Dorzolamide Hydrochloride and Timolol Maleate

Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) is contraindicated in patients with bronchial asthma, a history of bronchial asthma, or severe chronic obstructive pulmonary disease [see Warnings and Precautions (5.1)].

Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) is contraindicated in patients with sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, and cardiogenic shock [see Warnings and Precautions (5.2)].

Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) is contraindicated in patients who are hypersensitive to any component of this product [see Warnings and Precautions (5.3)].

Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) contains timolol maleate, a beta-adrenergic blocking agent; and although administered topically, is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate [see Contraindications (4.1) and Patient Counseling Information (17.1)].

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 continued depression of the myocardium with betablocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) should be discontinued [see Contraindications (4.2) and Patient Counseling Information (17.2)].

Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) contains dorzolamide, a sulfonamide; and although administered topically, it is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free). Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is readministered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation [see Contraindications (4.3) and Patient Counseling Information (17.3)].

Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which dorzolamide hydrochloride and timolol maleate ophthalmic solution (preservative free) is contraindicated) should, in general, not receive beta-blocking agents, including Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) [see Contraindications (4.1) and Patient Counseling Information (17.1)].

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.

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.

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 receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.

Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism.

Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm.

Dorzolamide has not been studied in patients with severe renal impairment (CrCl <30 mL/min). Because dorzolamide and its metabolite are excreted predominantly by the kidney, Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) is not recommended in such patients. Dorzolamide has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.

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 betaadrenergically 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.

Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Caution should be used when prescribing dorzolamide hydrochloride and timolol maleate ophthalmic solution (preservative free) to this group of patients.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions have been identified during post-approval use of COSOPT or Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: bradycardia, cardiac failure, cerebral vascular accident, chest pain, choroidal detachment following filtration surgery, depression, diarrhea, dry mouth, dyspnea, heart block, hypotension, iridocyclitis, myocardial infarction, nasal congestion, Stevens-Johnson syndrome, toxic epidermal necrolysis, paresthesia, photophobia, respiratory failure, skin rashes, urolithiasis, and vomiting.

There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free). The concomitant administration of dorzolamide hydrochloride and timolol maleate ophthalmic solution (preservative free) and oral carbonic anhydrase inhibitors is not recommended.

Although acid-base and electrolyte disturbances were not reported in the clinical trials with dorzolamide hydrochloride ophthalmic solution, 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 Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free).

Patients who are receiving a beta-adrenergic blocking agent orally and Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical betaadrenergic blocking agents is not recommended.

Caution should be used in the coadministration of beta-adrenergic blocking agents, such as Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free), and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, coadministration should be avoided.

Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, or postural hypotension.

The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

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.

Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate.

It is not known whether dorzolamide is excreted in human milk. Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of dorzolamide hydrochloride ophthalmic solution and timolol maleate ophthalmic solution have been established when administered individually in pediatric patients aged 2 years and older. Use of these drug products in these children is supported by evidence from adequate and well-controlled studies in children and adults. Safety and efficacy in pediatric patients below the age of 2 years have not been established.

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP (preservative free) is the combination of a topical carbonic anhydrase inhibitor and a topical beta-adrenergic receptor blocking agent. Dorzolamide hydrochloride USP is described chemically as: (4S, 6S)-4-(Ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulphonamide 7,7-dioxide monohydrochloride. Dorzolamide hydrochloride is optically active. The specific rotation is:

[α] 25°C (C=1, water) = ~ -17°.

405 nm

Its molecular formula is C₁₀H₁₆N₂O₄S₃∙ HCl and its structural formula is:

Chemical Structure

Dorzolamide hydrochloride USP 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 USP is described chemically as: (-)-1-(tert-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 C₁₃H₂₄N₄O₃S∙C₄H₄O₄ and its structural formula is:

Chemical Structure

Timolol maleate USP has a molecular weight of 432.49. It is a white to practically white powder which is soluble in water, methanol, and alcohol. Timolol maleate is stable at room temperature. Dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP (preservative free) is supplied as a sterile, clear, colorless to nearly colorless, isotonic, buffered, slightly viscous, aqueous solution. The pH of the solution is approximately 5.65, and the osmolality is 242 to 323 mOsM. Each mL of dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP (preservative free) contains 20 mg dorzolamide (22.26 mg of dorzolamide hydrochloride USP) and 5 mg timolol (6.83 mg timolol maleate USP). Inactive ingredients are hydroxyethyl cellulose, mannitol, sodium citrate dihydrate, sodium hydroxide, and water for injection.

Dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP (preservative free) does not contain a preservative.

Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) 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 beta₁ and beta₂ (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 dorzolamide hydrochloride and timolol maleate ophthalmic solution (preservative free) administered twice daily results in additional intraocular pressure reduction compared to either component administered alone, but the reduction is not as much as when dorzolamide administered three times daily and timolol twice daily are administered concomitantly. [See Clinical Studies (14).]

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) in vivo (mouse) cytogenetic assay; (2) in vitro chromosomal aberration assay; (3) alkaline elution assay; (4) V-79 assay; and (5) Ames test. Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/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.

Clinical studies of 3 to 15 months duration were conducted to compare the IOP-lowering effect over the course of the day of COSOPT twice daily (dosed morning and bedtime) to individually- and concomitantly-administered 0.5% timolol twice daily and 2.0% dorzolamide twice and three times daily. The IOP-lowering effect of COSOPT twice daily was greater (1 to 3 mmHg) than that of monotherapy with either 2.0% dorzolamide three times daily or 0.5% timolol twice daily. The IOP lowering effect of COSOPT twice daily was approximately 1 mmHg less than that of concomitant therapy with 2.0% dorzolamide three times daily and 0.5% timolol twice daily.

Open-label extensions of two studies were conducted for up to 12 months. During this period, the IOP lowering effect of COSOPT twice daily was consistent during the 12 month follow-up period.

In an active-treatment controlled, parallel, double-masked study in 261 patients with elevated intraocular pressure ≥22 mmHg in one or both eyes, Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) had an IOP-lowering effect equivalent to that of COSOPT.

Store Dorzolamide hydrochloride and Timolol maleate Ophthalmic Solution, USP (preservative free) at 20° to 25°C (68° to 77°F) [See USP controlled room temperature]. Do not freeze.

Store in the original pouch. After the pouch is opened, store the remaining single-use containers in the foil pouch to protect from light. Write down the date you open the foil pouch in the space provided on the pouch. Discard any unused containers 15 days after first opening the pouch.

Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) may cause severe worsening of asthma and COPD symptoms including death due to bronchospasm. Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease should be advised not to take this product. [See Contraindications (4.1).]

Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) may cause worsening of cardiac symptoms. Patients with sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be advised not to take this product. [See Contraindications (4.2).]

Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) 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 and seek their physician's advice. [See Warnings and Precautions (5.3).]

Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) is a sterile solution that does not contain a preservative. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the individual unit is opened, the remaining contents should be discarded immediately after administration.

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 this product.

If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.