Dorzolamide-SZ (Drops) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

S01EC03 (Dorzolamide)

Active Substance

Dorzolamide (Rec.INN registered by WHO)

Dosage Form

Dorzolamide-SZ

Eye drops 20 mg/1 ml: dropper bottles 5 ml 1 or 3 pcs.

Dosage Form, Packaging, and Composition

Eye drops as a clear, colorless or almost colorless, slightly viscous solution.

Excipients: benzalkonium chloride – 0.075 mg/ml, hyetellose (hydroxyethylcellulose), mannitol (mannitol), sodium citrate dihydrate, 1M sodium hydroxide solution, water for injections.

5 ml – polyethylene dropper bottles (1) with dropper caps – cardboard packs.
5 ml – polyethylene dropper bottles (3) with dropper caps – cardboard packs.

Clinical-Pharmacological Group

Antiglaucoma drug – topical carbonic anhydrase inhibitor

Pharmacotherapeutic Group

Drugs used in ophthalmology; antiglaucoma drugs and miotic agents; carbonic anhydrase inhibitors

Pharmacological Action

Mechanism of action

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

Dorzolamide hydrochloride is a potent selective inhibitor of human carbonic anhydrase II. After topical ophthalmic application, dorzolamide reduces elevated IOP regardless of whether it is associated with glaucoma or not. Elevated IOP is a major risk factor in the pathogenesis of optic nerve damage and visual field narrowing. Dorzolamide reduces IOP without the side effects common to miotic drugs, such as nyctalopia, accommodative spasm, and pupillary constriction. Dorzolamide has minimal or practically no effect on heart rate or blood pressure.

Topical ophthalmic beta-blockers also reduce IOP by reducing aqueous humor production, but their mechanism of action is different. Studies have shown that the addition of dorzolamide to topical ophthalmic beta-blockers results in an additional reduction in IOP. This confirms previous data on the additive effect of the combined use of beta-blockers and oral carbonic anhydrase inhibitors.

Clinical efficacy and safety

Adult patients

The efficacy of dorzolamide in patients with glaucoma or ocular hypertension when used three times daily as monotherapy (baseline IOP >23 mm Hg) or twice daily as adjunctive therapy to ophthalmic beta-blockers (baseline IOP >22 mm Hg) was demonstrated in large-scale clinical trials lasting up to one year. The IOP-lowering effect of dorzolamide as monotherapy and as adjunctive therapy was demonstrated throughout the day, and this effect was maintained with long-term use. Efficacy with long-term monotherapy was similar to betaxolol and somewhat less compared to timolol. When used as adjunctive therapy to ophthalmic beta-blockers, Dorzolamide demonstrated an additional IOP reduction similar to that of pilocarpine 2% once daily.

Children

A 3-month double-blind, multicenter study to evaluate the safety of topically applied dorzolamide three times daily, using an active drug as a control, was conducted in 184 children aged from 1 week to 6 years with glaucoma or elevated IOP (baseline IOP >22 mm Hg) (122 of them received Dorzolamide). Approximately half of the patients in both groups were diagnosed with congenital glaucoma; other common causes of elevated IOP were Sturge-Weber syndrome, iridocorneal mesodermal dysplasia, and aphakia. The distribution by age and treatment at the monotherapy stage was as follows:

In both age groups, approximately 70 patients received treatment for at least 61 days, and about 50 patients received treatment for 81-100 days.

If IOP was inadequately controlled with dorzolamide or timolol gel monotherapy, open-label therapy was changed as follows: 30 patients under 2 years of age were switched to concomitant therapy with 0.25% timolol gel once daily and dorzolamide 2% three times daily; 30 patients under 2 years of age were switched to a fixed combination of 2% dorzolamide and 0.5% timolol twice daily.

Overall, this study did not reveal any additional safety concerns for the drug in pediatric patients: approximately 26% (20% receiving dorzolamide monotherapy) of children experienced drug-related adverse effects, most of which were local non-serious ocular effects such as eye burning and stinging, conjunctival injection, and eye pain. A small percentage of patients (<4%) experienced corneal edema or clouding. Local reactions were reported at a frequency similar to that of the comparator drug. In the post-registration period, metabolic acidosis was observed in young patients, especially in children with immature kidneys or impaired renal function.

