Efmody

/ Medomie Pharma Ltd, Israel

Treatment should be initiated by physicians experienced in the management of CAH.
As maintenance therapy the dose must be individualised according to the response of the individual patient. The lowest possible dose should be used.
Monitoring of the clinical response is necessary and patients should be observed closely for signs that might require dose adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, changes in electrolytes particularly hypokalaemia, individual responsiveness to the medicinal product, and the effect of stress (e.g. surgery, infection, trauma). As the treatment has a modified-release profile, blood tests are used to monitor clinical response, assessment of the evening dose should be done with a morning blood test and assessment of the morning dose should be done with an early afternoon blood test.
During excessive physical and/or mental stress it may be necessary to increase the dose of modified-release hydrocortisone, and/or add additional immediate release hydrocortisone especially in the afternoon or evening.
Dose adjustments should be considered in case of concomitant use of potent CYP3A4 inducers or inhibitors.
Treatment in CAH
Recommended replacement doses of hydrocortisone are 10-15 mg/m2/day in adolescents aged 12 years and over who have not completed growth, and 15-25 mg/day in adolescents who have completed growth and adult patients with CAH. In patients with some remaining endogenous cortisol production a lower dose may be sufficient.
At initiation the total daily dose should be split into two doses with two thirds to three quarters of the dose given in the evening at bedtime and the rest given in the morning. Patients should then be titrated based on their individual response.
The morning dose should be taken on an empty stomach at least 1 hour before a meal and the evening dose taken at bedtime at least 2 hours after the last meal of the day.
A starting dose exceeding 40 mg per day of hydrocortisone is not recommended.
During serious trauma, intercurrent illness or periods of stress.
In severe situations, an increase in dose is immediately required and oral administration of hydrocortisone must be replaced with parenteral treatment.
In less severe situations when parenteral administration of hydrocortisone is not required, during periods of physical and/or mental stress, additional immediate release hydrocortisone at the same total daily dose as modified-release hydrocortisone should be given in three divided doses; this medicinal product should be continued as well with the usual regimen (i.e. a doubled daily dose of hydrocortisone) to allow for easy return to the normal replacement dose of Efmody once additional hydrocortisone is no longer required.
In case of long-term increases in hydrocortisone daily dose due to prolonged periods of stress or illness, the additional hydrocortisone should be carefully weaned off.
See prescribing information for full details.

Treatment of congenital adrenal hyperplasia (CAH) in adolescents aged 12 years and over and adults.

Hypersensitivity to the active substance or to any of the excipients.

Adrenal crisis
Acute adrenal insufficiency may develop in patients with known adrenal insufficiency who are on inadequate daily doses or in situations with increased cortisol need. Sudden discontinuation of therapy with hydrocortisone risks triggering an adrenal crisis and death.
During adrenal crisis parenteral, preferably intravenous administration of hydrocortisone in high doses, together with sodium chloride 9 mg/ml (0.9%) solution for infusion, should be administered according to current treatment guidelines.
Pre-operatively, during serious trauma or during intercurrent illness
Pre-operatively, anaesthetists must be informed if the patient is taking corticosteroids or has
previously taken corticosteroids.
Parenteral administration of hydrocortisone is warranted during transient illness episodes such as severe infections, in particular gastroenteritis associated with vomiting and/or diarrhoea, high fever of any aetiology or extensive physical stress, such as for instance serious accidents and surgery under general anaesthesia.
In less severe situations when parenteral administration of hydrocortisone is not required, for instance low grade infections, moderate fever of any aetiology and stressful situations such as minor surgical procedures, there should be high awareness of the risk of developing acute adrenal insufficiency.
Infections
Infection should not be more likely at a replacement dose of hydrocortisone, but all infections should be taken seriously, and an increase in steroid dose be initiated early. Patients with CAH are at risk of life-threatening adrenal crisis during infection so clinical suspicion of infection should be high and specialist advice should be sought early.
Immunisation
Treatment schedules of corticosteroids for people with CAH do not cause immunosuppression and are not, therefore, contraindications for administration of live vaccines.
Undesirable effects of corticosteroid replacement therapy
Most undesirable effects of corticosteroids are dose and duration of exposure related. Undesirable effects are therefore less likely when using corticosteroids as replacement therapy.
Impaired glucose tolerance and diabetes are associated with treatment with glucocorticoids.
All glucocorticoids increase calcium excretion and reduce the bone-remodelling rate. Long-term glucocorticoid replacement therapy may therefore reduce bone mineral density.
Patients should be warned that potentially severe psychiatric adverse reactions; euphoria, mania, psychosis with hallucinations and delirium have been seen in adult patients at replacement doses of hydrocortisone. Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure, although
dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary.
Patients should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients should also be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.
Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroids.
Gastric emptying and motility disorders
Modified-release formulations are not recommended in patients with increased gastrointestinal motility, i.e. chronic diarrhoea, due to the risk of impaired cortisol exposure. There are no data in patients with confirmed slow gastric emptying or decreased motility disease/disorder. The clinical response should be monitored in patients with these conditions.
Growth retardation
Corticosteroids may cause growth retardation in childhood and adolescence; this may be irreversible.
Treatment should be limited to the minimum dose required to achieve desired clinical response and when reduction in dose is possible, the reduction should be gradual. Excessive weight gain with decreased height velocity or other symptoms or signs of Cushing syndrome indicate excessive glucocorticoid replacement. Children require frequent assessment to assess growth, blood pressure, and general well-being.
Accelerated sexual maturation
Adolescents with CAH may show accelerated sexual maturation. Patients should be closely
monitored; and if signs of early puberty or accelerated sexual maturation are present, an increase in dose should be considered. Careful and regular monitoring of adolescent patients with dose adjustment according to the response of the individual patient is recommended.
Visual disturbance
Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy which have been reported after use of systemic and topical corticosteroids.
Precaution
In both men and women who have lower fertility due to CAH, fertility may be restored shortly after beginning the treatment, which can lead to unexpected pregnancies.
See prescribing information for more details.

