Maxidex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MAXIDEXÒ (MAXIDEXÒ)

Composition:

Active substance: 1 ml of suspension contains dexamethasone 1 mg;

Excipients: benzalkonium chloride, hydroxypropylmethylcellulose, sodium hydrogen phosphate anhydrous, polysorbate 80, edetate disodium, sodium chloride, citric acid, monohydrate and/or sodium hydroxide, purified water.

Pharmaceutical form. Eye drops.

Main physicochemical properties: opaque white to light yellow suspension, free from aggregates.

Pharmacotherapeutic group.
Anti-inflammatory agents used in ophthalmology. Corticosteroids. Dexamethasone. ATC code S01BA01.

Pharmacological properties.

Pharmacodynamics.

The efficacy of corticosteroids in treating inflammatory conditions of the eye is well established. Corticosteroids exert their anti-inflammatory action by inhibiting adhesion molecules on vascular endothelial cells, cyclooxygenase I or II, and cytokine release. As a result, the production of inflammatory mediators is reduced and leukocyte adhesion to vascular endothelium is suppressed, thereby preventing their migration into inflamed ocular tissues. Dexamethasone has potent anti-inflammatory activity with reduced mineralocorticoid effects compared to some other steroids and is one of the most potent corticosteroids available. Its high potency results from the addition of a methyl group and fluorine to the prednisolone molecule. This synthetic glucocorticoid suppresses inflammatory responses to mechanical, chemical, or immunological stimuli.

Currently, no explanation for this property has been found.

Mechanism of action

The precise mechanism of dexamethasone’s anti-inflammatory action is not fully understood. It suppresses numerous inflammatory cytokines and exerts multiple glucocorticoid and mineralocorticoid effects.

Pharmacodynamic effects

Dexamethasone is one of the most potent corticosteroids; it is 5−10 times more potent than prednisolone and 25 times more potent than cortisone and hydrocortisone.

The systemic toxicity of the active substance is well characterized. Systemic effects of dexamethasone may be associated with glucocorticosteroid imbalance.

Pharmacokinetics.

Ophthalmic bioavailability of dexamethasone after topical ocular administration of the medicinal product MACKSISDEX® was studied in patients undergoing cataract surgery. The maximum concentration of dexamethasone in intraocular fluid, approximately 31 ng/mL, was achieved within 90−120 minutes. Thereafter, concentration declined with a half-life of 3 hours. Systemic absorption after topical application is low.

Distribution

Following intravenous administration, the observed volume of distribution was 0.58 L/kg. In vitro, no changes in plasma protein binding were observed at dexamethasone concentrations ranging from 0.04 to 4 µg/mL, with an average plasma protein binding of 77.4%.

Biotransformation

Dexamethasone is primarily metabolized in the liver, predominantly by CYP3A4.

After topical application, low concentrations were detected in intraocular fluid 12 hours later, indicating that dexamethasone is stable against metabolism after penetration into intraocular fluid.

Elimination

After intravenous administration, 2.6% of unchanged parent compound was found in urine. Following oral administration (≤ 4 mg/day) over several weeks, 60% of the dose was recovered as 6β-hydroxydexamethasone and 5−10% as an additional metabolite, 6β-hydroxy-20-dihydrodexamethasone. Unchanged dexamethasone was not detected in urine. The systemic plasma half-life is relatively short—3−4 hours—but may be slightly longer in men. This difference was not related to changes in systemic clearance but rather to differences in volume of distribution and body weight. Dexamethasone is approximately 77−84% bound to serum albumin. Clearance ranges from 0.10 to 0.25 L/h/kg, and volume of distribution ranges from 0.576 to 1.15 L/kg. Oral bioavailability of dexamethasone is approximately 70%.

Linearity/non-linearity

AUC after oral administration of dexamethasone increased linearly with doses in the range of 0.5 mg−1.5 mg.

Pharmacokinetics in special populations

The pharmacokinetics of systemic dexamethasone do not differ significantly in patients with impaired renal function compared to healthy subjects.

