Highlights Of Prescribing Information

CYP3A4 Inhibitors

Give one third of the recommended dosage when KYMBEE is administered with moderate or strong CYP3A4 inhibitors. For example, a 36 mg per day dose would be reduced to a 12 mg per day dose when used with moderate or strong CYP3A4 inhibitors [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)].

Warnings and Precautions

Immunosuppression and Increased Risk of Infection (5.2) 6/2024

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

Patients receiving corticosteroids, including KYMBEE, 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.

The active ingredient in KYMBEE is deflazacort (a corticosteroid). Corticosteroids are adrenocortical steroids, both naturally occurring and synthetic. The molecular formula for deflazacort is C ₂₅H ₃₁NO ₆. The chemical name for deflazacort is (11β,16β)-21-(acetyloxy)-11-hydroxy-2'-methyl-5'H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione, and the structure is:

Deflazacort is a white to off white, odorless fine powder and has a molecular weight of 441.517. Deflazacort is freely soluble in acetic acid and dichloromethane and soluble in methanol and acetone.

KYMBEE for oral administration is available as an immediate-release tablet in strengths of 6, 18, 30 and 36 mg. Each tablet contains deflazacort and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, and pre-gelatinized starch.

Rare instances of anaphylaxis have occurred in patients receiving corticosteroid therapy, including KYMBEE.

KYMBEE^TM Tablets

• 6 mg are white, round tablets with "U6" debossed on one side. They are supplied as follows:
  • Bottles of 100 with a child-resistant closure, NDC 0245-0814-11
• 18 mg are white, round tablets with "U18" debossed on one side. They are supplied as follows:
  • Bottles of 30 with a child-resistant closure, NDC 0245-0815-30
• 30 mg are white, oval tablets with "U30" debossed on one side. They are supplied as follows:
  • Bottles of 30 with a child-resistant closure, NDC 0245-0816-30
• 36 mg are white, oval tablets with "U36" debossed on one side. They are supplied as follows:
  • Bottles of 30 with a child-resistant closure, NDC 0245-0817-30

Administer all immunizations according to immunization guidelines prior to starting KYMBEE. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting KYMBEE. Patients on KYMBEE may receive concurrent vaccinations, except for live-attenuated or live vaccines.

The safety and effectiveness of KYMBEE for the treatment of DMD have been established in patients 5 years of age and older. Use of KYMBEE 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.

DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with KYMBEE.

The effectiveness of KYMBEE 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).

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 KYMBEE 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.

Dosage of KYMBEE must be decreased gradually if the drug has been administered for more than a few days [see Warnings and Precautions (5.1)].

KYMBEE 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)].

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)]

• Moderate or strong CYP3A4 inhibitors: Give one third of the recommended dosage of KYMBEE (7.1)
• Avoid use of moderate or strong CYP3A4 inducers with KYMBEE, as they may reduce efficacy (7.1)

Additional pediatric use information is approved for PTC Therapeutics, Inc.'s Emflaza^® (deflazacort) tablets. However, due to PTC Therapeutics, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

No dose adjustment is required in patients with mild, moderate or severe renal impairment [see Clinical Pharmacology (12.3)].

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma.

The recommended oral dosage of KYMBEE 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 KYMBEE tablet strengths can be used to achieve this dose.

Use of corticosteroids, including KYMBEE, 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 KYMBEE is continued for more than 6 weeks, monitor intraocular pressure.

No dose adjustment is required in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3)]. There is no clinical experience in patients with severe hepatic impairment, and a dosing recommendation cannot be provided for patients with severe hepatic impairment.

KYMBEE is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older.

Additional pediatric use information is approved for PTC Therapeutics, Inc.'s Emflaza^® (deflazacort) tablets. However, due to PTC Therapeutics, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Toxic epidermal necrolysis has been reported with the use of deflazacort with symptoms beginning within 8 weeks of starting treatment. Discontinue at the first sign of rash, unless the rash is clearly not drug related.

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.

