AGAMREE 40mg / ml oral suspension medication leaflet

AGAMREE 40 mg/ml oral suspension

Each ml of suspension contains 40 mg of vamorolone.

The suspension contains 1 mg sodium benzoate (E 211) in each ml.

For the full list of excipients, see section 6.1.

Oral suspension.

White to off-white suspension.

AGAMREE is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients aged4 years and older.

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

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 to6 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 table6 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 ml12-13 72 1.8 48 1.2 24 0.614-15 84 2.1 56 1.4 28 0.716-17 96 2.4 64 1.6 32 0.818-19 108 2.7 72 1.8 36 0.920-21 120 3 80 2 40 122-23 132 3.3 88 2.2 44 1.124-25 144 3.6 96 2.4 48 1.226-27 156 3.9 104 2.6 52 1.328-29 168 4.2 112 2.8 56 1.430-31 180 4.5 120 3 60 1.532-33 192 4.8 128 3.2 64 1.634-35 204 5.1 136 3.4 68 1.736-37 216 5.4 144 3.6 72 1.838-39 228 5.7 152 3.8 76 1.940 kg andabove 240 6 160 4 80 2

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

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 of40 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.

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

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 bedispensed directly into the mouth.

The oral syringe should be disassembled after use, rinsed under running cold tap water and air dried. Itshould be stored in the box until next use. An oral syringe may be used for up to 45 days, then itshould 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).

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 thetreatment (see section 4.4).

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 forendocrine 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 persistfor months after discontinuation of prolonged therapy. The degree of chronic adrenal insufficiencyproduced 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 increasedstress or if vamorolone dose is reduced or withdrawn abruptly. This condition can be fatal. Symptomsof 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 (seesection 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 ofadrenal crisis. There is no data available on the effects of increasing AGAMREE dose for situations ofincreased stress.

The patient should be advised to carry the Patient Alert Card providing important safety information tosupport early recognition and treatment of adrenal crisis.

A steroid “withdrawal syndrome”, seemingly unrelated to adrenocortical insufficiency, may also occurfollowing abrupt discontinuation of glucocorticoids. This syndrome includes symptoms such asanorexia, nausea, vomiting, lethargy, headache, fever, joint pain, desquamation, myalgia, and/orweight loss. These effects are thought to be due to the sudden change in glucocorticoid concentrationrather 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 dosereduction. Patients previously on chronic glucocorticoids should switch to AGAMREE 6 mg/kg/day tominimise the risk for adrenal crisis.

Vamorolone is associated with dose-dependent increase in appetite and weight gain, mainly in the firstmonths of treatment. Age-appropriate dietary advice should be provided before and during treatmentwith 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 inhyperthyroid patients. It is unknown, whether vamorolone is affected in the same way, but changes inthyroid status of the patient may necessitate a dose adjustment.

Ophthalmic effects

Glucocorticoids may induce posterior subcapsular cataracts, glaucoma with potential damage to theoptic nerves, and may increase the risk of secondary ocular infections caused by bacteria, fungi, orviruses.

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 toinfections and their severity. Activation of latent infections or exacerbation of intercurrent infectionscould occur. The clinical presentation may often be atypical and serious infections may be masked andmay 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 clinicalstudies, 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 beapplied in patients with symptoms of infection while on chronic treatment with vamorolone.

Supplementation with hydrocortisone should be considered in patients presenting with moderate orsevere 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 clinicalstudies, long-term data is limited. Blood glucose should be monitored at regular intervals in patientschronically 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 AGAMREEtreatment.

For patients without a history of chicken pox or vaccination, vaccination against varicella zoster virusshould 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 haveor 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 whentreating patients with known hypersensitivity to glucocorticoids.

Vamorolone has not been studied in patients with severe pre-existing hepatic injury (Child-Pughclass C) and must not be used in these patients (see section 4.3).

UGT substrates

The potential for drug-drug-interactions involving UGTs has not been fully evaluated, therefore allinhibitors of UGTs should be avoided as concomitant medication and should be used with caution ifmedically required.

This medicinal product contains 1 mg sodium benzoate in each 1 ml which is equivalent to100 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 incombination with mineralocorticoid receptor antagonist may increase the risk of hyperkalaemia. Nocases of hyperkalaemia have been observed in patients using vamorolone alone or in combination witheplerenone or spironolactone. Monitoring potassium levels one month after starting a combinationbetween vamorolone and a mineralocorticoid receptor antagonist is recommended. In case ofhyperkalaemia, a reduction of the dose of the mineralocorticoid receptor antagonist should beconsidered.

