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ADVERSE REACTIONS SECTION.

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)] Kaposis 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)] 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)] Kaposis 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 EMFLAZA 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 PTC Therapeutics, Inc. at 1-866-562-4620 or PharmacovigilancePTCBio.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 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 [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 StudiesTable 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 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)1 At 12 weeks placebo patients were re-randomized to receive either deflazacort or an active comparator.Adverse ReactionDeflazacort0.9 mg/kg/d (N=51)% at 12 weeksPlacebo (N=50)% at 12 weeks1 Cushingoid appearance3312Weight increased206Increased appetite142Upper respiratory tract infection1210Cough126Pollakiuria122Nasopharyngitis106Hirsutism102Central obesity104Erythema86Irritability84Rhinorrhea80Abdominal discomfort62Common adverse reactions (>= 5% of deflazacort-treated patients) that occurred over 52 weeks of exposure to deflazacort 0.9 mg/kg/day in Study and at 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 also evaluated 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 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 EMFLAZA 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 StudiesOther 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 are shown below.Eye Disorders: Lacrimation increasedGastrointestinal Disorders: Dyspepsia, nausea, gastrointestinal disorderGeneral Disorders and Administration Site Conditions: ThirstInfections: Hordeolum, impetigo, influenza, otitis externa, pharyngitis, tooth abscess, urinary tract infection, viral infectionInjury, Poisoning and Procedural Complications: Back injury, contusion, face injury, fibula fracture, greenstick fracture, heat exhaustionInvestigations: Glucose urine present, heart rate irregularMusculoskeletal and Connective Tissue Disorders: Back pain, muscle spasms, myalgia, neck mass, neck pain, pain in extremityNervous System Disorders: Dizziness, psychomotor hyperactivityPsychiatric Disorders: Affect lability, aggression, depression, emotional disorder, middle insomnia, mood altered, mood swings, sleep disorderRenal and Urinary Disorders: Chromaturia, dysuria, hypertonic bladderReproductive System and Breast Disorders: Testicular painRespiratory, Thoracic, and Mediastinal Disorders: Hypoventilation, rhinorrheaSkin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis acneiformVascular 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 population of uncertain size; therefore, it is not always possible to estimate their frequency or establish causal relationship to drug exposure.Blood and Lymphatic System Disorders: LeukocytosisCardiac Disorder: Heart failureEye Disorders: Chorioretinopathy, corneal or scleral thinningGastrointestinal Disorders: Acute pancreatitis (especially in children), hemorrhage, peptic ulceration, perforation of peptic ulcerGeneral Disorders and Administration Site Conditions: Edema, impaired healingImmune System Disorders: Hypersensitivity including anaphylaxisMetabolism 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 xanthinesMusculoskeletal and Connective Tissue Disorders: Avascular necrosis, muscle wasting, negative nitrogen balance, tendonitis and tendon rupture when co-administered with quinolones, vertebral and long bone fracturesNervous System Disorders: Aggravation of epilepsy, increased intra-cranial pressure with papilledema in children (pseudotumor cerebri) usually after treatment withdrawal, vertigoPsychiatric Disorders: Anxiety, cognitive dysfunction including confusion and amnesia, delusions, hallucinations, mania, suicidal thoughtsSkin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysisVascular Disorders: Thromboembolism, in particular in patients with underlying conditions associated with increased thrombotic tendency, benign intracranial hypertension.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 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 marked decrease in survival.In 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 mg/kg/day in females) resulted in an increase in stomach tumors (adenoma) at the highest dose tested in males and females.MutagenesisDeflazacort 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 FertilityFertility 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 and times, respectively, that in humans at the recommended human dose of EMFLAZA (0.9 mg/kg/day).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Deflazacort is 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. AbsorptionAfter oral administration in the fasted state, the median Tmax with deflazacort tablets or suspension is about hour (range 0.25 to hours).Food Effect: Co-administration of deflazacort tablets with high-fat meal reduced Cmax by about 30% and delayed Tmax 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.DistributionThe protein binding of the active metabolite of deflazacort is about 40%.EliminationMetabolismDeflazacort 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 6-hydroxy-21-desacetyl deflazacort.ExcretionUrinary 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 PopulationsPediatric PatientsThe Cmax 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 after administration of 0.9 mg/kg deflazacort. The AUCinf (Geometric mean, %CV) of 21-desDFZ in children (ages 4-11, N=16) and adolescents (ages 12-16, N=8) was 400 ngoh/mL (87.5%) and 655 ngoh/mL (58.1%) on Day after administration of 0.9 mg/kg deflazacort.Male and Female PatientsThere are no differences in the pharmacokinetics of 21-desDFZ between males and females.Racial or Ethnic GroupsThere are no differences in the pharmacokinetics of 21-desDFZ between Caucasians and non-Caucasians.Patients with Renal ImpairmentIn 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 ImpairmentIn 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 StudiesIn Vivo Assessment of Drug InteractionsCompared to administration of deflazacort alone, administration of deflazacort following multiple doses of strong CYP3A4 and Pgp inhibitor (clarithromycin) resulted in markedly higher Cmax, AUClast, and AUCinf values of 21-desDFZ. Geometric mean exposure (Cmax, AUClast, and AUCinf) 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 strong CYP3A4 inducer (rifampicin) resulted in markedly lower Cmax, AUClast, and AUCinf values of 21-desDFZ. Geometric mean exposures (Cmax, AUCla st, and AUCinf) of 21-desDFZ were approximately 95% lower following administration of rifampin [see Drug Interactions (7.1)].6-Hydroxy-21-desacetyl deflazacort, secondary and inactive metabolite, is not expected to cause any clinically meaningful interactions with the CYP enzymes or transporters.In Vitro Assessment of Drug InteractionsDrug-Metabolizing Enzyme Inhibition21-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 UGT2B15.6-Hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly inhibit CYP2C19, 3A4 1A2, 2B6, 2C8, 2C9, or 2D6.Drug-Metabolizing Enzyme Induction21-desDFZ and 6-hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly induce CYP1A2, 2B6, or 3A4.TransportersBoth deflazacort and 21-desDFZ are substrates of Pgp. 21-desDFZ is not substrate for BCRP. Neither deflazacort nor 21-desDFZ inhibited Pgp or BCRP in vitro. 21-desDFZ was not substrate for SLC transporters OATP1B1 or OATP1B3, and did not inhibit SLC transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.6-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.