Efficacy evaluation results 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 slight quantitative advantage observed with timolol use.

Data from long-term efficacy studies (>12 weeks) are not available.

Pharmacokinetics

Unlike oral carbonic anhydrase inhibitors, when applied topically, Dorzolamide acts directly in the eye at significantly lower doses, resulting in less systemic exposure. In clinical studies, Dorzolamide reduced IOP without disturbances in acid-base balance or changes in electrolyte levels, which are characteristic of oral carbonic anhydrase inhibitors.

Absorption

When applied topically, Dorzolamide enters the systemic circulation.

Distribution

To assess the potential for systemic carbonic anhydrase inhibition after topical administration, concentrations of dorzolamide and its metabolite in red blood cells (RBC) and plasma, as well as inhibition of carbonic anhydrase in erythrocytes, were measured. With prolonged use, Dorzolamide accumulates in erythrocytes due to selective binding to carbonic anhydrase-II (CA-II), while extremely low concentrations of free dorzolamide are maintained in plasma.

Metabolism

Dorzolamide forms an N-desethyl metabolite, which inhibits CA-II to a lesser extent than the original active substance but also inhibits the less active isoenzyme CA-I. The metabolite also accumulates in erythrocytes, where it binds predominantly to CA-I.

Dorzolamide is moderately bound to plasma proteins (approximately 33%) and is excreted in the urine mainly unchanged; the metabolite is also excreted in the urine. After discontinuation of the drug, non-linear washout of dorzolamide occurs, first leading to a rapid decrease in dorzolamide concentration, followed by a slow elimination phase with a half-life of about 4 months.

When Dorzolamide was administered orally to simulate maximum systemic exposure after long-term topical administration, steady state was reached within 13 weeks. At steady state, there was virtually no free Dorzolamide or its metabolite in plasma; inhibition of CA in erythrocytes was less substantial than expected for the necessary pharmacological effect on kidney function or respiration. Similar pharmacokinetic results were observed after long-term topical application of dorzolamide hydrochloride. Nevertheless, some elderly patients with renal failure (established CC 30-60 ml/min) had higher metabolite concentrations in erythrocytes, but no significant differences in carbonic anhydrase inhibition and no clinically significant systemic adverse effects were directly associated with this.

Elimination

Dorzolamide and its metabolite are excreted primarily unchanged by the kidneys. After the end of treatment, Dorzolamide is washed out of erythrocytes unevenly, i.e., very intensively at the beginning, leading to a rapid and significant decrease in concentration, followed by a phase of slow washout with T_1/2 of about 4 months.

Indications

Dorzolamide-SZ is indicated for use in adults over 18 years of age for the treatment of elevated intraocular pressure (IOP)

• In ocular hypertension;
• In primary open-angle glaucoma;
• In pseudoexfoliative glaucoma;
• In secondary glaucoma (without angle closure);
• As adjunctive therapy to beta-blockers;
• As monotherapy in patients who do not respond to beta-blockers or for whom beta-blockers are contraindicated.

Dorzolamide-SZ is indicated for use in children from 1 week of age as monotherapy or as an adjunct to beta-blocker therapy.

ICD codes

Dosage Regimen

When used as monotherapy, 1 drop is prescribed 3 times/day.

When used as adjunctive therapy to an ophthalmic beta-blocker – 1 drop 2 times/day.

When replacing any other antiglaucoma drug with Dorzolamide-SZ, treatment with Dorzolamide-SZ should be started on the day following discontinuation of the previous drug.

When using Dorzolamide-SZ concomitantly with other topical ophthalmic agents, the drops should be instilled at least 10 minutes apart.

Children

Although there are limited clinical data on the use of dorzolamide in pediatric patients three times daily (see section “Pharmacological Action”), the dosage regimen for children is the same as for adults.

Method of administration

For topical use. Into the conjunctival sac of the affected eye (affected eyes).

