Cosopt bak

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT COSOPT BK

Composition:

Active substances: dorzolamide, timolol;

1 ml of ophthalmic solution contains 20 mg dorzolamide in the form of 22.26 mg dorzolamide hydrochloride, 5 mg timolol in the form of 6.83 mg timolol maleate;

Excipients: hydroxyethylcellulose, mannitol (E 421), sodium citrate, sodium hydroxide, water for injections.

Pharmaceutical form. Ophthalmic solution.

Main physicochemical properties: clear, colorless or almost colorless, slightly viscous solution practically free from visible particles.

Pharmacotherapeutic group. Anti-glaucoma preparations and miotics. Beta-adrenoreceptor blockers. Timolol, combinations. ATC code S01ED51.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The medicinal product Cosopt BC contains two active substances: dorzolamide hydrochloride and timolol maleate. Each of these two components reduces elevated intraocular pressure by decreasing the secretion of aqueous humor, but through different mechanisms of action.

Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase type II. Inhibition of carbonic anhydrase in the ciliary processes of the eye leads to a reduction in aqueous humor secretion, likely due to slowing the formation of bicarbonate ions, which in turn reduces sodium and fluid transport. Timolol maleate is a non-selective beta-adrenergic receptor blocker. The exact mechanism by which timolol maleate reduces intraocular pressure is not fully understood, although fluorescein and tonographic studies suggest that the primary effect of timolol may be related to reduced aqueous humor formation. However, in some studies, a slight increase in aqueous outflow has also been observed. The combined action of these two components results in an additive (greater) reduction in intraocular pressure (IOP) compared to monotherapy with either agent alone.

Following topical administration, Cosopt BC reduces elevated intraocular pressure regardless of whether the elevation is associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and visual field loss in glaucoma. This medicinal product reduces intraocular pressure without producing the side effects typical of miotic agents, such as night blindness, accommodative spasm, and pupillary constriction.

Pharmacodynamic effects

Clinical effects

Clinical studies of up to 15 months duration were conducted comparing the effect of Cosopt, administered twice daily (at specific morning and evening doses), with 0.5% timolol and 2.0% dorzolamide administered separately and in combination, in patients with glaucoma or ocular hypertension for whom combination therapy was considered appropriate and necessary in these studies. These studies included both untreated patients and patients not adequately controlled on timolol monotherapy. Most patients had been receiving treatment with a topical beta-blocker as monotherapy prior to enrollment. In the analysis of combined studies, the effect of Cosopt administered twice daily on reducing intraocular pressure was greater than that of monotherapy with 2% dorzolamide administered three times daily or 0.5% timolol administered twice daily. The effect of Cosopt administered twice daily on reducing intraocular pressure was equivalent to that of combination therapy with dorzolamide and timolol administered twice daily. The effect of Cosopt administered twice daily on reducing intraocular pressure was demonstrated at various time points throughout the day, and this effect was maintained during long-term use.

In a controlled, parallel-group, double-masked study with active comparator involving 261 patients with elevated intraocular pressure ≥ 22 mmHg in one or both eyes, the effect of Cosopt BC on reducing intraocular pressure was equivalent to that of Cosopt. The safety profile of Cosopt BC was similar to that of Cosopt.

Paediatric population

A 3-month controlled study was conducted with the primary objective of investigating and confirming the safety of 2% dorzolamide hydrochloride ophthalmic solution in children under 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 Cosopt in an open-label phase of the study. Efficacy in these patients was not established. In this small group of patients, 19 patients completed the treatment period and generally tolerated Cosopt twice daily well, while 11 patients discontinued treatment due to surgical intervention, change in medication, or other reasons.

Pharmacokinetics.

Dorzolamide hydrochloride

Unlike oral carbonic anhydrase inhibitors, topical application of dorzolamide hydrochloride delivers the active substance directly to the eye at significantly lower doses, thereby minimizing systemic exposure. In clinical studies, this resulted in reduced intraocular pressure (IOP) without the acid-base imbalances or electrolyte disturbances typical of oral carbonic anhydrase inhibitors.

After topical administration, dorzolamide enters the systemic circulation. To assess the systemic effects of carbonic anhydrase inhibitors following topical administration, concentrations of the active substance and its metabolite were measured in erythrocytes (RBCs) and plasma, along with carbonic anhydrase inhibition in erythrocytes. Dorzolamide accumulates in erythrocytes during chronic dosing due to selective binding to carbonic anhydrase type II, maintaining very low concentrations of free active substance in plasma. The parent/active substance forms a single N-desethyl metabolite, which is a less potent inhibitor of carbonic anhydrase type II compared to the parent compound and also inhibits the less active isoenzyme (carbonic anhydrase type I). The metabolite also accumulates in erythrocytes, where it binds primarily to carbonic anhydrase type I. Dorzolamide is moderately bound to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in urine; the metabolite is also excreted in urine. After discontinuation of dorzolamide, elimination from erythrocytes is non-linear, resulting in an initial rapid decline in concentration of the active substance, followed by a slower elimination phase with a half-life of approximately 4 months.

