Cosopt/Cosopt-S

Dorzolamide HCl, timolol maleate.

Cosopt: Each milliliter of DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) contains 20.00 mg dorzolamide (22.26 mg dorzolamide hydrochloride) and 5.00 mg timolol (6.83 mg of timolol maleate) as the active ingredients.
Sterile, isotonic, buffered, slightly viscous, aqueous solution.
DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) Ophthalmic Solution is the first combination of a topical carbonic anhydrase inhibitor and a topical beta-adrenergic receptor blocking agent.
DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) contains dorzolamide hydrochloride and timolol maleate.
Dorzolamide Hydrochloride: Dorzolamide hydrochloride is described chemically as: (4S-trans)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno [2,3-b]thiopyran-2- sulfonamide 7,7-dioxide monohydrochloride.
Its empirical formula is C₁₀H₁₆N₂O₄S₃ HCl.
Dorzolamide hydrochloride has a molecular weight of 360.91. It is a white to off-white, free flowing crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol.
Timolol Maleate: Timolol maleate is described chemically as: (S)-1-[(1,1-dimethylethyl)amino]-3-[[4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy]-2- propanol,(Z)-2-butenedioate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in the structure and is provided as the levo isomer.
The empirical formula is C₁₃H₂₄N₄O₃SC₄H₄O₄.
Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is soluble in water, methanol, and alcohol.
Cosopt-S: Dorzolamide HCl/Timolol Maleate (Cosopt-S) is a clear, colourless to nearly colourless, slightly viscous ophthalmic solution containing 22.26mg of Dorzolamide Hydrochloride corresponding to 20mg Dorzolamide and 6.83mg of Timolol Maleate corresponding to 5mg Timolol in each mL, or 4mg of Dorzolamide and 1mg of Timolol in each single-dose container (0.2 mL). It also contains hydroxyethylcellulose, mannitol, sodium citrate, sodium hydroxide (for pH adjustment) and water for injection.

