Trusopt, eye drops 20 mg/ml 5 ml

Pharmacotherapeutic group

A carboangidrase inhibitor antiglaucoma drug.

Code ATX: S01EC03

Pharmacological properties Pharmacodynamics

Mechanism of action

Carboanhydrase (CA) is an enzyme found in many body tissues, including the eye. In humans, carboanhydrase is represented by a number of isoenzymes, the most active of which is carboanhydrase II (CA-II), found mainly in erythrocytes but also in other tissues. Inhibition of carboanhydrase in the ciliary processes of the eye leads to a decrease in aqueous humor secretion, resulting in lower intraocular pressure (IOP).

Trusopt® contains dorzolamide hydrochloride, which is a strong selective inhibitor of human carboanhydrase II. Following topical ophthalmic application of dorzolamide, elevated IOP decreases whether or not it is related to glaucoma. Elevated IOP is a major risk factor in the pathogenesis of optic nerve damage and visual field narrowing. Dorzolamide reduces IOP without the common side effects of myotics such as nictalopia, accommodation spasm, and pupil constriction. Dorzolamide has little or no effect on heart rate or blood pressure. Beta-adrenoblockers for topical ophthalmic use also lower IOP by reducing aqueous humor production, but their mechanism of action is different. Studies have shown that when dorzolamide is added to beta-adrenoblockers for topical use in ophthalmology, there is an additional decrease in IOP. This confirms the previously obtained data on the additive effect when using beta-adrenoblockers and oral carboenhydrase inhibitors together.

Clinical efficacy and safety Adult patients

Efficacy of dorzolamide in patients with glaucoma or intraocular hypertension when administered 3 times daily as monotherapy (baseline IOP ≥23 mmHg Std.) or 2 times daily as adjunctive therapy to ophthalmic beta-adrenoblockers (baseline IOP ≥22 mm Hg) has been demonstrated in large-scale clinical trials lasting up to one year. The effect of IOP reduction with dorzolamide as monotherapy and as adjunctive therapy has been demonstrated throughout the day, and this effect has been maintained with prolonged use. Efficacy with prolonged monotherapy was similar to betaxolol and slightly less than with timolol. When used as adjunctive therapy to ophthalmic beta-blockers, dorzolamide demonstrated an additional reduction in IOP similar to that seen with pilocarpine 2% once daily. Children

A 3-month, double-blind, multicenter study to evaluate the safety of Trusopt® when administered topically three times daily, using the active drug as a control, was conducted in 184 children aged 1 week to 6 years with glaucoma or elevated IOP (IOP at baseline > 22 mmHg Hg) (122 of whom received dorzolamide). Congenital glaucoma was diagnosed in about half of the patients in both groups; other common causes of elevated IOP were Sturge-Weber syndrome, iridocorneal mesenchymal dysplasia, and aphakia. The distribution by age and treatment used in the monotherapy phase was as follows:

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In both age groups, about 70 patients were treated for at least 61 days, and about 50 patients were treated for 81-100 days.

If IOP was not sufficiently controlled with dorzolamide or

timolol-gel monotherapy, open therapy was modified as follows: 30 patients younger than 2 years were switched to concomitant therapy with 0.25% timolol-gel once daily and dorzolamide 2% three times daily; 30 patients younger than 2 years were switched to a fixed combination of 2% dorzolamide and 0.5% timolol twice daily.

In general, this study found no additional safety risks to the drug in pediatric patients: approximately 26% (20% received dorzolamide monotherapy) of children experienced drug-related side effects, most of which were local non-serious eye effects such as burning and tingling sensations in the eyes, hyperemia, and eye pain. A small percentage of patients (< 4%) experienced corneal edema or clouding. Local reactions were recorded with a frequency similar to that of the comparison drug. In the post-registration period, metabolic acidosis was observed in young patients, especially in children with immature kidneys or impaired renal function.

The results of the efficacy evaluation in children indicate that the mean IOP reduction observed in the dorzolamide group was comparable to the mean IOP reduction observed in the timolol group, even with a small quantitative advantage observed with timolol. Data from long-term efficacy studies (> 12 weeks) are not available.

Pharmacokinetics

In contrast to oral carboanhydrase inhibitors, dorzolamide acts directly in the eye at significantly lower doses, resulting in less systemic exposure. In clinical studies, dorzolamide reduced IOP without the acid-base balance or electrolyte changes that are common with oral carboane hydrase inhibitors.

Dorzolamide enters the systemic bloodstream when used topically. To assess the potential for systemic inhibition of carboanhydrase after topical administration, concentrations of dorzolamide and its metabolite in erythrocytes (RBC) and plasma as well as carboanhydrase inhibition in erythrocytes were measured. With long-term use, dorzolamide accumulates in erythrocytes as a result of selective binding to carboanhydrase-II (CA-II), while extremely low concentrations of free dorzolamide are maintained in plasma. Dorzolamide forms the metabolite N-dezethyl, which inhibits CA-II to a lesser extent than the original active ingredient, but also inhibits the less active CA-I isoenzyme. The metabolite also accumulates in erythrocytes, where it binds predominantly to CA-I. Dorzolamide binds moderately to plasma proteins (approximately 33%) and is excreted mainly unchanged in the urine; the metabolite is also excreted in the urine. Nonlinear washout of dorzolamide occurs after discontinuation of the drug, initially leading to a rapid decrease in dorzolamide concentrations, followed by a slow elimination phase with a half-life of approximately four months.

When dorzolamide was given orally to simulate maximum systemic effects after long-term topical administration, the steady state was reached within 13 weeks. At steady state, there was virtually no free dorzolamide or its metabolite in plasma; CA inhibition in erythrocytes was less significant than expected for the required pharmacological effects on renal function or respiration. Similar pharmacokinetic results were observed after prolonged topical administration of dorzolamide hydrochloride. However, some elderly patients with renal insufficiency (established creatinine clearance
30-60 ml/min) had higher concentrations of metabolites in erythrocytes, but no significant differences in carboenhydrase inhibition and no clinically significant systemic side effects were directly associated.

In some elderly patients with renal insufficiency (established creatinine clearance
30-60 ml/min), higher concentrations of metabolites were noted in the red blood cells.

Indications

Glaucoma, Elevated Intraocular Pressure

The drug Trusopt® is indicated in adults for the treatment of elevated IOP in:

• ophthalmohypertension
• primary open-angle glaucoma
• secondary glaucoma (without anterior chamber angle block) Also:
• as adjunctive therapy to beta-blockers
• as monotherapy in patients who do not respond to beta-adrenoblockers or to whom beta-adrenoblockers are contraindicated

Trusopt® is indicated in children

• for the treatment of glaucoma in children from 1 week of age as monotherapy or as an adjunct to treatment with beta-adrenoblockers

Active ingredient

Dorzolamide

Composition

1 ml of the preparation contains:
Active ingredient: dorzolamide hydrochloride – 22.26 mg (in terms of dorzolamide – 20.00 mg). Excipients: mannitol 23.00 mg, dietellose (hydroxyethylcellulose) 4.75 mg, sodium citrate 2.94 mg, benzalkonium chloride 0.075 mg, sodium hydroxide for pH correction 5.5-5.8, water for injection up to 1 ml.

How to take, the dosage

Dosing regimen
When used as monotherapy, place one drop of Trusopt® into the conjunctival sac of the affected eye(s) three times daily. When used as adjunctive therapy to an ophthalmic beta-blocker, one drop of Trusopt® in the conjunctival sac of the affected eye(s) twice daily.
When any anti-glaucoma drug is replaced by Trusopt® , treatment with Trusopt® must be started the day after the previous drug is taken away.
When using Trusopt® together with other drugs for local ophthalmic use the interval between their instillations must be kept at least 10 minutes.
Patients should be warned to wash their hands before use and not to allow the vial to come in contact with the eye or surrounding tissues.
Patients should also be warned that topical ophthalmic solutions may be contaminated with bacteria that can cause eye infections if used incorrectly. Use of contaminated eye drops can result in serious eye damage and subsequent vision loss.
Patients should be informed of the proper handling of the reusable bottle.
Children
While there are limited clinical data on the use of dorzolamide in pediatric patients three times daily (see Pharmacological properties section), the dosing regimen for children is the same as for adults.

Interaction

No special studies on interaction of the drug Trusopt® with other medicinal products have been conducted. In clinical trials, Trusopt® was prescribed concomitantly with other medicinal products, including timolol and betaxolol for local use in ophthalmology, as well as drugs for systemic use: ACE inhibitors, calcium channel blockers, diuretics, nonsteroidal anti-inflammatory drugs (including acetylsalicylic acid), hormones (estrogen, insulin, thyroxine). No adverse interactions have been noted. There is insufficient information about the combined use of dorzolamide, myotics and adrenergic receptor agonists as part of hypotensive therapy of glaucoma.

Special Instructions

The use of dorzolamide in patients with acute closed angle glaucoma has not been studied. Treatment of patients with acute closed angle glaucoma requires urgent therapeutic measures in addition to topical ophthalmic hypotensive agents.

