Cosopt

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KOSOPT (COSOPT®)

Composition:

Active substances: dorzolamide; timolod;

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

Excipients: benzalkonium chloride, sodium citrate, mannite (E 421), hydroxyethylcellulose, sodium hydroxide, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colorless or almost colorless, slightly viscous solution.

Pharmacotherapeutic group. Agents used in ophthalmology. Antiglaucoma preparations and miotics. Beta-adrenoreceptor blockers. ATC code S01E D51.

Pharmacological Properties.

Pharmacodynamics.

The medicinal product contains two active substances: dorzolamide hydrochloride and timolol maleate. Each of these 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 carbonic anhydrase type II. Inhibition of carbonic anhydrase in the ciliary processes leads to a reduction in aqueous humor secretion by slowing the formation of bicarbonate ions, which in turn results in decreased transport of sodium and fluid.

Timolol maleate is a non-selective beta-adrenergic receptor blocker. The precise mechanism of timolol’s action, which manifests as a reduction in intraocular pressure, is not fully understood. Fluorometric and tonographic studies indicate that the effect of timolol is due to reduced secretion of aqueous humor. Additionally, timolol may enhance outflow of fluid.

The combined action of the two components results in a greater reduction of intraocular pressure than monotherapy with either agent alone.

After topical administration, COSOPT reduces intraocular pressure regardless of whether the elevation is associated with glaucoma. Elevated intraocular pressure plays a significant role in the pathogenesis of optic nerve damage and visual field loss in glaucoma.

COSOPT reduces intraocular pressure without producing the typical side effects of miotics, such as night blindness, accommodative spasm, or pupillary constriction.

Pharmacodynamic Effects

Clinical Effects

Clinical studies lasting up to 15 months were conducted comparing the effect of COSOPT administered twice daily (with specific morning and evening doses) on reducing intraocular pressure with that of 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. The studies included both untreated patients and patients inadequately controlled on timolol monotherapy. Most patients had been receiving local beta-blocker therapy as monotherapy prior to inclusion in the studies. 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 combined 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.

Pediatric Patients

A 3-month controlled study was conducted with the primary objective of investigating and confirming the safety of using 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 the open-label phase of the study. Efficacy in these patients has not been established. In this small group, COSOPT administered twice daily was generally well tolerated by 19 patients who completed the treatment period, while 11 patients discontinued treatment due to surgical intervention, change of medication, or other reasons.

Pharmacokinetics.

Dorzolamide hydrochloride. After topical administration, dorzolamide enters the systemic circulation. With prolonged use, dorzolamide accumulates in erythrocytes due to binding with carbonic anhydrase type II, maintaining very low concentrations of free drug in plasma. Dorzolamide is metabolized to a single N-desethyl metabolite, which is less potent in inhibiting carbonic anhydrase type II compared to the parent compound and also inhibits carbonic anhydrase type I, a less active isoenzyme. The metabolite also accumulates in erythrocytes, where it binds primarily to carbonic anhydrase type I. Approximately 33% of dorzolamide is plasma protein-bound. Dorzolamide is excreted in urine unchanged and as metabolite. After discontinuation of the drug, dorzolamide is eliminated nonlinearly from erythrocytes, characterized by an initial rapid decline in concentration followed by a slower elimination phase with a half-life of approximately 4 months.

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

Timolol maleate. After topical ocular administration, timolol is systemically absorbed. Systemic exposure to timolol was measured after topical administration of the 0.5% ophthalmic solution twice daily. Maximum plasma concentration after the morning dose was 0.46 ng/mL, and after the evening dose was 0.35 ng/mL.

Clinical Characteristics.

Indications.

Indicated for the treatment of elevated intraocular pressure in patients with open-angle glaucoma or pseudoexfoliative glaucoma when topical use of beta-blockers alone is insufficient.

Contraindications.

COSOPT is contraindicated in patients with:

• reactive respiratory diseases, including bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease (COPD);
• sinus bradycardia, sick sinus syndrome, sinoatrial block, or second- or third-degree atrioventricular block not controlled by a pacemaker, overt heart failure, or cardiogenic shock;
• severe renal impairment (creatinine clearance CrCl < 30 mL/min) or hyperchloremic acidosis;
• hypersensitivity to either of the active substances or to any of the excipients, as well as during pregnancy and breastfeeding.

