Dexamethasone

Dexamethasone is a potent synthetic corticosteroid. It binds the glucocorticoid receptor and, over hours to days, changes the expression of many genes. This lowers inflammation and, at higher doses, suppresses immune responses. How long the effect lasts depends on the route of administration.

Mechanism of Action

• Receptor-mediated effects: the dexamethasone–receptor complex regulates gene transcription. Some effects appear quickly (less vasodilation and capillary leakage, fewer white blood cells entering inflamed tissue), while the gene-mediated effects develop over hours to days.
• Anti-inflammatory signalling: dexamethasone inhibits phospholipase A2, so fewer arachidonic acid derivatives are formed, and it inhibits NF-kappa B and other inflammatory transcription factors. It promotes anti-inflammatory genes such as interleukin-10 and inhibits neutrophil apoptosis and demargination.
• Dose dependence: lower doses are mainly anti-inflammatory and higher doses immunosuppressive. Long courses of high doses also activate the mineralocorticoid receptor, which raises sodium and lowers potassium.
• In the eye (Ozurdex): dexamethasone suppresses inflammation by inhibiting oedema, fibrin deposition, capillary leakage and the migration of phagocytes. It inhibits the expression of vascular endothelial growth factor (VEGF), a cytokine that is raised in macular oedema and strongly promotes vascular permeability, and it prevents the release of prostaglandins, some of which mediate cystoid macular oedema.
• Hormonal effect: systemic corticosteroids can suppress the hypothalamic–pituitary–adrenal axis and increase susceptibility to infection.

Pharmacokinetics

• Absorption (tablets and injection): oral bioavailability is about 70–78% in healthy subjects, with peak concentrations about 2 hours after a dose. Intramuscular absorption is slower than intravenous.
• Distribution: about 77% is bound to plasma proteins, mostly albumin, and there is no significant binding to corticosteroid-binding protein. The volume of distribution was about 51 L after a 1.5 mg oral dose and about 96 L after a 3 mg intramuscular dose.
• Metabolism: dexamethasone is hydroxylated by CYP3A4 to 6α- and 6β-hydroxydexamethasone, and is reversibly converted to 11-dehydrodexamethasone by 11β-hydroxysteroid dehydrogenase type 2 (and back by type 1).
• Elimination: unlike most corticosteroids, less than 10% is excreted in urine. Clearance was about 15.6 L/h after a 1.5 mg oral dose and about 9.9 L/h after a 3 mg intramuscular dose. The plasma half-life is a few hours: about 4 hours for a 20 mg tablet, 6.6 hours after 1.5 mg orally and 4.2 hours after 3 mg intramuscularly.
• Eye implant (Ozurdex): systemic exposure is minimal. After the 700 microgram implant, most plasma values were below the lower limit of quantitation (0.05 ng/mL): 86% in the retinal vein occlusion studies and 90% in the diabetic macular oedema studies. The highest value seen was 0.102 ng/mL, and plasma levels did not depend on age, weight or sex. In a 6-month monkey study the vitreous concentration peaked at 100 ng/mL on day 42 and was 5.57 ng/mL on day 91; dexamethasone was still detectable at 6 months, with the highest levels in the retina, then iris, ciliary body, vitreous and aqueous humour, and the lowest in plasma. No metabolites formed in human eye tissues in vitro. The polymer matrix of the implant degrades by hydrolysis to lactic acid and glycolic acid, then to carbon dioxide and water.

Dexamethasone is used in four product groups with different indications. Ozurdex and Neofordex are centrally authorised in the EU. The tablets and injections are nationally authorised and are described here from Spanish (AEMPS) SmPCs, so their exact indications can differ between member states.

Ozurdex (700 Micrograms Intravitreal Implant)

Ozurdex is indicated in adults for:

• Diabetic macular oedema (DME): visual impairment due to DME in patients who are pseudophakic (have an artificial lens) or who are considered insufficiently responsive to, or unsuitable for, non-corticosteroid therapy.
• Retinal vein occlusion: macular oedema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).
• Uveitis: inflammation of the posterior segment of the eye presenting as non-infectious uveitis.