Dorzolamide contains a sulfonamide group that is also found in sulfonamides, and although the drug is used topically, it is also absorbed into the systemic bloodstream. Thus, topical use may produce the same types of adverse reactions that have been found with systemic administration of sulfonamides, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs of serious reactions or hypersensitivity reactions appear, the use of this drug should be discontinued.

The treatment with oral carboenhydrase inhibitors is associated with the development of urolithiasis due to acid-base imbalance, especially in patients with a history of kidney stones. Despite the fact that when using dorzolamide no disorders of acid-base balance have been observed, there have been rare reports of cases of urolithiasis. Since dorzolamide contains a carboanhydrase inhibitor for topical use in ophthalmology, which is absorbed into the systemic bloodstream, patients with a history of urinary stones may have an increased risk of developing urolithiasis when using this drug.

If allergic reactions (such as conjunctivitis and eyelid reactions) are observed, discontinuing the drug should be considered.

There is potential for additive effects with respect to known systemic carboane hydrase inhibitor effects in patients receiving oral carboane hydrase inhibitor and dorzolamide.

Simultaneous use of dorzolamide and oral carboane hydrase inhibitors is not recommended. Corneal edema and irreversible corneal decompensation have been reported when using dorzolamide in patients with a history of recurrent corneal erosions and/or who had surgery that compromised the integrity of the eyeball. The likelihood of corneal edema also increases. Precautions should be observed when prescribing Trusopt® to these groups of patients.

There have been reports of ocular choroidal detachment accompanied by ocular hypotension when using ophthalmic solutions that reduce aqueous humor secretion after surgical interventions to restore outflow of intraocular fluid.

Dorzolamide has not been studied in patients with severe renal impairment (creatinine clearance

<30 ml/min) or with hyperchloremic acidosis. Since dorzolamide and its metabolites are mainly excreted by the kidneys, dorzolamide is contraindicated in these patients.

The drug Trusopt® contains the preservative benzalkonium chloride, which may cause eye irritation. Patients with corneal diseases and dry eye syndrome may develop ulcerative toxic keratopathy or pitting keratopathy when using a drug containing benzalkonium chloride as a preservative. During long-term therapy with Trusopt® in these patients corneal condition should be monitored.

Pre-application of the drug contact lenses should be removed and put on again not earlier than 15 minutes after injection. Benzalkonium chloride is able to discolour soft contact lenses. Application in children

Dorzolamide has not been studied in patients who are less than 36 weeks gestational age and less than 1 week of age. Patients with significant renal tubular immaturity may receive dorzolamide only after careful evaluation of the benefit-risk ratio associated with the likely risk of metabolic acidosis.

Influence on driving and operating machinery

There have been no studies of the effect of the drug on driving and operating machinery. However, possible adverse reactions such as dizziness and visual disturbances may affect the ability to drive and/or operate machinery.

Instructions for use Vial Ocumeter Plus

1. Before using the drug for the first time, make sure that the protective strip on the outside of the vial is not damaged. Unopened bottles may have a gap between the vial and the cap.
2. First, wash your hands, then remove the protective strip in order to open the cap.
3. In order to open the bottle, unscrew the cap, turning it in the direction of the arrows on the top surface of the cap. Do not pull the cap straight up and away from the vial.
4. Tilt your head back and gently pull your lower eyelid downward to create space between your eye and eyelid.
5. Turn the vial over, use your thumb or forefinger to press lightly at the position marked on the vial so that one drop enters the eye as directed by your doctor. DO NOT touch the surface of the eye or the eyelid with the tip of the bottle. Serious eye damage and subsequent vision loss can develop from the use of infected ophthalmic drugs. If you suspect that the medication may be contaminated, or if you develop an eye infection, you should contact your doctor immediately about the continued use of the vial.
   • If it is difficult to deliver the drops after the first opening, place the cap on the bottle and tighten (do not over tighten), then remove by turning the cap in opposite directions as shown by the arrows on the top of the cap.
   • Repeat steps 4 – 5 for the other eye, if prescribed by the doctor.
   • Close the bottle with the cap, twisting it until it is in full contact with the bottle. When closed correctly, the arrow on the cap of the bottle should align with the arrow on the label of the bottle. Do not tip the cap too tightly, as this could damage the vial or the cap.
   • The pipette tip is single drop and the opening of the specially designed pipette tip should not be enlarged.
   • After all the doses have been used, there may be residual Trusopt® in the vial. You should not worry because an additional amount of medication has been added and you will receive the full amount of Trusopt® prescribed by your doctor. Do not attempt to remove excess medication from the vial.

   PENP (Low Density Polyethylene)
   1. Wash your hands
   2. Open the bottle. Be careful that the pipette tip does not touch your eyes, the skin around your eyes or your fingers.
   3. Tilt your head back and invert the bottle over your eye.