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, Beta blocking agents, Timolol, combinations. ATC code: S01ED51.
Pharmacology: Cosopt-S: Pharmacodynamics: Mechanism of action: Dorzolamide HCl/Timolol Maleate (Cosopt-S) is comprised of two components: dorzolamide hydrochloride and timolol maleate. Each of these two components decreases elevated intraocular pressure by reducing aqueous humor secretion, but does so by a different mechanism of action.
Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase II. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Timolol maleate is a nonselective beta-adrenergic receptor blocking agent. The precise mechanism of action of timolol maleate in lowering intraocular pressure is not clearly established at this time, although a fluorescein study and tonography studies indicate that the predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed. The combined effect of these two agents results in additional intraocular pressure reduction (IOP) compared to either component administered alone.
Following topical administration, Dorzolamide HCl/Timolol Maleate (Cosopt-S) reduces elevated intraocular pressure, whether or not associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. This medicinal product reduces intraocular pressure without the common side effects of miotics such as night blindness, accommodative spasm and pupillary constriction.
Pharmacodynamic effects: Clinical Effects: Clinical studies of up to 15 months duration were conducted to compare the IOP-lowering effect of Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation b.i.d. (dosed morning and bedtime) to individually- and concomitantly-administered 0.5% timolol and 2.0% dorzolamide in patients with glaucoma or ocular hypertension for whom concomitant therapy was considered appropriate in the trials. This included both untreated patients and patients inadequately controlled with timolol monotherapy. The majority of patients were treated with topical beta-blocker monotherapy prior to study enrollment. In an analysis of the combined studies, the IOP-lowering effect of Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation b.i.d. was greater than that of monotherapy with either 2% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP-lowering effect of Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation b.i.d. was equivalent to that of concomitant therapy with dorzolamide b.i.d. and timolol b.i.d. The IOP-lowering effect of Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation b.i.d. was demonstrated when measured at various time points throughout the day and this effect was maintained during long-term administration.
In an active-treatment-controlled, parallel, double-masked study in 261 patients with elevated intraocular pressure ≥22 mmHg in one or both eyes, Dorzolamide HCl/Timolol Maleate (Cosopt-S) had an IOP-lowering effect equivalent to that of Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation. The safety profile of Dorzolamide HCl/Timolol Maleate (Cosopt-S) was similar to Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation.
Paediatric population: A 3 month controlled study, with the primary objective of documenting the safety of 2% dorzolamide hydrochloride ophthalmic solution in children under the age of 6 years has been conducted. In this study, 30 patients under 6 and greater than or equal to 2 years of age whose IOP was not adequately controlled with monotherapy by dorzolamide or timolol received Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation in an open label phase. Efficacy in those patients has not been established. In this small group of patients, twice daily administration of Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation was generally well tolerated with 19 patients completing the treatment period and 11 patients discontinuing for surgery, a change in medication, or other reasons.
Cosopt/Cosopt-S: Pharmacokinetics: Dorzolamide Hydrochloride: Unlike oral carbonic anhydrase inhibitors, topical administration of dorzolamide hydrochloride allows for the active substance to exert its effects directly in the eye at substantially lower doses and therefore with less systemic exposure.
In clinical trials, this resulted in a reduction in IOP without the acid-base disturbances or alterations in electrolytes characteristic of oral carbonic anhydrase inhibitors.
When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic carbonic anhydrase inhibition following topical administration, active substance and metabolite concentrations in red blood cells (RBCs) and plasma and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates in RBCs during chronic dosing as a result of selective binding to CA-II while extremely low concentrations of free active substance in plasma are maintained. The parent active substance forms a single N-desethyl metabolite that inhibits CA-II less potently than the parent active substance but also inhibits a less active isoenzyme (CA-I). The metabolite also accumulates in RBCs where it binds primarily to CA-I. Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite is also excreted in urine. After dosing ends, dorzolamide washes out of RBCs nonlinearly, resulting in a rapid decline of active substance concentration initially, followed by a slower elimination phase with a half-life of about four months.
When dorzolamide was given orally to simulate the maximum systemic exposure after long term topical ocular administration, steady state was reached within 13 weeks. At steady state, there was virtually no free active substance or metabolite in plasma; CA inhibition in RBCs was less than that anticipated to be necessary for a pharmacological effect on renal function or respiration. Similar pharmacokinetic results were observed after chronic, topical administration of dorzolamide hydrochloride. However, some elderly patients with renal impairment (estimated CrCl 30-60 mL/min) had higher metabolite concentrations in RBCs, but no meaningful differences in carbonic anhydrase inhibition and no clinically significant systemic side effects were directly attributable to this finding.
Timolol Maleate: In a study of plasma active substance concentration in six subjects, the systemic exposure to timolol was determined following twice daily topical administration of timolol maleate ophthalmic solution 0.5%. The mean peak plasma concentration following morning dosing was 0.46 ng/mL and following afternoon dosing was 0.35 ng/mL.

Treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension, open-angle glaucoma, pseudoexfoliative glaucoma or other secondary open-angle glaucoma when concomitant therapy is appropriate.

Cosopt: The dose is one drop of DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) in the affected eye(s) two times daily.
When substituting DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) for another ophthalmic antiglaucoma agent(s), discontinue the other agent(s) after proper dosing on one day, and start DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) on the next day.
If another topical ophthalmic agent is being used, DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) and the other agent should be administered at least ten minutes apart.
Safety and efficacy in pediatric patients below the age of 2 years have not been established. (For information regarding use in pediatric patients ≥2 years of age see Use in Children under Precautions.)
When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in an increase in local activity.
Mode of Administration: The dose is one drop of DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) in the affected eye(s) two times daily.
Cosopt-S: Dosage: The dose is one drop of Dorzolamide HCl/Timolol Maleate (Cosopt-S) in the (conjunctival sac of the) affected eye(s) two times daily.
If another topical ophthalmic agent is being used, Dorzolamide HCl/Timolol Maleate (Cosopt-S) and the other agent should be administered at least ten minutes apart.
This medicinal product is a sterile solution that does not contain a preservative. The solution from one individual single dose container is to be used immediately after opening for administration to the affected eye(s). Since sterility cannot be maintained after the individual single dose container is opened, any remaining contents must be discarded immediately after administration.
Patients should be instructed to wash their hands before use and avoid allowing the container to come into contact with the eye or surrounding structures as this could cause injury to the eye (see Instructions for Use under Cautions for Usage).
Patients should also be instructed that ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.
When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity.
Administration: Since different shapes of the single-dose containers are available, patients should be informed of the correct handling of the single-dose container. Please see Instructions for use for shape-specific diagrams and instructions for use.
Paediatric population: Efficacy in paediatric patients has not been established.
Safety in paediatric patients below the age of 2 years has not been established (For information regarding safety in paediatric patients ≥2 and <6 years of age).

