Symptoms
Acute intoxications with Максидекс are not known. In case of chronic overdosing, an increase in undesirable effects, especially endocrine, metabolic and electrolyte-related effects, can be expected.
Management
There is no known antidote to Максидекс.
Long-term intensive topical use may lead to systemic effects. Oral ingestion of the contents of the bottle (up to 10 mls) is unlikely to lead to any serious adverse effects.
An ocular overdose of Максидекс can be flushed from the eye(s) with lukewarm water.
- Vaccinia, varicella, or other viral diseases of cornea and conjunctiva (except herpes zoster keratitis)
- Herpes simplex keratitis
- Fungal diseases of ocular structures
- Mycobacterial ocular infections
- Acute, untreated bacterial infections
-
Not applicable.
None known.
- 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)
- Not known (cannot be estimated from the available data)
Hormone replacement therapy:
Low risk of undesirable effects with the use of recommended doses.
Pharmacotherapy:
The following undesirable effects may occur; they are highly dependent on the dose and duration of treatment, so their frequency cannot be specified:
| Infections and infestations | Masking of infections, manifestation and exacerbation of viral infections, fungal infections, bacterial, parasitic and opportunistic infections, activation of strongyloidiasis. |
| Blood and lymphatic system disorders | Moderate leukocytosis, lymphocytopenia, eosinopenia, polycythemia. |
| Immune system disorders | Hypersensitivity reactions (e.g. drug eruption), severe anaphylactic reactions, such as arrhythmias, bronchospasm, hypo- or hypertension, circulatory collapse, cardiac arrest, weakening of the immune system. |
| Endocrine disorders | Adrenal suppression and induction of Cushing's syndrome (typical symptoms: moon face, central obesity and plethora). |
| Metabolism and nutrition disorders | Sodium retention with oedema, increased potassium excretion (risk of arrhythmias), weight gain, reduced glucose tolerance, diabetes mellitus, hypercholesterolemia and hypertriglyceridemia, increased appetite. |
| Psychiatric disorders | Depression, irritability, euphoria, increased drive, psychoses, mania, hallucinations, emotional lability, anxiety, sleep disorders, suicidality. |
| Nervous system disorders | Pseudotumor cerebri, manifestation of latent epilepsy, increase in seizure susceptibility in manifest epilepsy. |
| Eye disorders | |
| Vascular disorders | Hypertension, increased risk of atherosclerosis and thrombosis, vasculitis (also as withdrawal syndrome after long-term therapy), increased capillary fragility. |
| Gastrointestinal disorders | Gastrointestinal ulcers, gastrointestinal bleeding, pancreatitis, stomach discomfort. |
| Skin and subcutaneous tissue disorders | Striae rubra, atrophy, telangiectasias, petechiae, ecchymosis, hypertrichosis, steroid acne, rosacea-like (perioral) dermatitis, changes in skin pigmentation. |
| Musculoskeletal and connective tissue disorders | Myopathy, muscle atrophy and weakness, osteoporosis (dose-dependent, possible also in short-term administration), aseptic bone necrosis, tendon disorders, tendinitis, tendon rupture, epidural lipomatosis, growth inhibition in children. Note: Too rapid dose reduction after long-term treatment may cause symptoms such as muscle and joint pain. |
| Reproductive system and breast disorders | Disorders of sexual hormone secretion (consequently: irregular menstruation up to amenorrhea, hirsutism, impotence). |
| General disorders and administration site conditions | Delayed wound healing. |
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
In clinical trials, the most common adverse reaction was ocular discomfort.
Tabulated list of adverse reactions
The following adverse reactions are classified according to the following convention: 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), or not known (cannot be estimated from the available data). Within each frequency-grouping, adverse reactions are presented in order of decreasing seriousness. The adverse reactions have been observed during clinical trials and post-marketing experience with Максидекс.
| System Organ Classification | MedDRA Preferred Term (v. 12.0) |
| Immune system disorders | Not known: hypersensitivity |
| Endocrine disorders | Not known: Cushing's syndrome, adrenal suppression |
| Nervous system disorders | Uncommon: dysgeusia Not known: dizziness, headache |
| Eye disorders | Common: ocular discomfort Uncommon: keratitis, conjunctivitis, keratoconjunctivitis sicca, corneal staining, photophobia, vision, blurred (see also section 4.4), eye pruritus, foreign body sensation in eyes, lacrimation increased, abnormal sensation in eyes, eyelid margin crusting, eye irritation, ocular hyperaemia Not known: intraocular pressure increased, visual acuity reduced, corneal erosion, eyelid ptosis, eye pain, mydriasis |
Description of selected adverse reactions
Prolonged topical ophthalmic corticosteroids may result in increased intraocular pressure with damage to the optic nerve, reduced visual acuity and visual field defects, and to posterior subcapsular cataract formation.
