Instructions for use Mardozia eye drops solution 20 mg/ml + 5 mg/ml dropper bottle 5 ml
Composition
active ingredients: dorzolamide, timolol;
1 ml of solution contains 20 mg of dorzolamide (as dorzolamide hydrochloride) and 5 mg of timolol (as timolol maleate);
Excipients: mannitol (E 421), benzalkonium chloride, hydroxyethylcellulose, sodium citrate, sodium hydroxide, water for injections.
Dosage form
Eye drops.
Main physicochemical properties: transparent, slightly viscous, colorless aqueous solution.
Pharmacotherapeutic group
Antiglaucoma drugs and miotics. Beta-adrenergic blockers. Timolol, combinations.
ATX code S01E D51.
Pharmacological properties
Pharmacodynamics
The drug contains two active ingredients: dorzolamide hydrochloride and timolol maleate. Each of these components reduces elevated intraocular pressure by reducing the secretion of intraocular fluid, but by a different mechanism of action.
Dorzolamide hydrochloride is a potent inhibitor of carbonic anhydrase type II. Inhibition of carbonic anhydrase in the ciliary process of the eye leads to a decrease in the secretion of intraocular fluid by slowing the formation of bicarbonate ions, which, in turn, leads to a decrease in sodium and fluid transport.
Timolol maleate is a non-selective beta-adrenergic receptor blocker. The exact mechanism of action of timolol, which is manifested in the reduction of intraocular pressure, is still unknown. Fluorescein studies and tonographic studies indicate that the effect of timolol is due to a decrease in aqueous secretion. In addition, timolol may increase the outflow of aqueous.
The combined action of the two components leads to a more pronounced reduction in intraocular pressure compared to the use of each component separately.
After topical application, Mardozia reduces intraocular pressure, regardless of whether the elevation is associated with glaucoma. Elevated intraocular pressure plays a significant role in the pathogenesis of optic nerve damage and visual field loss in glaucoma.
The drug reduces intraocular pressure without the development of side effects typical of miotic agents, such as night blindness, accommodation spasm, and pupil constriction.
Pharmacokinetics
Dorzolamide hydrochloride
When applied topically, dorzolamide penetrates the systemic circulation. With prolonged use, dorzolamide accumulates in erythrocytes as a result of binding to carbonic anhydrase type II, maintaining very low concentrations of free active substance in the blood plasma. As a result of metabolism, dorzolamide forms a single N-desethylated metabolite, which blocks carbonic anhydrase type II less strongly than the parent compound, but also inhibits the less active isoenzyme CA-I. The metabolite also accumulates in erythrocytes, where it binds mainly to carbonic anhydrase type I. Approximately 33% of dorzolamide binds to plasma proteins. Dorzolamide is excreted in the urine in unchanged form and as a metabolite. After discontinuation of dorzolamide, elimination from erythrocytes is non-linear, initially leading to a rapid decline in concentration followed by a slow elimination phase with a half-life of approximately 4 months.
Timolol maleate
Timolol is absorbed systemically after topical ocular administration. Systemic exposure to timolol was determined after topical application of a 0.5% ophthalmic solution twice daily. Peak plasma concentrations were 0.46 ng/mL after the morning dose and 0.35 ng/mL after the evening dose.
Indication
Treatment of elevated intraocular pressure in patients with open-angle glaucoma or pseudoexfoliative glaucoma in whom monotherapy with topical beta-adrenergic blocking agents is not sufficiently effective.
Contraindication
The drug Mardozia is contraindicated in patients:
- with reactive airway diseases, including bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease;
- with sinus bradycardia, sick sinus syndrome, sinoatrial block, second or third degree atrioventricular block not controlled by a pacemaker, severe heart failure, cardiogenic shock;
- with severe renal impairment (creatinine clearance CrCl < 30 ml/min) or hyperchloremic acidosis;
- with hypersensitivity to one or both active substances or to any of the components of the drug;
- during pregnancy or breastfeeding.
The above contraindications are based on information regarding the individual active ingredients and are not specific to the combination.
Interaction with other medicinal products and other types of interactions
No specific studies of interactions between Mardozia and other medicinal products have been conducted.
