Dorzopt Plus (Drops) Instructions for Use

Marketing Authorization Holder

S.C. Rompharm Company S.R.L. (Romania)

ATC Code

S01ED51 (Timolol in combination with other drugs)

Active Substances

Dorzolamide (Rec.INN registered by WHO)

Timolol (Rec.INN registered by WHO)

Dosage Form

Dorzopt Plus

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

Dosage Form, Packaging, and Composition

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

Excipients : hydroxyethyl cellulose – 1 mg, citric acid monohydrate – 4 mg, 1M sodium hydroxide solution – 0.066 ml, mannitol – 20 mg, benzalkonium chloride – 0.075 mg, 1M sodium hydroxide solution/1M hydrochloric acid solution – to pH 5.6±0.1, purified water – to 1 ml.

5 ml – polyethylene bottles (1) with a dropper cap – cardboard packs.

Clinical-Pharmacological Group

Antiglaucoma drug – carbonic anhydrase inhibitor + beta-adrenoblocker

Pharmacotherapeutic Group

Drugs used in ophthalmology; antiglaucoma drugs and miotic agents; beta-adrenergic blockers; timolol in combination with other agents

Pharmacological Action

Combined antiglaucoma agent.

Dorzolamide is a selective inhibitor of carbonic anhydrase type II. Inhibition of carbonic anhydrase in the ciliary body leads to a decrease in the secretion of intraocular fluid, presumably by reducing the formation of bicarbonate ions, which in turn leads to a slowdown in sodium and intraocular fluid transport.

Timolol is a non-selective beta-blocker. Although the exact mechanism of action of timolol in reducing intraocular pressure has not yet been established, a number of studies have shown a predominant reduction in the formation of intraocular fluid, as well as a slight increase in its outflow.

The combined action of these substances in the combined medicinal product leads to a more pronounced reduction in intraocular pressure.

Reduction of intraocular pressure occurs 20 minutes after instillation, reaches a maximum after 2 hours and lasts for at least 24 hours.

Pharmacokinetics

Dorzolamide penetrates into the eye mainly through the cornea (to a lesser extent through the sclera or limbus). When applied topically, dorzolamide penetrates into the systemic circulation. With prolonged use, dorzolamide accumulates in erythrocytes as a result of selective binding to carbonic anhydrase type II, maintaining extremely low concentrations of the free drug in plasma. Plasma protein binding is about 33%.

As a result of metabolism, it is transformed into an N-desethylated metabolite, which is less active against carbonic anhydrase II but capable of blocking carbonic anhydrase type I. The metabolite also accumulates in erythrocytes, where it binds mainly to carbonic anhydrase type I. It is excreted by the kidneys unchanged and in the form of metabolites. After discontinuation of the drug, dorzolamide is non-linearily washed out of erythrocytes, which first leads to a rapid decrease in its concentration, then the elimination slows down. T_1/2 is about 4 months.

When dorzolamide was taken orally to simulate the maximum systemic exposure during its topical application, a steady state was achieved after 13 weeks. At the same time, virtually no free dorzolamide or its metabolites were detected in the blood plasma. Inhibition of erythrocyte carbonic anhydrase was insufficient to achieve a pharmacological effect on renal and respiratory function. Similar pharmacological results were observed with long-term topical use of dorzolamide. However, in some elderly patients with renal failure (creatinine clearance 30-60 ml/min), higher concentrations of the metabolite in erythrocytes were detected, but this had no clinical significance.

When applied topically, timolol penetrates into the systemic circulation. The concentration of timolol in plasma was studied in 6 patients with topical application of timolol in the form of 0.5% eye drops 2 times/day. The mean C_max after morning application was 0.46 ng/ml, after afternoon application – 0.35 ng/ml.

Indications

Elevated intraocular pressure in open-angle glaucoma and pseudoexfoliative glaucoma with insufficient effectiveness of monotherapy.