No data are available in humans in regard to overdose by accidental or deliberate ingestion of Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation or Dorzolamide HCl/Timolol Maleate (Cosopt-S).
Symptoms: There have been reports of inadvertent overdoses with timolol maleate ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest. The most common signs and symptoms to be expected with overdoses of dorzolamide are electrolyte imbalance, development of an acidotic state, and possibly central nervous system effects.
Only limited information is available with regard to human overdose by accidental or deliberate ingestion of dorzolamide hydrochloride. With oral ingestion, somnolence has been reported. With topical application the following have been reported: nausea, dizziness, headache, fatigue, abnormal dreams, and dysphagia.
Treatment: Treatment should be symptomatic and supportive. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Studies have shown that timolol does not dialyze readily.

DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT)/(Cosopt-S) is contraindicated in patients with: reactive airway disease, including bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease; sinus bradycardia, sick sinus syndrome, sino‑atrial block, second or third degree atrioventricular block not controlled with pacemaker, overt cardiac failure, cardiogenic shock; hypersensitivity to one or both active substances or to any of the excipients.
The previously mentioned are based on the components and are not unique to the combination (see Description).
Cosopt-S: Severe renal impairment (CrCl <30 mL/min) or hyperchloraemic acidosis.

Cosopt: As with other topically-applied ophthalmic agents, this drug may be absorbed systemically. The timolol component is a beta-blocker.
Therefore, the same types of adverse reactions found with systemic administration of beta-blockers may occur with topical administration.
Cardio-Respiratory Reactions: Because of the timolol maleate component, cardiac failure should be adequately controlled before beginning therapy with DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT). Patients with a history of cardiovascular disease, including cardiac failure, should be watched for signs of deterioration of these diseases, and pulse rates should be checked.
Due to its negative effect on conduction time, beta‑blockers should be given with caution to patients with first degree heart block.
Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and rarely death in association with cardiac failure, have been reported following administration of timolol maleate ophthalmic solution.
In patients with mild/moderate chronic obstructive pulmonary disease (COPD), DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) should be used with caution, and only if the potential benefit outweighs the potential risk.
Vascular Disorders: Patients with severe peripheral circulatory disturbance/disorders (e.g. severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.
Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus: Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blocking agents may mask the signs and symptoms of acute hypoglycemia.
Masking of Thyrotoxicosis: Beta-adrenergic blocking agents may mask certain clinical signs of hyperthyroidism (e.g., tachycardia). Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents which might precipitate a thyroid storm.
Surgical Anesthesia: The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.
Renal and Hepatic Impairment: DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) has not been studied in patients with severe renal impairment (CrCl < 30 milliliter/min). Because dorzolamide hydrochloride and its metabolite are excreted predominantly by the kidney, DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) is not recommended in such patients.
DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) has not been studied in patients with hepatic impairment and therefore should be used with caution in such patients.
Immunology and Hypersensitivity: As with other topically-applied ophthalmic agents, this drug may be absorbed systemically. The dorzolamide component is a sulfonamide. Therefore, the same types of adverse reactions found with systemic administration of sulfonamides may occur with topical administration, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs of serious reactions or hypersensitivity occur, discontinue use of this preparation.
In clinical studies, local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of dorzolamide hydrochloride ophthalmic solution. Some of these reactions had the clinical appearance and course of an allergic-type reaction that resolved upon discontinuation of drug therapy. Similar reactions have been reported with DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT). If such reactions are observed, discontinuation of treatment with DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) should be considered.
While taking β-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to accidental, diagnostic, or therapeutic repeated challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.
Concomitant Therapy: There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving oral and topical carbonic anhydrase inhibitors concomitantly. The concomitant administration of DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) and oral carbonic anhydrase inhibitors has not been studied and is not recommended.
Patients who are already receiving a beta-adrenergic blocking agent systemically and who are given DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta-blockade. The use of two topical beta-adrenergic blocking agents is not recommended.
Other: The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) has not been studied in patients with acute angle-closure glaucoma.
Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g., timolol, acetazolamide, dorzolamide) after filtration procedures.
There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Precautions should be used when prescribing DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) to this group of patients.
Contact Lens Use: DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) contains the preservative benzalkonium chloride, which may be deposited in soft contact lenses; therefore, DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) should not be administered while wearing these lenses. The lenses should be removed before application of the drops and not be reinserted earlier than 15 minutes after use.
Cosopt-S: Cardiovascular/Respiratory Reactions: Like other topically applied ophthalmic agents timolol is absorbed systemically. Due to beta- adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions seen with systemic beta-adrenergic blocking agents may occur. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see Dosage & Administration.
Cardiac disorders: In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension therapy with beta-blockers should be critically assessed and the therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions.
Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
Vascular disorders: Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.
Respiratory disorders: Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers.
Dorzolamide HCl/Timolol Maleate (Cosopt-S) should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.
Hepatic Impairment: This medicinal product has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.
Immunology and Hypersensitivity: As with other topically-applied ophthalmic agents, this medicinal product may be absorbed systemically. Dorzolamide contains a sulfonamido group, which also occurs in sulfonamides. Therefore, the same types of adverse reactions found with systemic administration of sulfonamides may occur with topical administration, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs of serious reactions or hypersensitivity occur, discontinue use of this preparation.
Local ocular adverse effects, similar to those observed with dorzolamide hydrochloride eye drops, have been seen with this medicinal product. If such reactions occur, discontinuation of Dorzolamide HCl/Timolol Maleate (Cosopt-S) should be considered.
While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens and may be unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.
Concomitant therapy: The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol is given to the patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended (see Interactions).
The use of dorzolamide and oral carbonic anhydrase inhibitors is not recommended.
Withdrawal of Therapy: As with systemic beta-blockers, if discontinuation of ophthalmic timolol is needed in patients with coronary heart disease, therapy should be withdrawn gradually.
Additional Effects of Beta-Blockade: Hypoglycaemia/diabetes: Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.
Beta-blockers may also mask the signs of hyperthyroidism. Abrupt withdrawal of beta-blocker therapy may precipitate a worsening of symptoms.
Corneal diseases: Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
Surgical anaesthesia: Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.
Therapy with beta-blockers may aggravate symptoms of myasthenia gravis.
Additional Effects of Carbonic Anhydrase Inhibition: Therapy with oral carbonic anhydrase inhibitors has been associated with urolithiasis as a result of acid-base disturbances, especially in patients with a prior history of renal calculi. Although no acid-base disturbances have been observed with Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation, urolithiasis has been reported infrequently. Because Dorzolamide HCl/Timolol Maleate (Cosopt-S) contains a topical carbonic anhydrase inhibitor that is absorbed systemically, patients with a prior history of renal calculi may be at increased risk of urolithiasis while using this medicinal product.
Other: The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. This medicinal product has not been studied in patients with acute angle-closure glaucoma.
Corneal oedema and irreversible corneal decompensation have been reported in patients with pre- existing chronic corneal defects and/or a history of intraocular surgery while using dorzolamide. There is an increased potential for developing corneal oedema in patients with low endothelial cell counts. Precautions should be used when prescribing Dorzolamide HCl/Timolol Maleate (Cosopt-S) to these groups of patients.
Choroidal detachment has been reported with administration of aqueous suppressant therapies (e.g. timolol, acetazolamide) after filtration procedures.
As with the use of other antiglaucoma medicines, diminished responsiveness to ophthalmic timolol maleate after prolonged therapy has been reported in some patients. However, in clinical studies in which 164 patients have been followed for at least three years, no significant difference in mean intraocular pressure has been observed after initial stabilization.
Contact Lens Use: This medicinal product has not been studied in patients wearing contact lenses.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. Possible side effects such as blurred vision may affect some patients' ability to drive and/or operate machinery.
Use in Children: Cosopt: The safety and efficacy of 2% dorzolamide hydrochloride ophthalmic solution has been established in a clinical study of children under the age of 6 years. In this study patients under 6 and greater than 2 years of age whose IOP was not controlled with monotherapy received DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT). In those patients DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) was generally well tolerated.

