Cosopt Information
Cosopt () Description
Cosopt () (dorzolamide hydrochloride-timolol maleate ophthalmic solution) is the combination of a topical carbonic anhydrase inhibitor and a topical beta-adrenergic receptor blocking agent.
Dorzolamide hydrochloride is described chemically as: (4 )-4-(ethylamino)-5,6-dihydro-6-methyl-4-thieno[2,3-]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride. Dorzolamide hydrochloride is optically active. The specific rotation is:
[α] 25°C (C=1, water) = ~ -17°.
405 nm
Its empirical formula is CHNOS•HCl and its structural formula is:
Dorzolamide hydrochloride has a molecular weight of 360.91. It is a white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol.
Timolol maleate is described chemically as: (-)-1-(-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer. The optical rotation of timolol maleate is:
[α] 25°C in 1N HCl (C=5) = -12.2° (-11.7° to -12.5°).
405 nm
Its molecular formula is CHNOS•CHO and its structural formula is:
Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is soluble in water, methanol, and alcohol. Timolol maleate is stable at room temperature.
Cosopt () is supplied as a sterile, isotonic, buffered, slightly viscous, aqueous solution. The pH of the solution is approximately 5.65, and the osmolarity is 242-323 mOsM. Each mL of Cosopt () contains 20 mg dorzolamide (22.26 mg of dorzolamide hydrochloride) and 5 mg timolol (6.83 mg timolol maleate). Inactive ingredients are sodium citrate, hydroxyethyl cellulose, sodium hydroxide, mannitol, and water for injection. Benzalkonium chloride 0.0075% is added as a preservative.
Cosopt () Clinical Pharmacology
Cosopt () is comprised of two components: dorzolamide hydrochloride and timolol maleate. Each of these two components decreases elevated intraocular pressure, whether or not associated with glaucoma, by reducing aqueous humor secretion. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous field loss and optic nerve damage.
Dorzolamide hydrochloride is an 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 beta and beta (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity. The combined effect of these two agents administered as Cosopt () b.i.d. results in additional intraocular pressure reduction compared to either component administered alone, but the reduction is not as much as when dorzolamide t.i.d. and timolol b.i.d. are administered concomitantly (see ).
Clinical studies of 3 to 15 months duration were conducted to compare the IOP-lowering effect over the course of the day of Cosopt () b.i.d. (dosed morning and bedtime) to individually- and concomitantly-administered 0.5% timolol (b.i.d.) and 2.0% dorzolamide (b.i.d. and t.i.d.). The IOP-lowering effect of Cosopt () b.i.d. was greater (1-3 mmHg) than that of monotherapy with either 2.0% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP-lowering effect of Cosopt () b.i.d. was approximately 1 mmHg less than that of concomitant therapy with 2.0% dorzolamide t.i.d. and 0.5% timolol b.i.d.
Open-label extensions of two studies were conducted for up to 12 months. During this period, the IOP-lowering effect of Cosopt () b.i.d. was consistent during the 12 month follow-up period.
Cosopt () Indications And Usage
Cosopt () is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-blockers (failed to achieve target IOP determined after multiple measurements over time). The IOP-lowering of Cosopt () b.i.d. was slightly less than that seen with the concomitant administration of 0.5% timolol b.i.d. and 2.0% dorzolamide t.i.d. (see ).
Cosopt () Contraindications
Cosopt () is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease (see ); (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure (see ); (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.
Cosopt () Warnings
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure.
In Patients Without a History of Cardiac Failure
The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor blocking agents have experienced protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents.
If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.
Cosopt () Precautions
Dorzolamide has not been studied in patients with severe renal impairment (CrCl
Dorzolamide has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.
While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.
In clinical studies, local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of Cosopt () . Many of these reactions had the clinical appearance and course of an allergic-type reaction that resolved upon discontinuation of drug therapy. If such reactions are observed, Cosopt () should be discontinued and the patient evaluated before considering restarting the drug. (See .)
The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Cosopt () has not been studied in patients with acute angle-closure glaucoma.
Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol).
Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.
There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. (See .)
There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Precautions should be used when prescribing Cosopt () to this group of patients.
Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be advised not to take this product. (See .)
Cosopt () contains dorzolamide (which is a sulfonamide) and, although administered topically, is absorbed systemically. Therefore the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration, including severe skin reactions. Patients should be advised that if serious or unusual reactions or signs of hypersensitivity occur, they should discontinue the use of the product (see ).
Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis and lid reactions, they should discontinue use and seek their physician's advice.
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.
Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, 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. (See .)
Patients also should be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container.
If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart.
Patients should be advised that Cosopt () contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following administration of Cosopt () .
Carbonic anhydrase inhibitors:
Acid-base disturbances:
Beta-adrenergic blocking agents:
Calcium antagonists:
Catecholamine-depleting drugs:
Digitalis and calcium antagonists:
CYP2D6 inhibitors:
Clonidine:
Injectable Epinephrine:
PRECAUTIONS, General, Anaphylaxis
In a two-year study of dorzolamide hydrochloride administered orally to male and female Sprague-Dawley rats, urinary bladder papillomas were seen in male rats in the highest dosage group of 20 mg/kg/day (250 times the recommended human ophthalmic dose). Papillomas were not seen in rats given oral doses equivalent to approximately 12 times the recommended human ophthalmic dose. No treatment-related tumors were seen in a 21-month study in female and male mice given oral doses up to 75 mg/kg/day (~900 times the recommended human ophthalmic dose).
The increased incidence of urinary bladder papillomas seen in the high-dose male rats is a class-effect of carbonic anhydrase inhibitors in rats. Rats are particularly prone to developing papillomas in response to foreign bodies, compounds causing crystalluria, and diverse sodium salts.
No changes in bladder urothelium were seen in dogs given oral dorzolamide hydrochloride for one year at 2 mg/kg/day (25 times the recommended human ophthalmic dose) or monkeys dosed topically to the eye at 0.4 mg/kg/day (~5 times the recommended human ophthalmic dose) for one year.
In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Similar differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the maximum recommended human ophthalmic dose.
In a lifetime oral study of timolol maleate in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/kg/day, (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose). In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.
The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.
The following tests for mutagenic potential were negative for dorzolamide: (1) (mouse) cytogenetic assay; (2) chromosomal aberration assay; (3) alkaline elution assay; (4) V-79 assay; and (5) Ames test.
Timolol maleate was devoid of mutagenic potential when tested (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in a neoplastic cell transformation assay (up to 100 μg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 μg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA100, no consistent dose response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.
Reproduction and fertility studies in rats with either timolol maleate or dorzolamide hydrochloride demonstrated no adverse effect on male or female fertility at doses up to approximately 100 times the systemic exposure following the maximum recommended human ophthalmic dose.
Cosopt () Adverse Reactions
Cosopt () was evaluated for safety in 1035 patients with elevated intraocular pressure treated for open-angle glaucoma or ocular hypertension. Approximately 5% of all patients discontinued therapy with Cosopt () because of adverse reactions. The most frequently reported adverse events were taste perversion (bitter, sour, or unusual taste) or ocular burning and/or stinging in up to 30% of patients. Conjunctival hyperemia, blurred vision, superficial punctate keratitis or eye itching were reported between 5-15% of patients. The following adverse events were reported in 1-5% of patients: abdominal pain, back pain, blepharitis, bronchitis, cloudy vision, conjunctival discharge, conjunctival edema, conjunctival follicles, conjunctival injection, conjunctivitis, corneal erosion, corneal staining, cortical lens opacity, cough, dizziness, dryness of eyes, dyspepsia, eye debris, eye discharge, eye pain, eye tearing, eyelid edema, eyelid erythema, eyelid exudate/scales, eyelid pain or discomfort, foreign body sensation, glaucomatous cupping, headache, hypertension, influenza, lens nucleus coloration, lens opacity, nausea, nuclear lens opacity, pharyngitis, post-subcapsular cataract, sinusitis, upper respiratory infection, urinary tract infection, visual field defect, vitreous detachment.
The following adverse events have occurred either at low incidence (
Other adverse reactions that have been reported with the individual components are listed below:
The following additional adverse effects have been reported in clinical experience with ORAL timolol maleate or other ORAL beta-blocking agents and may be considered potential effects of ophthalmic timolol maleate: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Extremity pain, decreased exercise tolerance, weight loss; Worsening of arterial insufficiency, vasodilatation; Gastrointestinal pain, hepatomegaly, mesenteric arterial thrombosis, ischemic colitis; Nonthrombocytopenic purpura; thrombocytopenic purpura, agranulocytosis; Hyperglycemia, hypoglycemia; Pruritus, skin irritation, increased pigmentation, sweating; Arthralgia; Vertigo, local weakness, diminished concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics; Rales, bronchial obstruction; Urination difficulties.
Cosopt () Overdosage
There are no human data available on overdosage with Cosopt () .
Symptoms consistent with systemic administration of beta-blockers or carbonic anhydrase inhibitors may occur, including electrolyte imbalance, development of an acidotic state, dizziness, headache, shortness of breath, bradycardia, bronchospasm, cardiac arrest and possible central nervous system effects. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored (see also ).
A study of patients with renal failure showed that timolol did not dialyze readily.
Cosopt () Dosage And Administration
The dose is one drop of Cosopt () in the affected eye(s) two times daily.
If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart (see also ).
Cosopt () How Supplied
Cosopt () Ophthalmic Solution is a clear, colorless to nearly colorless, slightly viscous solution.
No. 3628 — Cosopt () Ophthalmic Solution is supplied in an OCUMETER PLUS container, a white, translucent, HDPE plastic ophthalmic dispenser with a controlled drop tip and a white polystyrene cap with dark blue label as follows:
Cosopt () Instructions For Use
Please follow these instructions carefully when using Cosopt () . Use Cosopt () as prescribed by your doctor.
WARNING: Keep out of reach of children.
If you have any questions about the use of Cosopt () , please consult your doctor.
Manuf. for: Merck Sharp & Dohme Corp., a subsidiary of Whitehouse Station, NJ 08889, USA
By: Laboratories Merck Sharp & Dohme-Chibret 63963 Clermont-Ferrand Cedex 9, France
Issued December 2009
9711305
219A-12/09 516149Z
Cosopt () Patient Package Insert
Read this information before you start using Cosopt () and each time you refill your prescription. This is in case any information has changed. This leaflet provides a summary of certain information about Cosopt () . Your doctor or pharmacist can give you more complete information about Cosopt () . This leaflet does not take the place of careful discussions with your doctor. You and your doctor should discuss Cosopt () when you start using your medicine and at regular checkups. Only your doctor can prescribe Cosopt () for you.
Cosopt () This Is A Representative Sample Of The Packaging. Please See How Supplied Section For A Complete List Of Available Packaging. Principal Display Panel - Carton Ml
NDC 0006-3628-36
10 mL OCUMETER® PLUSOPHTHALMIC DISPENSERSTERILE OPHTHALMIC SOLUTION
Cosopt () ®(DORZOLAMIDE HYDROCHLORIDE-TIMOLOL MALEATE OPHTHALMIC SOLUTION)
(Dorzolamide Hydrochloride 22.3 mg/mLTimolol Maleate 6.8 mg/mL)
Rx only
Mfg. for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC.Whitehouse Station, NJ 08889, USA
By: Laboratories Merck Sharp & Dohme-Chibret63963 Clermont-Ferrand Cedex 9, FranceMade in France
9358903