Effect of other medicinal products on vamorolone

Concomitant administration with the strong CYP3A4 inhibitor itraconazole led to an increase of thevamorolone area under the plasma concentration time curve of 1.45-fold in healthy subjects. Therecommended dose of vamorolone when administered with strong CYP3A4 inhibitors (e.gtelithromycin, 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, thereforealternative 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 theplasma concentration of vamorolone may be decreased relevantly.

There are no available data from the use of vamorolone in pregnant women. Animal reproductivetoxicity studies have not been conducted with vamorolone. Glucocorticoids were associated in animalstudies to various types of malformations (palate cleft, skeletal malformations), however the relevancein humans is unknown.

AGAMREE should not be used during pregnancy unless the clinical condition of the woman requirestreatment 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 thenewborns/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 aredose-dependent, usually reported in the first months of treatment and tend to decline or stabilise overtime with continuous treatment.

Vamorolone leads to the suppression of the hypothalamic-pituitary-adrenal axis, which correlates withdose and the duration of treatment. Acute adrenal insufficiency (adrenal crisis) is a serious effect thatcan occur during a period of increased stress or if the vamorolone dose is reduced or withdrawnabruptly (see section 4.4).

The adverse reactions are listed below according to MedDRA system organ class and frequency. Thetable contains adverse reactions in patients treated in the placebo-controlled study for patients treatedwith 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 theavailable data).

Table 2: Adverse reactions

System Organ Class (SOC) Adverse reaction (Preferred Frequencyterm)

Endocrine disorders Cushingoid Very common

Metabolism and nutrition Weight increased Very commondisorders Increased appetite

Psychiatric disorders Irritability Very common

Gastrointestinal disorders Vomiting Very common

Abdominal pain Common

Abdominal pain upper Common

Diarrhoea Common

Nervous system disorders Headache Common

Cushingoid features

Cushingoid features (hypercortisolism) was the most frequently reported adverse reaction withvamorolone 6 mg/kg/day (28.6%). The frequency of cushingoid features was lower in the vamorolone2 mg/kg/day group (6.7%). In the clinical study, cushingoid features were reported as mild tomoderate “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 to12 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 withvamorolone 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, nopatient in 2 mg/kg/day or placebo). The majority of behaviour problems occurred in the first 3 monthsof treatment and resolved without treatment discontinuation. Between month 6 and month 12, thefrequency of behaviour problems decreased in both vamorolone doses (10.7% for vamorolone6 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 weightgain in the vamorolone 6 mg/kg/day group were reported in the first 6 months of treatment (17.9% inmonth 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 duringtreatment with AGAMREE in line with general recommendations for nutrition management in patientswith DMD (see section 4.4).

Withdrawal signs and symptoms

Abruptly reducing or withdrawing the daily dose of vamorolone following prolonged treatment formore 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 infrequency 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 thoseseen in 4 to 7-year old patients. There is no available information on the effects of vamorolone onpubertal 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. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Glucocorticoids, ATC code: H02AB18

Vamorolone is a dissociative corticosteroid that selectively binds to the glucocorticoid receptor, whichtriggers anti-inflammatory effects via inhibition of NF-kB mediated gene transcripts, but leads to lesstranscriptional activation of other genes. In addition, vamorolone inhibits the activation of themineralocorticoid receptor by aldosterone. Due to its specific structure, vamorolone is likely not asubstrate for 11ß-hydroxysteroid dehydrogenases and is therefore not subject to local tissueamplification. The precise mechanism by which vamorolone exerts its therapeutic effects in patientswith DMD is unknown.

Vamorolone produced a dose-dependent decrease in morning cortisol levels in the clinical studies. Adose-dependent increase in haemoglobin, haematocrit values, erythrocytes, leukocyte counts andlymphocyte counts was observed with in clinical studies with vamorolone. No relevant changes inmean neutrophil counts or immature granulocytes were observed. High density lipoprotein (HDL)cholesterol and triglycerides values increased in a dose-dependent manner. There was no relevanteffect on glucose metabolism up to 30 months of treatment.

