4.1. Therapeutic indications

AGAMREE is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients aged 4 years and older.

4.2. Posology and method of administration

Treatment with AGAMREE should only be initiated by specialist physicians with experience in the management of Duchenne muscular dystrophy.

Posology

The recommended dose of vamorolone is 6 mg/kg once daily in patients weighing less than 40 kg.

In patients weighing 40 kg and above, the recommended dose of vamorolone is 240 mg (equivalent to 6 ml) once daily.

Daily dose may be down-titrated to 4 mg/kg/day or 2 mg/kg/day based on individual tolerability. Patients should be maintained at the highest tolerated dose within the dose range.

Table 1: Dosing table

6 mg/kg/day

4 mg/kg/day

2 mg/kg/day

Weight (kg)

Dose in mg

Dose in ml

Dose in mg

Dose in ml

Dose in mg

Dose in ml

12-13

72

1.8

48

1.2

24

0.6

14-15

84

2.1

56

1.4

28

0.7

16-17

96

2.4

64

1.6

32

0.8

18-19

108

2.7

72

1.8

36

0.9

20-21

120

3

80

2

40

1

22-23

132

3.3

88

2.2

44

1.1

24-25

144

3.6

96

2.4

48

1.2

26-27

156

3.9

104

2.6

52

1.3

28-29

168

4.2

112

2.8

56

1.4

30-31

180

4.5

120

3

60

1.5

32-33

192

4.8

128

3.2

64

1.6

34-35

204

5.1

136

3.4

68

1.7

36-37

216

5.4

144

3.6

72

1.8

38-39

228

5.7

152

3.8

76

1.9

40 kg and above

240

6

160

4

80

2

The dose of vamorolone must not be decreased abruptly if the treatment has been administered for more than one week (see section 4.4). Dose tapering should be done progressively over weeks, by steps of approximately 20% decrease from the previous dose level. The duration of each tapering step should be adjusted depending on individual tolerability.

Special populations

Hepatic impairment

No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh class A).

The recommended daily dose of vamorolone for patients with moderate hepatic impairment (Child-Pugh class B) is 2 mg/kg/day for patients up to 40 kg and 80 mg for patients with a body weight of 40 kg and above (see section 5.2). Patients with severe hepatic impairment (Child-Pugh class C) should not be treated with vamorolone. See sections 4.3 and 4.4.

Paediatric population

The safety and efficacy of AGAMREE in children below 4 years of age has not been established.

Method of administration

AGAMREE is for oral use. AGAMREE can be taken with or without a meal (see section 5.2).

The oral suspension requires redispersing by shaking the bottle prior to dosing.

Only the oral syringe provided with the medicinal product should be used to measure the dose of AGAMREE in ml. After the appropriate dose is withdrawn into the oral syringe, it should be dispensed directly into the mouth.

The oral syringe should be disassembled after use, rinsed under running cold tap water and air dried. It should be stored in the box until next use. An oral syringe may be used for up to 45 days, then it should be discarded and the second oral syringe provided in the pack should be used.

Administration of AGAMREE oral suspension via enteral feeding tube

AGAMREE oral suspension may be administered through an enteral feeding tube (see section 6.6).

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

Alterations in endocrine function

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.

Risk of adrenal insufficiency

Vamorolone produces dose-dependent and reversible suppression of the hypothalamic-pituitary-adrenal 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.

Switching from glucocorticoid treatment to AGAMREE

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.

Weight gain

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.

Considerations for use in patients with altered thyroid function

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.

Ophthalmic effects

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.

Increased risk of infections

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.

Diabetes mellitus

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.

Vaccination

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.

Thromboembolic events

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.

Anaphylaxis

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.

Hepatic impairment

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).

Concomitant use with other medicinal products

UGT substrates

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.

Excipients

Sodium benzoate

This medicinal product contains 1 mg sodium benzoate in each 1 ml which is equivalent to 100 mg/100 ml.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 7.5 ml, that is to say essentially `sodium-free`.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

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.

Pharmacokinetic interactions

Effect of other medicinal products on vamorolone

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no available data from the use of vamorolone in pregnant women. Animal reproductive toxicity studies with vamorolone have shown reproductive toxicity (see section°5.3). Glucocorticoids have been associated with various types of malformations (palate cleft, skeletal malformations) in animal studies.

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.

Breast-feeding

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.

Fertility

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).

4.7. Effects on ability to drive and use machines

AGAMREE has no influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

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).

Tabulated list of adverse reactions

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

Description of selected adverse reactions

Cushingoid features

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

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).

Weight gain

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).

Withdrawal signs and symptoms

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).

Paediatric population

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 of suspected adverse reactions

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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