DailyMed Label: Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution

DailyMed Label: Dorzolamide Hydrochloride and Timolol Maleate ophthalmic

2023

DailyMed Prescription

Dorzolamide Hydrochloride and Timolol Maleate ophthalmic

Dorzolamide Hydrochloride and Timolol Maleate

A-S Medication Solutions

NDC: 50090-6814

NDC: 50090-6814

NDC: 50090-6814

Dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP is the combination of a topical carbonic anhydrase inhibitor and a topical beta-adrenergic receptor blocking agent. Dorzolamide hydrochloride USP is described chemically as: (4 S-trans )-4-(ethylamino)-5,6-dihydro-6- methyl-4 H -thieno[2,3- b ]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride. Dorzolamide hydrochloride is optically active. The specific rotation is: [α]        25°C    (C=1, water) = ~ -17°.             405nm Its molecular formula is C 10 H 16 N 2 O 4 S 3 •HCl and its structural formula is:      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 C 13 H 24 N 4 O 3 S•C 4 H 4 O 4 and its structural formula is:   Timolol maleate USP 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. Dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP is supplied as a sterile, isotonic, buffered, clear, colorless to nearly colorless and slightly viscous solution. The pH of the solution is approximately 5.65, and the osmolarity is 242 to 323 mOsM. Each mL of dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP contains 20 mg dorzolamide (22.26 mg of dorzolamide hydrochloride USP) and 5 mg timolol (6.83 mg timolol maleate USP). Inactive ingredients are Mannitol, Hydroxyethyl cellulose, Sodium hydroxide, Tri Sodium citrate Dihydrate, and water for injection. Benzalkonium chloride 0.0075% is added as a preservative.

Dorzolamide hydrochloride and timolol maleate ophthalmic solution is indicated for the reduction of elevated intraocular pressure (IOP) 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 dorzolamide hydrochloride and timolol maleate ophthalmic solution administered twice a day was slightly less than that seen with the concomitant administration of 0.5% timolol administered twice a day and 2% dorzolamide administered three times a day [see Clinical Studies (14) ].

The dose is one drop of dorzolamide hydrochloride and timolol maleate ophthalmic solution 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 five minutes apart [see Drug Interactions (7.3) ].

Ophthalmic solution containing dorzolamide 20 mg/mL (2%) equivalent to 22.26 mg/mL of dorzolamide hydrochloride and timolol 5 mg/mL (0.5%) equivalent to 6.83 mg/mL of timolol maleate.

Dorzolamide hydrochloride and timolol maleate ophthalmic solution is contraindicated in patients with: Bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.( 4.1 ) Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, cardiogenic shock. ( 4.2 ) Hypersensitivity to any component of this product. ( 4.3 , 5.3 )

Potentiation of Respiratory Reactions Including Asthma ( 5.1 ) Cardiac Failure ( 5.2 ) Sulfonamide Hypersensitivity ( 5.3 ) Obstructive Pulmonary Disease ( 5.4 ) Increased Reactivity to Allergens ( 5.5 ) Potentiation of Muscle Weakness ( 5.6 ) Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus ( 5.7 ) Masking of Thyrotoxicosis ( 5.8 ) Renal and Hepatic Impairment ( 5.9 ) Impairment  of  Beta-Adrenergically  Mediated  Reflexes  During Surgery ( 5.10 )

The most frequently reported adverse reactions 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 to 15% of patients. (

Potential additive effect of oral carbonic anhydrase inhibitor with dorzolamide hydrochloride and timolol maleate ophthalmic solution. ( 7.1 ) Potential acid-base and electrolyte disturbances. ( 7.2 ) Concomitant use with systemic beta-blockers may  potentiate systemic beta-blockade. ( 7.3 ) Oral or intravenous calcium antagonists may cause atrioventricular conduction disturbances, left ventricular failure, and hypotension. ( 7.4 ) Catecholamine-depleting drugs may have additive effects  and produce hypotension and/or marked bradycardia. ( 7.5 ) Digitalis and calcium antagonists, may have additive effects in prolonging atrioventricular conduction time. ( 7.6 ) CYP2D6 inhibitors may potentiate systemic beta-blockade. ( 7.7 )

Teratogenic Effects . Developmental toxicity studies with dorzolamide hydrochloride in rabbits at oral doses of ≥2.5 mg/kg/day (37 times the recommended human ophthalmic dose) revealed malformations of the vertebral bodies. These malformations occurred at doses that caused metabolic acidosis with decreased body weight gain in dams and decreased fetal weights. No treatment-related malformations were seen at 1 mg/kg/day (15 times the recommended human ophthalmic dose). Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity. There are no adequate and well-controlled studies in pregnant women. Dorzolamide hydrochloride and timolol maleate ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Product: 50090-6814 NDC: 50090-6814-0 10 mL in a BOTTLE / 1 in a CARTON

Dorzolamide hydrochloride and timolol maleate ophthalmic solution 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 1   and  beta 2   (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 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 dorzolamide hydrochloride and timolol maleate ophthalmic solution twice daily (dosed morning and bedtime) to individually and concomitantly administered 0.5% timolol twice daily and 2% dorzolamide twice and three times daily. The IOP-lowering effect of dorzolamide hydrochloride and timolol maleate ophthalmic solution twice daily was greater (1 to 3 mmHg) than that of monotherapy with either 2% dorzolamide three times daily or 0.5% timolol twice daily. The IOP-lowering effect of dorzolamide hydrochloride and timolol maleate ophthalmic solution twice daily was approximately 1 mmHg less than that of concomitant therapy with 2% 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 dorzolamide hydrochloride and timolol maleate ophthalmic solution twice daily was consistent during the 12 month follow-up period.