When dorzolamide was administered orally to simulate the maximum systemic exposure following chronic topical ophthalmic use, steady state was reached within 13 weeks. At steady state, there was essentially 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 or respiratory function. Similar pharmacokinetic results were obtained following chronic topical administration of dorzolamide hydrochloride. However, in some elderly patients with impaired renal function (creatinine clearance CrCl 30–60 mL/min), higher concentrations of the metabolite in erythrocytes (RBCs) were observed, although significant differences in carbonic anhydrase inhibition and clinically significant systemic adverse effects were not directly associated with this finding.

Timolol maleate

In a study measuring plasma concentrations of the active substance involving 6 patients, systemic exposure to timolol was assessed after topical administration of 0.5% timolol maleate ophthalmic solution twice daily. The mean peak plasma concentration after the morning dose was 0.46 ng/mL, and after the evening dose was 0.35 ng/mL.

Clinical Characteristics.

Indications.

Treatment of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or pseudoexfoliative glaucoma when topical use of beta-blockers alone is insufficient.

Contraindications.

Cosopt BK 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, overt 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 excipients of the medicinal product.

The above contraindications are related to the active substances of the medicinal product and are not specific to the combination.

Interaction with other medicinal products and other forms of interaction.

Specific studies on the interaction between Cosopt BK and other drugs have not been conducted.

In clinical studies, this medicinal product was used concomitantly with the following systemically acting drugs without evidence of adverse drug interactions: angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, diuretics, nonsteroidal anti-inflammatory drugs including aspirin, and hormones (e.g., estrogen, insulin, thyroxine).

There is a possibility of additive effects leading to arterial hypotension and/or marked bradycardia when ophthalmic beta-blocker solutions are used concomitantly with oral calcium channel blockers, drugs that reduce catecholamine production or beta-adrenergic blockers, antiarrhythmic agents (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, narcotics, and monoamine oxidase inhibitors (MAO).

Potentiation of systemic beta-blockade (e.g., reduced heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) and timolol.

Although Cosopt alone has minimal or no effect on pupil size, mydriasis has occasionally been reported with concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine).

Beta-blockers may enhance the hypoglycemic effect of antidiabetic agents.

Oral beta-adrenergic blockers may provoke rebound arterial hypertension upon withdrawal of clonidine.

Special precautions for use.

Cardiovascular and respiratory system reactions

Like other topically acting ophthalmic medicinal products, timolol is systemically absorbed. Since timolol is a beta-blocker, similar adverse reactions affecting the cardiovascular and respiratory systems may occur as with systemic administration of such beta-adrenergic blockers. The frequency of systemic adverse drug reactions (ADRs) after topical application of ophthalmic agents is lower than with systemic administration of these agents. For measures to reduce systemic absorption, see section "Method of administration and dosage".

Cardiac disorders

Beta-blockers should be used with caution in patients with cardiovascular disorders (e.g., ischemic heart disease, vasospastic angina/Prinzmetal's angina, and heart failure) and arterial hypotension. Such patients should be carefully evaluated, and alternative active substances considered. Patients with cardiovascular disorders should be monitored for signs of worsening of their condition and adverse reactions.

Due to the negative effect on impulse conduction, beta-blockers should be administered cautiously in patients with first-degree heart block.

Vascular disorders

Patients with severe peripheral circulatory disorders (i.e., severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.

Respiratory disorders

Respiratory reactions, including fatal bronchospasm, have been reported in asthmatic patients after administration of certain ophthalmic beta-blockers.

COSOPT BK should be used with caution in patients with mild to moderate chronic obstructive pulmonary disease (COPD), and only if the expected benefit outweighs the potential risk.

Hepatic function impairment

This medicinal product has not been studied in patients with impaired liver function and should therefore be used with caution in such patients.

Immunological and hypersensitivity reactions

Like other topically acting ophthalmic medicinal products, dorzolamide may be systemically absorbed. Dorzolamide, like sulfonamides, contains a sulfonamide group. Therefore, similar adverse reactions observed with systemic administration of 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 occur, the use of this medicinal product should be discontinued.

Local ocular adverse reactions similar to those observed with dorzolamide hydrochloride eye drops have been reported during use of this medicinal product. If such reactions occur, discontinuation of COSOPT BK should be considered.

Patients with atopy or a history of severe anaphylactic reactions to multiple allergens may be more sensitive to re-exposure to such allergens when taking beta-blockers and may not respond to treatment of anaphylactic reactions with usual doses of adrenaline.