There is a risk of additive effects resulting in hypotension and/or marked bradycardia if ophthalmic beta-blocker solution is used concomitantly with oral calcium channel blockers, drugs that promote catecholamine depletion or beta-blockers, antiarrhythmic drugs (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, narcotics, and monoamine oxidase inhibitors (MAOIs).
Potentiation of systemic beta-blockade (e.g., decreased heart rate, depression) has been reported with concomitant use of CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) and timolol.
Although the drug itself (as monotherapy) has little or no effect on pupil size, mydriasis has occasionally been reported as a result of concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine).
Beta-blockers may enhance the hypoglycemic effect of antidiabetic drugs.
Beta-blockers for oral use may provoke the development of rebound hypertension upon withdrawal of clonidine.
Application features
Reactions from the cardiovascular and respiratory systems
Like other topical ophthalmic drugs, timolol is absorbed systemically. Since timolol is a beta-blocker, the development of adverse reactions from the cardiovascular and respiratory systems that occur with systemic use of such drugs is possible. The incidence of systemic adverse reactions after topical use of ophthalmic drugs is lower than with systemic use. Regarding reduced systemic absorption, see section "Method of administration and dosage".
Cardiac disorders
In patients with cardiovascular disease (e.g. coronary artery disease, vasospastic angina/Prinzmetal's angina and heart failure) and hypotension, beta-blocker treatment should be seriously evaluated and alternative treatment considered. Patients with cardiovascular disease should be monitored for signs of worsening of these conditions and adverse reactions. Beta-blockers should be used with caution in patients with first-degree heart block due to their negative effect on conduction time.
Vascular disorders
Patients with severe disorders and diseases of the peripheral vascular system (such as severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.
Respiratory system disorders
Respiratory reactions, including fatal bronchospasm, have been reported in patients with asthma following the use of some ophthalmic beta-blockers.
Mardozia should be used with caution in patients with mild/moderate chronic obstructive pulmonary disease and only if the expected benefit outweighs the potential risk.
Liver dysfunction
This medicinal product has not been studied in patients with hepatic impairment and should therefore be administered with caution to such patients.
Immunological and hypersensitivity reactions
Like other topical ophthalmic drugs, this drug may be absorbed systemically.
Dorzolamide, like sulfonamides, contains a sulfonamide group. Therefore, adverse reactions seen with systemic sulfonamides may occur with topical administration, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs of serious or hypersensitivity reactions occur, the drug should be discontinued.
Local ocular adverse reactions similar to those seen with dorzolamide hydrochloride eye drops have been observed with this medicinal product. If such reactions occur, discontinuation of this medicinal product should be considered.
When taking beta-blockers, patients with atopy or a history of severe anaphylactic reactions to multiple allergens may be more sensitive to re-exposure to such allergens in the event of anaphylactic reactions and may not respond to treatment with the usual dose of adrenaline.
Concomitant therapy
The effect on intraocular pressure or the known effects of systemic beta-blockers may be potentiated when timolol is used in patients already receiving a systemic beta-blocker. The response to treatment in such patients should be carefully monitored. The use of two topical beta-blockers is not recommended (see section 4.5).
The use of dorzolamide and oral carbonic anhydrase inhibitors is not recommended.
Treatment discontinuation
As with systemic beta-blockers, ophthalmic timolol should be tapered if discontinuation is necessary in patients with coronary artery disease (CAD).
Additional effects of beta-blockers
Beta-blockers should be used with caution in patients prone to spontaneous hypoglycemia or in patients with labile diabetes, as beta-blockers may mask the symptoms of hypoglycemia.
Beta-blockers may also mask the signs of hyperthyroidism. Abrupt discontinuation of beta-blockers may result in worsening of symptoms.
Treatment with beta-blockers may exacerbate symptoms of myasthenia gravis.
Corneal diseases
Ophthalmic beta-blockers may cause dry eyes. Patients with corneal diseases should be treated with caution.
Ophthalmic beta-blockers may block the systemic effects of beta-adrenergic agonists, such as adrenaline. The anesthesiologist should be informed that the patient is using timolol.
Additional effects of carbonic anhydrase inhibitors
Treatment with oral carbonic anhydrase inhibitors has been associated with the development of urolithiasis as a result of acid-base disturbances, especially in patients with a history of urolithiasis. Although acid-base disturbances have not been observed with this medicinal product, urolithiasis has been reported rarely. Since a topically administered carbonic anhydrase inhibitor is absorbed systemically, patients with a history of urolithiasis may be at higher risk of developing urolithiasis with Mardozia.