Store at 20° to 25°C (68° to 77°F); excursion permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

• Alterations in Endocrine Function:Hypothalamic-pituitary-adrenal axis suppression, Cushing's syndrome, and hyperglycemia can occur; Monitor patients for these conditions with chronic use of KYMBEE (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 KYMBEE (5.6)
• Ophthalmic Effects: May include cataracts, infections, and glaucoma; Monitor intraocular pressure if KYMBEE is continued for more than 6 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 4 to 6 weeks prior to starting KYMBEE (5.8)
• Serious Skin Rashes: Discontinue at the first sign of rash, unless the rash is clearly not drug related (5.9)

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 KYMBEE with caution in patients who have or may be predisposed to thromboembolic disorders.

Patients receiving corticosteroids, including KYMBEE, 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)].

• 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)

• 6 mg: White and round tablet with "U6" debossed on one side
• 18 mg: White and round tablet with "U18" debossed on one side
• 30 mg: White and oval tablet with "U30" debossed on one side
• 36 mg: White and oval tablet with "U36" debossed on one side

The following adverse reactions have been reported during post-approval use of deflazacort worldwide or during post-approval use of other corticosteroids. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Leukocytosis

Cardiac Disorder: Heart failure

Eye Disorders: Chorioretinopathy, corneal or scleral thinning

Gastrointestinal Disorders: Acute pancreatitis (especially in children), hemorrhage, peptic ulceration, perforation of peptic ulcer

General Disorders and Administration Site Conditions: Edema, impaired healing

Immune System Disorders: Hypersensitivity including anaphylaxis

Metabolism and Nutrition Disorders: Impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy, negative protein and calcium balance, potassium loss and hypokalemic alkalosis when co-administered with beta 2-agonist and xanthines

Musculoskeletal and Connective Tissue Disorders: Avascular necrosis, muscle wasting, negative nitrogen balance, tendonitis and tendon rupture when co-administered with quinolones, vertebral and long bone fractures

Nervous System Disorders: Aggravation of epilepsy, increased intra-cranial pressure with papilledema in children (pseudotumor cerebri) usually after treatment withdrawal, vertigo

Psychiatric Disorders: Anxiety, cognitive dysfunction including confusion and amnesia, delusions, hallucinations, mania, suicidal thoughts

Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis

Vascular Disorders: Thromboembolism, in particular in patients with underlying conditions associated with increased thrombotic tendency, benign intracranial hypertension

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In Study 1 [see Clinical Studies (14)], the adverse reactions that were associated with deflazacort treatment discontinuation, in decreasing order of frequency, were weight increased, obesity, cataract, and sleep disorder.

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 a probability of impending perforation, abscess, or other pyogenic infections; diverticulitis; fresh intestinal anastomoses; or active or latent peptic ulcer.

Potentially severe psychiatric adverse reactions may occur with systemic corticosteroids, including KYMBEE. Symptoms typically emerge within a 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.

Corticosteroids, such as KYMBEE, can cause serious and life-threatening alterations in endocrine function, especially with chronic use. Monitor patients receiving KYMBEE for Cushing’s syndrome, hyperglycemia, and adrenal insufficiency after KYMBEE 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.

Long-term use of corticosteroids, including KYMBEE, can have negative effects on growth and development in children.

Administer all immunizations according to immunization guidelines prior to starting KYMBEE. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting KYMBEE [see Warnings and Precautions (5.8)].

Corticosteroids, including KYMBEE, 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. KYMBEE 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 a recent myocardial infarction; therefore, therapy with KYMBEE should be used with great caution in these patients.

NDC 0245-0814-11

KYMBEE Tablets

6 mg

for Oral Use

100 Tablets

Rx only

UPSHER-SMITH

NDC 0245-0815-30

KYMBEE Tablets

18 mg

for Oral Use

30 Tablets

Rx only

UPSHER-SMITH

NDC 0245-0816-30

KYMBEE Tablets

30 mg

for Oral Use

30 Tablets

Rx only

UPSHER-SMITH

NDC 0245-0817-30

KYMBEE Tablets

36 mg

for Oral Use

30 Tablets

Rx only

UPSHER-SMITH

Corticosteroids, including KYMBEE, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can:

• Reduce resistance to new infections
• Exacerbate existing infections
• Increase the risk of disseminated infections
• Increase the risk of reactivation or exacerbation of latent infections
• Mask some signs of infections

Corticosteroid-associated infections can be mild but can be severe, and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages.

Monitor for the development of infection and consider deflazacort withdrawal or dosage reduction as needed.

Tuberculosis

If KYMBEE is used to treat a condition in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation. During prolonged deflazacort therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis.

Varicella Zoster and Measles Viral Infections

Varicella and measles can have a serious or even fatal course in non-immune patients taking corticosteroids, including KYMBEE. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles.

• If a KYMBEE-treated patient is exposed to varicella, prophylaxis with varicella zoster immunoglobulin may be indicated. If varicella develops, treatment with antiviral agents may be considered.
• If a KYMBEE-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated.

Hepatitis B Virus Reactivation

Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including KYMBEE. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection.

Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with KYMBEE. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy.

Fungal Infections

Corticosteroids, including KYMBEE, may exacerbate systemic fungal infections; therefore, avoid KYMBEE use in the presence of such infections unless KYMBEE is needed to control drug reactions. For patients on chronic KYMBEE therapy who develop systemic fungal infections, KYMBEE withdrawal or dose reduction is recommended.

Amebiasis

Corticosteroids, including KYMBEE, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating KYMBEE in patients who have spent time in the tropics or patients with unexplained diarrhea.

Strongyloides Infestation

Corticosteroids, including KYMBEE, should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, 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.

Cerebral Malaria

Avoid corticosteroids, including KYMBEE, in patients with cerebral malaria.

KYMBEE can be taken with or without food. Do not administer KYMBEE with grapefruit juice [see Drug Interactions (7.1)].

KYMBEE tablets can be administered whole or crushed and taken immediately after mixing with applesauce.

CYP3A4 Inhibitors

Give one third of the recommended dosage when KYMBEE is administered with moderate or strong CYP3A4 inhibitors. For example, a 36 mg per day dose would be reduced to a 12 mg per day dose when used with moderate or strong CYP3A4 inhibitors [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)].

Warnings and Precautions

Immunosuppression and Increased Risk of Infection (5.2) 6/2024

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

Patients receiving corticosteroids, including KYMBEE, 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.

The active ingredient in KYMBEE is deflazacort (a corticosteroid). Corticosteroids are adrenocortical steroids, both naturally occurring and synthetic. The molecular formula for deflazacort is C ₂₅H ₃₁NO ₆. The chemical name for deflazacort is (11β,16β)-21-(acetyloxy)-11-hydroxy-2'-methyl-5'H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione, and the structure is:

Deflazacort is a white to off white, odorless fine powder and has a molecular weight of 441.517. Deflazacort is freely soluble in acetic acid and dichloromethane and soluble in methanol and acetone.

KYMBEE for oral administration is available as an immediate-release tablet in strengths of 6, 18, 30 and 36 mg. Each tablet contains deflazacort and the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, and pre-gelatinized starch.

Rare instances of anaphylaxis have occurred in patients receiving corticosteroid therapy, including KYMBEE.

KYMBEE^TM Tablets

• 6 mg are white, round tablets with "U6" debossed on one side. They are supplied as follows:
  • Bottles of 100 with a child-resistant closure, NDC 0245-0814-11
• 18 mg are white, round tablets with "U18" debossed on one side. They are supplied as follows:
  • Bottles of 30 with a child-resistant closure, NDC 0245-0815-30
• 30 mg are white, oval tablets with "U30" debossed on one side. They are supplied as follows:
  • Bottles of 30 with a child-resistant closure, NDC 0245-0816-30
• 36 mg are white, oval tablets with "U36" debossed on one side. They are supplied as follows:
  • Bottles of 30 with a child-resistant closure, NDC 0245-0817-30

Administer all immunizations according to immunization guidelines prior to starting KYMBEE. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting KYMBEE. Patients on KYMBEE may receive concurrent vaccinations, except for live-attenuated or live vaccines.

