DEFLAZACORT- deflazacort_tablet

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. Absorption After oral administration in the fasted state, the median T max Food Effect: max max 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 6beta-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 inf 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 last inf max last inf [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 last inf max last inf [see Drug Interactions (7. 1) 6beta-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. 6beta-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 6beta-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 6beta-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.

Deflazacort tablets are indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older. Additional pediatric use information is approved for PTC Therapeutics, Inc. 's Emflaza registered Deflazacort tablets are a corticosteroid indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older ( 1.

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 Administer all immunizations according to immunization guidelines prior to starting deflazacort. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting deflazacort [see Warnings and Precautions (5. 8) The recommended oral dosage of deflazacort 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 deflazacort tablet strengths can be used to achieve this dose. Dosage of deflazacort must be decreased gradually if the drug has been administered for more than a few days [see Warnings and Precautions (5. 1) Deflazacort can be taken with or without food. Do not administer deflazacort with grapefruit juice [see Drug Interactions (7. 1) Deflazacort tablets can be administered whole or crushed and taken immediately after mixing with applesauce. CYP3A4 Inhibitors Give one third of the recommended dosage when deflazacort 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) Clinical Pharmacology (12. 3) CYP3A4 Inducers Avoid use with moderate or strong CYP3A4 inducers with deflazacort [see Drug Interactions (7.

The following serious adverse reactions are discussed in more detail in other sections: Alterations in Endocrine Function [see Warnings and Precautions (5. 1) Immunosuppression and Increased Risk of Infection [see Warnings and Precautions (5. 2) Alterations in Cardiovascular/Renal Function [see Warnings and Precautions (5. 3) Gastrointestinal Perforation [see Warnings and Precautions (5. 4) Behavioral and Mood Disturbances [see Warnings and Precautions (5. 5) Effects on Bones [see Warnings and Precautions (5. 6) Ophthalmic Effects [see Warnings and Precautions (5. 7) Immunizations [see Warnings and Precautions (5. 8) Serious Skin Rashes [see Warnings and Precautions (5. 9) Effects on Growth and Development [see Warnings and Precautions (5. 10) Myopathy [see Warnings and Precautions (5. 11) Kaposi's Sarcoma [see Warnings and Precautions (5. 12) Thromboembolic Events [see Warnings and Precautions (5. 14) Anaphylaxis [see Warnings and Precautions (5. 15) The most common adverse reactions (>= 10% for deflazacort and greater than placebo) are Cushingoid appearance, weight increased, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, and nasopharyngitis ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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) 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 Placebo At 12 weeks placebo patients were re-randomized to receive either deflazacort or an active comparator. Cushingoid appearance 33 12 Weight increased 20 6 Increased appetite 14 2 Upper respiratory tract infection 12 10 Cough 12 6 Pollakiuria 12 2 Nasopharyngitis 10 6 Hirsutism 10 2 Central obesity 10 4 Erythema 8 6 Irritability 8 4 Rhinorrhea 8 0 Abdominal discomfort 6 2 Common adverse reactions (>= 5% of deflazacort-treated patients) that occurred over 52 weeks of exposure to deflazacort 0. 9 mg/kg/day in Study 1 and at a higher rate than deflazacort 0. 9 mg/kg/day in the 12-week placebo-controlled phase of the trial include Cushingoid appearance (60%), hirsutism (35%), weight increased (28%), erythema (28%), central obesity (25%), abdominal pain/abdominal pain upper (18% combined), pollakiuria (15%), constipation (10%), irritability (10%), abnormal behavior (9%), pyrexia (9%), back pain (7%), rash (7%), contusion (6%), nausea (6%), psychomotor hyperactivity (6%), epistaxis (6%), and skin striae (6%). Study 1 also evaluated a higher dosage of deflazacort (1. 2 mg/kg/day). Compared with the 0. 9 mg/kg/day dosage, deflazacort 1. 2 mg/kg/day over 52 weeks was associated with a higher incidence of certain adverse reactions, including Cushingoid appearance (69%), erythema (49%), hirsutism (37%), headache (34%), weight increased (32%), constipation (15%), abdominal pain upper (14%), skin striae (11%), acne (11%), and abdominal discomfort (8%). As there was no additional benefit with the 1. 2 mg/kg/day dose of deflazacort, use of deflazacort 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: Gastrointestinal Disorders: General Disorders and Administration Site Conditions: Infections: Injury, Poisoning and Procedural Complications: Investigations: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Psychiatric Disorders: Renal and Urinary Disorders: Reproductive System and Breast Disorders: Respiratory, Thoracic, and Mediastinal Disorders: Skin and Subcutaneous Tissue Disorders: Vascular Disorders: 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: Cardiac Disorder: Eye Disorders: Gastrointestinal Disorders: General Disorders and Administration Site Conditions: Immune System Disorders: Metabolism and Nutrition Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Psychiatric Disorders: Skin and Subcutaneous Tissue Disorders: Vascular Disorders:.