Due to the corticosteroid component, in diseases causing thinning of the cornea or sclera there is a higher risk for perforation especially after long treatments.
Corticosteroids may reduce resistance to and aid in the establishment of infections.
Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.
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 national reporting system:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Acute toxicity:
In mice and rats, the LD50 for Максидекс after a single oral dose is 16 g/kg body and over 3 g/kg body weight, respectively, within the first 7 days. Following a single subcutaneous dose, the LD50 in mice is more than 700 mg/kg body weight and in rats about 120 mg/kg body weight, within the first 7 days.
Over a period of 21 days, these values become lower, which is interpreted as a consequence of serious infectious diseases caused by the hormone-induced immunosuppression.
Chronic toxicity:
There are no data on chronic toxicity in humans and animals. Corticoid-induced intoxications are not known. In longer-term treatment with doses above 1.5 mg/day, pronounced undesirable effects can be expected.
Mutagenic and tumorigenic potential:
The available study findings for glucocorticoids show no evidence of clinically relevant genotoxic properties.
Reproductive toxicity:
In animal studies, cleft palate was observed in rats, mice, hamsters, rabbits, dogs and primates; not in horses and sheep. In some cases these divergences were combined with defects of the central nervous system and of the heart. In primates, effects in the brain were seen after exposure. Moreover, intrauterine growth can be delayed. All these effects were seen at high dosages.
Repeat dose topical ocular safety studies with dexamethasone in rabbits have shown systemic corticosteroid effects. Such effects are considered to be unlikely when Максидекс is used as recommended.
Dexamethasone was clastogenic in the in vitro human lymphocyte assay and in vivo in the mouse micronucleus assay at doses in excess of those obtained following topical application. Conventional carcinogenicity studies with Максидекс have not been performed.
Dexamethasone has been found to be teratogenic in animal models. Dexamethasone induced abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development.
There are no other preclinical data of relevance to the prescriber which are additional to that included in other sections of the SPC.
Neurology
Cerebral oedema caused by brain tumours, neurosurgery, bacterial meningitis, brain abscess.
Pulmonary and respiratory diseases
Severe acute asthma attack.
Dermatology
Oral initial treatment of extensive, severe, acute skin diseases that respond to glucocorticoids, such as erythroderma, pemphigus vulgaris, acute eczema.
Autoimmune disorders/rheumatology
Oral initial treatment of autoimmune diseases, such as systemic lupus erythematosus (especially visceral forms).
Severely progressive form of active rheumatoid arthritis, e.g. rapidly destructive forms and/or with extra-articular manifestations.
Infectology
Severe infections with toxic conditions (e.g. tuberculosis, typhoid) only with concomitant anti-infective therapy.
Oncology
Palliative treatment of malignant tumours.
Endocrinology
Congenital adrenogenital syndrome in adulthood.
Indicated for treatment of steroid responsive inflammatory conditions of the conjunctiva, cornea and anterior segment of the eye, such as, anterior uveitis, iritis, cyclitis, allergic and vernal conjunctivitis, herpes zoster keratitis, superficial punctate keratitis and non-specific superficial keratitis.
Also indicated for the treatment of corneal injury from chemical, radiation or thermal burns or following penetration by foreign bodies. Indicated for post-operative use to reduce inflammatory reactions and suppress graft reaction.
Pharmacotherapeutic group: corticosteroids for systemic use, glucocorticoids, ATC code: H02AB02.
Mechanism of action
Максидекс is a mono-fluorinated glucocorticoid with pronounced anti-allergic, anti-inflammatory and membrane-stabilizing properties and effects on carbohydrate, protein and fat metabolism.
Максидекс has an approximately 7.5 times greater glucocorticoid effect than prednisolone, and compared to hydrocortisone it is 30 times more effective, lacking mineralocorticoid effects.
Glucocorticoids, such as Максидекс, exert their biological effects by activating the transcription of corticosteroid-sensitive genes. The anti-inflammatory, immunosuppressive and anti-proliferative effects are caused by decreased formation, release and activity of inflammatory mediators, by the inhibition of specific functions and the migration of inflammatory cells. In addition, the effect of sensitized T lymphocytes and macrophages on target cells may be prevented by corticosteroids.
When long-term corticoid treatment is required, the possibility of induction of transient adrenal insufficiency must be considered. The suppression of the hypothalamic-pituitary-adrenal axis also depends on individual factors.
