Agamree Drug Information

    Generic name: VAMOROLONE

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    Uses of Agamree

    is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 years of age and older. AGAMREE is a corticosteroid indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 years of age and older.

    Dosage & Administration of Agamree

    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.

    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.

    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 . Doses may be titrated down based on individual tolerability.

    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.

    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.

    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. Doses may be titrated down based on individual tolerability.

    Discontinuation Dosage of

    AGAMREE must be decreased gradually if the drug has been administered for more than one week.

    Side Effects of Agamree

    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. Common Adverse Reactions in Clinical Studies Table 1 lists the adverse reactions that occurred in ≥ 5% of the patients treated with AGAMREE 6 mg/kg/day (N=28) or AGAMREE 2 mg/kg/day (N=30) and that occurred more frequently than in the patients who received placebo (N=29) in Study 1 , which was 24 weeks and included patients with DMD between the ages of 4 and 7 years. Table 1: Adverse Reactions in Patients with DMD that Occurred in ≥ 5% of Patients Treated with AGAMREE and More Frequently than in Patients Who Received Placebo During 24 Weeks (Study 1) 1 Includes the following adverse reactions that occurred more frequently in the AGAMREE group than in placebo: abnormal behavior, aggression, agitation, anxiety, irritability, mood altered, sleep disorder, and stereotypy.

    Adverse Reaction AGAMREE 2 mg/kg/d (N=30) % AGAMREE 6 mg/kg/d (N=28) % Placebo (N=29) % Cushingoid Features 7 29 0 Psychiatric disorders 1 7 21 14 Vomiting 17 14 7 Weight increased 0 11 3 Vitamin D deficiency 7 11 0 Cough 10 7 3 Headache 7 7 3 Diarrhea 3 7 3 Increased appetite 3 7 3 Rhinitis 3 7 3 In a separate open-label safety study of pediatric patients aged 2 to less than 4 years (n=16) and pediatric patients aged 7 to less than 18 years (n=16) with DMD, adverse reactions were similar to those seen in the Study 1 pediatric patients.

    Warnings & Cautions for Agamree

    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.

    Risk of Adrenal Insufficiency Following Withdrawal AGAMREE produces reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, with the potential for the development of secondary adrenal insufficiency after withdrawal. Acute adrenal insufficiency can occur if AGAMREE is withdrawn abruptly, and could be fatal. The degree and duration of adrenocortical insufficiency produced is variable among patients and depends on the dose and duration of therapy.

    The risk of adrenal insufficiency is reduced by gradually tapering the dose when withdrawing treatment. The insufficiency may persist, however, for months after discontinuation of prolonged therapy; therefore, in any situation of stress occurring during that period of discontinuation, supplementation with a systemic corticosteroid is recommended. 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 too low corticosteroid levels.

    Cushing's Syndrome Cushing's syndrome (hypercortisolism) occurs with prolonged exposure to exogenous corticosteroids, including AGAMREE, and 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. Hyperglycemia Corticosteroids 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 in patients treated with AGAMREE. For patients with hyperglycemia, anti-diabetic treatment should be initiated or adjusted accordingly.

    Considerations for Use in Patients with Altered Thyroid Function Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate a dose adjustment of the corticosteroid. When concomitant administration of AGAMREE and levothyroxine is required, administration of AGAMREE should precede the initiation of levothyroxine therapy to reduce the risk of adrenal crisis.

    Pheochromocytoma Crisis There 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.

    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. Tuberculosis If AGAMREE 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 AGAMREE 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 AGAMREE. 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 an AGAMREE-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 an AGAMREE-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 AGAMREE. 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 AGAMREE. 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 AGAMREE, may exacerbate systemic fungal infections; therefore, avoid AGAMREE use in the presence of such infections unless AGAMREE is needed to control drug reactions. For patients on chronic AGAMREE therapy who develop systemic fungal infections, AGAMREE withdrawal or dosage reduction is recommended.

    Amebiasis Corticosteroids, including AGAMREE, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating AGAMREE in any patients who have spent time in the tropics or patients with unexplained diarrhea. Strongyloides Infestation Corticosteroids, including AGAMREE, 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 AGAMREE, in patients with cerebral malaria.

    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.

    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.

    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.

    Effects on Bones Decreased Bone Mineral Density Corticosteroids, such as

    AGAMREE, 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 a 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 a patient's risk of osteoporosis before initiating corticosteroid therapy. Monitor bone mineral density in patients on long-term treatment with AGAMREE. Avascular Necrosis Corticosteroids may cause avascular necrosis.

    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.

    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.

    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.

    Drug Interactions with Agamree

    Effect of Other Drugs on Vamorolone Co-administration of

    AGAMREE with itraconazole, a strong CYP3A4 inhibitor, increases vamorolone exposure . Reduce the dosage of AGAMREE in patients when strong CYP3A4 inhibitors are used concomitantly . No dosage adjustments are required when AGAMREE is concomitantly administered with moderate or weak CYP3A4 inhibitors.

    Pregnancy Safety for Agamree

    Pregnancy Risk Summary AGAMREE is indicated for use for the treatment of DMD, which is a disease of young male patients. However, corticosteroids in general 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 data on the use of AGAMREE during pregnancy. 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 during pregnancy. Some epidemiologic studies report an increased risk of orofacial clefts from about 1 per 1000 infants to 3 to 5 per 1000 infants; however, a risk for orofacial clefts has not been observed in all clinical 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 Clinical Considerations and Data ). Animal reproduction studies have not been conducted with AGAMREE. Animal reproduction studies conducted with 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. 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.