   4. Pull your lower eyelid down and look up. Holding and gently squeezing the vial on its flattened sides, drip one drop into the space between your lower eyelid and your eye.

   5. Press your finger into the inner corner of your eye, pressing it against your nose, or close your eyes for 2 minutes. This helps keep the medication from reaching other parts of the body.

   6. Repeat steps 3-5 with the second eye if prescribed by your doctor.
   7. Put the cap on and close the bottle tightly.

   .

Synopsis

Transparent, colorless or nearly colorless, slightly viscous solution.

Contraindications

• high sensitivity to the active ingredient or any of the excipients
• severe renal insufficiency
• hyperchloremic acidosis
• pregnancy

breast-feeding period

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• hyperchloremic acidosis
• pregnancy
• breastfeeding period
• children less than 1 week

Side effects

The use of Trusopt® has been evaluated in over 1400 patients in controlled and uncontrolled clinical trials. In clinical trials, Trusopt® was administered to 1108 patients as monotherapy or adjunctive therapy to topical beta-adrenoblocker therapy in ophthalmology. Approximately 3% of patients had the drug withdrawn due to local ocular adverse reactions associated with the drug, the most common being conjunctivitis and eyelid reactions.
The following adverse reactions to dorzolamide were reported either during clinical trials or during post-marketing use.
The frequency of possible adverse reactions listed below is determined using the following convention: [(very common (≥1/10), common (≥1/100, <1/10); infrequent (≥1/1000, <1/100); rare (≥1/10000, <1/1000) and frequency unknown (frequency cannot be determined from available data)]. Nervous system disorders
Frequently: headache
Rarely: dizziness, paresthesias Visual organ disorders Very common: burning and pain
Frequently: Superficial pitting keratitis, lacrimation, conjunctivitis, eyelid inflammation, eye itching, eyelid irritation, blurred vision
Infrequent: iridocyclitis
Rarely: Eye irritation, including eye redness, eye pain, eyelid hyperkeratosis, transient myopia (disappearing after drug withdrawal), corneal edema, eye hypotonia, chorioidal detachment after surgery to restore outflow of intraocular fluid Frequency unknown: Sensation of foreign body in the eye
Cardiac disorders
Frequency unknown: palpitation
Respiratory system, thoracic and mediastinal organs
Rarely: nasal bleeding Frequency unknown: shortness of breath
Gastrointestinal disorders
Frequently: nausea, bitter taste in mouth Rarely: Sore throat, dry mouth
Skin and subcutaneous tissue disorders
Rarely: contact dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis
Kidney and urinary tract disorders
Rarely: Urolithiasis
General disorders and disorders at the injection site
Frequently: asthenia/fatigue
Rarely: Allergic reactions – signs and symptoms of local reactions (eyelids) and systemic allergic reactions including angioedema, urticaria, pruritus, rash, difficulty breathing, rarely bronchospasm
Studies
With dorzolamide, no clinically significant electrolyte disturbances were noted.

Reporting potential adverse reactions
It is important to report suspected adverse reactions after use of the drug. This allows for continued monitoring of the benefit-risk ratio of the medication. Healthcare professionals should report any suspected adverse reactions through the national adverse reaction reporting system.

Overdose

Limited information is available about overdose in humans from accidental or intentional ingestion of dorzolamide hydrochloride.

Symptoms

Inadvertent ingestion may cause the following symptoms: drowsiness, nausea, dizziness, headache, weakness, unusual dreaming, and dysphagia.

Treatment

The treatment should be symptomatic and supportive. Impairment of electrolyte balance, development of acidosis and side effects on the central nervous system are possible. Serum electrolyte levels (particularly potassium) and blood pH should be monitored.

Pregnancy use

Pregnancy
Dorzolamide should not be used during pregnancy. There are no or limited data on the use of dorzolamide in pregnant women. In rabbits, dorzolamide caused teratogenic effects at doses toxic to pregnant females.
Breastfeeding
It is not known whether dorzolamide or its metabolites are excreted into breast milk. Available pharmacodynamic/toxicological data from animal studies suggest that its metabolites are excreted into breast milk. Considering the benefit of breastfeeding to the baby and the benefit of therapy to the woman, a decision must be made as to whether breastfeeding should be discontinued or whether therapy with Trusopt® should be discontinued/continued. Risks to newborns/infants also cannot be ruled out.
Fertility
Data from animal studies suggest no effect of dorzolamide therapy on male or female fertility. No data from human studies are available.

Similarities

Dorzopt, Dorzolamide-Solofarm, Dorzial