binding of the active metabolite of deflazacort is about 40%. Elimination Metabolism Deflazacort is rapidly converted to the active metabolite 21-desDFZ by esterases after oral administration. 21-desDFZ is further metabolized by CYP3A4 to several other inactive metabolites, including 6β-hydroxy-21-desacetyl deflazacort. Excretion Urinary excretion is the predominant route of deflazacort elimination (about 68% of the dose), and the elimination is almost completed by 24 hours post dose. 21-desDFZ accounts for 18% of the eliminated drug in the urine. Specific Populations Pediatric Patients The C max values (Geometric mean, %CV) of 21-desDFZ in children (ages 4-11, N=16) and adolescents (ages 12-16, N=8) was 206 ng/mL (95.6%) and 381 ng/mL (37.7%), respectively, on Day 1 after administration of 0.9 mg/kg deflazacort. The AUC inf (Geometric mean, %CV) of 21-desDFZ in children (ages 4-11, N=16) and adolescents (ages 12-16, N=8) was 400 ng•h/mL (87.5%) and 655 ng•h/mL (58.1%) on Day 1 after administration of 0.9 mg/kg deflazacort. Male and Female Patients There are no differences in the pharmacokinetics of 21-desDFZ between males and females. Racial or Ethnic Groups There are no differences in the pharmacokinetics of 21-desDFZ between Caucasians and non-Caucasians. Patients with Renal Impairment In a study (N=16) comparing subjects with end stage renal disease (creatinine clearance less than 15 mL/min) with healthy matched controls, 21-desDFZ exposure was similar between the groups. Patients with Hepatic Impairment In a study (N=16) comparing subjects with moderate hepatic impairment (Child-Pugh Class B) with healthy matched controls, 21-desDFZ exposure was similar between the groups. There is no experience in patients with severe hepatic impairment. Drug Interaction Studies In Vivo Assessment of Drug Interactions Compared to administration of deflazacort alone, administration of deflazacort following multiple doses of a strong CYP3A4 and Pgp inhibitor (clarithromycin) resulted in markedly higher C max , AUC last , and AUC inf values of 21-desDFZ. Geometric mean exposure (C max , AUC last , and AUC inf ) of 21-desDFZ ranged from 2.3-fold to 3.4-fold higher following administration of clarithromycin [see Dosage and Administration ( 2.5 )] . Compared to administration of deflazacort alone, administration of deflazacort following multiple doses of a strong CYP3A4 inducer (rifampicin) resulted in markedly lower C max , AUC last , and AUC inf values of 21-desDFZ. Geometric mean exposures (C max , AUC last , and AUC inf ) of 21-desDFZ were approximately 95% lower following administration of rifampin [see Drug Interactions ( 7.1 )] . 6β-Hydroxy-21-desacetyl deflazacort, a secondary and inactive metabolite, is not expected to cause any clinically meaningful interactions with the CYP enzymes or transporters. In Vitro Assessment of Drug Interactions Drug-Metabolizing Enzyme Inhibition 21-desDFZ at clinically relevant concentrations did not inhibit CYP1A2, 2C9, 2C19, 3A4, UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and exhibited weak and not likely clinically meaningful inhibition for 2B6, 2C8, 2D6, and 3A4, UGT1A3 and UGT2B15. 6β-Hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly inhibit CYP2C19, 3A4 1A2, 2B6, 2C8, 2C9, or 2D6. Drug-Metabolizing Enzyme Induction 21-desDFZ and 6β-hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly induce CYP1A2, 2B6, or 3A4. Transporters Both deflazacort and 21-desDFZ are substrates of Pgp. 21-desDFZ is not a substrate for BCRP. Neither deflazacort nor 21-desDFZ inhibited Pgp or BCRP in vitro . 21-desDFZ was not a substrate for SLC transporters OATP1B1 or OATP1B3, and did not inhibit SLC transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. 6β-Hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly inhibit BCRP, OAT1, OAT3, Pgp, OATP1B1, OATP1B3 MATE1, MATE2-K, OCT1, OCT2, or BSEP transporters.

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.