Cosopt: There are no adequate and well-controlled studies in pregnant women. DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether dorzolamide hydrochloride is excreted in human milk. Timolol maleate does appear in human milk. Because of the potential for serious adverse reactions on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pregnancy: Cosopt-S: Dorzolamide HCl/Timolol Maleate (Cosopt-S) should not be used during pregnancy.
Dorzolamide: No adequate clinical data in exposed pregnancies are available. In rabbits, dorzolamide produced teratogenic effect at maternotoxic doses.
Timolol: There are no adequate data for the use of timolol in pregnant women. Timolol should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see Dosage & Administration.
Epidemiological studies have not revealed malformative effects but show a risk for intra uterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. If this medicinal product is administered until delivery, the neonate should be carefully monitored during the first days of life.
Breast-feeding: It is not known whether dorzolamide is excreted in human milk. In lactating rats receiving dorzolamide, decreases in the body weight gain of offspring were observed.
Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce systemic absorption, see Dosage & Administration. If treatment with Dorzolamide HCl/Timolol Maleate (Cosopt-S) is required, then lactation is not recommended.

Cosopt: In clinical studies, DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) was generally well tolerated; no adverse experiences peculiar to this combination drug have been observed. Adverse experiences have been limited to those that were reported previously with dorzolamide hydrochloride and/or timolol maleate. In general, common adverse experiences were mild and did not cause discontinuation.
During clinical studies, 1035 patients were treated with DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT). Approximately 2.4% of all patients discontinued therapy with DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) because of local ocular adverse reactions. Approximately 1.2% of all patients discontinued because of local adverse reactions suggestive of allergy or hypersensitivity. The most frequently reported drug-related adverse effects were: ocular burning and stinging, taste perversion, corneal erosion, conjunctival injection, blurred vision, tearing, and ocular itching. Urolithiasis was reported rarely.
The following adverse reactions have been reported in post-marketing experience: dyspnea, respiratory failure, contact dermatitis, bradycardia, heart block, choroidal detachment following filtration surgery, nausea, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Cosopt-S: In a clinical study for Dorzolamide HCl/Timolol Maleate (Cosopt-S) the observed adverse reactions have been consistent with those that were reported previously with Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation, dorzolamide hydrochloride and/or timolol maleate.
During clinical studies, 1,035 patients were treated with Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation, approximately 2.4% of all patients discontinued therapy with Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation because of local ocular adverse reactions; approximately 1.2% of all patients discontinued because of local adverse reactions suggestive of allergy or hypersensitivity (such as lid inflammation and conjunctivitis).
Dorzolamide HCl/Timolol Maleate (Cosopt-S) has been shown to have a similar safety profile to Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation in a repeat dose double-masked, comparative study.
Like other topically applied ophthalmic medicines, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration.
The following adverse reactions have been reported with Dorzolamide HCl/Timolol Maleate (Cosopt-S) or one of its components either during clinical trials or during post-marketing experience: [Very Common: (≥1/10), Common: (≥1/100, <1/10), Uncommon: (≥1/1000, <1/100), and Rare: (≥1/10,000, <1/1000), Not known (cannot be estimated from the available data)]. (See Table A and B.)