Unlike corticosteroids, vamorolone did not result in a reduction of bone metabolism as measured bybone turnover markers, nor in a significant reduction in lumbar vertebral bone mineralisationparameters by Dual-Energy X-Ray Absorptiometry (DXA) after 48 weeks in the clinical studies. Therisk for bone fractures in patients with DMD treated with vamorolone has not been established.

The efficacy of AGAMREE for the treatment of DMD was evaluated in Study 1, a multi-centre,randomised, double-blind, parallel-group, placebo- and active-controlled study of 24 weeks durationfollowed by a double-blind extension phase. The study population consisted of 121 male paediatricpatients 4 to < 7 years of age at time of enrolment in the study who were corticosteroid naïve andambulatory, with a confirmed diagnosis of DMD.

Study 1 randomised 121 patients to one of the following treatments: vamorolone 6 mg/kg/day(n = 30), vamorolone 2 mg/kg/day (n = 30), active comparator prednisone 0.75 mg/kg/day (n = 31), orplacebo (n = 30). After 24 weeks (Period 1, primary efficacy analysis), patients who had beenreceiving prednisone or placebo were re-assigned according to an initially defined randomisationscheme to either vamorolone 6 mg/kg/day or 2 mg/kg/day for an additional 20 weeks of treatment(Period 2).

In Study 1, efficacy was evaluated by assessing the change from Baseline to Week 24 in Time to

Stand Test (TTSTAND) velocity for vamorolone 6 mg/kg/day compared to placebo. A pre-specifiedhierarchical analysis of relevant secondary endpoints consisted of change from baseline in TTSTANDvelocity for the vamorolone 2 mg/kg/day vs placebo group, change from baseline in 6 Minute Walk

Test (6MWT) distance for vamorolone 6 mg/kg/day followed by 2 mg/kg/day vs placebo.

Treatment with vamorolone 6 mg/kg/day and 2 mg/kg/day resulted in a statistically significantimprovement in change in TTSTAND velocity and change in 6MWT distance between baseline and

Week 24 compared to placebo (see table 2). Study 1 was not designed to maintain the overall Type Ierror rate for comparisons of each vamorolone group versus prednisone, therefore a global assessmentof treatment differences across endpoints, expressed in percentual change from baseline with 95%confidence intervals is presented in Figure 1 for these endpoints.

Table 3: Analysis of change from baseline with vamorolone 6 mg/kg/day or vamorolone2 mg/kg/day compared to placebo at Week 24 (Study 1)

TTSTAND velocity (rises/s)/Vam Vam Pred

TTSTAND in Seconds (s/rise) Placebo 2 mg/kg/day 6 mg/kg/day 0.75 mg/kg/day

Baseline mean rises/s 0.20 0.18 0.19 0.22

Baseline mean s/rise 5.555 6.07 5.97 4.92

Mean change at 24 weeks

Rises /s -0.012 0.031 0.046 0.066

Improvement in s/rise -0.62 0.31 1.05 1.24

Difference versus placebo* 0.043 0.059

Rises /s - (0.007 ; 0.079) (0.022 ; 0.095) not givens/rise 0.927 (0.042 ; 1.67 (0.684 ; not given1.895) 2.658)p-value - 0.020 0.002 not given6MWT distance (meters) Placebo Vam Vam Pred2 mg/kg/day 6 mg/kg/day 0.75 mg/kg/day

Baseline mean (m) 354.5 316.1 312.5 343.3

Mean change at 24 weeks -11.4 +25.0 +24.6 +44.1

Difference versus placebo* - 36.3 35.9(8.3 ; 64.4) (8.0 ; 63.9) not givenp-value - 0.011 0.012 not given

Mean changes and differences are model-based least-squares means (LSM) and mean differences.

Positive numbers indicate improvement as compared with the baseline value. *Differences in LSM presented with 95% CI

Figure 1 Comparisons between vamorolone and prednisone in timed tests for motorfunction, analysed as percentual changes from baseline (mITT-1 population)

TTSTANDV (VAM6 vs PDN)6MWT (VAM6 vs PDN)

TTSTANDV (VAM2 vs PDN)6MWT (VAM2 vs PDN)

- 40 -20 0 20 40% difference (95% CI)

Test data are standardised by using the percentual change from baseline as the endpoint. The percentile changes arecalculated as (value at visit - baseline value)/baseline value x 100%. VAM: Vamorolone, PDN: Prednisone

All the percent- change values from the two endpoints are entered to a single statistical model (MMRM)

For vamorolone 6 mg/kg/day, the improvements in all tested measurements of lower limb functionseen at 24 weeks were largely maintained for 48 weeks of treatment, while results across the efficacyoutcome measures for the vamorolone 2 mg/kg/day dose were rather inconsistent with declines inrelevant functional outcome parameters at Week 48, i.e. TTSTAND velocity and 6MWT, reachingclinically significant differences compared to vamorolone 6 mg/kg/day but only minimal decrease inthe NSAA score.