12.3 Pharmacokinetics Absorption After oral administration in the fasted state, the median T max with deflazacort suspension is about 1 hour (range 0.25 to 2 hours). Food Effect: Co-administration of deflazacort tablets with a high-fat meal reduced C max by about 30% and delayed T max by one hour, relative to administration under fasting conditions, but there was no effect on the overall systemic absorption as measured by AUC. The bioavailability of deflazacort tablets was similar to that of the oral suspension. The administration of deflazacort with food or crushed in applesauce did not affect the absorption and bioavailability of deflazacort. Distribution The protein binding of the active metabolite of deflazacort is about 40%. Elimination Metabolism Deflazacort is rapidly converted to the active metabolite 21-desDFZ by esterases after oral administration. 21-desDFZ is further metabolized by CYP3A4 to several other inactive metabolites, including 6β-hydroxy-21-desacetyl deflazacort. Excretion Urinary excretion is the predominant route of deflazacort elimination (about 68% of the dose), and the elimination is almost completed by 24 hours post dose. 21-desDFZ accounts for 18% of the eliminated drug in the urine. Specific Populations Pediatric Patients The C max values (Geometric mean, %CV) of 21-desDFZ in children (ages 4-11, N=16) and adolescents (ages 12-16, N=8) was 206 ng/mL (95.6%) and 381 ng/mL (37.7%), respectively, on Day 1 after administration of 0.9 mg/kg deflazacort. The AUC inf (Geometric mean, %CV) of 21-desDFZ in children (ages 4-11, N=16) and adolescents (ages 12-16, N=8) was 400 ng•h/mL (87.5%) and 655 ng•h/mL (58.1%) on Day 1 after administration of 0.9 mg/kg deflazacort. Male and Female Patients There are no differences in the pharmacokinetics of 21-desDFZ between males and females. Racial or Ethnic Groups There are no differences in the pharmacokinetics of 21-desDFZ between Caucasians and non-Caucasians. Patients with Renal Impairment In a study (N=16) comparing subjects with end stage renal disease (creatinine clearance less than 15 mL/min) with healthy matched controls, 21-desDFZ exposure was similar between the groups. Patients with Hepatic Impairment In a study (N=16) comparing subjects with moderate hepatic impairment (Child-Pugh Class B) with healthy matched controls, 21-desDFZ exposure was similar between the groups. There is no experience in patients with severe hepatic impairment. Drug Interaction Studies In Vivo Assessment of Drug Interactions Compared to administration of deflazacort alone, administration of deflazacort following multiple doses of a strong CYP3A4 and Pgp inhibitor (clarithromycin) resulted in markedly higher C max , AUC last , and AUC inf values of 21-desDFZ. Geometric mean exposure (C max , AUC last , and AUC inf ) of 21-desDFZ ranged from 2.3-fold to 3.4-fold higher following administration of clarithromycin [see Dosage and Administration ( 2.5 )] . Compared to administration of deflazacort alone, administration of deflazacort following multiple doses of a strong CYP3A4 inducer (rifampicin) resulted in markedly lower C max , AUC last , and AUC inf values of 21-desDFZ. Geometric mean exposures (C max , AUC last , and AUC inf ) of 21-desDFZ were approximately 95% lower following administration of rifampin [see Drug Interactions ( 7.1 )] . 6β-Hydroxy-21-desacetyl deflazacort, a secondary and inactive metabolite, is not expected to cause any clinically meaningful interactions with the CYP enzymes or transporters. In Vitro Assessment of Drug Interactions Drug-Metabolizing Enzyme Inhibition 21-desDFZ at clinically relevant concentrations did not inhibit CYP1A2, 2C9, 2C19, 3A4, UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 and exhibited weak and not likely clinically meaningful inhibition for 2B6, 2C8, 2D6, and 3A4, UGT1A3 and UGT2B15. 6β-Hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly inhibit CYP2C19, 3A4 1A2, 2B6, 2C8, 2C9, or 2D6. Drug-Metabolizing Enzyme Induction 21-desDFZ and 6β-hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly induce CYP1A2, 2B6, or 3A4. Transporters Both deflazacort and 21-desDFZ are substrates of Pgp. 21-desDFZ is not a substrate for BCRP. Neither deflazacort nor 21-desDFZ inhibited Pgp or BCRP in vitro . 21-desDFZ was not a substrate for SLC transporters OATP1B1 or OATP1B3, and did not inhibit SLC transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. 6β-Hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly inhibit BCRP, OAT1, OAT3, Pgp, OATP1B1, OATP1B3 MATE1, MATE2-K, OCT1, OCT2, or BSEP transporters.