The above-mentioned conditions are based on information regarding the individual active components and are not specific to the combination.

Interaction with other medicinal products and other forms of interaction.

No specific interaction studies between COSOPT and other medicinal products have been conducted.

In clinical studies, this medicinal product was used concomitantly with the following systemically acting medicinal products without evidence (without confirmation) 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 risk of additive effects leading to hypotension and/or marked bradycardia when ophthalmic beta-blocker solutions are used concomitantly with oral calcium channel blockers, agents that reduce catecholamine production, beta-adrenergic blockers, antiarrhythmic agents (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, narcotics, and monoamine oxidase inhibitors (MAO inhibitors).

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

Although COSOPT itself (as monotherapy) has minimal or no effect on pupil size, miosis 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 discontinuation of clonidine.

Special precautions for use.

Cardiovascular and respiratory system reactions

Like other topically applied ophthalmic medicinal products, timolol is systemically absorbed. Since timolol is a beta-blocker, there is a possibility of developing adverse reactions affecting the cardiovascular and respiratory systems, similar to those observed with systemic administration of such agents. The incidence of systemic adverse reactions after topical application of ophthalmic medicinal products is lower than with systemic administration. For information on reducing systemic absorption, see section "Dosage and administration".

Cardiac disorders

Patients with cardiovascular disorders (e.g., ischemic heart disease, vasospastic angina/Prinzmetal's angina, and heart failure) and those with arterial hypotension should be carefully evaluated before initiating beta-blocker therapy, and alternative active substances should be considered. Patients with cardiovascular disorders should be closely monitored for signs of worsening of these conditions and for adverse reactions.

Due to their negative effect on impulse conduction time, beta-blockers should be used with caution in patients with first-degree heart block.

Vascular disorders

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

Respiratory system disorders

Respiratory reactions, including fatal cases due to bronchospasm, have been reported in patients with asthma following administration of certain ophthalmic beta-blockers.

COSOPT 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

The use of this medicinal product in patients with hepatic impairment has not been studied, and therefore it should be administered with caution in such patients.

Immunological and hypersensitivity reactions

Like other topically applied ophthalmic medicinal products, this medicinal product may be systemically absorbed. Dorzolamide, like sulfonamides, contains a sulfonamide group. Therefore, adverse reactions associated with systemic administration of sulfonamide-containing drugs may occur with topical application, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs of serious reactions or hypersensitivity occur, the drug should be discontinued.

Local ocular adverse reactions similar to those observed with dorzolamide hydrochloride ophthalmic solutions have been reported during treatment with this medicinal product. If such reactions occur, discontinuation of this medicinal product should be considered.

Patients with atopy or a history of severe anaphylactic reactions to multiple allergens may be more sensitive to re-exposure to allergens while receiving beta-blockers and may not respond to the usual doses of adrenaline during anaphylactic reactions.

Concomitant therapy

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

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

Discontinuation of therapy

As with systemic beta-blockers, ophthalmic timolol should be withdrawn gradually if discontinuation is necessary in patients with ischemic heart disease (IHD).

Additional effects of beta-blockers

Hypoglycemia/Diabetes

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

Beta-blockers may also mask 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 during surgery

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

Beta-blocker therapy may exacerbate symptoms of 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 this medicinal product, rare cases of urolithiasis have been reported. Since carbonic anhydrase inhibitors are systemically absorbed after topical administration, patients with a history of nephrolithiasis may have an increased risk of developing urolithiasis when using COSOPT.

Other special considerations

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

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. Corneal edema is highly likely to occur in patients with a low number of endothelial cells. Precautions should be taken when prescribing COSOPT to such patients.

Choroidal 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 in some patients after prolonged treatment. 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.

Use of contact lenses

This medicinal product contains a preservative, benzalkonium chloride, which may cause eye irritation. Contact lenses should be removed prior to instillation of the drops and at least 15 minutes should elapse before reinsertion. Benzalkonium chloride is known to discolor soft contact lenses.