To reduce systemic absorption with subsequent reduction of systemic side effects and increase the local efficacy of the drug, it is recommended to press the nasolacrimal duct or close the eyelids for 2 minutes after instillation.

Patients should be warned to wash their hands before using the drug and to avoid contact of the bottle with the eye or surrounding tissues.

Patients should also be warned that if used improperly, topical ophthalmic solutions can be contaminated with bacteria capable of causing infectious eye diseases. The use of contaminated eye drops can lead to serious eye damage and subsequent loss of vision.

Patients should be informed about the proper handling of the multi-use bottle.

Adverse Reactions

Summary of the safety profile

The use of dorzolamide in the form of eye drops has been evaluated in more than 1400 patients in controlled and uncontrolled clinical trials. In clinical trials, Dorzolamide was prescribed to 1108 patients as monotherapy or adjunctive therapy to treatment with topical ophthalmic beta-blockers. Approximately 3% of patients discontinued Dorzolamide due to drug-related local ocular adverse reactions, the most frequent of which were conjunctivitis and eyelid reactions.

Tabulated summary of adverse reactions

The following adverse reactions have been observed in clinical trials and post-marketing use of the drug and are listed according to frequency: very common (≥1/10), common (≥1/100 but <1/10), uncommon (≥1/1000 but <1/100), rare (≥1/10000 but <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).

Children

In children under 6 years of age, the adverse reaction profile of dorzolamide is comparable to that in adult patients. The most frequent adverse reactions associated with the use of dorzolamide in children under 2 years of age were conjunctival injection (5.4%) and conjunctival discharge (3.6%). In children from 2 to 6 years of age, the most frequent adverse reactions were eye burning sensation (12.1%), conjunctival injection (7.6%), eye pain (3%), eyelid inflammation (3%).

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk ratio of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to dorzolamide or to any of the excipients included in the drug;
• Severe renal failure (CC <30 ml/min);
• Hyperchloremic acidosis.

With caution in patients with severe hepatic impairment.

Use in Pregnancy and Lactation

Pregnancy

Dorzolamide should not be used during pregnancy. Data on the use of dorzolamide in pregnant women are absent or limited.

Breastfeeding

It is not known whether Dorzolamide or its metabolites are excreted in breast milk. Considering the benefit of breastfeeding for the child and the benefit of therapy for the woman, a decision should be made on whether to discontinue breastfeeding or discontinue/refrain from dorzolamide therapy. The risk to newborns/infants cannot be excluded either.

Fertility

Data from animal studies do not suggest an effect of dorzolamide therapy on male and female fertility. Data from human studies are lacking.

Use in Hepatic Impairment

Use with caution in severe hepatic impairment.

Use in Renal Impairment

Contraindicated in severe renal impairment (CC<10 ml/min).

Pediatric Use

Dorzolamide-SZ is indicated for use in children from 1 week of age as monotherapy or as an adjunct to beta-blocker therapy.

Special Precautions

The use of dorzolamide in acute angle-closure glaucoma attacks has not been studied. Treatment of patients with acute angle-closure glaucoma requires urgent surgical interventions along with topical ophthalmic hypotensive agents.

Dorzolamide contains a sulfonamide group, which is also found in sulfonamides, and although the drug is applied topically, it is absorbed into the systemic circulation. Thus, the same types of adverse reactions that have been found with the systemic administration of sulfonamides 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 appear, the use of the drug should be discontinued.

Treatment with oral carbonic anhydrase inhibitors is associated with the development of urolithiasis due to acid-base imbalance, especially in patients with a history of kidney stones. Although acid-base imbalance was not observed with the use of dorzolamide preparations, there have been rare reports of urolithiasis cases. Since the drug Dorzolamide-SZ contains a topically applied ophthalmic carbonic anhydrase inhibitor that is absorbed into the systemic circulation, patients with a history of urinary tract stones may have an increased risk of developing urolithiasis when using this medication.

If allergic reactions occur (e.g., conjunctivitis and eyelid reactions), the possibility of discontinuing the drug should be considered.

