Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Santhera Pharmaceuticals (Deutschland) GmbH, Marie-Curie Strasse 8, D-79539 Lörrach, GERMANY, office@santhera.com
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Severe liver impairment (Child-Pugh class C).
Use of live or live-attenuated vaccines in the 6 weeks prior to starting treatment and during the treatment (see section 4.4).
Vamorolone causes alterations in endocrine function, especially with chronic use.
In addition, patients with altered thyroid function, or pheochromocytoma may be at increased risk for endocrine effects.
Vamorolone produces dose-dependent and reversible suppression of the hypothalamic-pituitaryadrenal axis (HPA-axis), potentially resulting in secondary adrenal insufficiency, which may persist for months after discontinuation of prolonged therapy. The degree of chronic adrenal insufficiency produced is variable among patients and depends on the dose, and duration of therapy.
Acute adrenal insufficiency (also known as adrenal crisis) can occur during a period of increased stress or if vamorolone dose is reduced or withdrawn abruptly. This condition can be fatal. Symptoms of adrenal crisis may include excess fatigue, unexpected weakness, vomiting, dizziness or confusion. The risk is reduced by gradually tapering the dose when down-titrating or withdrawing treatment (see section 4.2).
During periods of increased stress, such as acute infection, traumatic injuries or surgical procedure, patients should be monitored for signs of acute adrenal insufficiency and the regular treatment with AGAMREE should be temporarily supplemented with systemic hydrocortisone to prevent the risk of adrenal crisis. There is no data available on the effects of increasing AGAMREE dose for situations of increased stress.
The patient should be advised to carry the Patient Alert Card providing important safety information to support early recognition and treatment of adrenal crisis.
A steroid “withdrawal syndrome”, seemingly unrelated to adrenocortical insufficiency, may also occur following abrupt discontinuation of glucocorticoids. 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 glucocorticoid concentration rather than to low glucocorticoid levels.
Patients can be switched from oral glucocorticoid treatment (such as prednisone or deflazacort) to AGAMREE without the need for treatment interruption or period of prior glucocorticoid dose reduction. Patients previously on chronic glucocorticoids should switch to AGAMREE 6 mg/kg/day to minimise the risk for adrenal crisis.
Vamorolone is associated with dose-dependent increase in appetite and weight gain, mainly in the first months of treatment. Age-appropriate dietary advice should be provided before and during treatment with AGAMREE in line with general recommendations for nutrition management in patients with DMD.
Metabolic clearance of glucocorticoids can be decreased in hypothyroid patients and increased in hyperthyroid patients. It is unknown, whether vamorolone is affected in the same way, but changes in thyroid status of the patient may necessitate a dose adjustment.
Glucocorticoids may induce posterior subcapsular cataracts, glaucoma with potential damage to the optic nerves, and may increase the risk of secondary ocular infections caused by bacteria, fungi, or viruses.
The risk to cause ophthalmic effects with AGAMREE is unknown.
Suppression of the inflammatory response and immune function may increase the susceptibility to infections and their severity. Activation of latent infections or exacerbation of intercurrent infections could occur. The clinical presentation may often be atypical and serious infections may be masked and may reach an advanced stage before being recognised. These infections may be severe and at times fatal.
While no increased incidence or severity of infections was observed with vamorolone in the clinical studies, limited long-term experience does not allow to exclude an increased risk for infections.
The development of infections should be monitored. Diagnostic and therapeutic strategies should be applied in patients with symptoms of infection while on chronic treatment with vamorolone. Supplementation with hydrocortisone should be considered in patients presenting with moderate or severe infections, who are treated with vamorolone.
Long-term therapy with corticosteroids can increase the risk for diabetes mellitus.
No clinically relevant changes in glucose metabolism have been observed in vamorolone clinical studies, long-term data is limited. Blood glucose should be monitored at regular intervals in patients chronically treated with vamorolone.
Response to live or live attenuated vaccines can be altered in patients treated with glucocorticoids. The risk with AGAMREE is unknown.
Live attenuated or live vaccines should be administered at least 6 weeks prior to starting AGAMREE treatment.
For patients without a history of chicken pox or vaccination, vaccination against varicella zoster virus should be initiated before treatment with AGAMREE.
Observational studies with glucocorticoids have shown an increased risk of thromboembolism (including venous thromboembolism) particularly with higher cumulative doses of glucocorticoids.
The risk with AGAMREE is unknown. AGAMREE should be used with caution in patients who have or may be predisposed to thromboembolic disorders.
Rare instances of anaphylaxis have occurred in patients receiving glucocorticoid therapy.
Vamorolone shares structural similarities with glucocorticoids and should be used with caution when treating patients with known hypersensitivity to glucocorticoids.
Vamorolone has not been studied in patients with severe pre-existing hepatic injury (Child-Pugh class C) and must not be used in these patients (see section 4.3).
The potential for drug-drug-interactions involving UGTs has not been fully evaluated, therefore all inhibitors of UGTs should be avoided as concomitant medication and should be used with caution if medically required.
This medicinal product contains 1 mg sodium benzoate in each 1 ml which is equivalent to 100 mg/100 ml.
This medicinal product contains less than 1 mmol sodium (23 mg) per 7.5 ml, that is to say essentially ‘sodium-free’.
