44/23. Vamarolone- (AGAMREE)- (Oct 2023)- to treat Duchenne muscular dystrophy
Drug Name:44/23. Vamarolone- (AGAMREE)- (Oct 2023)- to treat Duchenne muscular dystrophy
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS-(summary)
1 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.
Indication:
BRIEF SUMMARY
VAMARONE-(Oct 2023)
Indn- to treat Duchenne muscular dystrophy
Comp- Oral Suspension: 40 mg/mL • 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.
• Decrease dosage gradually when administered for more than one week.
ADR- The most common adverse reactions (>10% for AGAMREE and greater than placebo) are cushingoid features, psychiatric disorders, vomiting, weight increased, and vitamin D deficiency
CI- Hypersensitivity to vamorolone or any of the inactive ingredients in AGAMREE
WARNINGS -
• Alterations in Endocrine Function: Hypothalamic-pituitary-adrenal axis suppression, cushingoid features, and hyperglycemia can occur. Monitor patients for these conditions with chronic use of AGAMREE.
• Immunosuppression and Increased Risk of Infection: Increased risk of new infections, exacerbation, dissemination, or reactivation of which can be severe and at times fatal; signs and symptoms of infections may be masked.
Pat Inform-
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.
• 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
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U.S. APPROVED DRUGS DURING 2023
Serial No 44
Name- AGAMREE
Active ingedient- Vamerolone
Indication to treat Duchenne muscular dystrophy
Date of approval 10/267/2023
HIGHLIGHTS OF PRESCRIBING INFORMATION-
These highlights do not include all the information needed to use AGAMREE® safely and effectively.
See full prescribing information for AGAMREE. AGAMREE (vamorolone) oral suspension
Initial U.S. Approval: 2023
INDICATIONS AND USAGE-
AGAMREE is a corticosteroid indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 2 years of age and older
Adverse Reaction:
ADVERSE REACTIONS-
The most common adverse reactions (>10% for AGAMREE and greater than placebo) are cushingoid features, psychiatric disorders, vomiting, weight increased, and vitamin D deficiency.
Contra-Indications:
CONTRAINDICATIONS-
Hypersensitivity to vamorolone or any of the inactive ingredients in AGAMREE
WARNINGS AND PRECAUTIONS-
• Alterations in Endocrine Function: Hypothalamic-pituitary-adrenal axis suppression, cushingoid features, and hyperglycemia can occur. Monitor patients for these conditions with chronic use of AGAMREE.
• Immunosuppression and Increased Risk of Infection: Increased risk of new infections, exacerbation, dissemination, or reactivation of which can be severe and at times fatal; signs and symptoms of infections may be masked.
• Alterations in Cardiovascular/Renal Function: Monitor for elevated blood pressure and monitor sodium and potassium levels in patients chronically treated with AGAMREE.
• Gastrointestinal Perforation: Increased risk in patients with certain GI disorders; signs and symptoms may be masked.
• Behavioral and Mood Disturbances: May include euphoria, insomnia, mood swings, personality changes, severe depression, and psychosis.
• Effects on Bones: Monitor for decreases in bone mineral density with chronic use of AGAMREE.
• Ophthalmic Effects: May include cataracts, infections, and glaucoma; monitor intraocular pressure in patients chronically treated with AGAMREE.
• Vaccination: Do not administer live or live attenuated vaccines to patients receiving immunosuppressive doses of corticosteroids. Administer liveattenuated or live vaccines at least 4 to 6 weeks prior to starting AGAMREE.
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Dosages/ Overdosage Etc:
DOSAGE AND ADMINISTRATION-
The recommended dosage 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.
• 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.
• Decrease dosage gradually when administered for more than one week.
DOSAGE FORMS AND STRENGTHS-
Oral Suspension: 40 mg/mL
Patient Information:
PATIENT COUNSELING INFORMATION-
Advise the patients and/or caregivers to read the FDA-approved patient labeling (Instructions for Use).
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.