There is a possibility of an additive effect regarding the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and the drug. The concomitant use of dorzolamide and oral carbonic anhydrase inhibitors is not recommended.

Corneal edema and irreversible corneal decompensation have been reported with the use of dorzolamide preparations in patients with pre-existing recurrent corneal erosions and/or who have undergone surgery with disruption of the eyeball integrity. The likelihood of developing corneal edema is also increased. Precautions should be taken when prescribing the drug to these patient groups.

Choroidal detachment accompanied by ocular hypotension has been reported with the use of ophthalmic solutions that reduce aqueous humor secretion following surgical procedures to restore intraocular fluid outflow.

Dorzolamide has not been studied in patients with severe renal failure (CrCl <30 ml/min) or with hyperchloremic acidosis. Since Dorzolamide and its metabolites are primarily excreted by the kidneys, Dorzolamide is contraindicated in such patients.

Children

Dorzolamide has not been studied in patients with a gestational age of less than 36 weeks and an age of less than 1 week. Patients with significant renal tubular immaturity should only receive the drug after a thorough assessment of the benefit-risk ratio associated with the probable risk of metabolic acidosis.

Excipients

The drug Dorzolamide-SZ contains the preservative benzalkonium chloride, which may cause eye irritation. In patients with corneal disease and dry eye syndrome using a drug containing benzalkonium chloride as a preservative, the development of ulcerative toxic keratopathy or punctate keratopathy is possible. During long-term therapy with Dorzolamide-SZ, the condition of the cornea should be monitored in such patients.

Contact lenses must be removed before using the drug and reinserted no earlier than 15 minutes after instillation. Benzalkonium chloride can discolor soft contact lenses.

Effect on the ability to drive vehicles and operate machinery

No studies have been conducted on the effect of dorzolamide on the ability to drive vehicles and operate machinery. Nevertheless, possible adverse reactions such as dizziness and visual disturbances may affect the ability to drive a vehicle and/or operate machinery. Caution should be exercised when driving vehicles and operating machinery, as well as when engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Limited information is available on human overdose following accidental or intentional ingestion of dorzolamide hydrochloride.

Symptoms of accidental oral ingestion: drowsiness, nausea, dizziness, headache, weakness, unusual dreams, and dysphagia may occur.

Treatment involves symptomatic and supportive therapy. Electrolyte imbalance, acidosis, and CNS side effects may develop. Serum electrolyte levels (particularly potassium) and blood pH should be monitored.

Drug Interactions

No specific studies have been conducted on the interaction of dorzolamide with other drugs.

In clinical studies, Dorzolamide was administered in combination with other drugs without negative manifestations of drug interactions, including with topical ophthalmic timolol and betaxolol, as well as systemically administered drugs: ACE inhibitors, calcium channel blockers, diuretics, NSAIDs (including acetylsalicylic acid), hormones (estrogen, insulin, thyroxine). No adverse interactions were noted. There is insufficient information on the concomitant use of dorzolamide, miotics, and adrenergic receptor agonists as part of antihypertensive therapy for glaucoma.

The possibility of mutual enhancement of systemic effects of oral carbonic anhydrase inhibitors and dorzolamide when used simultaneously cannot be excluded. Combined treatment with systemically acting drugs and topical carbonic anhydrase inhibitors (Dorzolamide) has not been studied in clinical trials.

Dorzolamide is a carbonic anhydrase inhibitor, and although applied topically, it is partially absorbed and may have systemic effects. In clinical studies, the use of dorzolamide was not accompanied by acid-base imbalance. However, such phenomena have been observed with the use of carbonic anhydrase inhibitors, including as a result of drug interactions with other drugs (as a manifestation of toxicity when taking high doses of salicylates). Thus, when using dorzolamide, the possibility of such drug interactions should not be forgotten.

The patient should inform the doctor about all medications they are using or plan to use, including those available without a prescription. Toxicity may be enhanced when taking high doses of acetylsalicylic acid.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date stated on the packaging.

The shelf life after opening the dropper bottle is 28 days.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.