Duocopt
Ukraine
Table of Contents
INSTRUCTIONS for medical use of the medicinal product Duokopt (Duokopt)
Composition:
Active substances: dorzolamide; timolol;
1 ml of solution contains dorzolamide hydrochloride 22.25 mg, equivalent to dorzolamide 20 mg, and timolol maleate 6.83 mg, equivalent to timolol 5 mg;
Excipients: hydroxyethylcellulose, mannitol (E 421), sodium citrate (E 331), sodium hydroxide (E 524), water for injections.
Pharmaceutical form. Eye drops, solution.
Main physicochemical properties: clear, colorless or slightly yellow solution, practically free from particles.
Pharmacotherapeutic group. Agents used in ophthalmology. Antiglaucoma preparations and miotics. Beta-blocking agents. Timolol, combinations. ATC code S01ED51.
Pharmacological properties.
Pharmacodynamics.
Duokopt is a preservative-free ophthalmic solution. The product contains two active substances: dorzolamide hydrochloride and timolol maleate. Each of these components reduces elevated intraocular pressure by decreasing the production of intraocular fluid, but through different mechanisms of action.
Dorzolamide hydrochloride is a potent inhibitor of carbonic anhydrase type II. Inhibition of carbonic anhydrase in the ciliary body leads to reduced secretion of intraocular fluid due to slowed formation of bicarbonate ions, which in turn causes decreased transport of sodium and fluid.
Timolol maleate is a non-selective beta-adrenergic receptor blocker. The exact mechanism of action of timolol, which results in reduced intraocular pressure, is not fully understood. Fluorometric and tonographic studies indicate that the effect of timolol is due to decreased secretion of aqueous humor. Additionally, timolol may enhance outflow of fluid.
The combination of these two components results in a more pronounced reduction of intraocular pressure than monotherapy with either agent alone.
Duokopt reduces intraocular pressure following topical administration, regardless of whether the elevated pressure is associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and visual field loss or blindness due to glaucoma.
Duokopt reduces intraocular pressure without causing the side effects typical of miotics, such as night blindness, accommodative spasm, or pupillary constriction.
Pharmacokinetics.
Dorzolamide hydrochloride
Unlike orally administered carbonic anhydrase inhibitors, topical administration of dorzolamide hydrochloride allows direct action of the active substance on the eye at substantially lower doses and minimizes systemic effects. Clinical trials have demonstrated reduction in intraocular pressure (IOP) without the acid-base or fluid-electrolyte imbalances typically associated with oral carbonic anhydrase inhibitors.
After topical administration, dorzolamide enters the systemic circulation. To assess the level of systemic carbonic anhydrase inhibition, concentrations of the drug and its metabolites were measured in erythrocytes and plasma following topical application. With long-term use, dorzolamide accumulates in erythrocytes due to binding to carbonic anhydrase type II, resulting in very low concentrations of free drug in plasma. During metabolism, one N-desethyl metabolite is formed, which inhibits carbonic anhydrase type II to a much lesser extent than the parent compound and also inhibits the less active isoenzyme, carbonic anhydrase type I. This metabolite also accumulates in erythrocytes, where it binds primarily to carbonic anhydrase type I. Approximately 33% of dorzolamide is protein-bound in plasma. Dorzolamide is excreted in urine, either unchanged or as metabolites. After discontinuation of the drug, elimination of dorzolamide from erythrocytes is nonlinear, characterized by an initial rapid decline in concentration followed by a slower elimination phase with a half-life of approximately 4 months.
Following oral administration of dorzolamide to simulate maximum systemic exposure during long-term ocular (ocular) use, steady state was achieved within 13 weeks. At this stage, dorzolamide was nearly undetectable in plasma in free form or as metabolite; inhibition of carbonic anhydrase in erythrocytes was lower than required for pharmacological effects on renal or respiratory function. A similar pharmacokinetic profile was observed after long-term topical administration of dorzolamide hydrochloride. However, in some elderly patients with impaired renal function (creatinine clearance 30–60 mL/min), higher concentrations of the metabolite in erythrocytes were observed, although significant differences in carbonic anhydrase inhibition and clinically relevant systemic adverse effects were not directly linked to these findings.