Concomitant therapy

The effect on intraocular pressure or known systemic effects of beta-blockers may be enhanced when timolol is administered to patients already receiving systemic beta-blockers. The response to treatment in such patients should be carefully monitored. The use of two topical beta-adrenergic blockers is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

The use of dorzolamide and oral carbonic anhydrase inhibitors is not recommended.

Discontinuation of treatment

As with systemic beta-blockers, ophthalmic timolol should be withdrawn gradually when discontinuation of the drug is necessary in patients with ischemic heart disease.

Additional effects of beta-blockers

Hypoglycemia/diabetes mellitus

Beta-blockers should be used with caution in patients prone to spontaneous hypoglycemia or in patients with labile diabetes mellitus, as beta-blockers may mask the symptoms of acute hypoglycemia.

Beta-blockers may also mask the signs of hyperthyroidism. Abrupt withdrawal of beta-blockers may lead to worsening of symptoms.

Corneal disorders

Ophthalmic beta-blockers may cause dry eyes. Patients with corneal disorders should be treated with caution.

Anesthesia for surgical procedures

Ophthalmic beta-blockers may block the systemic effects of beta-agonists, such as adrenaline. The anesthesiologist must be informed that the patient is receiving timolol.

Beta-blocker therapy may exacerbate symptoms in myasthenia gravis.

Additional effects of carbonic anhydrase inhibition

Treatment with oral carbonic anhydrase inhibitors has been associated with the development of urolithiasis due to disturbances in acid-base balance, particularly in patients with a history of nephrolithiasis. Although acid-base disturbances have not been observed with the use of COSOPT, rare cases of urolithiasis have been reported. Since COSOPT BK contains a carbonic anhydrase inhibitor that is systemically absorbed after topical administration, patients with a history of nephrolithiasis may have an increased risk of urolithiasis when using this medicinal product.

Other special considerations

Treatment of patients with acute angle-closure glaucoma requires additional therapeutic measures beyond intraocular pressure-lowering agents. This medicinal product has not been studied in patients with acute angle-closure glaucoma.

Corneal edema and irreversible corneal decompensation have been reported with dorzolamide use in patients with pre-existing chronic corneal disorders and/or a history of intraocular surgery. The risk of corneal edema is high. Precautions should be taken when prescribing COSOPT BK to such patient groups.

Ciliary detachment has been reported following filtration procedures when aqueous suppressants (e.g., timolol, acetazolamide) were administered.

As with other antiglaucoma agents, reduced responsiveness to ophthalmic timolol maleate has been reported after prolonged treatment in some patients. However, in clinical studies involving 164 patients monitored for at least three years, no significant difference in mean intraocular pressure was observed after initial pressure stabilization.

Patients with a history of contact hypersensitivity to silver should not use this medicinal product, as the dropper may contain traces of silver from the container.

Any unused medicinal product or waste material must be disposed of in accordance with local regulations.

Use of contact lenses

This medicinal product has not been studied in patients wearing contact lenses.

Use during pregnancy or breastfeeding.

Pregnancy

COSOPT BK should not be used during pregnancy.

Dorzolamide

There are no adequate clinical data on the use of dorzolamide during pregnancy. Dorzolamide was teratogenic in rabbits at doses toxic to the mother.

Timolol

There are no adequate data on the use of timolol in pregnant women. Timolol should not be used during pregnancy except when clearly necessary.

Epidemiological studies have not shown a malformative effect, but such studies have demonstrated a risk of intrauterine growth retardation with oral administration of beta-blockers. In addition, newborns exposed to beta-blockers before delivery have shown signs of beta-blockade (such as bradycardia, arterial hypotension, respiratory distress (dyspnea), and hypoglycemia). If this medicinal product was used before delivery, the newborn should be closely monitored during the first days of life.

Breastfeeding

It is unknown whether dorzolamide is excreted in human breast milk. In lactating rats receiving dorzolamide, reduced fetal body weight was observed.

Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops, it is unlikely that sufficient amounts are excreted in breast milk to cause clinical symptoms of beta-blockade in the infant. If treatment with COSOPT BK is necessary, breastfeeding is not recommended.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. Possible adverse reactions such as blurred vision may negatively affect the ability of some patients to drive or operate machinery.

Method of Administration and Dosage

Dosage

Cosopt BK is administered as 1 drop into the conjunctival sac of the affected eye(s) twice daily.

If another topical ophthalmic agent is being used concurrently, an interval of at least 10 minutes should be maintained between instillation of Cosopt BK and the other medication.

This medicinal product is a preservative-free sterile solution.

Patients should be advised to wash their hands before using the product and to avoid contact of the dropper tip with the eye or surrounding tissues, as this may lead to contamination and subsequent eye infection (see Instructions for Use).

Patients should also be informed that ophthalmic solutions may become contaminated with common bacteria known to cause eye infections if not properly handled. Use of contaminated solutions may result in serious ocular damage and potential loss of vision.