20240628

7

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

Deflazacort Oral Suspension Deflazacort Oral DEFLAZACORT DEFLAZACORT MAGNESIUM ALUMINUM SILICATE TYPE IIA BENZYL ALCOHOL CARBOXYMETHYLCELLULOSE SODIUM, UNSPECIFIED SORBITOL SOLUTION POLYSORBATE 80 ACETIC ACID WATER white to off-white

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a published 2-year carcinogenicity study in rats, oral administration of deflazacort (0, 0.03, 0.06, 0.12, 0.25, 0.50, or 1.0 mg/kg/day) resulted in bone tumors (osteosarcoma and osteoma) of the head at 0.25 mg/kg/day, the highest evaluable dose. Doses higher than 0.25 mg/kg/day could not be evaluated for tumors because of a marked decrease in survival. In a 6-month carcinogenicity study in transgenic (Tg.RasH2) mice, oral administration of deflazacort (0, 2, 5, or 20 mg/kg/day in males; 0, 0.5, 2, or 5 mg/kg/day in females) resulted in an increase in stomach tumors (adenoma) at the highest dose tested in males and females. Mutagenesis Deflazacort and 21-desDFZ were negative in in vitro (bacterial reverse mutation and human lymphocyte chromosomal aberration) assays and deflazacort was negative in an in vivo (rat micronucleus) assay. Impairment of Fertility Fertility studies in animals were not conducted with deflazacort. No effects on the male reproductive system were observed following oral administration of deflazacort to monkeys (0, 1.0, 3.0, or 6.0 mg/kg/day) for 39 weeks or rats (0, 0.05, 0.15, or 0.5 mg/kg/day) for 26 weeks. Plasma 21-desDFZ exposures (AUC) at the highest doses tested in monkey and rat were 4 and 2 times, respectively, that in humans at the recommended human dose of deflazacort oral suspension (0.9 mg/kg/day).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a published 2-year carcinogenicity study in rats, oral administration of deflazacort (0, 0.03, 0.06, 0.12, 0.25, 0.50, or 1.0 mg/kg/day) resulted in bone tumors (osteosarcoma and osteoma) of the head at 0.25 mg/kg/day, the highest evaluable dose. Doses higher than 0.25 mg/kg/day could not be evaluated for tumors because of a marked decrease in survival. In a 6-month carcinogenicity study in transgenic (Tg.RasH2) mice, oral administration of deflazacort (0, 2, 5, or 20 mg/kg/day in males; 0, 0.5, 2, or 5 mg/kg/day in females) resulted in an increase in stomach tumors (adenoma) at the highest dose tested in males and females. Mutagenesis Deflazacort and 21-desDFZ were negative in in vitro (bacterial reverse mutation and human lymphocyte chromosomal aberration) assays and deflazacort was negative in an in vivo (rat micronucleus) assay. Impairment of Fertility Fertility studies in animals were not conducted with deflazacort. No effects on the male reproductive system were observed following oral administration of deflazacort to monkeys (0, 1.0, 3.0, or 6.0 mg/kg/day) for 39 weeks or rats (0, 0.05, 0.15, or 0.5 mg/kg/day) for 26 weeks. Plasma 21-desDFZ exposures (AUC) at the highest doses tested in monkey and rat were 4 and 2 times, respectively, that in humans at the recommended human dose of deflazacort oral suspension (0.9 mg/kg/day).