• 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
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
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
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
Ophthalmic Effects- Inform patients and/or caregivers that AGAMREE may cause cataracts or glaucoma and advise monitoring if administered for more than 6 weeks
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
Drug Interactions - Certain medications can cause an interaction with AGAMREE
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: Santhera Pharmaceuticals (USA), Inc. Burlington, MA 01803, USA AGAMREE Oral Suspension made in Italy AGAMREE® is a trademark of Santhera Pharmaceuticals (Switzerland) Ltd Material ID 0264, October 2023
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action- Vamorolone is a corticosteroid that acts through the glucocorticoid receptor to exert antiinflammatory and immunosuppressive effects. The precise mechanism by which vamorolone exerts its effect in patients with DMD is unknown.
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
Cardiac Electrophysiology- Vamorolone does not cause a mean increase in the QTc interval >20 milliseconds (ms) at 1.6 times the approved recommended dose.
3. Pharmacokinetics- The major route of elimination is by metabolism with subsequent excretion of metabolites into urine.
Vamorolone does not accumulate with repeated administration after once daily dosing.
Absorption - After oral administration with food, the median Tmax is about 2 hours (range 0.5 to 5 hours).
Effect of Food- Co-administration of vamorolone (2 mg/kg) with a high-fat/high-calorie meal reduced Cmax by 18%, increased AUC by 13%, and delayed Tmax by one hour.
Co-administration of vamorolone (2 mg/kg) with a low-fat/low-calorie meal reduced Cmax by 4%, increased AUC by 14%, and delayed Tmax by one hou
Distribution- The apparent volume of distribution of vamorolone for a DMD patient with a body weight of 20 kg taking AGAMREE with a meal is 162 L based on the population PK analysis. Protein binding is 88.1% in vitro. The blood to plasma ratio is approximately 0.87.
Elimination- Vamorolone clearance for a DMD patient with a body weight of 20 kg taking AGAMREE with a meal is 58 L/h based on the population PK analysis. The terminal elimination half-life of vamorolone is approximately 2 hours.
Metabolism- Vamorolone is metabolized via multiple Phase I and Phase II metabolic pathways, such as glucuronidation, hydroxylation, and reduction. The main plasma and urine metabolites are formed through direct glucuronidation as well as hydrogenation with subsequent glucuronidation.
Metabolism of vamorolone is mediated through CYP3A4/5, CYP2C8, UGT1A3, UGT2B7, and UGT2B17.
Excretion- Approximately 30% of vamorolone dose is excreted in feces (15.4% unchanged) and 48% of vamorolone dose is excreted in urine as metabolites (<1% unchanged). The major metabolites in urine are glucuronides.
Specific Populations- No clinically significant differences in the pharmacokinetics of vamorolone were observed based on race and sex.
Pediatric Patients- In children ages 4 to 7 years (N=12) who were administered 6 mg/kg of AGAMREE daily, on Day 1 and Day 14, the Cmax values (arithmetic mean, SD) of vamorolone were 856 ng/mL (471) and 970 ng/mL (270), respectively, and the AUC24 values (arithmetic mean, SD) of vamorolone were 3279 ng•h/mL (1693) and 3606 ng•h/mL (897), respectively.
The pharmacokinetics of vamorolone was also characterized in DMD children ages 2 to 4 (N=6). Similar PK parameters were observed in younger children after administration of 6 mg/kg AGAMREE when compared to older children.
Patients with Hepatic Impairment - In a clinical study (N=16), vamorolone Cmax and AUC0inf values were increased by approximately 1.7 and 2.6-fold, respectively, in subjects with moderate hepatic impairment (Child-Pugh Class B) compared with healthy matched controls
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
.1 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.
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.
2. Lactation Risk Summary - There are no data on the presence of vamorolone in human milk or the effects on milk production. AGAMREE 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.
3.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
The safety and effectiveness in pediatric patients below the age of 2 years have not been established.
4.Geriatric Use DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with AGAMREE.
4. Hepatic Impairment- Moderate hepatic impairment increases vamorolone exposure.. Reduce the AGAMREE dosage in patients with mild to moderate hepatic impairment
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.
OVERDOSAGE- Treatment of acute overdosage of vamorolone is by immediate supportive and symptomatic therapy. Gastric lavage or emesis can be considered.
11 DESCRIPTION AGAMREE (vamorolone) oral suspension contains vamorolone, a corticosteroid. Vamorolone [17a,21-dihydroxy-16a-methyl-pregna-1,4,9(11)-triene-3,20-dione] is a white to off-white powder with a molecular formula of C22H28O4 and a molecular weight of 356.46 g/mol. Its structural formu