Pharmacotherapeutic Group: Ophthalmologicals: Anti-inflammatory Agents.
ATC Code S01B A01.
Dexamethasone has been demonstrated by animal and human studies based on oral application to possess approximately six to seven times the potency of prednisolone and at least 30 times the potency of cortisone. The potency of the compound is accomplished by the addition of a methyl radical and a fluorine atom to the prednisolone radical.
Absorption and distribution
After oral administration, Максидекс is rapidly and almost completely absorbed in the stomach and small intestine. Its bioavailability is 80-90%. Maximum blood levels are reached between 60 and 120 minutes. The binding of Максидекс to plasma albumins is dose-dependent. At very high doses, the largest portion circulates freely in the blood. In hypoalbuminaemia the proportion of the unbound (active) corticoid rises.
Biotransformation
The average (serum) elimination half-life of Максидекс in adults is 250 minutes (+ 80 minutes). Due to its long biological half-life of more than 36 hours, daily continuous administration of Максидекс can lead to accumulation and overdosing.
Elimination
The elimination is largely renal in the form of free Максидекс alcohol. Максидекс is partly metabolised, the metabolites are excreted as glucuronates or sulfates, also mainly by the kidneys.
Renal and hepatic impairment
Renal function impairment has no relevant effect on the clearance of Максидекс. However, the elimination half-life is prolonged in severe liver disease.
Dexamethasone is absorbed rapidly after oral administration with a half-life of about 190 minutes. Sufficient absorption may occur after topical application to the skin and eye to produce systemic effects. In plasma dexamethasone protein binding is less than for most other corticosteroids. Corticosteroids diffuse into tissue fluids and cerebrospinal fluid but transplacental diffusion in significant amounts has not been demonstrated. Corticosteroids are metabilised in the liver the kidney and excrete in the urine. Metabolism is similar to other corticosteroids. Intraocular penetration occurs in significant amounts and contributes to the effectiveness of dexamethasone in anterior segment inflammatory disease.
Depending on the dose and duration of therapy, adrenocortical insufficiency caused by glucocorticoid therapy can continue for several months and in individual cases more than a year after cessation of therapy. In cases of particular physical stress situations (trauma, surgery, childbirth, etc.) during treatment with Максидекс Krka, a temporary increase in dose may be required. Because of the potential risk in stress situations, patients on extended therapy should be issued a steroid card. Also in prolonged adrenal insufficiency after cessation of treatment, the administration of glucocorticoids may be necessary in physical stress situations. In case of intended withdrawal, treatment-induced acute adrenal insufficiency may be minimized by slow dose reduction.
Through immunosuppression, treatment with Максидекс Krka can lead to an increased risk of bacterial, viral, parasitic, opportunistic and fungal infections. It can mask the symptoms of an existing or developing infection, thereby making a diagnosis more difficult. Latent infections, like tuberculosis or hepatitis B, can be reactivated.
Treatment with Максидекс Krka should only be implemented in the event of the strongest indications and, if necessary, additional targeted anti-infective treatment administered for the following illnesses:
- Acute viral infections (Herpes zoster, Herpes simplex, Varicella, herpetic keratitis)
- HBsAG-positive chronic active hepatitis
- Approximately 8 weeks prior to 2 weeks after vaccinations with live vaccines
- Systemic mycoses and parasitoses (e.g. nematodes)
- In patients with suspected or confirmed strongyloidiasis (infection with threadworms), glucocorticoids can lead to activation and mass proliferation of these parasites
- Poliomyelitis
- Lymphadenitis after BCG vaccination
- Acute and chronic bacterial infections
- In a history of tuberculosis (reactivation risk), use only under tuberculostatic protection
In addition, treatment with Максидекс Krka should only be implemented under strong indications and, if necessary, additional specific treatment must be implemented for:
- Gastrointestinal ulcers
- Osteoporosis
- Severe cardiac insufficiency
- High blood pressure that is difficult to regulate
- Diabetes mellitus that is difficult to regulate
- Psychiatric disorders (also in the past), including suicidality: neurological or psychiatric monitoring is recommended
- Narrow- and wide-angle glaucoma, ophthalmic monitoring and adjunctive therapy are recommended
- Corneal ulcerations and corneal injuries, ophthalmic monitoring and adjunctive therapy are recommended
Because of the risk of an intestinal perforation, Максидекс Krka may only be used under urgent indication and under appropriate monitoring for:
- Severe ulcerative colitis with threatened perforation, possibly without peritoneal irritation
- Diverticulitis
- Enteroenterostomy (immediately postoperatively)
Signs of peritoneal irritation after gastrointestinal perforation may be absent in patients receiving high doses of glucocorticoids.
