No Information Provided
No special precautions or antidotes are likely to be needed.
There is no clinical syndrome of acute overdosage with corticosteroids. Hydrocortisone is dialysable. In the event of overdosage, no specific antidote is available; treatment is supportive and symptomatic.
Reports of acute toxicity and/or deaths following hydrocortisone overdose are rare. No antidote is available. Symptoms may range from excitement/arousal to mania or psychosis. Signs include high blood pressure, elevated plasma glucose levels and hypokalaemia. 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.
Not applicable.
No information provided.
None known.
Not applicable.
Not applicable
None known.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most frequent adverse reactions reported for PANDEL during clinical trials were application site reactions, including burning in 4, stinging in 2, and moderate paresthesia in 1 out of 226 subjects.
Postmarketing ExperienceThe following adverse reactions have been identified during postapproval use of PANDEL because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
These adverse reactions are as follows:
Skin and Subcutaneous Tissue Disorders:rash, papulovesicular rash
Application Site Reactions: dryness, erythema, pruritus, allergic contact dermatitis.
The following local adverse reactions are reported with topical corticosteroids, and they may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infections, skin atrophy, striae, and miliaria.
Treatment with Efficort is usually well tolerated but treatment should be stopped if symptoms of hypersensitivity occur.
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 at www.mhra.gov.uk/yellowcard.
Since Efficort is normally employed on a short-term basis it is unlikely that side effects will occur; however, the possibility of side effects attributable to corticosteroid therapy should be recognised. Such side effects include:
| Adverse Reactions table | |
| System Organ Class | Frequency Not Known (Cannot be estimated from available data) |
| Infections and infestations | Opportunistic infection |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Kaposi's sarcoma (has been reported to occur in patients receiving corticosteroid therapy) |
| Blood and lymphatic system disorders | Leucocytosis |
| Immune system disorders | Drug hypersensitivity; Anaphylactic reaction; Anaphylactoid reaction |
| Endocrine disorders | Cushingoid; Hypopituitarism; Steroid withdrawal syndrome WITHDRAWAL SYMPTOMS - Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. However, this is more applicable to corticosteroids with an indication where continuous therapy is given ; A 'withdrawal syndrome' may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight |
| Metabolism and nutrition disorders | Metabolic acidosis; Sodium retention; Water retention; Alkalosis hypokalaemic; Dyslipidaemia; Glucose tolerance impaired; Increased insulin requirement (or oral hypoglycemic agents in diabetics); Lipomatosis; Increased appetite; Weight increased |
| Psychiatric disorders | Affective disorders (including Depression, Euphoric mood, Affect lability, Drug dependence, Suicidal ideation); Psychotic disorder (including Mania, Delusion, Hallucination, and aggravation of Schizophrenia); Mental disorder; Personality change; Confusional state; Anxiety; Mood swings; Abnormal behaviour; Insomnia; Irritability. |
| Nervous system disorders | Epidural lipomatosis; Increased intra-cranial pressure with papilloedema in children (pseudotumour cerebri) has been reported, usually after treatment withdrawal of hydrocortisone; Benign intracranial hypertension; Seizure; Amnesia; Cognitive disorder; Dizziness; Headache. |
| Eye disorders | Central serous chorioretinopathy ; Cataract; Glaucoma; Exophthalmos; Increased intra-ocular pressure, with possible damage to the optic nerve; Corneal or scleral thinning; Exacerbation of ophthalmic viral or fungal disease; |
| Ear and labyrinth disorders | Vertigo |
| Cardiac disorders | Cardiac failure congestive (in susceptible patients); Myocardial rupture following a myocardial infarction |
| Vascular disorders | Thrombosis including Thromboembolism; Hypertension; Hypotension |
| Respiratory, thoracic and mediastinal disorders | Pulmonary embolism; Hiccups |
| Gastrointestinal disorders | Peptic ulcer (with possible Peptic ulcer perforation and Peptic ulcer haemorrhage); Intestinal perforation; Gastric haemorrhage; Pancreatitis; Oesophageal ulceration; Oesophageal candidiasis; Abdominal distension; Abdominal pain; Diarrhoea; Dyspepsia; Nausea |
| Skin and subcutaneous tissue disorders | Angioedema; Hirsutism; Petechiae; Ecchymosis; Skin atrophy; Erythema; Hyperhidrosis; Skin striae; Rash; Pruritus; Urticaria; Acne; Skin hypopigmentation; Telangiectasia; Skin hyperpigmentation; |
| Musculoskeletal and connective tissue disorders | Muscular weakness; Myalgia; Myopathy; Muscle atrophy; Osteoporosis Osteonecrosis; Pathological fracture; Neuropathic arthropathy; Arthralgia; Growth retardation |
| Reproductive system and breast disorders | Menstruation irregular; Amenorrhoea |
| General disorders and administration site conditions | Impaired healing; Oedema peripheral; Fatigue Abscess sterile; Malaise; Injection site reaction |
| Investigations | Carbohydrate tolerance decreased; Blood potassium decreased; Urine calcium increased; Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood alkaline phosphatase increased; Blood urea increased; Suppression of reactions to skin tests* |
| Injury, poisoning and procedural complications | Spinal compression fracture; Tendon rupture (particularly of the Achilles tendon) |
* Not a MedDRA PT
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 at www.mhra.gov.uk/yellowcard.
Summary of the safety profile
Hydrocortisone is given as replacement therapy aimed at restoring normal cortisol levels. The adverse reaction profile in the treatment of adrenal insufficiency is therefore not comparable to that in other conditions requiring much higher doses of oral or parenteral glucocorticoids.
Overall, the frequency and type of adverse reactions were similar for Efficort once daily modified-release tablets and hydrocortisone tablets given three times daily in a 12-week study. Fatigue has been reported as very common.
Tabulated list of adverse reactions
A total of 80 patients (173 patient-years of data) have been treated with modified-release hydrocortisone in clinical studies. Adverse reactions from these studies and from postmarketing surveillance are listed below by system organ class and frequency as follows:
Very common (>1/10); Common (>1/100 to <1/10).
| MedDRA System Organ Class | Frequency of adverse reactions | |
| Very common | Common | |
| Nervous system disorders | Vertigo Headache | |
| Gastrointestinal disorders | Diarrhoea | Upper abdominal pain Nausea |
| Skin and subcutaneous tissue disorders | Pruritus Rash | |
| Musculoskeletal and connective tissue disorders | Arthralgia | |
| General disorders and administration site conditions | Fatigue | |
In addition the following adverse reactions have been reported for other hydrocortisone medicinal products given for indications other than adrenal insufficiency replacement therapy in higher doses (frequencies not known).
Immune system disorders
Activation of infection (tuberculosis, fungal and viral infections including herpes).
Endocrine disorders
Induction of glucose intolerance or diabetes mellitus.
Metabolism and nutrition disorders
Sodium and water retention and oedema tendency, hypertension, hypokalemia.
Psychiatric disorders
Euphoria and psychosis, insomnia.
Eye disorders
Increased intraocular pressure and cataract.
Gastrointestinal disorders
Dyspepsia and deterioration of existing gastric ulcer.
Skin and subcutaneous tissue disorders
Cushing-like symptoms, stria, ecchymoses, acne and hirsutism, impaired wound healing.
Musculoskeletal and connective tissue disorders
Osteoporosis with spontaneous fractures.
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 United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
Although uncommon at this dosage, irritation may occur.
Side effects are very unusual with Efficort, but long term frequent use may cause problems in some people. This is particularly so if the medicine is not used as directed. Although uncommon at this dosage, the following side effects may occur; unexpected fattening of the face, neck and body, periods may stop unexpectedly and hair starts to grow on the face (in women), dusky complexion with purple markings, local irritation.
A wide range of psychiatric reactions including affective disorders (such as irritable, euphoric, depressed and labile mood, and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations, and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown.
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 at:
www.mhra.gov.uk/yellowcard
Fluid And Electrolyte DisturbancesSodium retention
Fluid retention
Congestive heart failure in susceptible patients
Potassium loss
Hypokalemic alkalosis
Hypertension
Muscle weakness
Steroid myopathy
Loss of muscle mass
Osteoporosis
Tendon rupture, particularly of the Achilles tendon
Vertebral compression fractures
Aseptic necrosis of femoral and humeral heads
Pathologic fracture of long bones
Peptic ulcer with possible perforation and hemorrhage
Pancreatitis
Abdominal distention
Ulcerative esophagitis
Increases in alanine transaminase (ALT, SGPT), aspartate transaminase (AST, SGOT) and alkaline phosphatase have been observed following corticosteroid treatment. These changes are usually small, not associated with any clinical syndrome and are reversible upon discontinuation.
Impaired wound healing
Thin fragile skin
Petechiae and ecchymoses
Facial erythema
Increased sweating
May suppress reactions to skin tests
Increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment
Convulsions
Vertigo
Headache
Development of Cushingoid state
Suppression of growth in children
Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness
Menstrual irregularities
Decreased carbohydrate tolerance
Manifestations of latent diabetes mellitus
Increased requirements for insulin or oral hypoglycemic agents in diabetics
Posterior subcapsular cataracts
Increased intraocular pressure
Glaucoma
Exophthalmos
Negative nitrogen balance due to protein catabolism
There are no preclinical safety data of relevance to the consumer.
Carcinogenesis:
Hydrocortisone did not increase tumor incidences in male and female rats during a 2-year carcinogenicity study.
Mutagenesis:
Corticosteroids, a class of steroid hormones that includes hydrocortisone, are consistently negative in the bacterial mutagenicity assay. Hydrocortisone and dexamethasone induced chromosome aberrations in human lymphocytes in vitro and in mice in vivo. However, the biological relevance of these findings is not clear since hydrocortisone did not increase tumor incidences in male and female rats during a 2-year carcinogenicity study. Fludrocortisone (9α-fluorohydrocortisone, structurally similar to hydrocortisone) was negative in the human lymphocyte chromosome aberration assay.
Reproductive toxicity:
Corticosteroids have been shown to reduce fertility when administered to rats. Male rats were administered corticosterone at doses of 0, 10, and 25 mg/kg/day by subcutaneous injection once daily for 6 weeks and mated with untreated females. The high dose was reduced to 20 mg/kg/day after Day 15. Decreased copulatory plugs were observed, which may have been secondary to decreased accessory organ weight. The numbers of implantations and live fetuses were reduced. Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. In animal reproduction studies, glucocorticoids have been shown to increase the incidence of malformations (cleft palate, skeletal malformations), embryo-fetal lethality (e.g., increase in resorptions), and intra-uterine growth retardation. With hydrocortisone, cleft palate was observed when administered to pregnant mice and hamsters during organogenesis
Animal experiments have shown that prenatal exposure to very high doses of glucocorticoids can induce malformations (cleft palate, skeletal malformations). Animal studies have also shown that prenatal exposure to high doses of glucocorticoids (but lower than teratogenic doses) may be associated with increased risk of intrauterine growth retardation, cardiovascular disease in adulthood and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour.
None stated.
Studies performed with PANDEL indicate that it is in the medium range of potency as demonstrated in vasoconstrictor trials in healthy subjects when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.
Hypothalamic-Pituitary-Adrenal (HPA) Axis SuppressionIn an open label HPA axis suppression trial, 19 adult subjects (ages 23 to 82 years) with atopic dermatitis or plaque psoriasis covering greater than 20% Body Surface Area (BSA) were treated with PANDEL twice daily for 21 days and were assessed for HPA axis suppression. At baseline, the mean disease BSA involvement was 36%. The criterion for HPA axis suppression was a serum cortisol level of less than or equal to 18 micrograms per deciliter at 30-minutes after cosyntropin stimulation. Of these subjects, 15 were considered evaluable with respect to their adrenal axis function post-treatment. One of the evaluable subjects (6.7%) showed laboratory evidence of suppression on Day 22. This subject had psoriasis covering 48% of BSA at baseline and was reported to have received 98% of the twice-daily applications of PANDEL over the 21 day treatment period. It is not known if this subject had recovery of adrenal function because follow-up testing was not performed.
Efficort is a corticosteroid which has anti-inflammatory activity.
Pharmacotherapeutic group: Glucocorticoids, ATC code: H02AB09
Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids.
Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their anti-inflammatory effects in disorders of many organ systems
Hydrocortisone sodium succinate has the same metabolic and anti-inflammatory actions as hydrocortisone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. The highly water-soluble sodium succinate ester of hydrocortisone permits the immediate intravenous administration of high doses of hydrocortisone in a small volume of diluent and is particularly useful where high blood levels of hydrocortisone are required rapidly. Following the intravenous injection of hydrocortisone sodium succinate, demonstrable effects are evident within one hour and persist for a variable period.
Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune response to diverse stimuli.
The relative potency of methylprednisolone sodium succinate and hydrocortisone sodium succinate, as indicated by depression of eosinophil count, following intravenous administration, is five to one. This is consistent with the relative oral potency of methylprednisolone and hydrocortisone.
Pharmacotherapeutic group: Corticosteroids for systemic use, glucocorticoids. ATC code: H02AB09.
Pharmacodynamic action
Hydrocortisone is a glucocorticoid and the synthetic form of endogenously produced cortisol. Glucocorticoids are important steroids for intermediary metabolism, immune function, musculoskeletal and connective tissue and the brain. Cortisol is the principal glucocorticoid secreted by the adrenal cortex.
Naturally-occurring glucocorticoids (hydrocortisone and cortisol), which also have salt-retaining properties, are used as replacement therapy in adrenal insufficiency. 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.
Clinical efficacy
The pivotal study was a randomised, two-period 12-week crossover multi-centre trial in 64 patients with primary adrenal insufficiency, 11 of whom had concomitant diabetes mellitus and 11 had hypertension. The study compared modified-release tablets given once daily with conventional tablets given three times daily using the same daily dose of hydrocortisone (20 to 40 mg).
Compared to conventional tablets given three times daily, once daily modified-release tablets resulted in an increased cortisol exposure during the first four hours after intake in the morning but reduced exposure in the late afternoon/evening and over the 24-hour period (Figure 1).
Figure 1. Observed mean serum cortisol concentration versus clock time following single and multiple dosing in primary adrenal insufficiency patients (n=62) after oral administration of Efficort given once daily and hydrocortisone thrice daily.
The use of topically applied steroids in the treatment of ulcerative colitis, proctosigmoiditis and granular proctitis is well known.
Not applicable.
The pharmacokinetics of hydrocortisone in healthy male subjects demonstrated nonlinear kinetics when a single intravenous dose of hydrocortisone sodium succinate higher than 20 mg was administered, and the corresponding pharmacokinetic parameters of hydrocortisone are presented in Table 2
Table 2. Mean (SD) hydrocortisone pharmacokinetic parameters following single intravenous doses
| Healthy Male Adults (21-29 years; N = 6) | ||||
| Dose (mg) | 5 | 10 | 20 | 40 |
| Total Exposure (AUC0-∞; ng·h/mL) | 410 (80) | 790 (100) | 1480 (310) | 2290 (260) |
| Clearance (CL; mL/min/m2) | 209 (42) | 218 (23) | 239 (44) | 294 (34) |
| Volume of Distribution at Steady State (Vdss; L) | 20.7 (7.3) | 20.8 (4.3) | 26.0 (4.1) | 37.5 (5.8) |
| Elimination Half-life (t1/2; hr) | 1.3 (0.3) | 1.3 (0.2) | 1.7 (0.2) | 1.9 (0.1) |
AUC0-∞ = Area under the curve from time zero to infinity.
Absorption
Following administration of 5, 10, 20, and 40 mg single intravenous doses of hydrocortisone sodium succinate in healthy male subjects, mean peak values obtained at 10 minutes after dosing were 312, 573, 1095, and 1854 ng/mL, respectively. Hydrocortisone sodium succinate is rapidly absorbed when administered intramuscularly.
Distribution
Hydrocortisone is widely distributed into the tissues, crosses the blood-brain barrier, and is secreted in breast milk. The volume of distribution at steady state for hydrocortisone ranged from approximately 20 to 40 L (Table 2). Hydrocortisone binds to the glycoprotein transcortin (i.e., corticosteroid binding globulin) and albumin. The plasma protein binding of hydrocortisone in humans is approximately 92%.
Metabolism
Hydrocortisone (i.e., cortisol) is metabolized by 11β-HSD2 to cortisone, and further to dihydrocortisone and tetrahydrocortisone. Other metabolites include dihydrocortisol, 5α-dihydrocortisol, tetrahydrocortisol, and 5α-tetrahydrocortisol. Cortisone can be converted to cortisol through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Hydrocortisone is also metabolized by CYP3A4 to 6β-hydroxycortisol (6β-OHF), and 6β-OHF varied from 2.8% to 31.7% of the total metabolites produced, demonstrating large inter-individual variability.
Excretion
Excretion of the administered dose is nearly complete within 12 hours. When hydrocortisone sodium succinate is administered intramuscularly, it is excreted in a pattern similar to that observed after intravenous injection.
Absorption
Following oral administration, hydrocortisone is rapidly and well absorbed from the gastrointestinal tract and the absorption has been reported to be more than 95% for an oral 20 mg dose (tablets). Hydrocortisone is a class II active substance according to the biopharmaceutical classification system (BCS) with a high intestinal permeability and a low dissolution rate, especially at higher doses. The modified-release tablet has an outer coating layer that provides an immediate release of the drug and an extended release core. The immediate-release part provides a rapid onset of absorption and the extended release part provides a more extended plasma profile of cortisol. The bioavailability (AUC0-24h) is 20% lower with the modified-release tablet compared to the same daily dose of hydrocortisone given as conventional tablets three times daily. When the oral dose is increased the total plasma exposure of cortisol increased less than proportional. The exposure increased three-fold when the dose of hydrocortisone modified-release increased from 5 mg to 20 mg.
The absorption rate of hydrocortisone was reduced after food intake resulting in a delay in the time to maximal concentration in plasma from on average less than 1 hour to over 2.5 hours. On the other hand, the extent of absorption and bioavailability was approximately 30% higher for the 20 mg tablet after food intake compared to fasting and there was no absorption failure or dose dumping.
Distribution
In plasma, cortisol is bound to corticosteroid-binding globulin (CBG, also called transcortin) and albumin. The binding is about 90%.
Elimination
The terminal half-life has been reported to be about 1.5 hours following intravenous and oral dosing of hydrocortisone tablets. The terminal half-life of cortisol following administration of Efficort was about 3 hours and formulation release controlled. This terminal half-life is similar to the pharmacokinetics of endogenous cortisol that also is secretion-controlled.
Hydrocortisone (cortisol) is a lipophilic drug that is eliminated completely via metabolism with a low clearance and accordingly low intestinal and hepatic extraction ratios.
Hydrocortisone is eliminated completely by metabolism by 11ßHSD type 1 and type 2 enzymes and CYP 3A4 in the liver and in peripheral tissue. CYP 3A4 is involved in the clearance of cortisol by the formation of 6β-hydroxycortisol which is excreted in urine. The transport of cortisol across membranes is expected to be mediated mainly by passive diffusion and therefore renal and biliary clearances are negligible.
Special populations
Renal impairment
A small amount of cortisol is excreted in the urine unchanged (<0.5% of the daily production), meaning that cortisol is eliminated completely by metabolism. Since severe renal impairment may affect medicinal products completely eliminated via metabolism, dose adjustment may be needed.
Hepatic impairment
No study has been performed in patients with hepatic impairment, however data in the literature for hydrocortisone support that no dose adjustment is required in mild to moderate hepatic impairment. In case of severe hepatic impairment, the functional liver mass decreases and thus the metabolising capacity for hydrocortisone. This may require dose individualisation.
Paediatric population
No pharmacokinetic data are available in children or adolescents.
The topically applied steroid acts locally and so pharmacokinetics are not relevant to its activity.
None.
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
SEE LEAFLET.
1 Shake the canister vigorously before each use.
2 Fill applicator so that the foam fills about ¼ of the applicator body. Only a short press is needed to do this.
3 Wait until foam has stopped expanding.
4 Repeat step 2 until the foam expands to just reach the “Fill†line. This normally takes 2-4 short press/waits.
5 Stand with one leg raised on a chair, or lie down on your left side. Insert gently into back passage and push plunger fully into the applicator.