The safety and effectiveness of KYMBEE for the treatment of DMD have been established in patients 5 years of age and older. Use of KYMBEE 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.

DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with KYMBEE.

The effectiveness of KYMBEE 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).

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 KYMBEE 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.

Dosage of KYMBEE must be decreased gradually if the drug has been administered for more than a few days [see Warnings and Precautions (5.1)].

KYMBEE 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)].

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)]

• Moderate or strong CYP3A4 inhibitors: Give one third of the recommended dosage of KYMBEE (7.1)
• Avoid use of moderate or strong CYP3A4 inducers with KYMBEE, as they may reduce efficacy (7.1)

Additional pediatric use information is approved for PTC Therapeutics, Inc.'s Emflaza^® (deflazacort) tablets. However, due to PTC Therapeutics, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

No dose adjustment is required in patients with mild, moderate or severe renal impairment [see Clinical Pharmacology (12.3)].

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma.

The recommended oral dosage of KYMBEE 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 KYMBEE tablet strengths can be used to achieve this dose.

Use of corticosteroids, including KYMBEE, 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 KYMBEE is continued for more than 6 weeks, monitor intraocular pressure.

No dose adjustment is required in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3)]. There is no clinical experience in patients with severe hepatic impairment, and a dosing recommendation cannot be provided for patients with severe hepatic impairment.

KYMBEE is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 5 years of age and older.

Additional pediatric use information is approved for PTC Therapeutics, Inc.'s Emflaza^® (deflazacort) tablets. However, due to PTC Therapeutics, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Toxic epidermal necrolysis has been reported with the use of deflazacort with symptoms beginning within 8 weeks of starting treatment. Discontinue at the first sign of rash, unless the rash is clearly not drug related.

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.

Store at 20° to 25°C (68° to 77°F); excursion permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

• Alterations in Endocrine Function:Hypothalamic-pituitary-adrenal axis suppression, Cushing's syndrome, and hyperglycemia can occur; Monitor patients for these conditions with chronic use of KYMBEE (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 KYMBEE (5.6)
• Ophthalmic Effects: May include cataracts, infections, and glaucoma; Monitor intraocular pressure if KYMBEE is continued for more than 6 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 4 to 6 weeks prior to starting KYMBEE (5.8)
• Serious Skin Rashes: Discontinue at the first sign of rash, unless the rash is clearly not drug related (5.9)

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 KYMBEE with caution in patients who have or may be predisposed to thromboembolic disorders.

Patients receiving corticosteroids, including KYMBEE, 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)].

• 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)

• 6 mg: White and round tablet with "U6" debossed on one side
• 18 mg: White and round tablet with "U18" debossed on one side
• 30 mg: White and oval tablet with "U30" debossed on one side
• 36 mg: White and oval tablet with "U36" debossed on one side

The following adverse reactions have been reported during post-approval use of deflazacort worldwide or during post-approval use of other corticosteroids. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: Leukocytosis

Cardiac Disorder: Heart failure

Eye Disorders: Chorioretinopathy, corneal or scleral thinning

Gastrointestinal Disorders: Acute pancreatitis (especially in children), hemorrhage, peptic ulceration, perforation of peptic ulcer

General Disorders and Administration Site Conditions: Edema, impaired healing

Immune System Disorders: Hypersensitivity including anaphylaxis

Metabolism and Nutrition Disorders: Impaired carbohydrate tolerance with increased requirement for anti-diabetic therapy, negative protein and calcium balance, potassium loss and hypokalemic alkalosis when co-administered with beta 2-agonist and xanthines

Musculoskeletal and Connective Tissue Disorders: Avascular necrosis, muscle wasting, negative nitrogen balance, tendonitis and tendon rupture when co-administered with quinolones, vertebral and long bone fractures

Nervous System Disorders: Aggravation of epilepsy, increased intra-cranial pressure with papilledema in children (pseudotumor cerebri) usually after treatment withdrawal, vertigo

Psychiatric Disorders: Anxiety, cognitive dysfunction including confusion and amnesia, delusions, hallucinations, mania, suicidal thoughts

Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis

Vascular Disorders: Thromboembolism, in particular in patients with underlying conditions associated with increased thrombotic tendency, benign intracranial hypertension

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In Study 1 [see Clinical Studies (14)], the adverse reactions that were associated with deflazacort treatment discontinuation, in decreasing order of frequency, were weight increased, obesity, cataract, and sleep disorder.

