HYDROCORTISONE 5 MG / 5 ML ORAL SOLUTION, HYDROCORTISONE 5 MG / 5 ML ORAL SOLUTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Hydrocortisone 5 mg/5 ml Oral Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml of the 5 mg/5 ml oral solution contains 5 mg hydrocortisone (as hydrocortisone sodium phosphate).

Excipients with known effect

Sodium methyl parahydroxyben­zoate: 1.20 mg per 1 ml dose.

Sodium propyl parahydroxyben­zoate: 0.10 mg per 1 ml dose.

Sodium: 1.24 mg per 1 ml dose.

Propylene glycol: 0.80 mg per 1 ml dose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral Solution

Clear, colourless to yellowish solution with orange odour.

4.1 Therapeutic indications

Replacement therapy in adrenal insufficiency in infants, children and adolescents (from 1 month to <18 years old).

4.2 Posology and method of administration

Posology

Dosage must be individualised according to the response of the individual patient. The lowest possible dosage should be used.

Monitoring of the clinical response is necessary and patients should be observed closely for signs that might require dosage adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness, and the effect of stress (e.g. surgery, infection, trauma). During stress it may be necessary to increase the dosage temporarily.

Replacement therapy in primary and secondary adrenal insufficiency

Hydrocortisone is given as replacement therapy by oral administration of the solution according to clinical practice, in a dose to be titrated against individual clinical response.

Recommended replacement doses of hydrocortisone are 8–10 mg/m2/day for patients with adrenal insufficiency alone and 10–15 mg/m2/day in patients with congenital adrenal hyperplasia (CAH), typically divided into 3 doses, adjusted according to response.

In patients with some remaining endogenous cortisol production a lower dose may be sufficient.

In situations when the body is exposed to excessive physical and/or mental stress, patients may need an increased dose, especially in the afternoon or evening.

Pre-operatively, during serious trauma or illness in patients with known adrenal insufficiency or doubtful adrenal reserve.

Anaesthetists must be informed if the patient is taking corticosteroids or has previously taken corticosteroids.

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, and the normal oral daily replacement dose should be increased temporarily; the hydrocortisone total daily dose should be increased by doubling or tripling the usual dose. Once the intercurrent illness episode is over, patients can return to the normal replacement dose of hydrocortisone.

In severe situations, an increase in dose is immediately required and oral administration of hydrocortisone must be replaced with parenteral treatment.

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 serious accidents and surgery under general anaesthesia. Where parenteral hydrocortisone is required, the patient should be treated in a facility with resuscitation facilities in case of an evolving adrenal crisis.

Hepatic impairment

The elimination of hydrocortisone may be slower in connection with hepatic diseases, and dose adjustment may therefore be necessary in patients with hepatic impairment.

Method of administration

Hydrocortisone Oral Solution is for oral use.

A 5 ml graduated oral syringe with intermediate graduations of 0.1 ml and a “PressIn” Bottle Adapter (PIBA) are provided with the product.

1. Open the bottle and at first use insert the “Press-In” Bottle Adapter (PIBA).

2. Insert the syringe into the PIBA and draw out the required volume from the inverted bottle.

3. Remove the filled syringe from the bottle in the upright position.

4. Discharge the syringe contents into the mouth. Repeat steps 2 to 4 as needed to achieve the required dose.

5. Rinse the syringe and replace the cap on the bottle (PIBA remains in place).

Note

If necessary, Hydrocortisone oral solution can be administered via intragastric feeding tubes (nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes). Tubes should be rinsed with 5 ml of water immediately after administration. For further information see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Patients should carry ‚steroid treatment‘ or/and ‘steroid emergency’ cards, depending upon indication and exogenous steroid dose. The steroid cards give clear guidance on the precautions to be taken to minimise risk and provide details of prescriber, drug, dosage, and the duration of treatment.

Adrenal crisis

Where a child is vomiting or acutely unwell parenteral hydrocortisone should be started without delay, carers should be trained in administering this in an emergency.

Sudden discontinuation of therapy with Hydrocortisone Oral Solution risks triggering an adrenal crisis and death. Medicinal product-induced secondary adrenocortical insufficiency may result from too rapid a withdrawal of corticosteroids and may be minimised by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, corticosteroid therapy should be reinstated.

Infections and immunisation

Replacement schedules of corticosteroids for people with adrenal insufficiency do not cause immunosuppression and are not, therefore, contraindications for administration of live vaccines.

Infection should not be more likely at a replacement dose of hydrocortisone, but all infections should be treated seriously and stress dosing of steroid initiated early (see section 4.2). Patients with adrenal insufficiency 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.

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.

Corticosteroids may cause growth retardation in infancy, childhood and adolescence; this may be irreversible. Treatment should be limited to the minimum dosage required to achieve desired clinical response and when reduction in dosage 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. Infants require frequent assessment and should be evaluated at a minimum every 3 to 4 months to assess growth, blood pressure, and general wellbeing.

Bone mineral density may be impacted in children when higher doses of replacement steroids are used. The lowest appropriate dose of steroid according to the response of the individual patient should be used.