ICD codes

Dosage Regimen

For topical use. Instill 1 drop into the conjunctival sac of the eye (or both eyes) 2 times/day.

If a drug containing this combination is prescribed as a replacement for another ophthalmic drug for the treatment of glaucoma, the latter must be discontinued 1 day before starting therapy with the drug containing this combination.

In case of concomitant use with other topical ophthalmic drugs, the administration of the drug containing this combination should be carried out at an interval of 10 minutes.

With nasolacrimal occlusion (eyelid closure) for 2 minutes after instillation of the drug containing this combination, its systemic absorption is reduced, which may lead to an increase in local action.

The duration of treatment is determined by the doctor depending on the clinical condition of the patient.

Adverse Reactions

The following possible undesirable reactions of the active components of the combination are known.

Dorzolamide

Nervous system disorders headache, dizziness, asthenia/fatigue, paresthesia.

Eye disorders eyelid inflammation, lacrimation, eyelid irritation and scaling, iridocyclitis, punctate keratitis, transient myopia (resolving after drug withdrawal).

Allergic reactions angioedema, bronchospasm, urticaria, itching, rash.

Respiratory system disorders epistaxis.

Timolol (topical application)

Psychiatric disorders: depression.

Immune system disorders: anaphylaxis, angioedema, urticaria, localized or generalized rash.

Nervous system disorders: tinnitus, paresthesia, headache, asthenia, fatigue, dizziness, insomnia, nightmares, memory impairment, worsening of myasthenia symptoms.

Respiratory system disorders: bronchospasm (mainly in patients with pre-existing bronchoo obstructive pathology), cough, chest pain.

Eye disorders: conjunctivitis, blepharitis, keratitis, decreased corneal sensitivity, dry eye syndrome; vision disorders, including changes in the refractive ability of the eye (in some cases due to withdrawal of miotics), diplopia, ptosis.

Cardiovascular system disorders: arrhythmia, cardiac arrest, decreased blood pressure, syncope, Raynaud’s syndrome, decreased temperature of hands and feet.

Gastrointestinal disorders: diarrhea, dyspepsia, dry mouth, pharyngeal irritation, abdominal pain.

Skin and subcutaneous tissue disorders: alopecia, psoriasis-like rash or exacerbation of psoriasis.

Musculoskeletal and connective tissue disorders: claudication, systemic lupus erythematosus.

Reproductive system disorders: decreased libido, Peyronie’s disease.

General disorders and administration site conditions: edema.

In the post-registration period, when using the dorzolamide+timolol combination, the following undesirable reactions were noted: dyspnea, respiratory failure, bradycardia, AV block, choroidal detachment, nausea, contact dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. Cases of corneal edema and irreversible destruction have been reported in patients with chronic corneal defects and/or those who have undergone intraocular surgery.

Contraindications

Hyperreactivity of the respiratory tract; bronchial asthma (including history); severe COPD; sinus bradycardia; sick sinus syndrome; sinoatrial block; AV block II-III degree; severe heart failure; cardiogenic shock; severe renal failure (creatinine clearance less than 30 ml/min); hyperchloremic acidosis; dystrophic processes in the cornea; pregnancy; lactation (breastfeeding); children and adolescents under 18 years of age; hypersensitivity to the components of the drug.

With caution

History of cardiovascular diseases, including heart failure, AV block I degree; mild to moderate COPD; severe peripheral circulatory disorders (severe forms of Raynaud’s disease or Raynaud’s syndrome); hepatic insufficiency; diabetes mellitus; urolithiasis (including history); hyperthyroidism; corneal disorders; elderly patients.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during lactation (breastfeeding).

Use in Hepatic Impairment

Use with caution in hepatic insufficiency.

Use in Renal Impairment

Contraindication: severe renal failure (creatinine clearance less than 30 ml/min).

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Should be used with caution in elderly patients.

Special Precautions

Components of the combined medicinal product can penetrate into the systemic circulation. Since timolol is a beta-blocker, undesirable reactions that develop with systemic use of beta-blockers may be noted with topical use of this combination.