Vamorolone acts as an antagonist at the mineralocorticoid receptor. The use of vamorolone in combination with mineralocorticoid receptor antagonist may increase the risk of hyperkalaemia. No cases of hyperkalaemia have been observed in patients using vamorolone alone or in combination with eplerenone or spironolactone. Monitoring potassium levels one month after starting a combination between vamorolone and a mineralocorticoid receptor antagonist is recommended. In case of hyperkalaemia, a reduction of the dose of the mineralocorticoid receptor antagonist should be considered.
Concomitant administration with the strong CYP3A4 inhibitor itraconazole led to an increase of the vamorolone area under the plasma concentration time curve of 1.45-fold in healthy subjects. The recommended dose of vamorolone when administered with strong CYP3A4 inhibitors (e.g telithromycin, clarithromycin, voriconazole, grapefruit juice) is 4 mg/kg/day.
Strong CYP3A4 inducers or strong PXR inducers (e.g. carbamazepine, phenytoin, rifampicin, St. John’s wort) may decrease plasma concentrations of vamorolone and lead to lack of efficacy, therefore alternative treatments that are not strong inducers of CYP3A4 activity should be considered. Concomitant treatment with a moderate PXR or CYP3A4 inducer should be used in caution as the plasma concentration of vamorolone may be decreased relevantly.
There are no available data from the use of vamorolone in pregnant women. Animal reproductive toxicity studies have not been conducted with vamorolone. Glucocorticoids were associated in animal studies to various types of malformations (palate cleft, skeletal malformations), however the relevance in humans is unknown.
AGAMREE should not be used during pregnancy unless the clinical condition of the woman requires treatment with vamorolone.
Women of childbearing potential have to use effective contraception during treatment with AGAMREE.
There are no data on the excretion of vamorolone or its metabolites in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with AGAMREE.
There are no clinical data on the effects of vamorolone on fertility.
Long-term vamorolone treatment inhibited male and female fertility in dogs (see section 5.3).
AGAMREE has no influence on the ability to drive and use machines.
The most commonly reported adverse reactions for vamorolone 6 mg/kg/day are Cushingoid features (28.6%), vomiting (14.3%), weight increased (10.7%) and irritability (10.7%). These reactions are dose-dependent, usually reported in the first months of treatment and tend to decline or stabilise over time with continuous treatment.
Vamorolone leads to the suppression of the hypothalamic-pituitary-adrenal axis, which correlates with dose and the duration of treatment. Acute adrenal insufficiency (adrenal crisis) is a serious effect that can occur during a period of increased stress or if the vamorolone dose is reduced or withdrawn abruptly (see section 4.4).
The adverse reactions are listed below according to MedDRA system organ class and frequency. The table contains adverse reactions in patients treated in the placebo-controlled study for patients treated with vamorolone 6 mg/kg/day (Pool 1). The frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) (including isolated cases), not known (cannot be estimated from the available data).
Table 2. Adverse reactions:
| System Organ Class (SOC) | Adverse reaction (Preferred term) | Frequency |
|---|---|---|
| Endocrine disorders | Cushingoid | Very common |
| Metabolism and nutrition disorders | Weight increased Increased appetite | Very common |
| Psychiatric disorders | Irritability | Very common |
| Gastrointestinal disorders | Vomiting Abdominal pain Abdominal pain upper Diarrhoea | Very common Common Common Common |
| Nervous system disorders | Headache | Common |
Cushingoid features (hypercortisolism) was the most frequently reported adverse reaction with vamorolone 6 mg/kg/day (28.6%). The frequency of cushingoid features was lower in the vamorolone 2 mg/kg/day group (6.7%). In the clinical study, cushingoid features were reported as mild to moderate “weight gain in the face”, or “rounded face”. The majority of the patients presented with Cushingoid features in the first 6 months of treatment (28.6% in Month 0 to 6 vs 3.6% in Month 6 to 12 in vamorolone 6 mg/kg/day) and did not result in discontinuation of treatment.
Behaviour problems were reported in the first 6 months of treatment at a higher frequency with vamorolone 6 mg/kg/day (21.4%) than with vamorolone 2 mg/kg/day (16.7%) or placebo (13.8%), due to an increased frequency of events described as mild irritability (10.7% in 6 mg/kg/day, no patient in 2 mg/kg/day or placebo). The majority of behaviour problems occurred in the first 3 months of treatment and resolved without treatment discontinuation. Between month 6 and month 12, the frequency of behaviour problems decreased in both vamorolone doses (10.7% for vamorolone 6 mg/kg/day and 7.1% for vamorolone 2 mg/kg/day).
Vamorolone is associated with increase in appetite and weight. The majority of the events of weight gain in the vamorolone 6 mg/kg/day group were reported in the first 6 months of treatment (17.9% in month 0 to 6 vs 0% in months 6 to 12). Weight gain was similar between vamorolone 2 mg/kg/day (3.3%) and placebo (6.9%). Age-appropriate dietary advice should be provided before and during treatment with AGAMREE in line with general recommendations for nutrition management in patients with DMD (see section 4.4).
Abruptly reducing or withdrawing the daily dose of vamorolone following prolonged treatment for more than one week can lead to adrenal crisis (see sections 4.2 and 4.4).
The adverse events in paediatric patients with DMD treated with vamorolone were similar in frequency and type in patients 4 years of age and older.
The type and frequency of adverse events in patients older than 7 years were consistent with those seen in 4 to 7-year old patients. There is no available information on the effects of vamorolone on pubertal development.
A higher frequency of behaviour problems was observed in patients <5 years compared to patients ≥5 years when treated with vamorolone 2-6 mg/kg/day.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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