Other features
Treatment of patients with acute angle-closure glaucoma requires the use of other therapeutic agents in addition to drugs that lower intraocular pressure. This medicinal product has not been studied in patients with acute angle-closure glaucoma.
Corneal edema and irreversible corneal decompensation have been reported with dorzolamide in patients with pre-existing chronic corneal defects and/or a history of intraocular surgery. Corneal edema is more likely to occur in patients with low endothelial cell counts. Caution should be exercised when prescribing Mardozia to such patients.
Choroid detachment has been reported following filtration procedures with treatment with aqueous suppressants (e.g., timolol, acetazolamide).
As with other antiglaucoma drugs, decreased sensitivity to ophthalmic timolol maleate has been reported after long-term treatment in some patients. However, in clinical trials in which 164 patients were followed for at least three years, no significant difference in mean intraocular pressure was observed after initial pressure stabilization.
Using contact lenses
Mardozia contains the preservative benzalkonium chloride, which may cause eye irritation. Contact lenses should be removed before instillation and wait at least 15 minutes before reinsertion. Benzalkonium chloride is known to discolor soft contact lenses.
Use during pregnancy or breastfeeding
The drug should not be used during pregnancy.
It is not known whether dorzolamide is excreted in human milk. Timolol is excreted in human milk, therefore breast-feeding should be discontinued during treatment.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies on the effects of the drug on the ability to drive or use machines have been conducted. Possible side effects, such as blurred vision, may adversely affect the ability of some patients to drive or use machines.
Method of administration and doses
Instill 1 drop of the drug into the conjunctival sac of the affected eye(s) twice daily.
If another topical ophthalmic drug is used simultaneously, the interval between instillation of Mardozia and the other drug should be at least 10 minutes.
Systemic absorption is reduced by applying nasolacrimal occlusion or closing the eyelids for 2 minutes. This may result in reduced systemic side effects and increased local activity.
Patients should wash their hands before using the product and avoid contact of the dropper tip with the surface of the eye or eyelids. To ensure correct dosing, the dropper tip opening should not be enlarged.
Patients should be advised that ophthalmic solutions, if handled improperly, may be contaminated with common bacteria known to cause eye infections. Use of contaminated solutions may result in serious eye damage and subsequent loss of vision.
To reduce systemic absorption with subsequent reduction of systemic side effects and increase local efficacy of the drug, it is recommended to pinch the nasolacrimal duct or close the eyelids for 2 minutes after instillation.
Children
Do not apply.
Overdose
There are no data on accidental overdose or intentional ingestion of eye drops containing dorzolamide and timolol.
There have been reports of unintentional overdose with timolol maleate ophthalmic solution, resulting in systemic effects including dizziness, headache, dyspnea, bradycardia, bronchospasm, and cardiac arrest, similar to those seen with systemic beta-blocker overdose. The most common expected symptoms of dorzolamide overdose are electrolyte imbalance, acidosis, and possible central nervous system effects.
There are limited data on accidental overdose or intentional ingestion of dorzolamide hydrochloride preparations. Drowsiness has been reported after oral administration. Nausea, dizziness, headache, weakness, abnormal dreams and dysphagia (difficulty swallowing) have been reported with topical administration.
Treatment
Treatment is symptomatic and supportive. Serum electrolyte levels (especially potassium) and blood pH should be monitored. Studies have shown that timolol is not completely removed by dialysis.
Adverse reactions
In clinical trials with the combination of dorzolamide/timolol, the adverse reactions observed were consistent with those previously reported with dorzolamide hydrochloride and/or timolol maleate.
Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic circulation. This may cause undesirable effects similar to those observed with systemic beta-blockers. The incidence of systemic adverse drug reactions following topical ophthalmic use is lower than with systemic administration.
Adverse reactions observed during clinical trials or during post-marketing surveillance with the combination of dorzolamide/timolol or its individual components are listed below by system organ class.
On the part of the immune system
Dorzolamide/timolol eye drops: symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylactic reaction.
Timolol maleate eye drops: symptoms of allergic reactions, including angioedema, urticaria, localized or generalized rash, anaphylactic reaction, pruritus**.