CLINICAL STUDIES SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 [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 StudiesTable 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 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)1 At 12 weeks placebo patients were re-randomized to receive either deflazacort or an active comparator.Adverse ReactionDeflazacort0.9 mg/kg/d (N=51)% at 12 weeksPlacebo (N=50)% at 12 weeks1 Cushingoid appearance3312Weight increased206Increased appetite142Upper respiratory tract infection1210Cough126Pollakiuria122Nasopharyngitis106Hirsutism102Central obesity104Erythema86Irritability84Rhinorrhea80Abdominal discomfort62Common adverse reactions (>= 5% of deflazacort-treated patients) that occurred over 52 weeks of exposure to deflazacort 0.9 mg/kg/day in Study and at 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 also evaluated 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 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 EMFLAZA 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 StudiesOther 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 are shown below.Eye Disorders: Lacrimation increasedGastrointestinal Disorders: Dyspepsia, nausea, gastrointestinal disorderGeneral Disorders and Administration Site Conditions: ThirstInfections: Hordeolum, impetigo, influenza, otitis externa, pharyngitis, tooth abscess, urinary tract infection, viral infectionInjury, Poisoning and Procedural Complications: Back injury, contusion, face injury, fibula fracture, greenstick fracture, heat exhaustionInvestigations: Glucose urine present, heart rate irregularMusculoskeletal and Connective Tissue Disorders: Back pain, muscle spasms, myalgia, neck mass, neck pain, pain in extremityNervous System Disorders: Dizziness, psychomotor hyperactivityPsychiatric Disorders: Affect lability, aggression, depression, emotional disorder, middle insomnia, mood altered, mood swings, sleep disorderRenal and Urinary Disorders: Chromaturia, dysuria, hypertonic bladderReproductive System and Breast Disorders: Testicular painRespiratory, Thoracic, and Mediastinal Disorders: Hypoventilation, rhinorrheaSkin and Subcutaneous Tissue Disorders: Acne, alopecia, dermatitis acneiformVascular Disorders: Hot flush.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. EMFLAZA 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 EMFLAZA (4).

DESCRIPTION SECTION.

11 DESCRIPTION. The active ingredient in EMFLAZA is deflazacort (a corticosteroid). Corticosteroids are adrenocortical steroids, both naturally occurring and synthetic. The molecular formula for deflazacort is C25H31NO6. The chemical name for deflazacort is (11,16)-21-(acetyloxy)-11-hydroxy-2-methyl-5H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione, and the structure is:Deflazacort is white to off white, odorless fine powder and has molecular weight of 441.517. Deflazacort is freely soluble in acetic acid and dichloromethane and soluble in methanol and acetone.EMFLAZA for oral administration is available as an immediate-release tablet in strengths of 6, 18, 30 and 36 mg and an immediate-release oral suspension in strength of 22.75 mg/mL. Each tablet contains deflazacort and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, and pre-gelatinized corn starch. The oral suspension contains deflazacort and the following inactive ingredients: acetic acid, aluminum magnesium silicate, benzyl alcohol, carboxymethylcellulose sodium, polysorbate 80, purified water, and sorbitol.. The structural formula for EMFLAZA is deflazacort (a corticosteroid). Corticosteroids are adrenocortical steroids, both naturally occurring and synthetic. The molecular formula for deflazacort is C25H31NO6. The chemical name for deflazacort is (11,16)-21-(acetyloxy)-11-hydroxy-2-methyl-5H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione.

DOSAGE & ADMINISTRATION SECTION.