Very common: Fatigue.
Common: Adrenal insufficiency including acute events, increased appetite, decreased appetite, impaired fasting glucose, insomnia, abnormal dreams, depressed mood,
sleep disorder, headache, dizziness, carpal tunnel syndrome, paraesthesia, nausea, abdominal pain upper, acne, hair growth abnormal, arthralgia, muscle fatigue, myalgia, pain in extremity, asthenia, weight increased, renin increased.
See prescribing information for more details.

Hydrocortisone is metabolised by cytochrome P450 3A4 (CYP3A4). Concomitant administration of medicinal products that are inhibitors or inducers of CYP3A4 may therefore lead to unwanted alterations in serum concentrations of hydrocortisone with the risk of adverse reactions, particularly adrenal crisis.
Medicinal products inducing CYP3A4, requiring a potential increase in Hydrocortisone dosing, include but are not limited to:
– Anticonvulsants: phenytoin, carbamazepine and oxcarbazepine
– Antibiotics: rifampicin and rifabutin
– Barbiturates including phenobarbital and primidone
– Antiretroviral medicinal products: efavirenz and nevirapine
– Herbal medicinal products such as St. John’s Wort
Medicinal products/substances inhibiting CYP3A4, requiring a potential decrease in hydrocortisone dosing, include but are not limited to:
– Anti-fungals: itraconazole, posaconazole, voriconazole
– Antibiotics: erythromycin and clarithromycin
– Antiretroviral medicinal products: ritonavir
– Grapefruit juice
– Liquorice
The desired actions of hypoglycaemic medicinal products including insulin are antagonised by corticosteroids.
See prescribing information for more details.

Pregnancy
Hydrocortisone crosses the placenta. Hydrocortisone is preferentially metabolised by placental 11βHSD2 to inactive cortisone reducing the fetal exposure. There are no indications that replacement therapy with hydrocortisone in pregnant women is associated with adverse consequences for the fetus.
Hydrocortisone for replacement therapy can be used during pregnancy.
See prescribing information for more details.
Breast-feeding
Hydrocortisone is excreted in breast milk. However, the doses of hydrocortisone used for replacement therapy probably do not clinically significantly affect the child. Hydrocortisone for replacement therapy can be used during breast-feeding.

Reports of acute toxicity and/or deaths following hydrocortisone overdose are rare. No antidote is available. Treatment is probably not indicated for reactions due to chronic poisoning unless the patient has a condition that would render him/her unusually susceptible to ill effects from hydrocortisone. In which case, symptomatic treatment should be instituted as necessary.

The capsules should not be chewed as chewing the capsule could affect the release profile.
Keep the bottle tightly closed in order to protect from moisture.