Deflazacort 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) Adverse Reactions (6. 2) Hypersensitivity to deflazacort or any of the inactive ingredients in deflazacort tablets ( 4.

Risk Summary Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. There are no adequate and well-controlled studies with deflazacort in pregnant women to inform drug-associated risks. Corticosteroids, including deflazacort, readily cross the placenta. Adverse developmental outcomes, including orofacial clefts (cleft lip, with or without cleft palate) and intrauterine growth restriction, and decreased birth weight, have been reported with maternal use of corticosteroids, including deflazacort, during pregnancy. Some epidemiologic studies report an increased risk of orofacial clefts from about 1 per 1,000 infants to 3 to 5 per 1,000 infants; however, a risk for orofacial clefts has not been observed in all studies. Intrauterine growth restriction and decreased birth weight appear to be dose-related; however, the underlying maternal condition may also contribute to these risks (see Data Animal reproduction studies have not been conducted with deflazacort. Animal reproduction studies conducted with other corticosteroids in pregnant mice, rats, hamsters, and rabbits using clinically relevant doses have shown an increased incidence of cleft palate. An increase in embryofetal death, intrauterine growth retardation, and constriction of the ductus arteriosus were observed in some animal species. Data Human Data Multiple cohort and case-controlled studies in humans suggest that maternal corticosteroid use during the first trimester increases the rate of cleft lip, with or without cleft palate, from about 1/1,000 infants to 3 to 5/1,000 infants. Two prospective case-controlled studies showed decreased birth weight in infants exposed to maternal corticosteroids in utero Risk Summary Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for deflazacort and any potential adverse effects on the breastfed infant from deflazacort. There are no data on the effects on milk production. The safety and effectiveness of deflazacort for the treatment of DMD have been established in patients 5 years of age and older. Use of deflazacort in pediatric patients is supported by a multicenter, randomized, double-blind, placebo- and active-controlled study in 196 males 5 to 15 years of age [see Clinical Studies (14) Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Juvenile Animal Toxicity Data Oral administration of deflazacort (0, 0. 0 mg/kg/day) to juvenile rats from postnatal day (PND) 21 to 80 resulted in decreased body weight gain and adverse effects on skeletal development (including decreased cellularity of growth plate and altered bone distribution) and on lymphoid tissue (decreased cellularity). A no-effect dose was not identified. In addition, neurological and neurobehavioral abnormalities were observed at the mid and/or high dose. Plasma 21-desDFZ exposure (AUC) at the lowest dose tested (0. 1 mg/kg/day) was lower than that in humans at the recommended human dose of deflazacort (0. 9 mg/kg/day). Additional pediatric use information is approved for PTC Therapeutics, Inc. 's Emflaza registered DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with deflazacort. No dose adjustment is required in patients with mild, moderate or severe renal impairment [see Clinical Pharmacology (12. 3) No dose adjustment is required in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.

Moderate or strong CYP3A4 inhibitors: Give one third of the recommended dosage of deflazacort ( 7. 1 Avoid use of moderate or strong CYP3A4 inducers with deflazacort, as they may reduce efficacy ( 7. 1 Additional pediatric use information is approved for PTC Therapeutics, Inc. 's Emflaza registered Moderate or Strong CYP3A4 Inhibitors The active metabolite of deflazacort, 21-desDFZ, is a substrate of CYP3A4 [see Clinical Pharmacology (12. 3) [see Dosage and Administration (2. 5) 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. , efavirenz) or moderate (e. , carbamazepine, phenytoin) CYP3A4 inducers with deflazacort [see Dosage and Administration (2. 3) Patients receiving corticosteroids, including deflazacort, and concomitant therapy with neuromuscular blocking drugs (e. , pancuronium) may be at increased risk of developing an acute myopathy [see Warnings and Precautions (5.

OVERDOSAGE
Treatment of acute overdosage is by immediate gastric lavage or emesis followed by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of deflazacort may be reduced temporarily, or alternate day treatment may be introduced.
NONCLINICAL TOXICOLOGY
Carcinogenesis In a published 2-year carcinogenicity study in rats, oral administration of deflazacort (0, 0. 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 in vivo 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 mg/kg/day) for 39 weeks or rats (0, 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 (0. 9 mg/kg/day).
CLINICAL STUDIES
The effectiveness of deflazacort 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 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 to 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.

Upsher-Smith Laboratories, LLC

DEFLAZACORT- deflazacort_tablet Product manual source documgent