Patients who switched during Study 1 from prednisone 0.75 mg/kg/day in Period 1 to vamorolone6 mg/kg/day in Period 2 appeared to retain the benefit in terms of these motor function endpoints,while declines were observed in patients that switched to vamorolone 2 mg/kg/day.

At baseline, children in vamorolone groups were smaller in height (median -0.74 SD and -1.04 SD inheight z-score for 2 mg/kg/day and 6 mg/kg/day groups, respectively) than children on placebo(-0.54 SD) or prednisone 0.75 mg/kg/day (-0.56 SD). The change in height percentile and height

Z-score was similar in children treated with vamorolone or placebo over 24 weeks while theydecreased with prednisone. The height percentiles and Z-scores did not decrease with vamorolone overthe 48-week study period in Study 1. Switching from prednisone after 24 weeks in Period 1 tovamorolone in Period 2 led to an increase in mean and median height z-score up to Week 48.

Endpoint (Comparison)

Vamorolone is well absorbed and distributes quickly into tissues. After oral administration with food,the median Tmax is about 2 hours (range 0.5 to 5 hours).

Co-administration of vamorolone with a meal reduced Cmax by up to 8% and delayed Tmax by 1 hour,relative to administration under fasting conditions. The overall systemic absorption as measured by

AUC was increased by up to 14% when vamorolone was taken with food. The observed differences inabsorption do not lead to clinically relevant differences in exposure and therefore vamorolone can beadministered either with or without food.

The apparent volume of distribution of vamorolone for a DMD patient with a body weight of 20 kgtaking vamorolone is 28.5 L based on the population PK analysis. Protein binding is 88.1% in vitro.

The blood to plasma ratio is approximately 0.87.

Vamorolone is metabolised via multiple Phase I and Phase II pathways, such as glucuronidation,hydroxylation, and reduction. The main plasma and urine metabolites are formed through directglucuronidation as well as hydrogenation with subsequent glucuronidation. The involvement ofspecific UGT and CYP enzymes in the metabolism of vamorolone has not been conclusivelydemonstrated.

The major route of elimination is by metabolism with subsequent excretion of metabolites into urineand faeces. Vamorolone clearance for a DMD patient with a body weight of 20 kg taking vamoroloneis 58 L/h based on the population PK analysis. The terminal elimination half-life of vamorolone inchildren with DMD is approximately 2 hours.

Approximately 30% of vamorolone dose is excreted in faeces (15.4% unchanged) and 57% ofvamorolone dose is excreted in urine as metabolites (< 1% unchanged). The major metabolites in urineare glucuronides.

The PK are linear and vamorolone exposure increases proportionally with either single or multipledoses. Vamorolone does not accumulate with repeated administration.

The effect of moderate hepatic impairment (Child-Pugh class B) of vamorolone was studied inhumans. Vamorolone Cmax and AUC0inf values were approximately 1.7- and 2.6-fold higher insubjects with moderate hepatic impairment compared to age, weight and sex matched healthy adults.

AGAMREE dose should be reduced in patients with moderate hepatic impairment to 2 mg/kg/day forpatients up to 40 kg and to 80 mg for patients with a body weight of 40 kg and above

Based on the available data, the increase in vamorolone exposure is proportional to the severity ofhepatic dysfunction. Patients with mild hepatic impairment (Child-Pugh class A) are not expected tohave a significant increase in exposure and therefore no dose adjustment is recommended.

There is no experience with vamorolone in patients with severe hepatic impairment (Child-Pughclass C) and vamorolone should not be administered to these patients (see section 4.3).

There is no clinical experience in patients with renal impairment. Vamorolone is not excretedunchanged via the kidney, and increases in exposure due to renal impairment are considered unlikely.

Vamorolone is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, MATE1, or

BSEP. Vamorolone shows weak inhibition of OAT3 and MATE2-K transporters in vitro. Vamoroloneis not a substrate of P-gp, BCRP, OATP1A2, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1,

MATE2-K or BSEP.

At steady state, the geometric mean Cmax and the geometric mean AUC of vamorolone in children(ages 4-7 years) were estimated by Population PK to 1200 ng/ml (CV%=26.8) and 3650 ng/ml.hrespectively after administration of 6 mg/kg vamorolone daily.

Repeated vamorolone administration resulted in transient increases of triglycerides and cholesterol aswell as liver enzymes in mice and dogs. Focal hepatic inflammation/necrosis observed in both speciesmight have developed secondary to the hepatocellular hypertrophy and vacuolation containingglycogen and lipid accumulations that likely reflect the stimulation of gluconeogenesis.

Long-term vamorolone dosing also caused adrenal cortex atrophy in mice and dogs, which areascribable to the known suppression of the hypothalamic-pituitary-adrenal axis by glucocorticoidagents.

The primary anti-inflammatory activity of vamorolone further accounted for mild to moderatelymphocyte depletion in spleen, thymus and lymph nodes of both species. The adverse liver andadrenal gland findings and the lymphoid changes in mice and dogs developed with no safety marginsto the MRHD based on AUC.

Vamorolone did not exert any genotoxic potential in the standard test battery. Carcinogenicity studieshave not been conducted with vamorolone, but the absence of pre-neoplastic lesions in long-termtoxicity studies and experience with other glucocorticoid agents do not suggest a particularcarcinogenic hazard.

No standard reproductive and developmental toxicity studies have been performed. Vamorolone didnot adversely affect the development of sperm and reproductive tissues in the chronic toxicity study inmice. Following chronic dosing in dogs, incompletely reversible spermatocyte/spermatiddegenerations were observed in testes leading to oligospermia and germ cell debris in epididymides.

Furthermore, the prostate glands were reduced and contained less secretory product.

In female animals, long-term repeated dosing in dogs additionally resulted in partially reversiblebilateral absence of corpora lutea in the ovaries. The inhibition of male and female fertility isattributable to the known interference of long-term glucocorticoid treatment with the hypothalamus-pituitary-gonadal axis and developed without AUC-based safety margin to humans at the MRHD.

Juvenile toxicity

The main target organs of vamorolone in male and female juvenile mice overlap with those of adultmice such as adrenal cortical atrophy and vamorolone-related adverse hepatocellulardegeneration/necrosis.

Vamorolone-related effects exclusively observed in juvenile mice were non-adverse tibia and bodylengths reductions in male and female animals and were attributed to the induction of slower growths.

In addition, acinar cell hypertrophy of mandibular salivary glands were detected in female animals.

Whereas growth retardation is a well known effect associated with glucocorticoid treatment ofchildren, the relevance of the salivary gland findings for children is unknown. At the no observedadverse effect level (NOAEL) for general toxicity in male and female juvenile mice, no safety marginwith respect to human exposure at the MRHD exists.

Citric acid (monohydrate) (E 330)

Disodium phosphate (E 339)

Glycerol (E 422)

Orange flavour

Purified water

Sodium benzoate (E 211)

Sucralose (E 955)

Xanthan gum (E 415)

Hydrochloric acid (for pH adjustment)

Not applicable.

Before opening3 years.

After first opening3 months.

Store in a refrigerator (2 °C - 8 °C) in upright position

This medicinal product does not require any special temperature storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

Amber coloured glass bottle containing 100 ml oral suspension with a polypropylene tamper evidentchild resistant closure with low density polyethylene liner.

Each pack contains one bottle, one press-in bottle adapter (low density polyethylene) and two identicaloral syringes (low density polyethylene) graduated from 0 to 8 ml by increments of 0.1 ml.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Each oral syringe supplied with AGAMREE may be used for up to 45 days.

Use with an enteral feeding tube:

AGAMREE can be administered through an enteral feeding tube (12 - 24 fr) without modification ordilution of the usual prescribed dose. AGAMREE should not be mixed with the feeding formula orother products. Flushing the enteral feeding tube with a minimum of 20 ml of water before and afteradministration of AGAMREE should be performed.

Santhera Pharmaceuticals (Deutschland) GmbH

Marie-Curie Strasse 8

D-79539 Lörrach

GERMANYoffice@santhera.com

EU/1/23/1776/001

Date of first authorisation: 14 December 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu,.