Preclinical safety data

Repeated-dose toxicity studies of MACKSISDEX® eye drops in rabbits revealed systemic corticosteroid-related effects; however, even at doses substantially exceeding the human dose, these findings were not considered clinically relevant. The occurrence of such effects is unlikely when MACKSISDEX® is used at recommended doses.

Dexamethasone showed clastogenic properties in an in vitro chromosomal aberration test in human lymphocytes and in an in vivo micronucleus test in mice.

Standard carcinogenicity studies with dexamethasone have not been conducted.

Standard fertility studies with dexamethasone have not been conducted.

It has been established that dexamethasone is teratogenic in animals when administered orally: dexamethasone caused fetal developmental abnormalities, including cleft palate, intrauterine growth retardation, retrognathia, umbilical hernia, thymic hypoplasia, skeletal deformities (including impaired development of long bones), and effects on brain growth and development.

Clinical characteristics.

Indications.

Treatment of steroid-sensitive non-infectious inflammatory and allergic conditions of the conjunctiva, cornea, and anterior segment of the eye, including inflammatory reactions in the postoperative period.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Acute untreated bacterial infections.
• Cowpox and smallpox, and other viral infections of the cornea and conjunctiva (except keratitis caused by Herpes zoster).
• Fungal diseases of ocular structures or untreated parasitic infections of the eye.
• Mycobacterial infections of the eye.
• Acute epithelial keratitis caused by Herpes zoster (dendritic keratitis).
• Acute untreated purulent bacterial infections of the eye.
• Infections or injuries limited to the superficial corneal epithelium.
• The medicinal product MAXIDEX should not be used after removal of a corneal foreign body without complications.

Interaction with other medicinal products and other forms of interaction.

Studies on interaction with other medicinal products have not been conducted.

Concomitant use of locally applied steroids and non-steroidal anti-inflammatory drugs (NSAIDs) for local application increases the risk of corneal wound healing complications.

In patients receiving ritonavir or other potent CYP3A4 inhibitors, plasma concentrations of dexamethasone may be increased.

CYP3A4 inhibitors (including ritonavir and cobicistat) may reduce the clearance of dexamethasone, leading to more severe adverse effects and suppression of adrenal cortex function/Cushing's syndrome. Such combination should be avoided unless the benefit outweighs the risk of systemic side effects of corticosteroids. If the benefit of treatment outweighs the risk, systemic adverse effects of corticosteroids should be monitored in patients.

When using mydriatic eye drops (e.g., atropine and other anticholinergic agents), which may increase intraocular pressure, concomitant use of MAXIDEX® may lead to additional elevation of intraocular pressure.

If several locally applied ophthalmic medicinal products are used simultaneously, the interval between their administration should be at least 5 minutes. Ophthalmic ointments should be administered last.

Special precautions for use.