ANDA217813

Deflazacort Oral Suspension

Deflazacort Oral

27808-249

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NDC-27808-249-01 Deflazacort Oral Suspension 22.75 mg/mL For Oral Administration Only Rx only 13 mL Label

Warnings and Precautions Immunosuppression and Increased Risk of Infection ( 5.2 ) 06/2024

17 PATIENT COUNSELING INFORMATION Advise the patients and/or caregivers to read the FDA-approved patient labeling if deflazacort oral suspension is prescribed (Instructions for Use). Administration Warn patients and/or caregivers to not stop taking deflazacort oral suspension abruptly or without first checking with their healthcare providers as there may be a need for gradual dose reduction to decrease the risk of adrenal insufficiency [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.1 )] . Deflazacort oral suspension may be taken with or without food. Do not take deflazacort oral suspension with grapefruit juice. Oral Suspension Deflazacort oral suspension must be shaken well prior to measuring out each dose with the enclosed oral dispenser. The deflazacort oral suspension dose may be placed in 3-4 ounces of juice (except grapefruit juice) or milk, mixed thoroughly, and immediately administered. Discard any unused deflazacort oral suspension remaining after 1 month of first opening the bottle. Increased Risk of Infection Tell patients and/or caregivers to inform their healthcare provider if the patient has had recent or ongoing infections or if they have recently received a vaccine. Medical advice should be sought immediately if the patient develops fever or other signs of infection. Patients and/or caregivers should be made aware that some infections can potentially be severe and fatal. Warn patients who are on corticosteroids to avoid exposure to chickenpox or measles and to alert their healthcare provider immediately if they are exposed [see Warnings and Precautions ( 5.2 )] . Alterations in Cardiovascular/Renal Function Inform patients and/or caregivers that deflazacort oral suspension can cause an increase in blood pressure and water retention. If this occurs, dietary salt restriction and potassium supplementation may be needed [see Warnings and Precautions ( 5.3 )] . Behavioral and Mood Disturbances Advise patients and/or caregivers about the potential for severe behavioral and mood changes with deflazacort oral suspension and encourage them to seek medical attention if psychiatric symptoms develop [see Warnings and Precautions ( 5.5 )] . Decreases in Bone Mineral Density Advise patients and/or caregivers about the risk of osteoporosis with prolonged use of deflazacort oral suspension, which can predispose the patient to vertebral and long bone fractures [see Warnings and Precautions ( 5.6 )] . Ophthalmic Effects Inform patients and/or caregivers that deflazacort oral suspension may cause cataracts or glaucoma and advise monitoring if corticosteroid therapy is continued for more than 6 weeks [see Warnings and Precautions ( 5.7 )] . Vaccination Advise patients and/or caregivers to bring immunizations up-to-date according to immunization guidelines prior to starting therapy with deflazacort oral suspension. Live-attenuated or live vaccines should be administered at least 4 to 6 weeks prior to starting deflazacort oral suspension. Inform patients and/or caregivers that they may receive concurrent vaccinations with use of deflazacort oral suspension, except for live-attenuated or live vaccines. [see Warnings and Precautions ( 5.8 )] . Serious Skin Rashes Instruct patients and/or caregivers to seek medical attention at the first sign of a rash [see Warnings and Precautions ( 5.9 )] . Drug Interactions Certain medications can cause an interaction with deflazacort oral suspension. Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines (such as insulin, aspirin or other NSAIDS), dietary supplements, and herbal products. Inform patients and/or caregivers that alternate therapy, dosage adjustment, and/or special test(s) may be needed during the treatment. Manufactured by: Tris Pharma, Inc. Monmouth Junction, NJ 08852 www.trispharma.com LB8698 Rev. 01 06/2024