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Specific drug interaction studies have not been performed with DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT)/(COSOPT-S).
Cosopt: In clinical studies, DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) was used concomitantly with the following systemic medications without evidence of adverse interactions: ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory drugs including aspirin, and hormones (e.g., estrogen, insulin, thyroxine).
However, the potential exists for additive effects and production of hypotension and/or marked bradycardia when timolol maleate ophthalmic solution is administered together with oral calcium channel blockers, catecholamine-depleting drugs, antiarrhythmics, parasympathomimetics or beta-adrenergic blocking agents.
Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, SSRIs) and timolol.
The dorzolamide component of DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT) is a carbonic anhydrase inhibitor and although administered topically, is absorbed systemically. In clinical studies, dorzolamide hydrochloride ophthalmic solution was not associated with acid-base disturbances. However, these disturbances have been reported with oral carbonic anhydrase inhibitors and have in some instances, resulted in drug interactions (e.g., toxicity associated with high-dose salicylate therapy). Therefore, the potential for such drug interactions should be considered in patients receiving DORZOLAMIDE HCl + TIMOLOL MALEATE (COSOPT).
Oral β-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.
Cosopt-S: In a clinical study, this medicinal product was used concomitantly with the following systemic medications without evidence of adverse interactions: ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory medicines including aspirin, and hormones (e.g., estrogen, insulin, thyroxine).
There is a potential for additive effects resulting in hypotension and/or marked bradycardia when ophthalmic beta-blockers solution is administered concomitantly with oral calcium channel blockers, catecholamine-depleting medicines or beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, narcotics, and monoamine oxidase (MAO) inhibitors.
Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.
Although Dorzolamide HCl/Timolol Maleate (Cosopt) preserved formulation alone has little or no effect on pupil size, mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.
Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents.
Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.
Precaution for concomitant use with omidenepag isopropyl.

Cosopt-S: Instructions for use: Open the foil sachet which contains the individual single-dose containers.
Write the date of first opening on the sachet.
Every time the patient uses Dorzolamide HCl/Timolol Maleate (Cosopt-S): 1. Wash the patient's hands.
2. Take the strip of containers from the sachet.
3. Detach one single-dose container from the strip.
4. Put the remaining strip back in the sachet and fold the edge to close the sachet.
5. To open the container, twist off the tab.
6. Hold the container between the thumb and index finger. Note that the tip of the container must not show more than 5 mm above the edge of the index finger.
7. Tilt the head backwards or lie down. Place a hand on the forehead. The index finger should be aligned with the eyebrow or resting on the bridge of the nose. Look up. Pull the lower eyelid downwards with the other hand. Do not allow any part of the container to touch the eye or any area around the eye. Gently squeeze the container to let one drop fall into the space between the lid and the eye. Do not blink while applying the drop to the eye. Each single-dose container contains enough solution for both eyes.
8. Close the eye and press the inner corner of the eye with a finger for about two minutes. This helps to stop the medicine from getting into the rest of the body.
9. Wipe off any excess solution from the skin around the eye.
If the doctor has told the patient to use drops in both eyes, repeat steps 7 to 9 for the other eye.
After putting the drop into the eye(s), throw away the used single-dose container even if there is solution remaining to avoid contamination of the preservative free solution.

Cosopt: Store at temperatures not exceeding 25°C. Protect from light.
Cosopt-S: Store at temperatures not exceeding 30°C. Store in the original package in order to protect from light.
Dorzolamide HCl/Timolol Maleate (Cosopt-S) should be used no longer than 1 month after first opening the sachet. Discard any unused single dose containers after that time.

Antiglaucoma Preparations

S01ED51 - timolol, combinations ; Belongs to the class of beta blocking agents. Used in the treatment of glaucoma.
S01EC03 - dorzolamide ; Belongs to the class of carbonic anhydrase inhibitors. Used in the treatment of glaucoma.

Rx