Vamorolone (Monograph)

Brand name: Agamree
Drug class: Adrenals

Introduction

Vamorolone is a corticosteroid.

Uses for Vamorolone

Vamorolone has the following uses:

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

Vamorolone Dosage and Administration

General

Vamorolone is available in the following dosage form(s) and strength(s):

Oral suspension: 40 mg/mL

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

• Administer vamorolone oral suspension using the oral syringe provided by the manufacturer.

• Shake the oral suspension well for about 30 seconds before administration.

• The recommended dosage in adults and pediatric patients 2 years of age and older 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.

• In patients with mild to moderate hepatic impairment, the recommended dosage 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.

• The recommended dosage of vamorolone 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.

• Patients can be switched from oral corticosteroid treatment (such as prednisone or deflazacort) to vamorolone 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 vamorolone at a dosage of 6 mg/kg/day.

• When discontinuing therapy, decrease dosage gradually when administered for more than one week.

Related/similar drugs

Elevidys, deflazacort, Emflaza, Exondys 51, Agamree, Duvyzat

Cautions for Vamorolone

Contraindications

Hypersensitivity to vamorolone or any of the inactive ingredients in the formulation.

Warnings/Precautions

Alterations in Endocrine Function

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

Vamorolone 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 vamorolone 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 (hypercortisolism) occurs with prolonged exposure to exogenous corticosteroids, including vamorolone, 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.

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 vamorolone. For patients with hyperglycemia, anti-diabetic treatment should be initiated or adjusted accordingly.

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 vamorolone and levothyroxine is required, administration of vamorolone should precede the initiation of levothyroxine therapy to reduce the risk of adrenal 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 vamorolone, 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 infection, and mask some signs of infection. Corticosteroid-associated infections can be severe, and at times fatal infections can occur. The rate of infectious complications increases with increasing corticosteroid dosages. Corticosteroids cause a dose-dependent increase in lymphocyte and neutrophil counts. Monitor for the development of infection and consider vamorolone withdrawal or dosage reduction as needed.

Varicella and measles can have a serious or even fatal course in non-immune patients taking corticosteroids. 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 vamorolone-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 vamorolone-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated.

Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids. Reactivation can also occur 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 vamorolone. 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.

Corticosteroids may exacerbate systemic fungal infections; therefore, avoid vamorolone use in the presence of such infections. For patients on chronic vamorolone therapy who develop systemic fungal infections, vamorolone withdrawal or dosage reduction is recommended.

Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating vamorolone in any patient who has spent time in the tropics or any patient with unexplained diarrhea.

Corticosteroids 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. For patients on corticosteroids who develop known or suspected Strongyloides (threadworm) infestation, withdrawal of corticosteroids or reduction of the dose of corticosteroids is recommended.

Alterations in Cardiovascular/Renal Function

Corticosteroids, including vamorolone, 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. Vamorolone 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 vamorolone 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 vamorolone 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 vamorolone. 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 vamorolone 6 mg/kg, 10% of patients on vamorolone 2 mg/kg, and 14% of patients on placebo. Psychiatric adverse reactions reported on vamorolone 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

Corticosteroids, such as vamorolone, 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 vamorolone.

Corticosteroids may cause avascular necrosis.

Ophthalmic Effects

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

Immunizations

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

Effects on Growth and Development

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

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.

Kaposi's Sarcoma

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

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

Anaphylaxis

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

Specific Populations

Pregnancy

Vamorolone 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 vamorolone 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.

Animal reproduction studies have not been conducted with vamorolone.

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.

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.

Lactation

There are no data on the presence of vamorolone in human milk or the effects on milk production.

Vamorolone is indicated for use for the treatment of DMD, which is a disease of young male patients. However, 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 and any potential adverse effects on the breastfed infant.

Pediatric Use

The safety and effectiveness of vamorolone for the treatment of DMD have been established in patients 2 years of age and older. Use of vamorolone 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 vamorolone 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.

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).

Geriatric Use

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

Hepatic Impairment

Moderate hepatic impairment increases vamorolone exposure. Reduce the vamorolone dosage in patients with mild to moderate hepatic impairment. There is no clinical experience with vamorolone in patients with severe hepatic impairment, and a dosing recommendation cannot be provided for patients with severe hepatic impairment.

Common Adverse Effects

The most common adverse reactions (>10% for vamorolone and greater than placebo) are cushingoid features, psychiatric disorders, vomiting, weight increased, and vitamin D deficiency.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong CYP3A4 inhibitors: The maximum recommended daily dose is 4 mg/kg up to a maximum daily dosage of 200 mg for patients weighing more than 50 kg.

Actions

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 Duchenne muscular dystrophy (DMD) is unknown.

Advice to Patients

• Advise the patients and/or caregivers to read the FDA-approved patient labeling.

• Warn patients and/or caregivers to not stop taking vamorolone 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.

• Vamorolone oral suspension should be taken once daily, preferably with a meal.

• Vamorolone oral suspension must be shaken well for about 30 seconds prior to measuring out each dose with the enclosed oral syringe.

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

• 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.

• Inform patients and/or caregivers that corticosteroids, including vamorolone, can cause an increase in blood pressure and water retention. If this occurs, dietary salt restriction and potassium supplementation may be needed.

• Advise patients and/or caregivers about the potential for severe behavioral and mood changes with vamorolone and encourage them to seek medical attention if psychiatric symptoms develop.

• Advise patients and/or caregivers about the risk of osteoporosis with prolonged use of vamorolone, which can predispose the patient to vertebral and long bone fractures.

• Inform patients and/or caregivers that vamorolone may cause cataracts or glaucoma and advise monitoring if administered for more than 6 weeks.

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

• Certain medications can cause an interaction with vamorolone. 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.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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