Before starting use, adequate control of the cardiovascular system condition must be ensured.

Patients with a history of cardiovascular diseases, including heart failure, should be carefully monitored for signs of worsening of these diseases (monitoring of heart rate and blood pressure).

Reports of cases of fatal heart failure during the use of timolol in the form of eye drops have been registered.

If the first signs or symptoms of heart failure appear, the use of this medicinal product must be discontinued.

Patients with first-degree heart block should be prescribed beta-blockers with caution due to their ability to slow impulse conduction.

Reports of cases of fatal bronchospasm in patients with bronchial asthma during the use of timolol in the form of eye drops have been registered.

In patients with mild to moderate COPD, use with caution and only if the expected benefit of treatment outweighs the potential risk.

The drug should be used with caution in patients with severe peripheral circulatory disorders (severe forms of Raynaud’s disease or syndrome).

Use with caution in patients with spontaneous hypoglycemia or in patients with diabetes mellitus (especially with an unstable course) while using insulin or oral hypoglycemic drugs, since beta-blockers can mask the symptoms of hypoglycemia.

Beta-blockers can mask some clinical signs of hyperthyroidism (e.g., tachycardia). If hyperthyroidism is suspected, patients should be carefully monitored. Abrupt withdrawal of beta-blockers should be avoided due to the risk of thyrotoxic crisis.

Dorzolamide is a sulfonamide. Undesirable reactions identified with systemic use of sulfonamides may be noted with topical use (Stevens-Johnson syndrome and toxic epidermal necrolysis). If signs of serious hypersensitivity reactions appear, the use of the medicinal product must be discontinued.

When treating patients with atopy or a history of severe anaphylactic reactions to various allergens with beta-blockers, an enhanced response upon repeated contact with these allergens is possible. In this group of patients, the use of epinephrine in a standard therapeutic dose to relieve allergic reactions may be ineffective.

When used in patients taking systemic beta-blockers, the possible mutual enhancement of the pharmacological action of the drugs, both in relation to the known systemic effects of beta-blockers and in relation to the reduction of intraocular pressure, must be taken into account. Concomitant use with other beta-blockers is not recommended.

If it is necessary to discontinue topical use of timolol, as in the case of withdrawal of systemic beta-blockers, discontinuation of therapy in patients with coronary artery disease should be carried out gradually.

Beta-blockers used in ophthalmology can cause dryness of the eye mucosa. In patients with corneal disorders, the drug should be used with caution. In patients with a low number of endothelial cells, there is an increased risk of developing corneal edema.

The use of systemic carbonic anhydrase inhibitors can lead to a violation of the acid-base balance and be accompanied by urolithiasis, especially in patients with a history of urolithiasis.

Influence on the ability to drive vehicles and mechanisms

During the period of use, it is necessary to refrain from driving vehicles and mechanisms and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

There is a possibility of enhanced hypotensive effect and/or development of marked bradycardia with concomitant use of ophthalmic timolol solution and slow calcium channel blockers, sympatholytics, beta-blockers, antiarrhythmic drugs (including amiodarone), cardiac glycosides, parasympathomimetics, opioid analgesics and MAO inhibitors.

With concomitant use of timolol and inhibitors of the CYP2D6 isoenzyme (e.g., quinidine or selective serotonin reuptake inhibitors), a potentiated effect of systemic beta-adrenergic receptor blockade (e.g., decreased heart rate, depression) has been reported.

Systemic beta-blockers may enhance the effect of hypoglycemic drugs.

Systemic beta-blockers may enhance the severity of arterial hypertension, which is an effect of clonidine withdrawal.

There are isolated data on the development of mydriasis with concomitant use of timolol and adrenaline.

There is a possibility of enhancement of known systemic effects of carbonic anhydrase inhibition with combined use of topical and systemic carbonic anhydrase inhibitors.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.