2.1 Assessments Prior to First Dose of AGAMREE

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

2.2 Dosing Information

The recommended dosage of AGAMREE is 6 mg/kg taken orally once daily preferably with a meal, up to a maximum daily dosage of 300 mg for patients weighing more than 50 kg.

Some patients may respond to a dose of 2 mg/kg daily. Doses may be titrated down to 2 mg/kg/day as needed, based on individual tolerability.

2.3 Recommended Dosage for Hepatic Impairment

The recommended dosage of AGAMREE in patients with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment is 2 mg/kg taken orally once daily preferably with a meal, up to a maximum daily dosage of 100 mg for patients weighing more than 50 kg [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Doses may be titrated down based on individual tolerability.

2.4 Important Preparation and Administration Instructions

Shake AGAMREE oral suspension well for about 30 seconds before administration.

Use only the oral syringe provided with the product. After withdrawing the appropriate dose into the oral syringe, dispense directly into the mouth.

Discard any unused AGAMREE oral suspension remaining after 3 months of first opening the bottle.

2.5 Switching from Corticosteroid Treatment to AGAMREE

Patients can be switched from oral corticosteroid treatment (such as prednisone or deflazacort) to AGAMREE without treatment interruption or period of prior corticosteroid dosage reduction to minimize the risk for adrenal insufficiency.

Patients switching after long-term treatment with oral corticosteroids should start AGAMREE at a dosage of 6 mg/kg/day.

2.6 Dosage Modification for Use with Strong CYP3A4 Inhibitors

The recommended dosage of AGAMREE when administered with strong CYP3A4 inhibitors is 4 mg/kg taken orally once daily preferably with a meal, up to a maximum daily dosage of 200 mg for patients weighing more than 50 kg [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Doses may be titrated down based on individual tolerability.

2.7 Discontinuation

Dosage of AGAMREE must be decreased gradually if the drug has been administered for more than one week [see Warnings and Precautions (5.1)].

5.1 Alterations in Endocrine Function

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

5.2 Immunosuppression and Increased Risk of Infection

Corticosteroids, including AGAMREE, 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 infection

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 AGAMREE withdrawal or dosage reduction as needed.

5.3 Alterations in Cardiovascular/Renal Function

Corticosteroids, including AGAMREE, 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.

AGAMREE 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 free wall rupture after a recent myocardial infarction; therefore, therapy with AGAMREE should be used with great caution in these patients.

5.4 Gastrointestinal Perforation

There is an increased risk of gastrointestinal perforation with use of corticosteroids 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 AGAMREE if there is a 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 AGAMREE. 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.

In Study 1, psychiatric adverse reactions were reported in 21% of patients on AGAMREE 6 mg/kg, 10% of patients on AGAMREE 2 mg/kg, and 14% of patients on placebo. Psychiatric adverse reactions reported on AGAMREE resolved without requiring treatment or drug discontinuation.

In adults, psychiatric adverse reactions with corticosteroids usually involve hypomanic or manic symptoms (e.g., euphoria, insomnia, mood swings) during treatment and depressive episodes after discontinuation of treatment. In children receiving corticosteroids, psychiatric adverse reactions usually involve hyperactivity symptoms (e.g., irritability, aggressive behavior, increased frequency of tantrums, and mood swings) and sleep disorder during 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

5.7 Ophthalmic Effects

The use of corticosteroids, such as AGAMREE, 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 AGAMREE is continued for more than 6 weeks, monitor intraocular pressure.

5.8 Immunizations

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

5.9 Effects on Growth and Development

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

5.10 Myopathy

Patients receiving corticosteroids 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. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

5.11 Kaposi's Sarcoma

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.

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

5.13 Anaphylaxis

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

6.1 Clinical Trials Experience

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

7.1 Effect of Other Drugs on Vamorolone

Co-administration of AGAMREE with itraconazole, a strong CYP3A4 inhibitor, increases vamorolone exposure [see Clinical Pharmacology (12.3)]. Reduce the dosage of AGAMREE in patients when strong CYP3A4 inhibitors are used concomitantly [see Dosage and Administration (2.6)]. No dosage adjustments are required when AGAMREE is concomitantly administered with moderate or weak CYP3A4 inhibitors.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of AGAMREE for the treatment of DMD have been established in patients 2 years of age and older. Use of AGAMREE in pediatric patients is supported by a multicenter, randomized, double-blind, placebo- and active-controlled study in 121 males 4 to less than 7 years of age [see Clinical Studies (14)]. Use of AGAMREE in patients 2 years to less than 4 years of age and 7 to less than 18 years of age is supported by findings of efficacy and safety in patients 4 to less than 7 years of age with DMD, and by pharmacokinetic and safety data from patients 2 to 4 years of age and 7 to less than 18 years of age [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

The safety and effectiveness in pediatric patients below the age of 2 years have not been established.

8.5 Geriatric Use

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

8.6 Hepatic Impairment

Moderate hepatic impairment increases vamorolone exposure [see Clinical Pharmacology (12.3)]. Reduce the AGAMREE dosage in patients with mild to moderate hepatic impairment [see Dosage and Administration (2.3)]. There is no clinical experience with AGAMREE in patients with severe hepatic impairment, and a dosing recommendation cannot be provided for patients with severe hepatic impairment.

12.1 Mechanism of Action

Vamorolone is a corticosteroid that acts through the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects. The precise mechanism by which vamorolone exerts its effect in patients with DMD is unknown.

12.2 Pharmacodynamics

Vamorolone produced a dose-dependent decrease in morning cortisol levels in the clinical studies. Treatment with corticosteroids is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. A dose-dependent increase in leukocyte counts and lymphocyte counts was observed in clinical studies with vamorolone.

12.3 Pharmacokinetics

The major route of elimination is by metabolism with subsequent excretion of metabolites into urine. The pharmacokinetics (PK) are linear and vamorolone exposure increases proportionally with either single (0.1 to 20 mg/kg) or multiple (0.25 to 20 mg/kg) doses. Vamorolone does not accumulate with repeated administration after once daily dosing.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

AGAMREE oral suspension is an orange flavored homogeneous white to off-white suspension, containing 40 mg/mL of vamorolone.

AGAMREE is supplied as 100 mL in 125 mL glass bottle packaged with one bottle adapter, two 5 mL oral syringes, and an Instructions for Use: NDC 69616-264-38.

16.2 Storage and Handling

Store the bottle upright at room temperature between 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C to 30°C (59°F to 86°F) in the original carton. See USP controlled room temperature.

After opening, store the bottle upright in a refrigerator 2°C to 8°C (36°F to 46°F). Do not freeze.

Discard any unused AGAMREE oral suspension remaining after 3 months of first opening the bottle.

Administration

• Warn patients and/or caregivers to not stop taking AGAMREE abruptly or without first checking with their healthcare providers as there may be a need for gradual dose reductions to decrease the risk of adrenal insufficiency crisis [see Dosage and Administration (2.7) and Warnings and Precautions (5.1)].
• AGAMREE oral suspension should be taken once daily, preferably with a meal.
• AGAMREE oral suspension must be shaken well for about 30 seconds prior to measuring out each dose with the enclosed oral syringe.
• Discard any unused AGAMREE oral suspension remaining after 3 months of first opening the bottle.

Immunosuppression and Increased Risk of Infection

Tell patients and/or caregivers to inform their healthcare provider if the patient has had recent or ongoing infections or if they have recently received a vaccine. Medical advice should be sought immediately if the patient develops fever or other signs of infection. Patients and/or caregivers should be made aware that some infections can potentially be severe and fatal.

Warn patients who are on corticosteroids to avoid exposure to chickenpox or measles and to alert their healthcare provider immediately if they are exposed [see Warnings and Precautions (5.2)].

Alterations in Cardiovascular/Renal Function

Inform patients and/or caregivers that corticosteroids, including AGAMREE, can cause an increase in blood pressure and water retention. If this occurs, dietary salt restriction and potassium supplementation may be needed [see Warnings and Precautions (5.3)].

Behavioral and Mood Disturbances

Advise patients and/or caregivers about the potential for severe behavioral and mood changes with AGAMREE and encourage them to seek medical attention if psychiatric symptoms develop [see Warnings and Precautions (5.5)].

Decreases in Bone Mineral Density

Advise patients and/or caregivers about the risk of osteoporosis with prolonged use of AGAMREE, which can predispose the patient to vertebral and long bone fractures [see Warnings and Precautions (5.6)].

Ophthalmic Effects

Inform patients and/or caregivers that AGAMREE may cause cataracts or glaucoma and advise monitoring if administered for more than 6 weeks [see Warnings and Precautions (5.7)].

Vaccination

Advise patients and/or caregivers to bring immunizations up-to-date according to immunization guidelines prior to starting therapy with AGAMREE. Live-attenuated or live vaccines should be administered at least 4 to 6 weeks prior to starting AGAMREE. Inform patients and/or caregivers that they may receive concurrent vaccinations with use of AGAMREE, except for live-attenuated or live vaccines [see Warnings and Precautions (5.8)].

Drug Interactions

Certain medications can cause an interaction with AGAMREE [see Drug Interactions (7.1)]. Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines (such as insulin, aspirin or other NSAIDS), dietary supplements, and herbal products. Inform patients and/or caregivers that alternate therapy, dosage adjustment, and/or special test(s) may be needed during the treatment.

Manufactured for:
Catalyst Pharmaceuticals, Inc.
Coral Gables, FL 33134, USA

AGAMREE Oral Suspension made in Italy.

AGAMREE® is a registered trademark of Santhera Pharmaceuticals (Schweiz) AG.

6010 Rev. B.