Neofordex (40 mg Tablets)

• Multiple myeloma: treatment of symptomatic multiple myeloma in adults, in combination with other medicinal products.

Tablets (1 mg, 4 mg and 8 mg; for Example Fortecortin)

Conditions that require anti-inflammatory and immunosuppressive treatment, including:

• cerebral oedema secondary to brain tumours, neurosurgery or brain abscesses;
• severe acute asthma;
• initial treatment of severe acute skin diseases;
• initial treatment of autoimmune diseases;
• active rheumatoid arthritis;
• prophylaxis and treatment of nausea and vomiting induced by cytostatic medicines, within antiemetic regimens;
• for the 1 mg and 4 mg tablets only: COVID-19 in adults and adolescents (at least 12 years old and weighing at least 40 kg) who need supplemental oxygen therapy.

Solution for Injection (for Example Fortecortin 4 mg/mL and 40 mg/5 mL)

By intravenous or intramuscular injection, 4 mg/mL:

• cerebral oedema secondary to brain tumours, head injury, neurosurgery, brain abscess or bacterial meningitis;
• traumatic shock;
• severe acute asthma or status asthmaticus;
• initial parenteral treatment of extensive, severe acute skin diseases such as erythroderma, pemphigus vulgaris or acute eczema;
• initial parenteral treatment of active phases of collagen diseases such as systemic lupus erythematosus, especially visceral forms;
• severe infectious diseases (for example typhoid fever, brucellosis, tuberculosis), only as an adjunct to appropriate anti-infective treatment;
• prophylaxis and treatment of nausea and vomiting caused by cytostatic medicines and after surgery, within antiemetic regimens;
• short-term adjunct treatment during acute episodes or exacerbations of rheumatic diseases.

By intravenous or intramuscular injection, 40 mg/5 mL:

• cerebral oedema secondary to brain tumours and head injury;
• traumatic shock;
• anaphylactic shock, as treatment after the first injection of adrenaline.

Other routes, 4 mg/mL:

• Intravenous: COVID-19 in adults and adolescents (at least 12 years old and weighing at least 40 kg) who need supplemental oxygen therapy.
• Intra-articular: persistent inflammation in one or several joints after systemic treatment of chronic joint inflammation, activated osteoarthritis and acute forms of periarthropathy of the shoulder.
• Infiltration (only where justified): non-bacterial tenosynovitis and bursitis, periarthropathy and tendinopathy.

• Ozurdex: hypersensitivity to dexamethasone or any excipient; active or suspected infection of the eye or the tissue around it, including most viral diseases of the cornea and conjunctiva (active epithelial herpes simplex keratitis, vaccinia, varicella), mycobacterial infections and fungal diseases; advanced glaucoma that cannot be adequately controlled by medicines alone; aphakic eyes (no lens) with a ruptured posterior lens capsule; eyes with an anterior chamber intraocular lens, an iris-fixated or transsclerally fixated lens, and a ruptured posterior lens capsule.
• Tablets (Fortecortin): hypersensitivity to dexamethasone or any excipient.
• Solution for injection (Fortecortin): hypersensitivity to dexamethasone or any excipient. Intravenous injection is contraindicated in systemic infections unless specific anti-infective treatment is given. Intra-articular injection is contraindicated with infection in or very near the joint, bacterial arthritis, an unstable joint, a bleeding tendency (spontaneous or from anticoagulants), periarticular calcification, avascular osteonecrosis, tendon rupture and Charcot joint. Infiltration without additional treatment of the cause is contraindicated when there is infection at the injection site.
• Neofordex: see the SmPC for the contraindications of this product.

The side effects depend on the form. The Ozurdex implant acts locally; apart from headache and migraine, no systemic adverse drug reactions were identified with it. Tablets, injections and Neofordex act on the whole body, and their effects depend on dose and duration of treatment.

Ozurdex (Intravitreal Implant)

The most commonly reported events are those expected with ophthalmic steroid treatment and with intravitreal injections: raised intraocular pressure, cataract formation, and conjunctival or vitreous haemorrhage. Less frequent but more serious reactions include endophthalmitis, necrotising retinitis, retinal detachment and retinal tear.