14 CLINICAL STUDIES The effectiveness of deflazacort oral suspension for the treatment of DMD was established in Study 1, a multicenter, randomized, double-blind, placebo-controlled, 52-week study conducted in the US and Canada. The study population consisted of 196 male pediatric patients 5 to 15 years of age with documented mutation of the dystrophin gene, onset of weakness before 5 years of age, and serum creatinine kinase activity at least 10 times the upper limit of normal (ULN) at some stage in their illness. Patients were randomized to therapy with deflazacort (0.9 or 1.2 mg/kg/day), an active comparator, or placebo. A comparison to placebo was made after 12 weeks of treatment. After 12 weeks, placebo patients were re-randomized to receive either deflazacort or the active comparator; all patients continued treatment for an additional 40 weeks. Baseline characteristics were comparable between the treatment arms. In Study 1, efficacy was evaluated by assessing the change between Baseline and Week 12 in average strength of 18 muscle groups. Individual muscle strength was graded using a modified Medical Research Council (MRC) 11-point scale, with higher scores representing greater strength. The change in average muscle strength score between Baseline and Week 12 was significantly greater for the deflazacort 0.9 mg/kg/day dose group than for the placebo group (see Table 2). Table 2: Analysis of Change from Baseline at Week 12 in Average Muscle Strength Score (Study 1) Treatment N Change from Baseline LS Mean (95% CI) P-value Deflazacort 0.9 mg/kg/day 51 0.15 (0.01, 0.28) 0.017 Placebo 50 -0.10 (-0.23, 0.03) Compared with the deflazacort 0.9 mg/kg/day group, the deflazacort 1.2 mg/kg/day group demonstrated a small additional benefit compared to placebo at Week 12, but had a greater incidence of adverse reactions. Therefore, use of a 1.2 mg/kg/day dosage of deflazacort oral suspension is not recommended [see Dosage and Administration ( 2.2 )] . Although not a pre-specified statistical analysis, compared with placebo, the deflazacort 0.9 mg/kg/day dose group demonstrated at Week 52 the persistence of the treatment effect observed at Week 12 and the small advantage of the 1.2 mg/kg/day dose that was observed at Week 12 was no longer present. Also not statistically controlled for multiple comparisons, results on several timed measures of patient function (i.e., time to stand from supine, time to climb 4 stairs, and time to walk or run 30 feet) numerically favored deflazacort 0.9 mg/kg/day at Week 12, in comparison with placebo. An additional randomized, double-blind, placebo-controlled, 104-week clinical trial evaluated deflazacort in comparison to placebo (Study 2). The study population consisted of 29 male children 6 to 12 years of age with a DMD diagnosis confirmed by the documented presence of abnormal dystrophin or a confirmed mutation of the dystrophin gene. The results of the analysis of the primary endpoint of average muscle strength scores in Study 2 (graded on a 0-5 scale) at 2 years were not statistically significant, possibly because of a limited number of patients remaining in the placebo arm (subjects were discontinued from the trial when they lost ambulation). Although not statistically controlled for multiple comparisons, average muscle strength scores at Months 6 and 12, as well as the average time to loss of ambulation, numerically favored deflazacort in comparison with placebo.

8.5 Geriatric Use DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with deflazacort oral suspension.

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 5 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 )] . 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). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. When prescribing deflazacort oral suspension consider the combined daily metabolic load of benzyl alcohol from all sources including deflazacort oral suspension (Deflazacort oral suspension contains 10.45 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. At the recommended dose of 0.9 mg/kg/day of deflazacort oral suspension, patients would receive approximately 0.4 mg/kg/day of benzyl alcohol [see Warnings and Precautions ( 5.13 )] . 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 oral suspension (0.9 mg/kg/day). 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.

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 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 5 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 )] . 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). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. When prescribing deflazacort oral suspension consider the combined daily metabolic load of benzyl alcohol from all sources including deflazacort oral suspension (Deflazacort oral suspension contains 10.45 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. At the recommended dose of 0.9 mg/kg/day of deflazacort oral suspension, patients would receive approximately 0.4 mg/kg/day of benzyl alcohol [see Warnings and Precautions ( 5.13 )] . 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 oral suspension (0.9 mg/kg/day). 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. 8.5 Geriatric Use DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with deflazacort oral suspension. 8.6 Renal Impairment No dose adjustment is required in patients with mild, moderate or severe renal impairment [see Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment No dose adjustment is required in patients with mild or moderate hepatic impairment [see Clinical Pharmacology ( 12.3 )] . There is no clinical experience in patients with severe hepatic impairment, and a dosing recommendation cannot be provided for patients with severe hepatic impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Deflazacort oral suspension 22.75 mg/mL is a white to off-white suspension. Supplied as 13 mL in a 30 mL bottle packaged with one press-in bottle adapter and two 1 mL oral dispensers. NDC 27808-249-01 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F). Excursion 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.