Use during pregnancy or breastfeeding.

Pregnancy

COSOPT should not be used during pregnancy.

Dorzolamide

There are no clinical data on the effects of dorzolamide during pregnancy. Dorzolamide has shown teratogenic effects in rabbits during pregnancy.

Timolol

There are insufficient data on the use of timolol during pregnancy. Timolol should not be used during pregnancy unless clearly necessary. For information on reducing systemic absorption, see section "Dosage and administration".

Epidemiological studies have not provided evidence of an increased risk of intrauterine growth retardation associated with the use of oral beta-blockers during pregnancy. However, newborns exposed to beta-blockers before delivery have shown signs of beta-blockade (e.g., bradycardia, hypotension, respiratory distress syndrome, and hypoglycemia). If this medicinal product is used before delivery, newborns should be closely monitored during the first few days after birth.

Breastfeeding

It is unknown whether dorzolamide is excreted in human milk. In rats administered dorzolamide, reduced body weight gain in offspring was observed. Beta-blockers are excreted in breast milk. However, when ophthalmic timolol drops are used at therapeutic doses, it is unlikely that sufficient amounts will be present in breast milk to cause clinical symptoms of beta-blockade in the infant. Information on reducing systemic absorption can be found in the section "Dosage and administration".

If treatment with COSOPT is necessary, breastfeeding is not recommended.

Effect on ability to drive and use machines.

No studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted. Possible adverse reactions such as blurred vision may impair the ability of some patients to drive or operate machinery.

Method of administration and dosage.

Dosage

COSOPT should be administered as 1 drop into the conjunctival sac of the affected eye(s) twice daily.

If another topical ophthalmic agent is used simultaneously, the interval between instillation of COSOPT and the other medicinal product should be at least 10 minutes.

Patients should wash their hands before using the medication and avoid contact of the dropper tip with the surface of the eye or eyelids.

Patients should be advised that ophthalmic solutions may become contaminated with common bacteria known to cause eye infections if not properly handled. Use of contaminated solutions may lead to serious eye damage and subsequent loss of vision.

Children

The efficacy of use in children has not been established.

The safety of use in children under 2 years of age has not been established. (For information on safety in children aged ≥ 2 to < 6 years, see section "Pharmacodynamics".)

Overdose

There is no data on overdose in humans following accidental or intentional ingestion of COSOPT.

Symptoms

There have been reports of accidental overdose with ophthalmic timolol maleate solution, which may lead to the development of systemic effects such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest—similar to those observed in systemic beta-adrenergic blockers overdose. The most common expected symptoms following dorzolamide overdose include electrolyte imbalance, development of acidosis, and possible effects on the central nervous system.

Limited data are available on dorzolamide hydrochloride overdose in humans following accidental or intentional ingestion. 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 is 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 trials of the drug COSOPT, the adverse reactions observed were consistent with those previously reported with dorzolamide hydrochloride and/or timolol maleate.

During clinical studies, 1035 patients received treatment with COSOPT. Approximately 2.4% of all patients discontinued treatment with this medicinal product 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 blepharitis and conjunctivitis).

Like other topically applied ophthalmic agents, timolol is absorbed into the systemic circulation. This may cause systemic adverse effects similar to those seen with systemic beta-blockers. The incidence of systemic adverse reactions following topical ophthalmic administration is lower than with systemic administration.

The adverse reactions listed below have been reported during clinical trials or post-marketing surveillance with COSOPT or one of its components.

Frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

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* These adverse reactions were also observed during post-marketing surveillance with COSOPT.

** Additional adverse reactions have been reported with ophthalmic beta-blockers and may possibly occur with the use of COSOPT.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

Shelf life.

3 years. After opening the bottle, do not use for longer than 4 weeks.

Storage conditions.

Store at a temperature not exceeding 25 °C in a light-protected and child-inaccessible place.

Packaging.

5 ml in a white, semi-transparent plastic type 6 bottle with a white cap. One bottle in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Santen AT/Santen Oy.

Manufacturer's address.

Kelloportinkatu 1, Tampere, 33100, Finland / Kelloportinkatu 1, Tampere, 33100, Finland.