Dorzoculin^® (Drops) Instructions for Use

Marketing Authorization Holder

Jadran-Galenski Laboratorij, D.D. (Croatia)

Contact Information

Jadran-Galenski Laboratorij D.D. (Croatia)

ATC Code

S01EC03 (Dorzolamide)

Active Substance

Dorzolamide (Rec.INN registered by WHO)

Dosage Form

Dorzoculin®

Eye drops 20 mg/1 ml: bottle 5 ml 1 pc.

Dosage Form, Packaging, and Composition

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

Excipients : mannitol, hydroxyethylcellulose, sodium citrate, benzalkonium chloride solution 50%, sodium hydroxide, purified water.

5 ml – polyethylene bottles (1) with a built-in dropper – cardboard packs.

Clinical-Pharmacological Group

Antiglaucoma drug – topical carbonic anhydrase inhibitor

Pharmacotherapeutic Group

Antiglaucoma agent – carbonic anhydrase inhibitor

Pharmacological 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).

The drug Dorzoculin^® contains dorzolamide hydrochloride, which is a potent selective inhibitor of human CA-II. After topical ophthalmic application of dorzolamide, elevated IOP is reduced 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 systemic 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 previously obtained data on the additive effect when beta-blockers and oral carbonic anhydrase inhibitors are used together.

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 the acid-base balance disturbances or electrolyte changes characteristic of oral carbonic anhydrase inhibitors.

When applied topically, Dorzolamide enters the systemic circulation. 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 red blood cells, were measured. With long-term use, Dorzolamide accumulates in red blood cells due to selective binding to CA-II, while extremely low concentrations of free dorzolamide are maintained in plasma. Dorzolamide forms an N-desethyl metabolite, which inhibits CA-II to a lesser extent than the parent active substance, but also inhibits the less active isoenzyme CA-I. The metabolite also accumulates in red blood cells, 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 red blood cells was less significant than expected for the necessary pharmacological effect on renal or respiratory function. Similar pharmacokinetic results were observed after prolonged topical application of dorzolamide hydrochloride. However, some elderly patients with renal impairment (established CrCl 30-60 ml/min) had higher metabolite concentrations in red blood cells, but no significant differences in carbonic anhydrase inhibition and no clinically significant systemic side effects were directly associated with this.

Indications

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

• Ocular hypertension;
• Primary open-angle glaucoma;
• Pseudoexfoliative glaucoma;
• Secondary glaucoma (without anterior chamber angle block).

The drug is also used:

• As an adjunctive therapy to beta-blockers;
• As monotherapy in patients who do not respond to beta-blockers or for whom beta-blockers are contraindicated.

The drug Dorzoculin^® is indicated for the treatment of glaucoma in children from 1 week of age as monotherapy or as an adjunct to beta-blocker therapy.

ICD codes

Dosage Regimen

Topically.

Adults

For monotherapy

1 drop into the conjunctival sac of the affected eye (or both eyes) 3 times/day.

In combination with topical beta-blockers

1 drop into the conjunctival sac of the affected eye (or both eyes) 2 times/day.

When replacing any other antiglaucoma drug with Dorzolamide, treatment with it should be started the day after discontinuation of the previous drug.

When using the drug Dorzoculin^® simultaneously with other ophthalmic agents, they should be instilled at least 10 minutes apart.

Applying nasolacrimal occlusion or closing the eyelids for 2 minutes after instillation of the drug reduces systemic absorption. This helps reduce the frequency of systemic side effects and increase the local activity of the drug.

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

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

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

Children

Although there is limited clinical data on the use of dorzolamide in pediatric patients 3 times/day, the dosage regimen for children is the same as for adults.

Adverse Reactions

Adverse reactions

Classification of adverse reactions by frequency of occurrence: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000) and frequency unknown (frequency cannot be estimated from the available data).

Nervous system disorders: common – headache; rare – dizziness, paresthesia.

Eye disorders: very common – burning and pain; common – superficial punctate keratitis, lacrimation, conjunctivitis, eyelid inflammation, itching, eyelid irritation, blurred vision; uncommon – iridocyclitis; rare – eye redness, pain, eyelid hyperkeratosis, transient myopia (disappearing after drug withdrawal), corneal edema, ocular hypotension, choroidal detachment after surgical interventions to restore aqueous humor outflow.