The possibility of a higher need for insulin or oral antidiabetics must be taken into consideration when administering Максидекс Krka to diabetics.
Regular blood pressure monitoring is necessary during treatment with Максидекс Krka, particularly during administration of higher doses and in patients with high blood pressure that is difficult to regulate.
Because of the risk of deterioration, patients with severe cardiac insufficiency should be carefully monitored.
With high doses of Максидекс bradycardia may occur.
Severe anaphylactic reactions may occur.
The risk of tendon disorders, tendinitis and tendon rupture is increased when fluoroquinolones and glucocorticoids are administered together.
A concurrent myasthenia gravis may initially worsen during treatment with Максидекс Krka.
Vaccinations with inactivated vaccines are generally possible. However, it should be noted that the immune response and thus the vaccine may be compromised at higher doses of corticosteroids.
During long-term therapy with Максидекс Krka, regular medical checkups (including ophthalmologic every three months) are indicated.
At high doses, sufficient calcium intake and sodium restriction should be ensured and serum potassium levels should be monitored.
Depending on the dose and duration of treatment, a negative effect on calcium metabolism can be expected; therefore, the prevention of osteoporosis is recommended. This applies especially to patients with concomitant risk factors, such as familial predisposition, advanced age, postmenopausal period, insufficient protein and calcium intake, heavy smoking, excessive alcohol consumption and lack of physical activity. Prevention consists of sufficient calcium and vitamin D intake and physical activity. In already existing osteoporosis, additional drug therapy should be considered.
Upon termination of long-term administration of glucocorticoids, the following risks must be taken into account: exacerbation or relapse of the underlying disease, acute adrenal insufficiency, cortisone withdrawal syndrome.
Certain viral diseases (chickenpox, measles) may be very severe in patients treated with glucocorticoids. Immunocompromised patients without previous chickenpox or measles infection are particularly at risk. If these patients have contact with people infected with measles or chickenpox while undergoing treatment with Максидекс Krka, a preventative treatment should be introduced, if necessary.
In post marketing experience tumour lysis syndrome (TLS) has been reported in patients with haematological malignancies following the use of Максидекс alone or in combination with other chemotherapeutic agents. Patient at high risk of TLS, such as patients with high proliferative rate, high tumour burden, and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precaution taken.
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 (CSCR) which have been reported after use of systemic and topical corticosteroids.
Paediatric population
In the growth phase of children, the benefit-risk balance of treatment with Максидекс Krka should be carefully weighed.
Therapy should be of limited duration or in case of long-term therapy, it should be carried out alternatingly.
Preterm neonates: Available evidence suggests long-term neurodevelopmental adverse events after early treatment (< 96 hours) of premature infants with chronic lung disease at starting doses of 0.25mg/kg twice daily.
Elderly patients
Because elderly patients are at an increased risk of osteoporosis, the benefit-risk balance of treatment with Максидекс Krka should be carefully weighed.
Note
The use of Максидекс Krka can lead to positive results in doping controls.
Максидекс Krka contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
- For ocular use only.
- Prolonged use of topical ophthalmic corticosteroids may result in ocular hypertension and/or glaucoma, with damage to the optic nerve, reduced visual acuity, visual field defects and posterior subcapsular cataract formation. In patients receiving prolonged ophthalmic corticosteroid therapy, intraocular pressure and the lens should be checked routinely and frequently, particularly in patients with a history or presence of glaucoma. This is especially important in paediatric patients as the risk of corticosteroid-induced ocular hypertension may be greater in children and may occur earlier than in adults. The risk of corticosteroid-induced raised intraocular pressure and/or cataract formation is increased in predisposed patients (e.g. diabetes).
- Topical corticosteroids should not be used for longer than one week except under ophthalmic supervision, with regular checks of intraocular pressure.
- Cushing's syndrome and/or adrenal suppression associated with systemic absorption of ocular dexamethasone may occur after intensive or long-term continuous therapy in predisposed patients, including children and patients treated with CYP3A4 inhibitors (including ritonavir and cobicistat). In these cases, treatment should be progressively discontinued.
- Corticosteroids may reduce resistance to and aid in the establishment of bacterial, viral and fungal infections and mask the clinical signs of infections. In such cases antibiotic therapy is mandatory. Fungal infection should be suspected in patients with persistent corneal ulceration and corticosteroids therapy should be discontinued if fungal infection occurs.