Nasolacrimal occlusion or keeping the eyelids closed for 2 minutes after instillation may reduce systemic absorption. This can lead to a reduction in systemic side effects and enhance local action.

Method of Administration

Patients should be instructed on the proper handling of the multidose container.

Instructions for Use

Before instilling Cosopt BK eye drops:

• Wash your hands before opening the bottle.
• Before first use, check that the protective seal on the bottle neck is intact. Do not use the product if the seal is damaged.
• When using the bottle for the first time, practice by holding the bottle in your hand, gently squeezing it to release one drop outside the eye.
• Once you are confident you can administer one drop at a time, choose the most comfortable position for instillation (sitting, lying down, or standing in front of a mirror).
• Each time a new bottle is opened, one drop should be dispensed to prime the bottle.

Instillation

1. Hold the bottle just below the cap and unscrew the cap to open. Avoid touching the dropper tip to any surface to prevent contamination.

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2. Tilt the head backward and hold the bottle over the eye.
3. Pull the lower eyelid downward and look upward. Gently squeeze the bottle in the middle to release one drop into the eye. Note that there may be a delay of several seconds between squeezing and drop release. Do not squeeze too hard.

4. Close the eye and press gently with a finger on the inner corner of the eye for approximately two minutes. This helps retain the drop in the eye and prevents systemic absorption.

5. Repeat steps 2–4 for the other eye, if prescribed by your doctor. Sometimes only one eye requires treatment; your doctor will advise which eye to treat.
6. After each use and before recapping, tap the bottle once downward without touching the dropper tip to remove any residual liquid. This ensures proper delivery of subsequent doses.

7. Wipe away any excess liquid from the skin around the eye.
8. After 2 months from the first opening of the bottle, some Cosopt BK solution will remain in the bottle. Do not attempt to use any remaining solution after completing the treatment course. Do not use the eye drops more than 2 months after first opening the bottle.

Children

Efficacy in pediatric patients has not been established.

Safety in patients under 2 years of age has not been established. Available safety data in patients aged ≥ 2 and < 6 years are described in section "Pharmacodynamics".

Overdose

There are no data on overdose in humans following accidental or intentional ingestion of Cosopt or Cosopt BK.

Symptoms

There have been reports of accidental overdose with ophthalmic timolol maleate solution, which may result in systemic effects similar to those seen with systemic beta-blockers, including dizziness, headache, dyspnea, bradycardia, bronchospasm, and cardiac arrest. The most common expected signs and symptoms of dorzolamide overdose include electrolyte imbalance, development of acidosis, and effects on the central nervous system.

Limited data are available on overdose with accidental or intentional ingestion of dorzolamide hydrochloride in humans. Drowsiness has been reported after oral intake. With topical administration, nausea, dizziness, headache, weakness, unusual dreams, and dysphagia (difficulty swallowing) have been reported.

Treatment

Treatment should be symptomatic and supportive. Serum electrolyte levels (particularly potassium) and blood pH should be monitored. Studies have shown that timolol is not completely removed by dialysis.

Adverse reactions

In clinical studies, adverse reactions observed with the use of Cosopt BK were consistent with those previously reported for Cosopt, dorzolamide hydrochloride, and/or timolol maleate.

During clinical trials, 1035 patients received treatment with the medicinal product. Approximately 2.4% of all patients discontinued treatment with Cosopt due to the occurrence of local ocular adverse reactions, and approximately 1.2% of all patients discontinued treatment due to local adverse reactions indicative of allergy or hypersensitivity (specifically, eyelid inflammation and conjunctivitis).

Cosopt BK demonstrated a safety profile similar to that of Cosopt in a double-masked, comparative repeated-dose study.

As with other ophthalmic medicinal products administered locally, timolol is absorbed into the systemic circulation. This may cause adverse effects similar to those observed with systemic beta-blockers. The incidence of systemic adverse drug reactions (ADRs) following topical ophthalmic administration is lower than with systemic administration.

The following adverse reactions have been reported during clinical trials or post-marketing experience with Cosopt BK or one of its components: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), and not known (cannot be estimated from the available data).

*These adverse reactions were also observed during post-marketing surveillance of Cosopt.

**Additional adverse reactions were observed with ophthalmic beta-blockers and may likely occur with the use of Cosopt BK.

Suspected adverse reactions reporting

Reporting of suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions in accordance with current legislation.

Shelf life.

2 years.

Use within 2 months after first opening of the bottle.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 ml in a bottle with a dropper and a cap with a first-opening control. One bottle with a dropper and a cap with a first-opening control in a cardboard box.

Prescription status.

Prescription only.

Manufacturer: Santen AT.

Manufacturer's address and place of business:

Kelloportinkatu 1, Tampere, 33100, Finland.