Respiratory, thoracic and mediastinal disorders: rare – epistaxis.

Gastrointestinal disorders: common – nausea, bitter taste in the mouth; rare – throat irritation, dry mouth.

Skin and subcutaneous tissue disorders: rare – contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Renal and urinary disorders: rare – urolithiasis.

General disorders and administration site conditions: common – asthenia, fatigue; rare – allergic reactions (signs and symptoms of local reactions (on the eyelids) and systemic allergic reactions, including angioedema, urticaria, itching, rash, difficulty breathing, less commonly – bronchospasm).

Investigations

No clinically significant electrolyte disturbances were observed with the use of dorzolamide.

If any of the side effects listed in the instructions get worse, or the patient notices any other side effects not listed in the instructions, they should inform their doctor.

Contraindications

• Hypersensitivity to the active substance or any of the excipients;
• Severe renal failure;
• Hyperchloremic acidosis;
• Pregnancy;
• Breastfeeding period;
• Children under 1 week of age.

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. In rabbits, Dorzolamide caused a teratogenic effect at doses toxic to pregnant females.

Breastfeeding period

It is not known whether Dorzolamide or its metabolites are excreted in breast milk. Available pharmacodynamic/toxicology data from animal studies indicate that 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 therapy with Dorzoculin^®. 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 Renal Impairment

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

Pediatric Use

The drug is used in children from 1 week of age according to the indications.

Special Precautions

The use of dorzolamide in patients with acute angle-closure glaucoma has not been studied. Treatment of patients with acute angle-closure glaucoma requires urgent therapeutic measures in addition to 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 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 this 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 balance disturbances were not observed with the use of dorzolamide, there have been rare reports of urolithiasis. Since Dorzolamide contains a topical 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 drug.

If allergic reactions occur (e.g., conjunctivitis and eyelid reactions), the possibility of discontinuing the use of 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 Dorzolamide. 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 in patients with pre-existing recurrent corneal erosions and/or who have undergone surgery with disruption of the integrity of the eyeball. The likelihood of developing corneal edema is also increased. Precautions should be taken when prescribing the drug Dorzoculin^® to these groups of patients.

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

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

The drug Dorzoculin^® contains the preservative benzalkonium chloride, which may cause eye irritation. In patients with corneal disease and dry eye syndrome, when using a drug containing benzalkonium chloride as a preservative, ulcerative toxic keratopathy or punctate keratopathy may develop. During long-term therapy with Dorzoculin^®, 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.

Use in 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 receive Dorzolamide only after a careful assessment of the benefit-risk ratio associated with the likely risk of metabolic acidosis.

Effect on ability to drive vehicles and operate machinery

No studies on the effect of the drug on the ability to drive vehicles and operate machinery have been conducted. Nevertheless, possible adverse reactions such as dizziness and visual disturbances may affect the ability to drive a vehicle and/or operate machinery.

Overdose

Only limited information is available on human overdose with accidental or intentional ingestion of dorzolamide hydrochloride.

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

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

Drug Interactions

No specific studies on the interaction of the drug with other drugs have been conducted. In clinical studies, the drug was prescribed in combination with other drugs without negative manifestations of drug-drug interactions, including with timolol and betaxolol eye drops, as well as systemic drugs: ACE inhibitors, calcium channel blockers, diuretics, NSAIDs (including acetylsalicylic acid), hormones (estrogen, insulin, thyroxine).

The possibility of mutual enhancement of systemic effects of oral carbonic anhydrase inhibitors and the drug Dorzoculin^® when used together cannot be excluded.

Data on the combined use of dorzolamide, miotics, and adrenergic receptor agonists as part of hypotensive therapy for glaucoma are insufficient.

The patient should inform the doctor about all medications they are using or plan to use.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F) in the original packaging (bottle in a carton).

Shelf Life

Shelf life – 2 years. Do not use after the expiration date printed on the packaging.

After first opening the bottle, the drug should be used within 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.