Timolol maleate
After topical ocular administration, timolol is systemically absorbed. Systemic exposure to timolol was assessed following topical administration of a 0.5% ophthalmic solution twice daily. The maximum plasma concentration after the morning dose was 0.46 ng/mL, and after the evening dose, 0.35 ng/mL.
Clinical characteristics.
Indications.
Duokopt is indicated for the treatment of elevated intraocular pressure in patients with open-angle glaucoma or pseudoexfoliative glau游戏副本
Special precautions for use.
Systemic effects
Like other topically acting ophthalmic medicinal products, timolol is systemically absorbed. Since timolol is a beta-blocker, adverse reactions affecting the cardiovascular and respiratory systems, typical of systemic administration of such agents, may occur. The frequency of systemic adverse reactions after topical administration of ophthalmic medicinal products is lower than with systemic administration. For methods to reduce systemic absorption, see section "Instructions for use and dosage".
Cardiac disorders
Beta-blockers should be used with caution in patients with cardiovascular disorders (e.g., ischemic heart disease, vasospastic angina/Prinzmetal's angina, heart failure) and hypotension. The patient's condition should be carefully evaluated, and consideration should be given to alternative treatment with a different mechanism of action. Patients with cardiovascular disorders 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 impulse conduction velocity.
Vascular disorders
This medicinal product should be used with caution in patients with severe peripheral circulatory disorders (e.g., severe forms of Raynaud's disease/syndrome).
Respiratory disorders
Respiratory reactions (including fatal cases due to bronchospasm) have been reported in patients with asthma treated with ophthalmic beta-blockers.
Duokopt should be used with caution in patients with mild to moderate chronic obstructive pulmonary disease (COPD), and only if the expected benefit outweighs the potential risk.
Hepatic impairment
The use of this medicinal product has not been studied in patients with hepatic impairment; therefore, it should be used with caution in such patients.
Renal impairment
The use of this medicinal product has not been studied in patients with renal impairment; therefore, it should be used with caution in such patients.
Immunological and hypersensitivity reactions
Like other topically acting ophthalmic medicinal products, this medicinal product may be systemically absorbed. Dorzolamide contains a sulfonamide group. Therefore, adverse reactions observed with systemic administration of sulfonamides may also occur with topical use, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs of serious or hypersensitivity reactions occur, the use of the medicinal product should be discontinued.
Local ocular adverse reactions similar to those observed with dorzolamide hydrochloride eye drops have been reported during treatment with this medicinal product. If such reactions occur, discontinuation of the medicinal product should be considered.
Anaphylactic reactions
Patients with atopy or a history of severe anaphylactic reactions to multiple allergens may be more sensitive to re-exposure to allergens during anaphylactic reactions when treated with beta-blockers and may not respond to usual doses of adrenaline used to treat such reactions.
Concomitant therapy
Additive carbonic anhydrase inhibition effects
Treatment with oral carbonic anhydrase inhibitors has been associated with the development of urolithiasis due to acid-base imbalance, especially in patients with a history of nephrolithiasis. Although acid-base imbalances have not been observed with the use of the preserved dorzolamide/timolol combination formulation, there have been isolated reports of urolithiasis.
Since carbonic anhydrase inhibitors are systemically absorbed after topical administration, patients with a history of nephrolithiasis may have an increased risk of developing urolithiasis when treated with Duokopt.
Other beta-blockers
The effect on IOP or other known systemic effects of beta-blockers may be enhanced when timolol is used in patients already receiving systemic beta-blockers. Close monitoring of clinical efficacy is required when treating such patients. The use of two topical beta-adrenergic blockers is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Concomitant topical use of dorzolamide and oral carbonic anhydrase inhibitors is not recommended.
Discontinuation of treatment
When discontinuation of the medicinal product is necessary, ophthalmic timolol should be withdrawn gradually in patients with ischemic heart disease (IHD), as with systemic beta-blockers.
Other effects of beta-blockers
Hypoglycemia/diabetes
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 acute hypoglycemia.
Beta-blockers may also mask the signs of hyperthyroidism. Abrupt withdrawal of beta-blockers may lead to symptom exacerbation.
Anesthesia during surgical procedures
Ophthalmic beta-blockers may block the systemic effects of beta-agonists, such as adrenaline. The anesthesiologist must be informed that the patient is using timolol.
Ophthalmic effects
Treatment of patients with acute angle-closure glaucoma requires additional therapeutic measures beyond intraocular pressure (IOP)-lowering agents. The use of this medicinal product in patients with acute angle-closure glaucoma has not been studied.
Corneal edema and irreversible corneal decompensation have been reported in patients with pre-existing chronic corneal disorders and/or a history of intraocular surgery receiving dorzolamide. There is a high likelihood of corneal edema in patients with a low number of endothelial cells. Precautions should be taken when prescribing Duokopt to such patients.
Choroidal detachment
Choroidal detachment has been reported following filtration surgery and treatment with aqueous suppressants (e.g., timolol, acetazolamide).
Corneal disorders
Ophthalmic beta-blockers may cause dry eye. This medicinal product should be used with caution in patients with corneal disorders.
Other special considerations
Beta-blocker treatment may exacerbate symptoms in patients with myasthenia gravis.
As with other antiglaucoma agents, reduced sensitivity to ophthalmic timolol maleate has been reported in some patients after prolonged treatment. However, in clinical studies where 164 patients were followed for at least three years, no significant difference in mean IOP was observed after initial pressure stabilization.
Contact lens use
The use of this medicinal product has not been studied in patients wearing contact lenses.
Athletes
Use of Duokopt may result in false-positive results in doping controls.
Use during pregnancy or breastfeeding.
Pregnancy
This medicinal product is not used during pregnancy.
Dorzolamide
There are no clinical data on the use of dorzolamide in pregnant women. Dorzolamide has shown teratogenic effects in animals when administered to pregnant animals.
Timolol
There are insufficient data on the use of timolol in pregnant women. Timolol should not be used during pregnancy unless absolutely necessary. To reduce systemic absorption, see section "Instructions for use and dosage".
Epidemiological studies have not shown teratogenic effects but have demonstrated a risk of fetal growth retardation with oral use of beta-blockers. Additionally, signs and symptoms of beta-blocker effects (e.g., bradycardia, hypotension, respiratory distress syndrome, hypoglycemia) have been observed in infants born to mothers who received beta-blockers before delivery. Therefore, if the medicinal product is used before delivery, the newborn should be closely monitored during the first days of life.
Breastfeeding period
It is unknown whether dorzolamide is excreted in human breast milk. In animal studies, reduced body weight was observed in offspring of rats nursed by dams receiving dorzolamide.
Timolol, like other beta-blockers, is excreted in human breast milk. However, even with therapeutic doses of timolol administered as eye drops, it is highly unlikely that its concentration in milk would be sufficient to cause clinical symptoms in infants. To reduce systemic absorption, see section "Instructions for use and dosage". If treatment with Duokopt is necessary, breastfeeding should be discontinued during the treatment period.
Fertility
Data are available for each active ingredient, but there is no information on the fixed combination of dorzolamide hydrochloride and timolol maleate. However, when this medicinal product is used as eye drops at therapeutic doses, no effect on fertility is expected.
Ability to affect reaction speed when driving or operating machinery.
No studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted. Duokopt has a minor influence on the ability to drive and operate machinery. As with other ophthalmic medicinal products, instillation of Duokopt eye drops may cause transient blurred vision. Until this effect resolves, patients should not drive or operate machinery.
Method of administration and dosage.
Dosage
Duokopt should be administered as 1 drop into the conjunctival sac of the affected eye(s) twice daily. The product is a sterile solution and contains no preservatives.
If several ophthalmic agents are used simultaneously, the interval between instillation of Duokopt and another medicinal product should be at least 10 minutes.
Before administration, hands must be washed, and contact between the dropper tip and the surface of the eye or eyelids should be avoided.
Patients should be advised that ophthalmic solutions may become contaminated with bacteria if not stored properly, which may lead to ocular infections. Use of contaminated solutions may result in serious eye damage and even vision loss.
Instructions for use
Important!
The 5 ml multidose bottle contains at least 125 drops of the preservative-free solution;
the 10 ml multidose bottle contains at least 250 drops of the preservative-free solution.
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Before first use, please check the integrity of the first-opening control stopper on the protective cap. Then unscrew it firmly to allow subsequent opening of the bottle. |
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| First, prime the pump mechanism by pressing the bottle several times until the first drop appears. This step is required only upon first use and should not be repeated thereafter. |
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To instill one drop into the conjunctival sac of the affected eye(s), press quickly and firmly on the bottle’s protrusions. Thanks to the automatic dosing mechanism, one drop is dispensed precisely with each press. |
| If the drop does not come out, gently tap the bottle to dislodge the drop from the dropper tip and repeat the steps starting from point 3. |
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Children.
Not applicable.
Overdose.
There is no data regarding overdose in humans following accidental or intentional ingestion of Duokopt.
Symptoms
There have been reports of accidental overdose with ophthalmic timolol maleate solution, leading to potential development of systemic effects similar to those observed with systemic administration of beta-blockers, including dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest. The most common expected symptoms following dorzolamide overdose are disturbances in electrolyte balance, development of acidosis, and possible effects on the central nervous system.
Limited data are available on dorzolamide hydrochloride overdose in humans following accidental or intentional ingestion. Drowsiness has been reported after oral intake; with topical use, nausea, dizziness, headache, weakness, sleep disturbances, and dysphagia (difficulty swallowing) have been reported.
Treatment
Treatment is symptomatic and supportive. Serum electrolyte levels (particularly potassium) and blood pH should be monitored. Studies have shown that dialysis is not effective for removing timolol from the body.
Side effects.
In clinical studies of the preservative-free dorzolamide/timolol combination, the observed adverse reactions were consistent with those established for dorzolamide/timolol with preservatives, dorzolamide hydrochloride, and/or timolol maleate.
During clinical trials, 1035 patients received treatment with dorzolamide/timolol containing a preservative. Approximately 2.4% of all patients discontinued treatment due to the occurrence of local ocular adverse reactions; approximately 1.2% of all patients discontinued treatment due to local adverse reactions characterized by allergy or hypersensitivity (eyelid inflammation and conjunctivitis).
In a double-blind comparative study, the preservative-free dorzolamide/timolol combination administered at the same doses demonstrated a similar safety profile compared to the dorzolamide/timolol combination containing a preservative.
As with other ophthalmic medications administered locally, timolol is absorbed into the systemic circulation. This may lead to undesirable effects similar to those observed with other systemic beta-blockers. The frequency of systemic adverse reactions with topical ophthalmic administration is lower than with systemic administration.
The adverse reactions listed below have been reported during clinical trials or post-marketing surveillance when using the preservative-free dorzolamide/timolol combination or one of its components.
Preservative-free dorzolamide hydrochloride/timolol maleate combination.
Immune system disorders
Rare: symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylactic reaction.
Eye disorders
Very common: burning, stinging.
Common: conjunctival injection, blurred vision, corneal erosion, eye itching, lacrimation.
Respiratory, thoracic and mediastinal disorders
Common: sinusitis.
Rare: dyspnea, respiratory failure, rhinitis. Rare – bronchospasm.
Gastrointestinal disorders
Very common: dysgeusia (altered taste sensation).
Skin and subcutaneous tissue disorders
Rare: contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Renal and urinary disorders
Rare: urolithiasis.
Timolol maleate
Immune system disorders
Rare: symptoms of allergic reactions, including angioedema, urticaria, localized and generalized rash, anaphylactic reaction.
Frequency not known: pruritus.
Metabolism and nutrition disorders
Frequency not known: hypoglycemia.
Psychiatric disorders
Uncommon: depression*.
Rare: insomnia*, nightmares*, memory loss.
Frequency not known: hallucinations**.
Nervous system disorders
Common: headache*.
Uncommon: dizziness*, syncope*, paresthesia*, worsening of signs and symptoms of myasthenia gravis, decreased libido (sex drive)*, hemorrhagic stroke*, cerebral ischemia.
Eye disorders
Common: ocular irritation symptoms, including blepharitis*, keratitis*, decreased corneal sensitivity, dry eyes*.
Uncommon: visual disturbances, including refractive changes (in some cases due to discontinuation of miotic agents)*.
Rare: ptosis, diplopia, choroidal detachment after filtration surgery* (see section "Special precautions").
Frequency not known: pruritus**, lacrimation**, redness**, blurred vision**, corneal erosion**.
Ear and labyrinth disorders
Rare: tinnitus*.
Cardiac disorders
Uncommon: bradycardia*.
Rare: chest pain*, palpitations*, arrhythmia*, edema, congestive heart failure*, cardiac arrest*, heart block.
Frequency not known: atrioventricular block**, heart failure**.
Vascular disorders
Rare: arterial hypotension*, claudication, Raynaud's phenomenon*, cold sensation in hands and feet*.
Respiratory, thoracic and mediastinal disorders
Uncommon: dyspnea (shortness of breath)*.
Rare: bronchospasm (predominantly in patients with a history of bronchospastic disorders)*, respiratory failure, cough*.
Gastrointestinal disorders
Uncommon: nausea*, dyspepsia*.
Rare: diarrhea, dry mouth*.
Frequency not known: dysgeusia (altered taste sensation)**, abdominal pain**, vomiting**.
Skin and subcutaneous tissue disorders
Rare: alopecia*, psoriatic rash or exacerbation of psoriasis.
Frequency not known: skin rash**.
Musculoskeletal and connective tissue disorders
Rare: systemic lupus erythematosus.
Frequency not known: myalgia**.
Reproductive system and breast disorders
Rare: Peyronie's disease*.
Frequency not known: decreased libido, sexual dysfunction**.
General disorders and administration site conditions
Uncommon: asthenia/fatigue*.
Dorzolamide hydrochloride
Nervous system disorders
Common: headache*, dizziness*, paresthesia* (skin sensory disturbances).
Eye disorders
Common: eyelid inflammation*, eyelid irritation*.
Uncommon: iridocyclitis*, eye irritation including redness*, eye pain*, eyelid scaling*, transient myopia (resolves upon discontinuation of treatment), corneal edema*, decreased IOP*, choroidal detachment after filtration surgery*.
Frequency not known: foreign body sensation**.
Cardiac disorders
Frequency not known: palpitations**, tachycardia.
Vascular disorders
Frequency not known: hypertension.
Respiratory, thoracic and mediastinal disorders
Uncommon: epistaxis*.
Frequency not known: dyspnea**.
Gastrointestinal disorders
Uncommon: nausea*.
Rare: throat irritation, dry mouth*.
Skin and subcutaneous tissue disorders
Rare: rash*.
General disorders and administration site conditions
Common: asthenia/fatigue*.
* These adverse reactions were observed during post-marketing surveillance of the dorzolamide/timolol combination with preservative.
** These adverse reactions were observed with ophthalmic beta-blockers and may likely occur with the preservative-free dorzolamide/timolol combination.
Reporting suspected adverse reactions
Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.
In case of adverse events, side effects, or lack of therapeutic effect, please send information to the contact person at LABORATOIRES THEA, responsible for pharmacovigilance in Ukraine, via email at [email protected] or call (044) 585-04-60, (044) 467-57-70 (24/7).
Shelf life.
2 years. Shelf life after first opening of the bottle – 2 months.
Storage conditions.
No special storage conditions required.
Keep out of reach and sight of children.
Packaging.
5 ml in a multidose bottle with pump and protective cap; 1 bottle in an auxiliary delivery device; pack of 1 or 3 in a box.
10 ml in a multidose bottle with pump and protective cap; 1 bottle in an auxiliary delivery device; pack of 1 or 2 in a box.
Prescription status.
Prescription only.
Manufacturer.
DELPHARM TOUR/DELPHARM TOURS.
Manufacturer's address.
Rue Paul Langevin, CHAMBRAY LES TOURS, 37170, France.
Marketing authorization holder.
LABORATOIRES THEA/LABORATOIRES THEA.
Address of marketing authorization holder.
12 rue Louis Bleriot, 63100 Clermont-Ferrand Cedex 2, France.
Date of last review.