Patients/and or carers 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 (see section 4.8). Symptoms typically emerge within a few days or weeks of starting the treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5), 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/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers 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, especially when a patient has a history of allergies to medicinal products.

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.

Hydrocortisone 5 mg/5 ml Oral Solution

This medicinal product contains sodium methyl parahydroxybenzoate and sodium propyl parahydroxyben­zoate. May cause allergic reactions (possibly delayed).

This medicinal product contains 1.24 mg sodium per ml, equivalent to 0.06 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains 0.80 mg propylene glycol in each ml.

4.5 Interaction with other medicinal products and other forms of interaction

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 Oral Solution with the risk of adverse effects, particularly adrenal crisis. The need for dose adjustment when such medicinal products are used can be anticipated and patients should be closely monitored.

Medicinal products inducing CYP3A4, requiring a potential increase in Hydrocortisone Oral Solution 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

Medicinal products/substances inhibiting CYP3A4, requiring a potential decrease in Hydrocortisone Oral Solution dosing, include but are not limited to:

– Anti-fungals: itraconazole, posaconazole, voriconazole

– Antibiotics: erythromycin and clarithromycin

– Antiretroviral medicinal products: ritonavir

– Grapefruit juice

– Liquorice

4.6 Fertility, pregnancy and lactation

Pregnancy

Hydrocortisone for replacement therapy can be used during pregnancy. The ability of corticosteroids to cross the placenta varies between the different types of corticosteroids, however, hydrocortisone readily crosses the placenta.

Studies in animals have shown reproductive toxicity of corticosteroids (see section 5.3).

Breast-feeding

Hydrocortisone for replacement therapy can be used during breast-feeding.

Fertility

There are no data available for possible effects of Hydrocortisone Oral Solution on fertility.

4.7 Effects on ability to drive and use machines

Hydrocortisone Oral Solution has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Tabulated list of adverse reactions

The following adverse reactions have been reported in the scientific literature in adult patients for other hydrocortisone medicinal products when given as adrenal insufficiency replacement therapy with frequency not known (cannot be estimated from the available data).

Historical cohorts of adults treated from childhood for Congenital Adrenal Hyperplasia have been found to have reduced bone mineral density and increased fracture rates and growth retardation (see section 4.4) – it is unclear if these relate to hydrocortisone therapy using current replacement regimens.

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

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 biological half-life of hydrocortisone is about 100 minutes.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Corticosteroids for systemic use; Glucocorticoids. ATC code: H02AB09

Mechanism of action

Hydrocortisone is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally-occurring and synthetic, which are readily absorbed from the gastrointesti­nal tract.

Pharmacodynamic effects

Hydrocortisone is believed to be the principal corticosteroid secreted by the adrenal cortex. Naturally-occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. They are also used for their potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body’s immune responses to diverse stimuli.

5.2 Pharmacokinetic properties

Absorption

Following oral administration, hydrocortisone is rapidly absorbed from the gastrointesti­nal tract.

Distribution

90% or more of circulating hydrocortisone is reversibly bound to protein.

The binding is accounted for by two protein fractions. One, corticosteroid-binding globulin is a glycoprotein; the other is albumin.

Biotransformation and elimination

Hydrocortisone is metabolised in the liver and most body tissues to hydrogenated and degraded forms such as tetrahydrocortisone and tetrahydrocortisol which are excreted in the urine, mainly conjugated as glucuronides, together with a very small proportion of unchanged hydrocortisone.

The terminal half-life of hydrocortisone is about 1.5 hours.

No studies have been conducted in patients with hepatic or renal impairment.

5.3 Preclinical safety data

Administration of corticosteroids to pregnant animals can cause abnormalities of fetal development including cleft palate, intrauterine growth retardation and effects on brain growth and development.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium edetate

Sodium propyl parahydroxybenzoate (E217)

Sodium methyl parahydroxybenzoate (E219)

Sodium dihydrogen phosphate dihydrate (E339)

Orange flavour (including propylene glycol, triacetine, orange oil, ethyl butyrate and acetaldehyde)

Sucralose

Sodium Hydroxide (E524)

Purified Water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

After first opening use within 3 months.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

6.5 Nature and contents of container

Amber type III glass bottle safely closed with a child-resistant screw cap with tamper evident closure. Each bottle contains 100 ml or 150 ml of this medicinal product. Not all pack sizes may be marketed.

A 5 ml graduated oral syringe with intermediate graduations of 0.1 ml and a “pressin” syringe/bottle adapter are also provided.

6.6 Special precautions for disposal

Instructions for administration of Hydrocortisone 5 mg/5 ml Oral Solution via nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes.

1. Ensure the enteral feeding tube is free from any obstructions before administering this medicine.

2. Administer the required dose of Hydrocortisone oral solution into the tube using a suitable measuring device.

3. Immediately flush the tube with 5 ml of boiled cooled water.

Please note that studies have not been performed using an air flushing procedure. To ensure the correct dose is received by the patient, it is recommended that only water flushing is used.

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

7 MARKETING AUTHORISATION HOLDER

Regulis Consulting Limited

1st Floor St Peters House

Market Place, Tring

Hertfordshire

HP23 5AE, UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 20646/0041

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

18/03/2022