Very common (≥1/10): increased intraocular pressure, cataract, conjunctival haemorrhage.

Common (≥1/100 to <1/10): headache, ocular hypertension, subcapsular cataract, vitreous haemorrhage, reduced visual acuity, visual impairment or disturbance, vitreous detachment, vitreous floaters, vitreous opacities, blepharitis, eye pain, photopsia, conjunctival oedema, conjunctival hyperaemia.

Uncommon (≥1/1,000 to <1/100): migraine, necrotising retinitis, endophthalmitis, glaucoma, retinal detachment, retinal tear, hypotony of the eye, anterior chamber inflammation, cells and flare in the anterior chamber, abnormal sensation in the eye, eyelid pruritus, scleral hyperaemia, device dislocation (implant migration, with or without corneal oedema or corneal decompensation), complication of device insertion with injury to eye tissue (implant misplacement).

Many of the eye reactions are related to the injection procedure, and their frequency rises with the number of treatments. In a 24-month observational study in macular oedema after retinal vein occlusion and in non-infectious posterior uveitis, patients who received more than 2 injections reported more cataract formation (24.7% against 17.7%), cataract progression (32.0% against 13.1%), vitreous haemorrhage (6.0% against 2.0%) and raised eye pressure (24.0% against 16.6%) than those who received 2 or fewer.

Tablets, Injections and Neofordex (Systemic Use)

The Fortecortin tablets SmPC says that, depending on the dose and duration of treatment, the reactions below can occur. It lists them by organ class and gives no frequency groups, except hiccups, which it lists as frequency not known.

• Blood and lymphatic system: moderate leucocytosis, lymphopenia, eosinopenia and polycythaemia.
• Endocrine: adrenal suppression and Cushing syndrome (moon face, fat accumulation around the trunk).
• Eye: glaucoma, cataract (in particular with posterior subcapsular opacities), worsening of corneal ulcer symptoms, fungal, viral and bacterial eye infections, worsening of bacterial corneal infections, drooping eyelid (ptosis), dilated pupil (mydriasis), conjunctival swelling (chemosis), iatrogenic scleral perforation, chorioretinopathy and blurred vision.
• Stomach and gut: peptic ulcer, gastrointestinal bleeding, pancreatitis and stomach discomfort.
• General: delayed wound healing.
• Immune system: hypersensitivity reactions (for example rash) and severe anaphylactic reactions such as arrhythmia, bronchospasm, a fall or rise in blood pressure, circulatory failure and cardiac arrest.
• Infections: masking of infections; appearance, worsening or reactivation of bacterial, viral, fungal, parasitic and opportunistic infections; activation of strongyloidiasis.
• Metabolism and nutrition: sodium retention with oedema, increased potassium excretion (which can cause arrhythmias), weight gain, reduced glucose tolerance, diabetes mellitus, hypercholesterolaemia, hypertriglyceridaemia and increased appetite.
• Muscle, bone and connective tissue: muscle wasting and weakness, myopathy, tendon disorders, tendinitis and tendon rupture, osteoporosis (dose-dependent; it can occur even after short courses), aseptic osteonecrosis, growth retardation in children and epidural lipomatosis. Lowering the dose too fast after long treatment can cause muscle and joint pain.
• Nervous system: pseudotumour cerebri (especially in children), and first appearance or worsening of epilepsy (seizures).
• Psychiatric: depression, hallucinations, emotional instability, irritability, increased activity, psychosis, mania, euphoria, anxiety, sleep disturbance and suicidal thoughts.
• Reproductive system and breast: disturbed secretion of sex hormones (absent periods, excess hair growth and impotence).
• Skin: steroid acne, red stretch marks, skin atrophy, petechiae, bruising (ecchymosis), telangiectasia, excess hair growth (hypertrichosis), perioral rosacea-like dermatitis and changes in skin pigmentation.
• Blood vessels: hypertension, a higher risk of atherosclerosis and thrombosis, vasculitis (also as a withdrawal symptom after long treatment) and capillary fragility.
• Respiratory system (frequency not known): hiccups.