    Clinical Considerations Fetal/Neonatal Adverse Reactions Hypoadrenalism may occur in infants born to mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly. Data Human Data Multiple cohort and case-controlled studies in humans suggest that maternal corticosteroid use during the first trimester increases the rate of cleft lip, with or without cleft palate, from about 1/1000 infants to 3-5/1000 infants.

    Two prospective case-controlled studies showed decreased birth weight in infants exposed to maternal corticosteroids in utero.

    Pediatric Use of Agamree

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

    Juvenile Animal Toxicity Data Oral administration of vamorolone (0, 15, 30, or 100 mg/kg/day) to juvenile mice from postnatal days 21 to 81 resulted in no adverse effects on neurobehavioral function, sexual maturation, or reproductive function. Atrophy of the adrenal cortex, degeneration/necrosis of the liver, and decreased lymphocytes in lymphatic tissues were observed at all doses. A no-effect dose for general toxicity was not identified.

    Plasma exposures (AUC) at the lowest dose tested (15 mg/kg/day) were lower than that in humans at the maximum recommended human dose (300 mg/day).

    Contraindications for Agamree

    is contraindicated in patients with known hypersensitivity to vamorolone or to any of the inactive ingredients of AGAMREE. Instances of hypersensitivity, including anaphylaxis, have occurred in patients receiving corticosteroid therapy. Hypersensitivity to vamorolone or any of the inactive ingredients in AGAMREE

    Overdosage Information for Agamree

    Treatment of acute overdosage of vamorolone is by immediate supportive and symptomatic therapy. Gastric lavage or emesis can be considered.

    Clinical Studies of Agamree

    The effectiveness of AGAMREE for the treatment of Duchenne muscular dystrophy (DMD) was evaluated in a multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled, multinational 24-week study (Study 1; NCT03439670). The study randomized 121 male patients with DMD to one of the following treatment groups: AGAMREE 6 mg/kg/day (n=30), AGAMREE 2 mg/kg/day (n=30), prednisone 0.75 mg/kg/day (n=31), or placebo (n=30) for 24 weeks. After 24 weeks, patients on prednisone and placebo received either AGAMREE 6 mg/kg/day (n=29) or AGAMREE 2 mg/kg/day (n=29) for an additional 20 weeks. The study included patients 4 to less than 7 years of age at time of enrollment in the study who were corticosteroid naïve and ambulatory, with a confirmed diagnosis of DMD. At baseline, patients had a mean age of 5.4 years, 83% were Caucasian, 10% were Asian, and 96% were not Hispanic or Latino.

    The primary endpoint was the change from baseline to Week 24 in Time to Stand Test (TTSTAND) velocity for AGAMREE 6 mg/kg/day compared to placebo. TTSTAND velocity is a measure of muscle function that measures the time required for the patient to stand to an erect position from a supine position (floor). The key secondary endpoints consisted of change from baseline to Week 24 in TTSTAND velocity (AGAMREE 2 mg/kg/day vs placebo), 6 Minute Walk Test (6MWT) distance (AGAMREE 6 mg/kg/day vs placebo and 2 mg/kg/day vs placebo) and Time to Run/Walk 10 meters (TTRW) velocity (AGAMREE 6 mg/kg/day vs placebo and 2 mg/kg/day vs placebo). The 6MWT measures the distance that a patient can walk on a flat, hard surface in a period of 6 minutes and TTRW measures the time that it takes a patient to run or walk 10 meters. The fixed sequential testing process was applied to the key secondary endpoints in the order listed above.

    The primary endpoint and key secondary endpoints were met for the AGAMREE 6 mg/kg/day treatment group. The AGAMREE 2 mg/kg/day treatment group was statistically significant vs. placebo for TTSTAND and 6MWT, but was not statistically significant vs. placebo for TTRW. See Figure 1 and Table 2 for efficacy results from Week 24. Figure 1: Least-Squares Mean Change in Time to Stand (TTSTAND) Velocity (rises/sec) Table 2: Change from Baseline to Week 24 on TTSTAND, 6MWT, and TTRW Compared to Placebo Baseline values are presented with descriptive statistics (mean). Mean changes and differences are model-based least-squares means and mean differences. Positive numbers indicate improvement as compared with the baseline value. *Primary endpoint Parameter Placebo AGAMREE 2 mg/kg/d AGAMREE 6 mg/kg/d TTSTAND velocity (rises/sec) Baseline Mean change from baseline Difference from placebo (95% CI) p-value 0.200 -0.012 N/A N/A 0.184 0.033 0.045 0.017 0.186 0.048 0.060 0.002 * 6MWT distance (meters) Baseline Mean change from baseline Difference from placebo (95% CI) p-value 355 -14 N/A N/A 316 27 40 0.004 313 29 42 0.002 TTRW velocity (meters/sec) Baseline Mean change from baseline Difference from placebo (95% CI) p-value 1.735 0.014 N/A N/A 1.563 0.141 0.127 (-0.026, 0.281) 0.103 1.600 0.258 0.244 0.002 Figure 1

    Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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