• For ophthalmic use only. The medicinal product is not intended for injection or oral administration.
• Do not use without medical examination. The medicinal product should be prescribed only after biomicroscopic examination using a slit lamp and fluorescein testing.
• This medicinal product is not effective for the treatment of Sjögren's keratoconjunctivitis.
• Excessive and/or prolonged use of ophthalmic corticosteroids increases the risk of ocular complications and may lead to systemic adverse effects. If inflammation does not subside during the course of therapy, alternative treatment options should be considered to reduce these risks.
• Prolonged treatment with locally applied ophthalmic corticosteroids may lead to ocular hypertension and/or glaucoma, resulting in optic nerve damage, decreased visual acuity, visual field constriction, and development of posterior subcapsular cataract. Patients receiving long-term topical ocular corticosteroid therapy should have regular and frequent monitoring of intraocular pressure. This is particularly important for children, as the risk of corticosteroid-induced ocular hypertension is higher in children than in adults. The medicinal product MAXIDEX® is not indicated for use in children. Patients with a personal or family history of glaucoma have an increased risk of developing corticosteroid-induced intraocular pressure. In patients with glaucoma, eye examinations should be performed weekly.
• In acute purulent ocular diseases, corticosteroids may mask infections or promote the spread of existing infection. If treatment lasts longer than 10 days, intraocular pressure should be monitored.
• The risk of corticosteroid-induced elevation of intraocular pressure and/or corticosteroid-induced cataract formation increases in predisposed patients (e.g., patients with diabetes mellitus).
• Visual disturbances may occur with both systemic and topical administration of corticosteroids. If a patient experiences symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist to evaluate possible causes, which may include cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSCR), which has been reported following systemic and topical corticosteroid use.
• Cushing's syndrome and/or adrenal suppression due to systemic absorption of ophthalmic formulations of dexamethasone may occur after intensive or long-term continuous therapy in susceptible patients, including children and patients receiving CYP3A4 inhibitors (e.g., ritonavir and cobicistat). In such cases, treatment should be gradually discontinued.
• Corticosteroids may reduce resistance to bacterial, viral, fungal, or parasitic infections and may mask clinical signs of infection, thereby interfering with the detection of antibiotic inefficacy.
• Fungal infection should be considered in patients with persistent corneal ulceration who are receiving or have received these medications. If fungal infection develops, corticosteroid therapy should be discontinued.
• Ophthalmic corticosteroids may delay corneal wound healing. It is also known that topically applied NSAIDs may slow or delay wound healing. Concomitant use of topical NSAIDs and topical corticosteroids may increase the risk of wound healing complications (see section "Interaction with other medicinal products and other forms of interaction").
• It is known that in conditions causing thinning of the cornea or sclera, topical corticosteroid use may lead to perforation.
• Treatment should not be prematurely discontinued due to the risk of inflammatory recurrence following abrupt cessation of high-dose corticosteroid therapy.
• The product should be used with special caution and only in combination with antiviral therapy when treating stromal keratitis or uveitis caused by Herpes simplex; periodic slit-lamp microscopy is required.
• Wearing contact lenses during treatment of ocular inflammation is not recommended.
• Additionally, the product contains benzalkonium chloride, which may cause eye irritation and is known to discolor soft contact lenses. Contact with soft contact lenses should be avoided. However, if the physician considers contact lens use acceptable, patients should be advised to remove contact lenses before instilling MAXIDEX® eye drops and to wait 15 minutes after instillation before reinserting contact lenses. Benzalkonium chloride may cause eye irritation, especially in patients with symptoms of dry eye or corneal disease (diseases of the transparent front layer of the eye).
• After instillation of eye drops, the following measures are recommended to reduce systemic absorption:
  • Keep eyelids closed for 2 minutes;
  • Apply digital pressure to the tear duct (punctal occlusion) for 2 minutes.

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate and well-controlled studies in pregnant women to assess the effects of the medicinal product MAXIDEX®. An increased risk of intrauterine growth restriction has been associated with prolonged or repeated use of corticosteroids during pregnancy. Infants born to mothers who received significant doses of corticosteroids during pregnancy should be carefully monitored for signs of adrenal insufficiency (see section "Special precautions for use"). Reproductive toxicity has been demonstrated in animal studies following systemic administration. Ophthalmic administration of 0.1% dexamethasone solution resulted in fetal abnormalities in rabbits. The use of the medicinal product MAXIDEX® is not recommended during pregnancy.

Breastfeeding

Systemic administration of corticosteroids results in their presence in human breast milk in amounts that may affect the breastfed infant. However, systemic exposure following topical ophthalmic use of MAXIDEX® is minimal. It is not known whether MAXIDEX® is excreted in human breast milk. Data on the mechanism of dexamethasone transfer into breast milk are lacking. It is unlikely that dexamethasone will be present in breast milk or will cause clinical effects in infants after maternal use of the medicinal product. Nevertheless, a risk to the breastfed infant cannot be excluded. The possibility of temporarily discontinuing breastfeeding during treatment with MAXIDEX® or discontinuing/abstaining from treatment with the medicinal product should be considered, taking into account the potential benefit of the drug for the mother and the benefits of breastfeeding for the infant.