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 a probability of impending perforation, abscess, or other pyogenic infections; diverticulitis; fresh intestinal anastomoses; or active or latent peptic ulcer.

Potentially severe psychiatric adverse reactions may occur with systemic corticosteroids, including KYMBEE. Symptoms typically emerge within a 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.

Corticosteroids, such as KYMBEE, can cause serious and life-threatening alterations in endocrine function, especially with chronic use. Monitor patients receiving KYMBEE for Cushing’s syndrome, hyperglycemia, and adrenal insufficiency after KYMBEE 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.

Long-term use of corticosteroids, including KYMBEE, can have negative effects on growth and development in children.

Administer all immunizations according to immunization guidelines prior to starting KYMBEE. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting KYMBEE [see Warnings and Precautions (5.8)].

Corticosteroids, including KYMBEE, 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. KYMBEE 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 a recent myocardial infarction; therefore, therapy with KYMBEE should be used with great caution in these patients.

NDC 0245-0814-11

KYMBEE Tablets

6 mg

for Oral Use

100 Tablets

Rx only

UPSHER-SMITH

NDC 0245-0815-30

KYMBEE Tablets

18 mg

for Oral Use

30 Tablets

Rx only

UPSHER-SMITH

NDC 0245-0816-30

KYMBEE Tablets

30 mg

for Oral Use

30 Tablets

Rx only

UPSHER-SMITH

NDC 0245-0817-30

KYMBEE Tablets

36 mg

for Oral Use

30 Tablets

Rx only

UPSHER-SMITH

Corticosteroids, including KYMBEE, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can:

• Reduce resistance to new infections
• Exacerbate existing infections
• Increase the risk of disseminated infections
• Increase the risk of reactivation or exacerbation of latent infections
• Mask some signs of infections

Corticosteroid-associated infections can be mild but can be severe, and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages.

Monitor for the development of infection and consider deflazacort withdrawal or dosage reduction as needed.

Tuberculosis

If KYMBEE is used to treat a condition in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation. During prolonged deflazacort therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis.

Varicella Zoster and Measles Viral Infections

Varicella and measles can have a serious or even fatal course in non-immune patients taking corticosteroids, including KYMBEE. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles.

• If a KYMBEE-treated patient is exposed to varicella, prophylaxis with varicella zoster immunoglobulin may be indicated. If varicella develops, treatment with antiviral agents may be considered.
• If a KYMBEE-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated.

Hepatitis B Virus Reactivation

Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including KYMBEE. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection.

Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with KYMBEE. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy.

Fungal Infections

Corticosteroids, including KYMBEE, may exacerbate systemic fungal infections; therefore, avoid KYMBEE use in the presence of such infections unless KYMBEE is needed to control drug reactions. For patients on chronic KYMBEE therapy who develop systemic fungal infections, KYMBEE withdrawal or dose reduction is recommended.

Amebiasis

Corticosteroids, including KYMBEE, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating KYMBEE in patients who have spent time in the tropics or patients with unexplained diarrhea.

Strongyloides Infestation

Corticosteroids, including KYMBEE, should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, 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.

Cerebral Malaria

Avoid corticosteroids, including KYMBEE, in patients with cerebral malaria.

KYMBEE can be taken with or without food. Do not administer KYMBEE with grapefruit juice [see Drug Interactions (7.1)].

KYMBEE tablets can be administered whole or crushed and taken immediately after mixing with applesauce.