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 few days (2.3). The recommended once-daily dosage is approximately 0.9 mg/kg/day administered orally (2.2). Discontinue gradually when administered for more than few days (2.3). 2.1 Assessments Prior to First Dose of EMFLAZA. Administer all immunizations according to immunization guidelines prior to starting EMFLAZA. Administer live-attenuated or live vaccines at least to weeks prior to starting EMFLAZA [see Warnings and Precautions (5.8)].. 2.2 Dosing Information. The recommended oral dosage of EMFLAZA 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 EMFLAZA tablet strengths can be used to achieve this dose. If the oral suspension is used, round up to the nearest tenth of milliliter (mL).. 2.3 Discontinuation. Dosage of EMFLAZA must be decreased gradually if the drug has been administered for more than few days [see Warnings and Precautions (5.1)].. 2.4 Important Preparation and Administration Instructions. EMFLAZA Tablets and Oral Suspension can be taken with or without food. Do not administer EMFLAZA with grapefruit juice [see Drug Interactions (7.1)] EMFLAZA TabletsEMFLAZA Tablets can be administered whole or crushed and taken immediately after mixing with applesauce.EMFLAZA Oral SuspensionShake EMFLAZA 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 EMFLAZA Oral Suspension into to ounces of juice (except grapefruit juice) or milk and mix well. The dose should then be administered immediately.Discard any unused EMFLAZA Oral Suspension remaining after month of first opening the bottle.. 2.5 Dosage Modification for Use with CYP3A4 Inhibitors and Inducers. CYP3A4 InhibitorsGive one third of the recommended dosage when EMFLAZA is administered with moderate or strong CYP3A4 inhibitors. For example, 36 mg per day dose would be reduced to 12 mg per day dose when used with moderate or strong CYP3A4 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].CYP3A4 InducersAvoid use with moderate or strong CYP3A4 inducers with EMFLAZA [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets6 mg: White and round with 6 debossed on one side18 mg: White and round with 18 debossed on one side30 mg: White and oval with 30 debossed on one side36 mg: White and oval with 36 debossed on one sideOral Suspension22.75 mg/mL: Whitish suspension. mg: White and round with 6 debossed on one side. 18 mg: White and round with 18 debossed on one side. 30 mg: White and oval with 30 debossed on one side. 36 mg: White and oval with 36 debossed on one side. 22.75 mg/mL: Whitish suspension. Tablets: mg, 18 mg, 30 mg, and 36 mg (3)Oral Suspension: 22.75 mg/mL (3). Tablets: mg, 18 mg, 30 mg, and 36 mg (3). Oral Suspension: 22.75 mg/mL (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Moderate or strong CYP3A4 inhibitors: Give one third of the recommended dosage of EMFLAZA (7.1)Avoid use of moderate or strong CYP3A4 inducers with EMFLAZA, as they may reduce efficacy (7.1). Moderate or strong CYP3A4 inhibitors: Give one third of the recommended dosage of EMFLAZA (7.1). Avoid use of moderate or strong CYP3A4 inducers with EMFLAZA, as they may reduce efficacy (7.1). 7.1 CYP3A4 Inhibitors and Inducers. Moderate or Strong CYP3A4 InhibitorsThe active metabolite of deflazacort, 21-desDFZ, is substrate of CYP3A4 [see Clinical Pharmacology (12.3)]. Co-administration of deflazacort with clarithromycin, strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold. Therefore, give one third the recommended dosage of EMFLAZA when moderate or strong CYP3A4 inhibitors (e.g., clarithromycin, fluconazole, diltiazem, verapamil, grapefruit juice) are used concomitantly with EMFLAZA [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].Moderate or Strong CYP3A4 InducersCo-administration of deflazacort with rifampin, 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 EMFLAZA [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].. 7.2 Neuromuscular Blockers. Patients receiving corticosteroids, including EMFLAZA, 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)].

GERIATRIC USE SECTION.

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

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. EMFLAZA Tablets6 mg are white, round with 6 debossed on one side. They are supplied as follows:NDC 52856-501-01 Bottle of 100 tablets 18 mg are white, round with 18 debossed on one side. They are supplied as follows:NDC 52856-502-03 Bottle of 30 tablets 30 mg are white, oval with 30 debossed on one side. They are supplied as follows:NDC 52856-503-03 Bottle of 30 tablets 36 mg are white, oval with 36 debossed on one side. They are supplied as follows:NDC 52856-504-03 Bottle of 30 tabletsEMFLAZA Oral Suspension22.75 mg/mL is whitish colored suspension. Supplied as 13 mL in 30 mL bottle packaged with one bottle adapter and two mL oral dispensers.NDC 52856-505-22. mg are white, round with 6 debossed on one side. They are supplied as follows:NDC 52856-501-01 Bottle of 100 tablets 18 mg are white, round with 18 debossed on one side. They are supplied as follows:NDC 52856-502-03 Bottle of 30 tablets 30 mg are white, oval with 30 debossed on one side. They are supplied as follows:NDC 52856-503-03 Bottle of 30 tablets 36 mg are white, oval with 36 debossed on one side. They are supplied as follows:NDC 52856-504-03 Bottle of 30 tablets. 22.75 mg/mL is whitish colored suspension. Supplied as 13 mL in 30 mL bottle packaged with one bottle adapter and two mL oral dispensers.NDC 52856-505-22. 16.2 Storage and Handling. Store at 20C to 25C (68F to 77F). Excursion permitted between 15C to 30C (59F to 86F). See USP controlled room temperature.Discard any unused EMFLAZA Oral Suspension remaining after month of first opening the bottle.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. EMFLAZA is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients years of age and older.. EMFLAZA is corticosteroid indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients years of age and older (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patients and/or caregivers to read the FDA-approved patient labeling if EMFLAZA Oral Suspension is prescribed (Instructions for Use).AdministrationWarn patients and/or caregivers to not stop taking EMFLAZA abruptly or without first checking with their healthcare providers as there may be need for gradual dose reduction to decrease the risk of adrenal insufficiency [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].EMFLAZA may be taken with or without food. Do not take EMFLAZA with grapefruit juice.TabletsEMFLAZA Tablets may be taken whole or crushed and taken immediately after mixing with applesauce.Oral SuspensionEMFLAZA Oral Suspension must be shaken well prior to measuring out each dose with the enclosed oral dispenser.The EMFLAZA 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 EMFLAZA Oral Suspension remaining after month of first opening the bottle.Increased Risk of InfectionTell patients and/or caregivers to inform their healthcare provider if the patient has had recent or ongoing infections or if they have recently received 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 FunctionInform patients and/or caregivers that EMFLAZA 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 DisturbancesAdvise patients and/or caregivers about the potential for severe behavioral and mood changes with EMFLAZA and encourage them to seek medical attention if psychiatric symptoms develop [see Warnings and Precautions (5.5)].Decreases in Bone Mineral DensityAdvise patients and/or caregivers about the risk of osteoporosis with prolonged use of EMFLAZA, which can predispose the patient to vertebral and long bone fractures [see Warnings and Precautions (5.6)].Ophthalmic EffectsInform patients and/or caregivers that EMFLAZA may cause cataracts or glaucoma and advise monitoring if corticosteroid therapy is continued for more than weeks [see Warnings and Precautions (5.7)].VaccinationAdvise patients and/or caregivers to bring immunizations up-to-date according to immunization guidelines prior to starting therapy with EMFLAZA. Live-attenuated or live vaccines should be administered at least to weeks prior to starting EMFLAZA. Inform patients and/or caregivers that they may receive concurrent vaccinations with use of EMFLAZA, except for live-attenuated or live vaccines. [see Warnings and Precautions (5.8)].Serious Skin RashesInstruct patients and/or caregivers to seek medical attention at the first sign of rash [see Warnings and Precautions (5.9)].Drug InteractionsCertain medications can cause an interaction with EMFLAZA. 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.PTC TherapeuticsManufactured for:PTC Therapeutics, Inc.South Plainfield, NJ 07080 U.S.A.EMFLAZA Oral Suspension made in SpainEMFLAZA(R) is trademark of PTC Therapeutics, Inc.. Warn patients and/or caregivers to not stop taking EMFLAZA abruptly or without first checking with their healthcare providers as there may be need for gradual dose reduction to decrease the risk of adrenal insufficiency [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].. EMFLAZA may be taken with or without food. Do not take EMFLAZA with grapefruit juice.. EMFLAZA Tablets may be taken whole or crushed and taken immediately after mixing with applesauce.. EMFLAZA Oral Suspension must be shaken well prior to measuring out each dose with the enclosed oral dispenser.. The EMFLAZA 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 EMFLAZA Oral Suspension remaining after month of first opening the bottle.

INSTRUCTIONS FOR USE SECTION.

Instructions for UseEMFLAZA(TM) (em fla zah)(deflazacort)oral suspensionRead this Instructions for Use before you start using EMFLAZA oral suspension and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.Important information before you use EMFLAZA oral suspension:Only use the oral dispenser (see Figure below) that comes in your EMFLAZA carton when using this medicine.EMFLAZA oral suspension can be taken with or without food.Take your dose of EMFLAZA oral suspension with juice or milk. Do not take EMFLAZA with grapefruit juice.Throw away (discard) any unused EMFLAZA oral suspension after month of first opening the bottle.Do not stop taking EMFLAZA oral suspension without talking to your healthcare provider first.Preparing for your EMFLAZA oral suspension dose:You will need the following supplies: See Figure A.1 EMFLAZA oral suspension bottle1 oral dispenser (2 oral dispensers are included in the EMFLAZA oral suspension carton. is to be used to give (administer) the product and extra oral dispenser is included as spare, if needed.)1 household cup filled with to ounces of juice or milk1 spoonFigure AHow to prepare your dose of EMFLAZA oral suspension:Step 1. Remove the EMFLAZA oral suspension bottle and of the oral dispensers from the carton.Step 2. Make sure the bottle cap is put on tightly and shake well before each use. See Figure B. Figure BStep 3. Remove the cap from the bottle by pushing down firmly on the cap and turning the cap in counter-clockwise direction (to the left). See Figure C. Place the open bottle upright on flat surface.Figure CFirst time use of bottle only:Unwrap the bottle adapter.Place the ribbed end of the bottle adapter in the bottle top.Wrap both hands around the bottle. Press down on the bottle adapter using both thumbs. Push the ribbed end of the bottle adapter firmly into the neck of the bottle until the adapter top is even with the bottle top. See Figure D. Do not remove the bottle adapter from the bottle after it is inserted.Write the date that you first open the bottle on the bottle label.Figure DStep 4. Unwrap the oral dispenser if it is the first time you are using the oral dispenser.Check your dose in milliliters (mL) as prescribed by your healthcare provider. Find this number on the barrel of the oral dispenser. See Figure E. Figure EThe oral dispenser only holds mL of medicine at time. If your dose is more than mL, you will need to repeat Steps through using the same oral dispenser until your entire dose has been drawn from the bottle.Step 5. Push the plunger of the oral dispenser all the way down. Insert the oral dispenser into the bottle adapter. See Figure F. Figure FStep 6. With the oral dispenser in the bottle adapter, carefully turn the bottle upside down. Slowly pull back on the plunger until the widest part of the plunger is at the line marking on the oral dispenser of the number of mL needed for your dose. See Figure G. Do not use the narrow tip on the end of the plunger to measure the dose.If you see air bubbles in the oral suspension, fully push in the plunger so the oral suspension flows back into the bottle. Then withdraw the dose of oral suspension that you need.Figure GStep 7. Leave the oral dispenser in the bottle adapter and turn the bottle to an upright position. Place the bottle onto flat surface. Remove the oral dispenser from the bottle adapter by gently twisting the oral dispenser while pulling it straight up. See Figure H. Figure HStep 8. Slowly push all the way down on the plunger of the oral dispenser to add the EMFLAZA oral suspension dose to household cup filled with to ounces of juice or milk. See Figure I. Figure IStep 9. Stir the EMFLAZA oral suspension and juice or milk with spoon to mix well. See Figure J. Figure JStep 10. Immediately drink the juice or milk that is mixed with EMFLAZA oral suspension.Step 11. Replace the cap tightly on the bottle by turning the cap in clockwise direction (to the right). See Figure K. Figure KStep 12. Wash the oral dispenser after each use. The oral dispenser should be taken apart by pulling back on the plunger and removing it from the barrel of the oral dispenser. See Figure L. Figure LStep 13. After the barrel and plunger are dry, put the oral dispenser back together by pushing the plunger back into the barrel.How should store EMFLAZA oral suspensionStore the bottle upright at room temperature between 68F to 77F (20C to 25C).Throw away (discard) any unused EMFLAZA oral suspension after month of first opening the bottle.What are the ingredients in EMFLAZA oral suspensionActive ingredient: deflazacort Inactive ingredients: acetic acid, aluminum magnesium silicate, benzyl alcohol, carboxymethylcellulose sodium, polysorbate 80, purified water, and sorbitol.Manufactured for: PTC Therapeutics, Inc., South Plainfield, NJ 07080, U.S.A.This Instructions for Use has been approved by the U.S. Food and Drug Administration. EMFLAZA(TM) is trademark of PTC Therapeutics, Inc.Issued: April 2019. Only use the oral dispenser (see Figure below) that comes in your EMFLAZA carton when using this medicine.. EMFLAZA oral suspension can be taken with or without food.. Take your dose of EMFLAZA oral suspension with juice or milk. Do not take EMFLAZA with grapefruit juice.. Throw away (discard) any unused EMFLAZA oral suspension after month of first opening the bottle.. Do not stop taking EMFLAZA oral suspension without talking to your healthcare provider first.. EMFLAZA oral suspension bottle. oral dispenser (2 oral dispensers are included in the EMFLAZA oral suspension carton. is to be used to give (administer) the product and extra oral dispenser is included as spare, if needed.). household cup filled with to ounces of juice or milk. spoon. Store the bottle upright at room temperature between 68F to 77F (20C to 25C).. Throw away (discard) any unused EMFLAZA oral suspension after month of first opening the bottle.. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Figure K. Figure L.

LACTATION SECTION.

8.2 Lactation. Risk SummarySystemically 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 mothers clinical need for EMFLAZA and any potential adverse effects on the breastfed infant from EMFLAZA. There are no data on the effects on milk production.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Deflazacort is 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 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 marked decrease in survival.In 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 mg/kg/day in females) resulted in an increase in stomach tumors (adenoma) at the highest dose tested in males and females.MutagenesisDeflazacort 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 FertilityFertility 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 and times, respectively, that in humans at the recommended human dose of EMFLAZA (0.9 mg/kg/day).

OVERDOSAGE SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL NDC: 52856-501-01 6 mg Tablet 100-Count Bottle Label. NDC 52856-501-01100 TabletsEmflaza(TM)(deflazacort)Tabletsfor oral use6 mgRx Only. mg Tablet 100-Count Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of EMFLAZA for the treatment of DMD have been established in patients years of age and older. Use of EMFLAZA in pediatric patients is supported by multicenter, randomized, double-blind, placebo- and active-controlled study in 196 males to 15 years of age [see Clinical Studies (14)]. Use of EMFLAZA in patients years to less than years of age is supported by the findings of efficacy and safety in patients years and older with DMD.Safety and effectiveness in pediatric patients below the age of years have not been established.EMFLAZA Oral Suspension contains benzyl alcohol and is not approved for use in pediatric patients less than 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 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 EMFLAZA Oral Suspension consider the combined daily metabolic load of benzyl alcohol from all sources including EMFLAZA Oral Suspension (EMFLAZA Oral Suspension contains 10.45 mg of benzyl alcohol per mL; EMFLAZA Tablets do not contain benzyl alcohol) 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 EMFLAZA Oral Suspension, patients would receive approximately 0.4 mg/kg/day of benzyl alcohol [see Warnings and Precautions (5.13)].Juvenile Animal Toxicity DataOral 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). 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 EMFLAZA (0.9 mg/kg/day).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionAfter oral administration in the fasted state, the median Tmax with deflazacort tablets or suspension is about hour (range 0.25 to hours).Food Effect: Co-administration of deflazacort tablets with high-fat meal reduced Cmax by about 30% and delayed Tmax 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.DistributionThe protein binding of the active metabolite of deflazacort is about 40%.EliminationMetabolismDeflazacort 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 6-hydroxy-21-desacetyl deflazacort.ExcretionUrinary 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 PopulationsPediatric PatientsThe Cmax 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 after administration of 0.9 mg/kg deflazacort. The AUCinf (Geometric mean, %CV) of 21-desDFZ in children (ages 4-11, N=16) and adolescents (ages 12-16, N=8) was 400 ngoh/mL (87.5%) and 655 ngoh/mL (58.1%) on Day after administration of 0.9 mg/kg deflazacort.Male and Female PatientsThere are no differences in the pharmacokinetics of 21-desDFZ between males and females.Racial or Ethnic GroupsThere are no differences in the pharmacokinetics of 21-desDFZ between Caucasians and non-Caucasians.Patients with Renal ImpairmentIn 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 ImpairmentIn 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 StudiesIn Vivo Assessment of Drug InteractionsCompared to administration of deflazacort alone, administration of deflazacort following multiple doses of strong CYP3A4 and Pgp inhibitor (clarithromycin) resulted in markedly higher Cmax, AUClast, and AUCinf values of 21-desDFZ. Geometric mean exposure (Cmax, AUClast, and AUCinf) 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 strong CYP3A4 inducer (rifampicin) resulted in markedly lower Cmax, AUClast, and AUCinf values of 21-desDFZ. Geometric mean exposures (Cmax, AUCla st, and AUCinf) of 21-desDFZ were approximately 95% lower following administration of rifampin [see Drug Interactions (7.1)].6-Hydroxy-21-desacetyl deflazacort, secondary and inactive metabolite, is not expected to cause any clinically meaningful interactions with the CYP enzymes or transporters.In Vitro Assessment of Drug InteractionsDrug-Metabolizing Enzyme Inhibition21-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 UGT2B15.6-Hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly inhibit CYP2C19, 3A4 1A2, 2B6, 2C8, 2C9, or 2D6.Drug-Metabolizing Enzyme Induction21-desDFZ and 6-hydroxy-21-desacetyl deflazacort at clinically relevant concentrations did not significantly induce CYP1A2, 2B6, or 3A4.TransportersBoth deflazacort and 21-desDFZ are substrates of Pgp. 21-desDFZ is not substrate for BCRP. Neither deflazacort nor 21-desDFZ inhibited Pgp or BCRP in vitro. 21-desDFZ was not substrate for SLC transporters OATP1B1 or OATP1B3, and did not inhibit SLC transporters OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.6-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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryCorticosteroids 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 EMFLAZA in pregnant women to inform drug-associated risks.Corticosteroids, including EMFLAZA, 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 EMFLAZA, during pregnancy. Some epidemiologic studies report an increased risk of orofacial clefts from about per 1000 infants to to per 1000 infants; however, 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.DataHuman DataMultiple 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.