- Topical ophthalmic corticosteroids may slow corneal wound healing. Topical NSAIDs are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems..
- In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical corticosteroids.
- 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 be cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
- Contact lens wear is not recommended during treatment of an ocular inflammation.
- Additionally, this product contains benzalkonium chloride which may cause eye irritation and is known to discolour soft contact lenses. Avoid contact with soft contact lenses. Patients must be instructed to remove contact lenses prior to application of Максидекс and wait at least 15 minutes before reinsertion.
- There is no evidence of safety in use in children under two years of age.
There have been no studies on the effects on the ability to drive and use machines.
Максидекс has no or negligible influence on the ability to drive and use machines. As with any topical ophthalmic medicinal product, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs upon instillation, the patient must wait until the vision clears before driving or using machinery.
Posology
Dosage depends on the nature and severity of the disease and the individual response of the patient to treatment. In general, relatively high initial doses are administered, and they should be significantly higher in acute severe forms than in chronic diseases.
Unless otherwise prescribed, the following dosage recommendations apply:
- Cerebral oedema: Depending on the cause and severity, initial dose of 8-10 mg (up to 80 mg) i.v., followed by 16-24 mg (up to 48 mg)/day orally, divided into 3-4 (up to 6) individual doses for 4-8 days. A longer-term, lower-dose administration of Максидекс Krka may be required during irradiation and in the conservative treatment of inoperable brain tumours.
- Cerebral oedema due to bacterial meningitis: 0.15 mg/kg body weight every 6 hours for 4 days, children: 0.4 mg/kg body weight every 12 hours for 2 days, starting before the first antibiotics.
- Severe acute asthma attack: Adults: 8-20 mg, then, if necessary, 8 mg every 4 hours. Children: 0.15-0.3 mg/kg body weight.
- Acute skin diseases: Depending on the nature and extent of the disease, daily doses of 8-40 mg. Followed by treatment with decreasing doses.
- Active phases of rheumatic systemic diseases: systemic lupus erythematosus 6-16 mg/day.
- Severely progressive form of active rheumatoid arthritis: in rapidly destructive forms 12-16 mg/day, in extra-articular manifestations 6-12 mg/day
- Severe infectious diseases, toxic states (e.g. tuberculosis, typhoid): 4-20 mg for a few days, only with concomitant anti-infective therapy.
- Palliative treatment of malignant tumours: initially 8-16 mg/day, in prolonged treatment 4-12 mg/day.
- Congenital adrenogenital syndrome in adulthood: 0.25-0.75 mg/day as a single dose. If necessary, addition of a mineralcorticoid (fludrocortisone). In cases of particular physical stress (e.g. trauma, surgery), intercurrent infections, etc., a 2- to 3-fold dose increase may be required and under extreme stress (e.g. birth) a 10-fold increase.
The tablets should not be split to adjust doses. If patients need a dose that cannot be provided by one or more tablets of 0.5mg, other appropriate formulations should be used.
Method of administration
The tablets should be taken during or after a meal. They should be swallowed whole, with a sufficient amount of liquid. The daily dose should be administered as a single dose in the morning, if possible (circadian therapy). In patients who require a high-dose therapy because of their disease, multiple daily dosing is often required to achieve maximum effect.
Depending on the underlying disease, clinical symptoms and response to therapy, the dose can be reduced at a faster or slower rate and the therapy stopped, or the patient is stabilised on a maintenance dose as low as possible and, if necessary, adrenal axis monitored. Basically, the dose and duration of treatment should be kept as high and long as necessary, but as low and short as possible. In principle, the dose should be reduced gradually.
In long-term therapy which is deemed necessary following initial treatment, patients should be switched to prednisone/prednisolone, because this leads to lower adrenal suppression.
In hypothyroidism or liver cirrhosis, low doses may be sufficient or a dose reduction may be necessary.
Adults, adolescents, and children (2 years of age and above)
The frequency of instillation of drops and the duration of treatment will vary depending upon the severity of the underlying condition and the response to treatment.
Severe inflammations require one to two drops instilled into the eye every thirty to sixty minutes until a satisfactory response occurs.
Subconjunctival or systemic steroid therapy should be considered if there is no response. When a favourable response has been observed reduce the dosage towards one drop every four hours.
Nasolacrimal occlusion or gently closing the eyelid after administration is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic adverse reactions.
Paediatric patients
The safety and efficacy of this product has not been established in children below 2 years of age.
No special requirements for disposal.
Do not touch dropper tip to any surface as this may contaminate the contents.
If the drop of medication is not retained in the eye upon dosing for any reason then instill another drop.