Metabolism and nutrition
Timolol maleate eye drops: hypoglycemia**.
Mental disorders
Timolol maleate eye drops: depression*, insomnia*, nightmares*, memory loss, hallucinations**.
From the nervous system
Dorzolamide hydrochloride eye drops: headache*, dizziness*, paresthesia* (skin sensitivity disorders).
Timolol maleate eye drops: headache*, dizziness*, syncope*, paresthesia*, increased signs and symptoms of myasthenia gravis, decreased libido*, hemorrhagic stroke*, cerebral ischemia.
From the organ of vision
Dorzolamide/timolol eye drops: burning and stinging, conjunctival injection, blurred vision, corneal erosion, eye itching, tearing.
Dorzolamide hydrochloride eye drops: eyelid inflammation*, eyelid irritation*, iridocyclitis*, eye irritation including redness*, eye pain*, eyelid skin peeling*, temporary myopia (reversible on discontinuation of treatment), corneal edema*, decreased intraocular pressure*, choroid detachment (after filtration surgery), foreign body sensation in the eye*.
Timolol maleate eye drops: symptoms of eye irritation, including blepharitis*, keratitis*, decreased corneal sensitivity, dry eyes*, visual disturbances including refractive changes (in some cases due to withdrawal of miotics)*, ptosis, diplopia, choroid detachment after filtration surgery*, itching**, tearing**, redness**, blurred vision**, corneal erosion**.
From the organ of hearing and balance
Timolol maleate eye drops: ringing in the ears*.
From the heart
Timolol maleate eye drops: bradycardia*, chest pain*, palpitations*, arrhythmia*, congestive heart failure*, cardiac arrest*, heart block*, atrioventricular block**, heart failure**.
Dorzolamide hydrochloride eye drops: palpitations*, tachycardia* with a frequency of "not known".
From the vascular side
Timolol maleate eye drops: hypotension*, claudication, Raynaud's phenomenon*, coldness in hands and feet*,
Dorzolamide hydrochloride eye drops: hypertension* with a frequency of “not known”.
Respiratory, thoracic and mediastinal disorders
Dorzolamide/timolol eye drops: sinusitis, shortness of breath, respiratory failure, rhinitis, rarely bronchospasm.
Dorzolamide hydrochloride eye drops: nosebleed*, shortness of breath*.
Timolol maleate eye drops: difficulty breathing (dyspnea)*, bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, respiratory failure, cough*.
Gastrointestinal tract
Dorzolamide/timolol eye drops: dysgeusia (change in taste).
Dorzolamide hydrochloride eye drops: nausea*, dyspepsia*, throat irritation, dry mouth*.
Timolol maleate eye drops: diarrhea, dry mouth*, dysgeusia (change in taste)**, abdominal pain**, vomiting**.
Skin and subcutaneous tissue disorders
Dorzolamide/timolol eye drops: contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Timolol maleate eye drops: alopecia*, psoriatic rash or exacerbation of psoriasis*, skin rash**.
Musculoskeletal and connective tissue disorders
Timolol maleate eye drops: systemic lupus erythematosus, myalgia**.
Renal and urinary tract disorders
Dorzolamide/timolol eye drops: urolithiasis.
From the genitals and mammary glands
Timolol maleate eye drops: Peyronie's disease*, decreased libido, sexual dysfunction**.
General disorders and administration site conditions
Dorzolamide hydrochloride eye drops: asthenia/weakness*.
Timolol maleate eye drops: asthenia/weakness*.
* These adverse reactions have also been observed with dorzolamide/timolol ophthalmic solution during post-marketing surveillance.
** Additional adverse reactions that have been observed with ophthalmic beta-blockers and that are likely to occur with dorzolamide/timolol.
Expiration date
3 years.
Do not use after the expiry date stated on the packaging. Use no more than 28 days after first opening the bottle.
Storage conditions
Store at a temperature not exceeding 25 °C in the original packaging to protect from light. Keep out of the reach of children.
Packaging
5 ml of eye drop solution in dropper bottles, closed with tamper-evident caps. 1 dropper bottle in a cardboard box.
Vacation category
According to the recipe.
Producer
Pharmathen SA/Pharmathen SA
Location of the manufacturer and address of its place of business
Dervenakion 6, Pallini Attiki 15351, Greece.