SPL PATIENT PACKAGE INSERT SECTION.

SPL UNCLASSIFIED SECTION.

2.1 Assessments Prior to First Dose of EMFLAZA. Administer all immunizations according to immunization guidelines prior to starting EMFLAZA. Administer live-attenuated or live vaccines at least to weeks prior to starting EMFLAZA [see Warnings and Precautions (5.8)].

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Store at 20C to 25C (68F to 77F). Excursion permitted between 15C to 30C (59F to 86F). See USP controlled room temperature.Discard any unused EMFLAZA Oral Suspension remaining after month of first opening the bottle.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryCorticosteroids 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 EMFLAZA in pregnant women to inform drug-associated risks.Corticosteroids, including EMFLAZA, 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 EMFLAZA, during pregnancy. Some epidemiologic studies report an increased risk of orofacial clefts from about per 1000 infants to to per 1000 infants; however, 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.DataHuman DataMultiple 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 SummarySystemically 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 mothers clinical need for EMFLAZA and any potential adverse effects on the breastfed infant from EMFLAZA. There are no data on the effects on milk production.. 8.4 Pediatric Use. The safety and effectiveness of EMFLAZA for the treatment of DMD have been established in patients years of age and older. Use of EMFLAZA in pediatric patients is supported by multicenter, randomized, double-blind, placebo- and active-controlled study in 196 males to 15 years of age [see Clinical Studies (14)]. Use of EMFLAZA in patients years to less than years of age is supported by the findings of efficacy and safety in patients years and older with DMD.Safety and effectiveness in pediatric patients below the age of years have not been established.EMFLAZA Oral Suspension contains benzyl alcohol and is not approved for use in pediatric patients less than 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 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 EMFLAZA Oral Suspension consider the combined daily metabolic load of benzyl alcohol from all sources including EMFLAZA Oral Suspension (EMFLAZA Oral Suspension contains 10.45 mg of benzyl alcohol per mL; EMFLAZA Tablets do not contain benzyl alcohol) 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 EMFLAZA Oral Suspension, patients would receive approximately 0.4 mg/kg/day of benzyl alcohol [see Warnings and Precautions (5.13)].Juvenile Animal Toxicity DataOral 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). 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 EMFLAZA (0.9 mg/kg/day).. 8.5 Geriatric Use. DMD is largely disease of children and young adults; therefore, there is no geriatric experience with EMFLAZA.. 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 dosing recommendation cannot be provided for patients with severe hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Alterations in Endocrine Function: Hypothalamic-pituitary-adrenal axis suppression, Cushings syndrome, and hyperglycemia can occur; Monitor patients for these conditions with chronic use of EMFLAZA (2.3, 5.1)Immunosuppression and Increased Risk of Infection: Increased risk of new, exacerbation, dissemination, or reactivation of latent infections, which can be severe and at times fatal; Signs and symptoms of infection may be masked (5.2)Alterations in Cardiovascular/Renal Function: Monitor for elevated blood pressure and sodium, and for decreased potassium levels (5.3)Gastrointestinal Perforation: Increased risk in patients with certain GI disorders; Signs and symptoms may be masked (5.4)Behavioral and Mood Disturbances: May include euphoria, insomnia, mood swings, personality changes, severe depression, and psychosis (5.5)Effects on Bones: Monitor for decreases in bone mineral density with chronic use of EMFLAZA (5.6)Ophthalmic Effects: May include cataracts, infections, and glaucoma; Monitor intraocular pressure if EMFLAZA is continued for more than weeks (5.7)Vaccination: Do not administer live or live attenuated vaccines to patients receiving immunosuppressive doses of corticosteroids. Administer live-attenuated or live vaccines at least to weeks prior to starting EMFLAZA (5.8)Serious Skin Rashes: Discontinue at the first sign of rash, unless the rash is clearly not drug related (5.9). Alterations in Endocrine Function: Hypothalamic-pituitary-adrenal axis suppression, Cushings syndrome, and hyperglycemia can occur; Monitor patients for these conditions with chronic use of EMFLAZA (2.3, 5.1). Immunosuppression and Increased Risk of Infection: Increased risk of new, exacerbation, dissemination, or reactivation of latent infections, which can be severe and at times fatal; Signs and symptoms of infection may be masked (5.2). Alterations in Cardiovascular/Renal Function: Monitor for elevated blood pressure and sodium, and for decreased potassium levels (5.3). Gastrointestinal Perforation: Increased risk in patients with certain GI disorders; Signs and symptoms may be masked (5.4). Behavioral and Mood Disturbances: May include euphoria, insomnia, mood swings, personality changes, severe depression, and psychosis (5.5). Effects on Bones: Monitor for decreases in bone mineral density with chronic use of EMFLAZA (5.6). Ophthalmic Effects: May include cataracts, infections, and glaucoma; Monitor intraocular pressure if EMFLAZA is continued for more than weeks (5.7). Vaccination: Do not administer live or live attenuated vaccines to patients receiving immunosuppressive doses of corticosteroids. Administer live-attenuated or live vaccines at least to weeks prior to starting EMFLAZA (5.8). Serious Skin Rashes: Discontinue at the first sign of rash, unless the rash is clearly not drug related (5.9). 5.1 Alterations in Endocrine Function. Corticosteroids, such as EMFLAZA, can cause serious and life-threatening alterations in endocrine function, especially with chronic use. Monitor patients receiving EMFLAZA for Cushings syndrome, hyperglycemia, and adrenal insufficiency after EMFLAZA withdrawal. In addition, patients with hypopituitarism, primary adrenal insufficiency or congenital adrenal hyperplasia, altered thyroid function, or pheochromocytoma may be at increased risk for adverse endocrine events.Risk of Adrenal Insufficiency Following Corticosteroid WithdrawalCorticosteroids produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, with the potential for the development of secondary adrenal insufficiency after withdrawal of corticosteroid treatment. Acute adrenal insufficiency can occur if corticosteroids are withdrawn abruptly, and can be fatal. The degree and duration of adrenocortical insufficiency produced is variable among patients and depends on the dose, frequency, and duration of corticosteroid therapy. The risk is reduced by gradually tapering the corticosteroid dose when withdrawing treatment. This insufficiency may persist, however, for months after discontinuation of prolonged therapy; therefore, in any situation of stress occurring during that period of discontinuation, corticosteroid therapy should be reinstituted. For patients already taking corticosteroids during times of stress, the dosage may need to be increased.A steroid withdrawal syndrome, seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuance of corticosteroids. This syndrome includes symptoms such as anorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, and/or weight loss. These effects are thought to be due to the sudden change in corticosteroid concentration rather than to low corticosteroid levels.Cushings SyndromeCushings syndrome (hypercortisolism) occurs with prolonged exposure to exogenous corticosteroids, including EMFLAZA. Symptoms include hypertension, truncal obesity and thinning of the limbs, purple striae, facial rounding, facial plethora, muscle weakness, easy and frequent bruising with thin fragile skin, posterior neck fat deposition, osteopenia, acne, amenorrhea, hirsutism and psychiatric abnormalities.HyperglycemiaCorticosteroids can increase blood glucose, worsen pre-existing diabetes, predispose those on long-term therapy to diabetes mellitus, and may reduce the effect of anti-diabetic drugs. Monitor blood glucose at regular intervals. For patients with hyperglycemia, anti-diabetic treatment should be initiated or adjusted accordingly.Considerations for Use in Patients with Altered Thyroid FunctionMetabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate dose adjustment of the corticosteroid. When concomitant administration of corticosteroids and levothyroxine is required, administration of corticosteroid should precede the initiation of levothyroxine therapy to reduce the risk of adrenal crisis.Pheochromocytoma CrisisThere have been reports of pheochromocytoma crisis, which can be fatal, after administration of systemic corticosteroids. In patients with suspected or identified pheochromocytoma, consider the risk of pheochromocytoma crisis prior to administering corticosteroids.. 5.2 Immunosuppression and Increased Risk of Infection. Corticosteroids, including EMFLAZA, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic. Corticosteroids reduce resistance to new infections, exacerbate existing infections, increase the risk of disseminated infections, increase the risk of reactivation or exacerbation of latent infections, and mask some signs of infection. These infections can be severe, and at times fatal. The degree to which the dose, route, and duration of corticosteroid administration correlates with the specific risks of infection is not well characterized; however, the rate of occurrence of infectious complications increases with increasing doses of corticosteroids.Monitor for the development of infection and consider withdrawal of corticosteroids or reduction of the dose of corticosteroids as needed. Varicella Zoster and Measles Viral Infections Chickenpox caused by Varicella Zoster virus and measles can have serious or even fatal course in non-immune children or adults on corticosteroids, including EMFLAZA. In children or adults who have not had these diseases, particular care should be taken to avoid exposure. If patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If patient is exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.Hepatitis Virus ReactivationHepatitis virus reactivation can occur in patients who are hepatitis carriers undergoing treatment with immunosuppressive drugs including corticosteroids. Reactivation can also occur in patients who appear to have resolved hepatitis infection.Fungal InfectionsCorticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections. For patients on corticosteroids who develop systemic fungal infections, withdrawal of corticosteroids or reduction of the dose of corticosteroids is recommended.AmebiasisCorticosteroids may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics, or any patient with unexplained diarrhea.Strongyloides InfestationIn patients with known or suspected Strongyloides (threadworm) infestation, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia. For patients on corticosteroids who develop known or suspected Strongyloides (threadworm) infestation, withdrawal of corticosteroids or reduction of the dose of corticosteroids is recommended.. 5.3 Alterations in Cardiovascular/Renal Function. Corticosteroids, including EMFLAZA, can cause elevation of blood pressure, salt, and water retention, and increased excretion of potassium and calcium. Monitor blood pressure and assess for signs and symptoms of volume overload. Monitor serum potassium levels. Dietary salt restriction and potassium supplementation may be necessary. EMFLAZA should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.Literature reports suggest an association between use of corticosteroids and left ventricular free wall rupture after recent myocardial infarction; therefore, therapy with EMFLAZA should be used with great caution in these patients.. 5.4 Gastrointestinal Perforation. There is an increased risk of gastrointestinal perforation during corticosteroid use in patients with certain gastrointestinal disorders such as active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and non-specific ulcerative colitis. Signs of gastrointestinal perforation, such as peritoneal irritation, may be masked in patients receiving corticosteroids.Avoid corticosteroids if there is probability of impending perforation, abscess, or other pyogenic infections; diverticulitis; fresh intestinal anastomoses; or active or latent peptic ulcer.. 5.5 Behavioral and Mood Disturbances. Potentially severe psychiatric adverse reactions may occur with systemic corticosteroids, including EMFLAZA. Symptoms typically emerge within few days or weeks of starting treatment and may be dose-related. These reactions may improve after either dose reduction or withdrawal, although pharmacologic treatment may be necessary. Psychiatric adverse reactions usually involve hypomanic or manic symptoms (e.g., euphoria, insomnia, mood swings) during treatment and depressive episodes after discontinuation of treatment. Inform patients or caregivers of the potential for behavioral and mood changes and encourage them to seek medical attention if psychiatric symptoms develop, especially if depressed mood or suicidal ideation is suspected.. 5.6 Effects on Bones. Decreased Bone Mineral DensityCorticosteroids, including EMFLAZA, decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with decrease in the protein matrix of the bone secondary to an increase in protein catabolism and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of bone loss at any age. Bone loss can predispose patients to vertebral and long bone fractures. Consider patients risk of osteoporosis before initiating corticosteroid therapy. Monitor bone mineral density in patients on long-term treatment with EMFLAZA.Avascular NecrosisCorticosteroids, including EMFLAZA, may cause avascular necrosis.. 5.7 Ophthalmic Effects. Use of corticosteroids, including EMFLAZA, may produce posterior subcapsular cataracts. Corticosteroids may also cause glaucoma with possible damage to the optic nerves, and may increase the risk of secondary ocular infections caused by bacteria, fungi, or viruses. Corticosteroids are not recommended for patients with active ocular herpes simplex.Intraocular pressure may become elevated in some patients taking corticosteroids. If treatment with EMFLAZA is continued for more than weeks, monitor intraocular pressure.. 5.8 Immunizations. Administer all immunizations according to immunization guidelines prior to starting EMFLAZA. Administer live-attenuated or live vaccines at least to weeks prior to starting EMFLAZA. Patients on EMFLAZA may receive concurrent vaccinations, except for live-attenuated or live vaccines.. 5.9 Serious Skin Rashes. Toxic epidermal necrolysis has been reported with the use of deflazacort with symptoms beginning within weeks of starting treatment. Discontinue at the first sign of rash, unless the rash is clearly not drug related.. 5.10 Effects on Growth and Development. Long-term use of corticosteroids, including EMFLAZA, can have negative effects on growth and development in children.. 5.11 Myopathy. Patients receiving corticosteroids, including EMFLAZA, and concomitant therapy with neuromuscular blocking agents (e.g., pancuronium) or patients with disorders of neuromuscular transmission (e.g., myasthenia gravis) may be at increased risk of developing acute myopathy. This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.. 5.12 Kaposis Sarcoma. Kaposis sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.. 5.13 Risk of Serious Adverse Reactions in Infants because of Benzyl Alcohol Preservative. EMFLAZA Oral Suspension contains benzyl alcohol and is not approved for use in pediatric patients less than years of age. Serious and fatal adverse reactions including gasping syndrome can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including EMFLAZA. The gasping syndrome is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing EMFLAZA Oral Suspension, consider the combined daily metabolic load of benzyl alcohol from all sources, including EMFLAZA Oral Suspension (EMFLAZA Oral Suspension contains 10.45 mg of benzyl alcohol per mL; EMFLAZA Tablets do not contain benzyl alcohol) 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 EMFLAZA Oral Suspension, patients would receive approximately 0.4 mg/kg/day of benzyl alcohol [see Use in Specific Populations (8.4)].. 5.14 Thromboembolic Events. Observational studies have shown an increased risk of thromboembolism (including venous thromboembolism) particularly with higher cumulative doses of corticosteroids. It is unclear if risk differs by daily dose or duration of use. Use EMFLAZA with caution in patients who have or may be predisposed to thromboembolic disorders.. 5.15 Anaphylaxis. Rare instances of anaphylaxis have occurred in patients receiving corticosteroid therapy, including EMFLAZA.