Fertility

Studies evaluating the effect of dexamethasone on reproductive function following topical ophthalmic administration have not been conducted. There are limited clinical data on the effect of dexamethasone on reproductive function in men and women.

In rat models exposed to chorionic gonadotropin, no adverse effects of dexamethasone on reproductive function were observed.

Method of Administration and Dosage

Use in adults, including elderly patients.

In cases of severe or acute inflammation, instill 1–2 drops into the conjunctival sac(s) of the affected eye(s) every 30–60 minutes as initial therapy.

If a favorable response is observed, the dosage should be reduced to 1–2 drops into the conjunctival sac(s) of the affected eye(s) every 2–4 hours.

Subsequently, the dosage may be further reduced to 1 drop 3–4 times daily, if this dose is sufficient to control inflammation.

If the desired therapeutic effect is not achieved within 3–4 days, additional systemic or subconjunctival therapy may be prescribed.

For chronic inflammation, the dosage is 1 or 2 drops into the conjunctival sac(s) of the affected eye(s) every 3–6 hours, or more frequently if necessary.

For allergy or mild inflammation, the dosage is 1–2 drops into the conjunctival sac(s) of the affected eye(s) every 3–4 hours until the desired effect is achieved.

Treatment should not be discontinued prematurely (see section "Special Warnings and Precautions for Use").

Regular monitoring of intraocular pressure is recommended.

After instillation, gentle closure of the eyelids or nasolacrimal occlusion is recommended. This reduces systemic absorption of drugs administered into the eye, thereby decreasing the likelihood of systemic adverse effects.

If several ophthalmic medicinal products are used simultaneously, at least a 5-minute interval should be maintained between administrations. Ophthalmic ointments should be applied last.

Use in patients with hepatic or renal impairment.

MAKSIDEX® has not been studied in patients with renal or hepatic diseases. However, due to the low systemic absorption of dexamethasone following topical administration of this product, dosage adjustment is not required.

Method of Administration.

Shake the bottle well before use.

To prevent contamination of the dropper tip and the bottle contents, care should be taken to avoid touching the eyelids, adjacent areas, or other surfaces with the tip of the dropper bottle.

Children.

The efficacy and safety of this medicinal product in children have not been established.

Overdose.

No cases of overdose have been reported.

In case of overdose with MAKSIDEX® used topically, wash out the excess of the product from the eye(s) with warm water. In case of acute overdose during ophthalmic use or accidental ingestion of the bottle contents, considering the properties/characteristics of this medicinal product, no additional toxic effects are expected.

In case of accidental ingestion, symptomatic and supportive therapy should be administered.

Adverse Reactions

The most frequently reported adverse effect observed during clinical studies was eye discomfort.

The adverse reactions listed below occurred during clinical studies with MAXIDEX® and are classified according to the following frequency categories: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10000 to <1/1000), very rare (<1/10000), or unknown (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity. Data on adverse effects were obtained from clinical trials and post-marketing experience with dexamethasone ophthalmic solution.

Description of some adverse reactions.

Prolonged treatment with corticosteroids for local ophthalmic use may lead to ocular hypertension and/or glaucoma, with subsequent damage to the optic nerve, decreased visual acuity and visual field, as well as development of posterior subcapsular cataract (see section "Special precautions").

Since the medicinal product contains corticosteroids, in the presence of diseases causing thinning of the cornea or sclera, the risk of perforation increases, especially after prolonged use.

Corticosteroids may reduce resistance to infections (see section "Special precautions").

Shelf life. 2 years.

Storage period after first opening of the bottle – 4 weeks.

Storage conditions.

Store the bottle tightly closed in an upright position at a temperature not exceeding 25°C, in places inaccessible to children. Do not freeze.

Packaging.

5 ml in dropper bottles.

Prescription status. Prescription only.

Manufacturer.

Novartis Manufacturing NV / Novartis Manufacturing NV.

Manufacturer's address.

Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium / Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium.