Instructions Dorzopt Plus eye drops 20 mg/ml + 5 mg/ml 5 ml
Composition
active ingredients: dorzolamide, timolol;
1 ml of eye drops, solution, contains 20 mg of dorzolamide as 22.26 mg of dorzolamide hydrochloride and 5 mg of timolol as 6.84 mg of timolol maleate;
Excipients: hydroxyethylcellulose; citric acid, monohydrate; sodium hydroxide 1 M solution; mannitol (E 421); benzalkonium chloride; 1 M solution of sodium hydroxide or hydrochloric acid; purified water.
Dosage form
Eye drops, solution.
Main physicochemical properties: transparent, slightly viscous solution without mechanical impurities.
Pharmacotherapeutic group
Drugs used in ophthalmology. Antiglaucoma drugs and miotics. Beta-adrenergic blockers.
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 type II carbonic anhydrase. Inhibition of miliary carbonic anhydrase results in a decrease in aqueous humor secretion 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. Fluorimetric and tonographic studies indicate that the effect of timolol is due to a decrease in the secretion of humoral fluid. In addition, timolol may increase the outflow of moisture.
The combined effect of the two components leads to a more pronounced reduction in intraocular pressure than monotherapy with these drugs.
After topical application, DORZOPT PLUS 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.
DORZOPT PLUS reduces intraocular pressure without the development of side effects typical of miotic agents, such as night blindness, accommodation spasm, and pupil constriction.
Pharmacodynamic effects
Clinical effects
Clinical trials of up to 15 months duration were conducted to compare the intraocular pressure-lowering effects of a product containing two active substances: dorzolamide hydrochloride and timolol maleate, administered twice daily (in fixed doses in the morning and evening), with 0.5% timolol and 2.0% dorzolamide, administered alone and in combination, in patients with glaucoma or intraocular hypertension for whom combination therapy was considered appropriate and necessary in these trials. Both untreated patients and patients inadequately controlled on timolol monotherapy were included in the studies. The majority of patients were receiving topical beta-blocker monotherapy prior to study entry. In an analysis of combined studies, the IOP-lowering effect of the dual-agent dorzolamide hydrochloride/timolol maleate solution administered twice daily was greater than that of monotherapy with 2% dorzolamide administered three times daily or 0.5% timolol administered twice daily. The IOP-lowering effect of the dual-agent dorzolamide hydrochloride/timolol maleate solution administered twice daily was equivalent to that of the combination therapy with dorzolamide and timolol administered twice daily. The IOP-lowering effect of the dual-agent dorzolamide hydrochloride/timolol maleate solution administered twice daily was observed when measured at different times during the day and was maintained during long-term use.
Pediatric patients
A three-month controlled study was conducted with the primary objective of investigating and confirming the safety of dorzolamide hydrochloride ophthalmic solution 2% in children up to 6 years of age. In this study, 30 patients aged 2 to 6 years whose intraocular pressure was not adequately controlled with dorzolamide or timolol monotherapy received a formulation containing the two active substances dorzolamide hydrochloride and timolol maleate in an open-label phase of the study. Efficacy in these patients has not been established. In this small group, the use of a formulation containing the two active substances dorzolamide hydrochloride and timolol maleate twice daily was well tolerated with a total of 19 patients completing the treatment period, and 11 patients discontinued treatment due to surgery, drug change, or other reasons.
Pharmacokinetics.
In contrast to oral carbonic anhydrase inhibitors, topical application of dorzolamide hydrochloride allows the active substance to exert its effect directly in the eye at significantly lower doses and, therefore, with lower systemic exposure. In clinical studies, this resulted in a reduction in intraocular pressure without the acid-base disturbances or electrolyte changes characteristic of oral carbonic anhydrase inhibitors.
When applied topically, dorzolamide penetrates the systemic circulation. To assess the potential for systemic inhibition of carbonic anhydrase after topical application, the concentration of the active substance and metabolite in erythrocytes (erythrocytes), as well as inhibition of carbonic anhydrase in plasma, was measured. With prolonged use, dorzolamide accumulates in erythrocytes as a result of binding to carbonic anhydrase type II, maintaining very low concentrations of free drug in the blood plasma. As a result of metabolism, dorzolamide forms a single N-desethyl metabolite, which is less pronouncedly blocks carbonic anhydrase type II compared to its original form: it incubates carbonic anhydrase type I, a less active isoenzyme. 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 the drug, dorzolamide is eliminated non-linearly from erythrocytes, characterized by an initial rapid decrease in concentration and a subsequent phase of slow elimination with a half-life of approximately 4 months.
When dorzolamide was administered orally to mimic the maximum systemic exposure after chronic topical ophthalmic administration, steady state was reached within 13 weeks. At steady state, there was virtually no free active substance or metabolite in plasma; inhibition of carbonic anhydrase in erythrocytes was less than that expected to be necessary for pharmacological effects on renal function or respiration. Similar pharmacokinetic results were obtained after chronic topical administration of dorzolamide hydrochloride. However, some elderly patients with impaired renal function (defined as creatinine clearance (CrCl) of 30–60 mL/min) had higher metabolite concentrations in red blood cells (RBCs), but significant differences in carbonic anhydrase inhibition and clinically significant systemic adverse events were not directly related to this finding.
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
Indicated for the treatment of elevated intraocular pressure in patients with open-angle glaucoma or pseudoexfoliative glaucoma when topical beta-blockers alone are insufficient.
Contraindication
The drug is contraindicated in patients with:
reactive airway diseases, including bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease;
sinus bradycardia, sick sinus syndrome, sinoatrial block, second or third degree atrioventricular block not controlled by a pacemaker, severe heart failure, cardiogenic shock;
severe renal impairment (creatinine clearance (CrCl) < 30 mL/min) or hyperchloremic acidosis;
hypersensitivity to one or both active substances, or to any of the components of the drug, as well as during pregnancy or breastfeeding.
The above diseases 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 the interaction of DORZOPT PLUS with other drugs have been conducted.
In clinical studies, this drug was used concomitantly with the following systemic drugs without evidence of (unconfirmed) adverse drug interactions: ACE inhibitors, calcium channel blockers, diuretics, nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid, and hormones (e.g., estrogen, insulin, thyroxine).
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, catecholamine-depleting drugs or beta-blockers, antiarrhythmic drugs (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, narcotics, and monoamine oxidase (MAO) inhibitors.
Although DORZOPT PLUS 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.
Oral beta-blockers 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. For reduced systemic absorption, see section "Method of administration and dosage".
Cardiac disorders
In patients with cardiovascular disease (e.g. coronary artery disease (CAD), vasospastic angina/Prinzmetal's angina and heart failure) and hypotension, treatment with beta-blockers should be carefully evaluated and treatment with other active substances should be considered. Patients with cardiovascular disease should be monitored for signs of worsening of these conditions and adverse reactions.
Due to the negative effect on impulse conduction time, beta-blockers should be prescribed with caution in patients with first-degree heart block.
Vascular disorders
Patients with severe peripheral/circulatory disorders (i.e. severe Raynaud's disease or Raynaud's syndrome) should be treated with caution.
Respiratory system disorders
Respiratory reactions, including fatal ones, due to bronchospasm have been reported in patients with asthma following the use of some ophthalmic beta-blockers.
DORZOPT PLUS 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 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 sulfonamide drugs may occur with topical use, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs of serious reactions 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 the 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.
Discontinuation of treatment
As with systemic beta-blockers, ophthalmic timolol should be tapered off if discontinuation is necessary in patients with coronary artery disease.
Additional 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 hypoglycemia.
Beta-blockers may also mask the signs of hyperthyroidism. Abrupt discontinuation of beta-blockers may result in worsening of symptoms.
Corneal diseases
Ophthalmic beta-blockers may cause dry eyes. Patients with corneal diseases should be treated with caution.
Anesthesia for surgery
Ophthalmic beta-blockers may block the systemic effects of beta-agonists, such as adrenaline. The anaesthetist should be informed that the patient is receiving timolol.
Treatment with beta-blockers may exacerbate symptoms of myasthenia gravis.
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 DORZOPT PLUS.
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. 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 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 DORZOPT PLUS 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 stabilization of pressure.
Using contact lenses
This medicine 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 discolour soft contact lenses.
Use during pregnancy or breastfeeding
Pregnancy
Do not use the drug during pregnancy.
Dorzolamide
There are no clinical data on the effects on pregnancy. Dorzolamide was teratogenic in rabbits during pregnancy.
Timolol
There are no adequate data on the use of timolol during pregnancy. Timolol should not be used during pregnancy unless clearly necessary. For reduced systemic absorption, see section "Method of administration and dosage".
Epidemiological studies have not shown a risk of intrauterine growth retardation when oral beta-blockers are used during pregnancy. In addition, symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress syndrome and hypoglycaemia) have been observed in neonates when beta-blockers were administered antepartum. If this drug is used antepartum, the neonate should be closely monitored during the first few days after birth.
Breast-feeding
It is not known whether dorzolamide is excreted in human milk. In rats treated with dorzolamide, reduced body weight gain of offspring was observed. Beta-blockers are excreted in human milk. However, when timolol eye drops is used at therapeutic doses, it is unlikely that sufficient amounts will be present in breast milk to cause clinical symptoms of beta-blockade in the infant. For information on reduced systemic absorption, see section 4.2.
If the use of DORZOPT PLUS is necessary, breastfeeding is not recommended.
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
Doses
DORZOPT PLUS should be administered 1 drop into the conjunctival sac of the affected eye(s) 2 times a day.
If another topical ophthalmic drug is used simultaneously, the interval between instillation of DORZOPT PLUS and the other drug should be at least 10 minutes.
Patients should wash their hands before applying the product and avoid contact of the tip of the vial with the surface of the eye or eyelids.
Patients should be advised that ophthalmic solutions, if not properly cared for, may become contaminated with common bacteria known to cause eye infections. Use of contaminated solutions may result in serious eye damage and subsequent vision loss.
Instructions for use
The instructions for use of DORZOPT PLUS should be carefully followed. It is recommended to wash your hands thoroughly before using the eye drops.
1. Before using the drug for the first time, make sure that the protective strip on the outside of the bottle is not damaged.
3. Tilt your head back and pull the lower eyelid down to create space between the eyelid and the eye.
4. Turn the bottle upside down and gently press the specially marked spot on the bottle with your thumb or index finger so that one drop enters the eye. DO NOT TOUCH THE SURFACE OF THE EYE OR EYELIDS WITH THE TIP OF THE BOTTLE.
Repeat steps 3 and 4 for both eyes if prescribed by your doctor.
Close the bottle cap by turning it until it is tightly closed. To confirm that the bottle is securely closed, the arrow on the left side of the cap must align with the arrow on the left side of the bottle label. Do not overtighten the cap as this may damage the bottle and cap.
7. After all required doses have been administered, there may be some medicine left in the vial. Since the vial contains an additional amount of medicine, this ensures that patients receive the full amount of DORZOPT PLUS prescribed by their doctor. Do not attempt to remove any excess medicine from the vial.
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.
Children.
The effectiveness of use in children has not been determined.
The safety of use in children under 2 years of age has not been established (for information on the safety of use in children aged ≥ 2 and < 6 years, see the Pharmacodynamics section).
Overdose
There is no data on overdose of the drug in case of accidental or intentional ingestion.
Symptoms
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 is limited data on overdose in humans following accidental or intentional ingestion. 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.
Side effects
In clinical studies of a product containing two active substances: dorzolamide hydrochloride and timolol maleate, the adverse reactions observed were consistent with those previously reported with dorzolamide hydrochloride and/or timolol maleate.
In clinical trials, 1035 patients were treated with a product containing the two active substances dorzolamide hydrochloride and timolol maleate. Approximately 2.4% of all patients discontinued treatment with this product due to local ocular adverse reactions, approximately 1.2% of all patients discontinued treatment due to local adverse reactions characterized by allergy or hypersensitivity (namely eyelid inflammation and conjunctivitis).
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.
The following adverse reactions have been reported with DORZOPT PLUS or one of its components.
Frequency: 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), frequency unknown (cannot be estimated from the available data).
On the part of the immune system
DORZOPT PLUS
Rare: symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylactic reaction.
Timolol maleate, eye drops, solution
Rare: symptoms of allergic reactions, including angioedema, urticaria, focal and multiple rashes, anaphylactic reaction.
Frequency unknown**: itching.
Metabolism and nutrition
Timolol maleate, eye drops, solution
Frequency unknown**: hypoglycemia.
From the psyche
Timolol maleate, eye drops, solution
Uncommon: depression*.
Uncommon: insomnia*, night terrors*, memory loss.
Frequency unknown**: hallucinations.
From the nervous system
Dorzolamide hydrochloride, eye drops, solution
Common: headache*.
Uncommon: dizziness*, paraesthesia* (skin sensitivity disorders).
Timolol maleate, eye drops, solution
Common: headache*.
Uncommon: dizziness*, syncope*.
Rare: paraesthesia*, increased signs and symptoms of myasthenia gravis, decreased libido*, cerebrovascular accident*, cerebral ischemia.
From the organs of vision
DORZOPT PLUS
Very common: burning and tingling.
Dorzolamide hydrochloride, eye drops, solution
Common: eyelid inflammation*, eyelid irritation*.
Uncommon: iridocyclitis*.
Rare: eye irritation, including redness*, eye pain*, eyelid peeling*, transient myopia (reversible upon discontinuation of treatment), corneal edema*, decreased intraocular pressure*, choroid detachment (with subsequent filtering surgery)*.
Frequency unknown: sensation of a foreign body in the eye.
Timolol maleate, eye drops, solution
Common: eye irritation symptoms including blepharitis*, keratitis*, decreased corneal sensitivity, dry eyes*.
Uncommon: visual disturbances, including refractive changes (in some cases due to withdrawal of miotics)*.
Rare: ptosis, diplopia, choroid detachment with subsequent filtering surgery* (see section "Special warnings and precautions for use").
Frequency unknown**: itching, tearing, redness, blurred vision, corneal erosion.
Hearing and balance disorders
Timolol maleate, eye drops, solution
Rarely: ringing in the ears*.
From the heart
Timolol maleate, eye drops, solution
Uncommon: bradycardia*.
Rare: chest pain*, palpitations*, edema*, arrhythmia*, congestive heart failure*, cardiac arrest*, heart block.
Frequency unknown**: atrioventricular block, heart failure.
Dorzolamide hydrochloride, eye drops, solution
Frequency unknown: tachycardia, rapid heartbeat.
From the vascular side
Timolol maleate, eye drops, solution
Rare: hypotension*, claudication, Raynaud's phenomenon*, cold hands and feet*.
Dorzolamide hydrochloride, eye drops, solution
Frequency unknown: hypertension.
Respiratory, thoracic and mediastinal disorders
DORZOPT PLUS
Common: sinusitis.
Uncommon: dyspnea, respiratory failure, rhinitis, rarely bronchospasm.
Dorzolamide hydrochloride, eye drops, solution
Rare: nosebleed*.
Frequency unknown: shortness of breath.
Timolol maleate, eye drops, solution
Uncommon: difficulty breathing (dyspnea)*.
Rare: bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, respiratory failure, cough*.
Gastrointestinal tract
DORZOPT PLUS
Very common: dysgeusia (change in taste).
Dorzolamide hydrochloride, eye drops, solution
Common: nausea*.
Rare: throat irritation, dry mouth*.
Timolol maleate, eye drops, solution
Uncommon: nausea*, dyspepsia*.
Uncommon: diarrhoea, dry mouth*.
Frequency unknown**: dysgeusia (change in taste), abdominal pain, vomiting.
Skin and subcutaneous tissue disorders
DORZOPT PLUS
Rare: contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Dorzolamide hydrochloride, eye drops, solution
Rare: rash*.
Timolol maleate, eye drops, solution
Rare: alopecia*, psoriatic eruptions or exacerbation of psoriasis.
Frequency unknown**: skin rash.
Musculoskeletal and connective tissue disorders
Timolol maleate, eye drops, solution
Rare: systemic lupus erythematosus.
Frequency unknown**: myalgia.
Renal and urinary tract disorders
DORZOPT PLUS
Uncommon: urolithiasis.
Genital and breast disorders
Timolol maleate, eye drops, solution
Rare: Peyronie's disease*, decreased libido.
Frequency unknown**: sexual dysfunction.
General disorders and administration site conditions
Dorzolamide hydrochloride, eye drops, solution
Common: asthenia/weakness*.
Timolol maleate, eye drops, solution
Uncommon: asthenia/weakness*.
_________________________
* Adverse reaction observed after use of dorzolamide with timolol in therapy.
**Additional adverse reaction that has been observed after the use of ophthalmic beta-blockers and may likely occur after the use of dorzolamide with timolol.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua.
Expiration date
3 years.
After opening the bottle, use the drug for no more than 4 weeks.
Storage conditions
Store in original packaging at a temperature not exceeding 25 0C.
Keep out of reach of children.
Packaging
5 ml in a dropper bottle and a cardboard box.
Vacation category
According to the recipe.
Producer
K.T. ROMPHARM COMPANY SRL
Location of the manufacturer and address of its place of business.
Eroilor St. No. 1A, Otopeni, 075100, Ilfov County, Romania – Romfarm Building 1
and Romfarm 2.