Neofordex is taken in the morning to minimise insomnia. See the SmPC of Neofordex and of the solution for injection for their own lists of reactions.

• Ozurdex: no interaction studies have been performed. Systemic absorption is minimal and no interactions are anticipated.
• Systemic dexamethasone (tablets, injection, Neofordex): the points below are those of the Fortecortin tablets SmPC; check the SmPC of the product used.
• NSAIDs (for example indometacin and salicylates): higher risk of gastrointestinal ulcer and bleeding.
• Oral antidiabetic medicines and insulin: the blood-glucose-lowering effect can be reduced.
• CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, barbiturates, primidone): can reduce the effect of corticosteroids.
• CYP3A inhibitors (ketoconazole, itraconazole, and medicines containing cobicistat): expected to raise the risk of systemic side effects. The combination should be avoided unless the benefit outweighs that risk, in which case patients are monitored for systemic corticosteroid reactions.
• Ephedrine: can speed the metabolism of glucocorticoids and so reduce their efficacy.
• Coumarin anticoagulants: the anticoagulant effect can be reduced or increased, so the anticoagulant dose may need adjusting.
• Oestrogens (for example in contraceptives): can prolong the half-life of glucocorticoids and so intensify their clinical effect.
• Atropine and other anticholinergic medicines: intraocular pressure may rise during treatment.
• Cardiac glycosides: their effect can be intensified by potassium deficiency.
• Saluretics (diuretics) and laxatives: can increase potassium excretion further when used with dexamethasone.
• Praziquantel: glucocorticoids can lower its blood levels.
• ACE inhibitors: higher risk of changes in blood count parameters.
• Chloroquine, hydroxychloroquine and mefloquine: higher risk of myopathy and cardiomyopathy.
• Immunosuppressants: greater susceptibility to infection and possible worsening or first appearance of latent infections (viral, bacterial, fungal, parasitic and opportunistic). With ciclosporin, blood levels of ciclosporin can rise, which carries a high risk of cerebral seizures.
• Non-depolarising muscle relaxants (rocuronium, vecuronium): muscle relaxation may be prolonged.
• Protirelin: glucocorticoids can reduce the rise in thyroid-stimulating hormone (TSH).
• Fluoroquinolones: higher risk of tendon disorders.
• Somatropin (growth hormone): its effect can be weakened by long-term corticosteroid treatment.
• Antacids (magnesium hydroxide, aluminium hydroxide): can reduce the absorption of glucocorticoids and so the efficacy of dexamethasone, so the doses should be taken 2 hours apart.
• Vaccines: special attention is needed from 8 weeks before to 2 weeks after vaccination with live vaccines, and the response to inactivated vaccines may be weaker with high doses (see Special Instructions).
• Laboratory tests: results of immune-modulated tests, for example allergy tests, may be suppressed.
• Alcohol and food: avoid alcohol. Tablets are taken with or after food, which reduces stomach irritation.

Dosing differs for each form. Systemic treatment is started and supervised by a physician. Neofordex must be started and monitored by physicians experienced in the management of multiple myeloma. Ozurdex must be given by a qualified ophthalmologist experienced in intravitreal injections.

Ozurdex Intravitreal Implant

• Dose: one implant, 700 micrograms, into the vitreous of the affected eye. Treating both eyes at the same time is not recommended.
• Diabetic macular oedema: patients who had an initial response and may benefit from retreatment without significant risk can be retreated after about 6 months if vision falls and/or retinal thickness increases because of recurrent or worsening oedema. There is no experience of efficacy or safety beyond 7 implants.
• Retinal vein occlusion and uveitis: repeat doses can be considered when a response is followed by a loss of visual acuity and the physician judges that retreatment may benefit the patient without significant risk. Patients who keep their improved vision should not be retreated, and neither should patients whose vision worsens despite Ozurdex. There is very limited information on intervals shorter than 6 months.
• After the injection: patients are monitored to allow early treatment of infection or raised eye pressure.
• Elderly: no dose adjustment. Renal and hepatic impairment: not studied, but no special considerations are needed.
• Children: there is no relevant use in diabetic macular oedema or retinal vein occlusion. Safety and efficacy in uveitis have not been established.
• Procedure: Ozurdex is a single-use implant in an applicator for intravitreal use only, and each applicator treats one eye. The injection is carried out under controlled aseptic conditions (sterile gloves, drape and eyelid speculum). The patient uses broad-spectrum antimicrobial drops daily for 3 days before and after each injection. The skin around the eye, the eyelid and the eye surface are disinfected (for example with 5% povidone iodine), and adequate local anaesthesia is given. Once the foil pouch is opened, the applicator is used immediately. Placement of the implant is confirmed straight afterwards by indirect ophthalmoscopy, and antimicrobial drops continue after the injection.

Neofordex 40 mg Tablets (Multiple Myeloma)

• Dose: the dose and frequency depend on the treatment protocol and the medicines combined with it. Neofordex follows the dexamethasone instructions in the SmPC of the associated treatment; if there are none, local or international protocols are used, and the prescriber chooses the dose according to the patient’s condition and disease status. The usual dose of dexamethasone is 40 mg once on each day of administration.
• End of treatment: the dose is tapered stepwise until a complete stop.
• Missed dose: take the tablet straight away if it is less than 12 hours late. If it is more than 12 hours late, take the next tablet at the usual time. Never take a double dose.
• Elderly or frail patients: if the dose needs to be reduced, another product with a lower dexamethasone dose can be prescribed.
• Hepatic impairment: appropriate monitoring and cautious dosing, as there are no data. Renal impairment: appropriate monitoring.
• Children: there is no relevant use in multiple myeloma.
• Taking the tablet: by mouth, preferably in the morning to minimise insomnia. Keep tablets in the blister until use; single tablets in intact packaging can be separated along the perforation, for example for compliance aids.

Dexamethasone Tablets (1 mg, 4 mg and 8 mg; for Example Fortecortin)

• General rule: the dose depends on the type and severity of the disease and on the patient’s response. Initial doses are usually high, and higher in severe acute illness than in chronic disease. The dose should be high enough and the treatment long enough to work, while the lowest dose is kept for the shortest time. The dose is reduced stepwise, and if maintenance treatment is needed after the initial course, prednisone or prednisolone can be considered because they suppress the adrenal cortex less. Lower doses may be enough in hypothyroidism or liver cirrhosis.
• Cerebral oedema: 16–24 mg (up to 48 mg) a day, divided into 3–4 (up to 6) doses, for 4–8 days. During radiotherapy and in conservative treatment of inoperable brain tumours, low maintenance doses may be needed.
• Severe acute asthma: adults 8–20 mg, with repeat doses of 8 mg every 4 hours.
• Severe acute skin disease: 8–40 mg a day, up to 100 mg in some cases depending on the type and extent of the disease, followed by decreasing doses.
• Autoimmune disease in the active phase: for example systemic lupus erythematosus, 6–16 mg a day.
• Active rheumatoid arthritis: rapidly destructive forms 12–16 mg a day; extra-articular manifestations 6–12 mg a day.
• Nausea and vomiting from cytostatic treatment (within antiemetic regimens): 10–20 mg before chemotherapy, then 4–8 mg two to three times a day for 1–3 days (moderately emetogenic chemotherapy) or, if needed, up to a total of 6 days (highly emetogenic chemotherapy).
• COVID-19 (1 mg and 4 mg tablets only): adults 6 mg by mouth once a day for up to 10 days. Adolescents of at least 12 years: 6 mg once a day for up to 10 days.
• Children: severe acute asthma 0.15–0.3 mg/kg, followed by 0.3 mg/kg every 4–6 hours.
• Elderly, renal or hepatic impairment: no dose adjustment.
• Taking the tablets: during or after meals, with enough liquid. The whole daily dose is given once in the morning where possible, but patients who need high doses often need several doses a day for the full effect.

Dexamethasone Solution for Injection (for Example Fortecortin 4 mg/mL and 40 mg/5 mL)

• General rule: treatment usually starts with high doses by intravenous or intramuscular injection in an emergency. The starting dose continues for some days, then is reduced gradually or replaced by the necessary maintenance dose, which can later be given by mouth. Needs vary, so the dose is individualised to the disease and the patient’s response. The doses below are expressed as dexamethasone phosphate.
• Cerebral oedema: 8 mg intravenously at first, then 4 mg every 6 hours intramuscularly until the oedema symptoms have subsided. A response usually comes within 12–24 hours; the dose can be reduced after 2 to 4 days and withdrawn gradually over 5 to 7 days.
• Brain abscess: 4–8 mg a day, given 4–6 times a day, tapering gradually in long treatments.
• Bacterial meningitis: 0.15 mg/kg before the first dose of antibiotic, continued four times a day during the first days of treatment.
• Traumatic shock: start with 40–100 mg intravenously. Repeat after 12 hours, or give 16–40 mg every 6 hours for 2–3 days.
• Anaphylactic shock: after the intravenous injection of adrenaline, 100 mg intravenously; injections may need repeating. Plasma expanders and assisted ventilation follow.
• Severe acute asthma and status asthmaticus: 8–20 mg intravenously as soon as possible; if needed, repeat 8 mg every 4 hours. Aminophylline and secretolytic medicines can be added.
• Severe acute skin diseases and collagen diseases: 0.5–9 mg a day intravenously or intramuscularly, adjusted to the response.
• Severe infectious diseases: 4–20 mg intravenously. See the SmPC for the doses in the other indications (nausea and vomiting, rheumatic disease, COVID-19, intra-articular injection and infiltration).

Eye Implant: Injection-Related Risks

Intravitreal injections, including those with Ozurdex, can be associated with endophthalmitis, intraocular inflammation, raised intraocular pressure and retinal detachment, so proper aseptic technique is always required. After the injection, monitoring may consist of a check of perfusion of the optic nerve head straight away, tonometry within 30 minutes, and biomicroscopy between 2 and 7 days later. Patients must be told to report symptoms of endophthalmitis or the events above without delay, for example eye pain or blurred vision.

Eye Implant: Migration

Patients with a posterior capsule tear (for example after cataract surgery) and/or an iris opening to the vitreous cavity (for example after iridectomy), with or without a history of vitrectomy, are at risk of implant migration into the anterior chamber. This can cause corneal oedema or decompensation and, if persistent, may lead to the need for a corneal transplant. In these patients Ozurdex is used with caution, only after a careful risk–benefit assessment, and with close monitoring.

Eye Implant: Cataract, Eye Pressure and Infection

• Cataract: corticosteroids, including Ozurdex, may induce cataract (including posterior subcapsular cataract). In the 3-year diabetic macular oedema studies, 59% of patients with their own lens in the treated eye had cataract surgery. After the first injection, cataract appears more frequent in non-infectious uveitis than after retinal vein occlusion. In the retinal vein occlusion studies, cataract was reported more often after a second injection; 1 of 368 patients needed cataract surgery during the first treatment and 3 of 302 during the second. In the uveitis study, 1 of 62 patients with their own lens had surgery after a single injection.
• Eye pressure: pressure can rise, usually manageably with pressure-lowering medicines. Of the patients with a rise of at least 10 mmHg, most showed it between 45 and 60 days after an injection, so pressure must be checked regularly, whatever the baseline. Patients under 45 years of age with macular oedema after retinal vein occlusion or with non-infectious uveitis are more likely to have a rise.
• Glaucoma and infection: corticosteroids may cause steroid-induced glaucoma and secondary eye infections.
• Viral infection: corticosteroids are used cautiously in patients with a history of ocular viral infection such as herpes simplex, and are not used in active ocular herpes simplex.

Eye Implant: Bleeding and Other Cautions

• Conjunctival haemorrhage is more common in non-infectious uveitis; it may relate to the injection or to concomitant corticosteroids or NSAIDs, needs no treatment and resolves by itself.
• Anticoagulant or antiplatelet medicines: Ozurdex is used with caution. In diabetic macular oedema, vitreous haemorrhage was reported more often in patients on anticoagulants (11%) than in those not on them (6%).
• Both eyes: safety and efficacy of treating both eyes at once have not been studied, so it is not recommended.
• Retinal ischaemia: Ozurdex has not been studied in macular oedema after retinal vein occlusion with significant retinal ischaemia, so it is not recommended there.
• Type 1 diabetes: few patients were studied, and their response was not significantly different from patients with type 2 diabetes.
• Visual disturbance: blurred vision or other visual disturbance with corticosteroid use should prompt a search for causes such as cataract, glaucoma or central serous chorioretinopathy.

Tablets, Injections and Neofordex: General Precautions

The points below come from the Fortecortin tablets SmPC, apart from the Neofordex and injection items.

• Adrenal suppression: depending on the dose and duration of treatment, adrenocortical insufficiency caused by glucocorticoids can last for months after treatment stops, and in individual cases up to a year. Lowering the dose slowly when withdrawal is planned minimises acute adrenocortical insufficiency, so after prolonged treatment the dose is reduced stepwise, with adrenal function monitored if needed.
• Ending long-term treatment: when long-term glucocorticoid treatment ends or has to be interrupted, there is a risk of relapse or worsening of the underlying disease, acute adrenocortical insufficiency and a cortisone withdrawal syndrome.
• Lowest dose, shortest time: the dose has to be high enough and the course long enough to work, but the minimum effective dose is kept for the shortest time possible.
• Physical stress: in special situations of physical stress during treatment (for example febrile illness, accidents, operations or childbirth), the daily dose may need a temporary increase.
• Infections: because of immunosuppression, treatment can raise the risk of bacterial, viral, fungal, parasitic and opportunistic infections. Symptoms of existing or developing infection can be masked, which makes diagnosis harder, and latent infections, including tuberculosis and hepatitis B, can be reactivated. Special care is needed in acute and chronic bacterial infections (specific antibiotic treatment is used, and patients with a history of tuberculosis are treated only under the protection of antituberculosis medicines), lymphadenitis after BCG vaccination, a positive hepatitis B surface antigen and chronic hepatitis, acute viral infections (for example hepatitis B, chickenpox and herpes zoster), herpes simplex, poliomyelitis, herpetic keratitis and measles. In parasitic infections and systemic fungal infections (for example nematodes and amoebic infection), antifungal and antiparasitic treatment is given at the same time. In patients with known or suspected heavy strongyloides infestation, glucocorticoids can cause activation and spread.
• Chickenpox and measles: particular caution is advised in immunosuppressed patients, and in patients who have not had measles or chickenpox and are in contact with someone who has. These diseases can run an especially severe course in people treated with glucocorticoids.
• Vaccines: special attention is needed from 8 weeks before to 2 weeks after prophylactic vaccination with live vaccines. Inactivated vaccines can generally be given, but the immune response, and so the result of vaccination, can be weaker with high doses of glucocorticoids.
• Existing corticosteroid treatment: systemic corticosteroids are not stopped in patients who already take them by mouth for other reasons (for example chronic obstructive pulmonary disease) but who do not need supplemental oxygen.
• Hepatic and renal impairment (Neofordex): monitor appropriately and dose with caution.
• Injection routes: intravenous injection is avoided in systemic infection unless specific anti-infective treatment is given, and intra-articular injection and infiltration follow the contraindications above.

Tablets, Injections and Neofordex: Conditions That Need Special Care

The Fortecortin tablets SmPC asks for special attention in severe heart failure and in the conditions below.

• Peptic ulcer: anti-ulcer medicines are recommended at the same time.
• Osteoporosis: depending on the duration and dose of treatment, a negative effect on calcium metabolism is expected. Calcium and, if necessary, vitamin D are recommended alongside; with existing osteoporosis, extra treatment should be considered; in severe osteoporosis, dexamethasone is considered only for life-threatening indications or for short periods.
• Hypertension that is hard to control: combined antihypertensive treatment, with regular monitoring.
• Diabetes mellitus that is hard to control: clinical follow-up and adjustment of the antidiabetic treatment.
• Psychiatric illness, including a risk of suicide (also in the history): neurological and psychiatric follow-up is recommended.
• Glaucoma (open-angle or closed-angle), corneal ulcers or lesions: close ophthalmological monitoring and suitable treatment.
• Risk of intestinal perforation: dexamethasone is given only where strictly necessary and with proper monitoring in severe ulcerative colitis with a risk of perforation without peritoneal irritation, in diverticulitis and with an intestinal anastomosis (immediately after surgery). In patients on high-dose glucocorticoids, the signs of peritoneal irritation after gastrointestinal perforation may be absent.
• Fluoroquinolones: together with corticosteroids they raise the risk of tendon disorders, tendinitis and tendon rupture.
• Myasthenia gravis: existing myasthenia gravis may worsen at first during treatment.

Tablets, Injections and Neofordex: Monitoring, Older Patients and Children

• Allergic reactions: severe anaphylactic reactions can occur.
• High doses: they require adequate potassium supplements and a diet low in sodium, with plasma potassium monitored. High doses of dexamethasone can cause a slow heart rate (bradycardia).
• Tumour lysis syndrome: it has been reported after marketing in patients with haematological malignancy who took dexamethasone alone or with chemotherapy. Patients at high risk, such as those with a high rate of tumour growth, a high tumour burden and high sensitivity to cytotoxic medicines, are monitored closely and given suitable precautions.
• Long-term treatment: it requires regular medical monitoring, including an eye examination every 3 months.
• Visual disturbance: systemic and topical corticosteroids can cause it. A patient with blurred vision or other visual symptoms should see an ophthalmologist to look for causes such as cataract, glaucoma or rare diseases such as central serous chorioretinopathy, which has been reported after systemic and topical corticosteroids.
• Older patients: because of the high risk of osteoporosis, dexamethasone is given only after a strict assessment of benefit and risk.
• Children: use during the growth phase needs a strict assessment of benefit and risk (see the effect on growth under Side Effects). In long-term treatment, it should be intermittent or on alternate days. Available evidence suggests adverse long-term effects on neurodevelopment after early treatment (less than 96 hours) of premature infants with chronic lung disease.
• Doping control: the medicine can give a positive result in a doping test.

Lactose

Fortecortin tablets contain lactose (44 mg in the 1 mg and 4 mg tablets, 88 mg in the 8 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose–galactose malabsorption should not take them.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: animal studies showed teratogenic effects after topical ophthalmic dexamethasone. There are no adequate data on intravitreal dexamethasone in pregnant women. Long-term systemic glucocorticoid treatment during pregnancy increases the risk of intra-uterine growth retardation and of adrenal insufficiency in the newborn. Ozurdex is not recommended in pregnancy unless the potential benefit justifies the potential risk to the foetus, and pregnancy should be discussed with the prescriber before any systemic form is used.
• Breastfeeding: dexamethasone is excreted in breast milk. No effects on the child are expected from the eye implant because of the route and the very low systemic levels, but Ozurdex is not recommended during breastfeeding unless clearly necessary.
• Fertility: no fertility data are available.

Effect on Driving

Ozurdex may have a moderate influence on the ability to drive and use machines. Vision can be temporarily reduced after an injection, and patients should not drive or use machines until it has recovered.

• Ozurdex: no special storage conditions. The applicator is supplied in a sealed foil pouch with desiccant and is used immediately once the pouch is opened.
• Fortecortin 1 mg tablets: store below 30 °C. Fortecortin 4 mg and 8 mg tablets: no special storage conditions.
• Fortecortin solution for injection: do not store above 25 °C. Keep the ampoules in the outer carton to protect them from light.
• Neofordex: keep the tablets in the blister until use. See the SmPC for further storage advice.

• Ozurdex: 3 years.
• Fortecortin 1 mg tablets: 5 years. Fortecortin 4 mg and 8 mg tablets: 3 years.
• For the other products, the shelf life is stated on the pack and in the SmPC.

Prescription only (Rx). Ozurdex must be given by a qualified ophthalmologist experienced in intravitreal injections and is supplied to the hospital or clinic that administers it. Neofordex is started and monitored by physicians experienced in the management of multiple myeloma. Dexamethasone tablets, including Neofordex, are taken at home and are supplied to the patient or the treating clinic on prescription. Dexamethasone solution for injection is given by healthcare professionals and is supplied to the hospital or clinic that administers it.