DORZOLAMIDE Drug Interactions: What You Need to Know

INTERACTIONS Potential additive effect of oral carbonic anhydrase inhibitor with Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free). ( 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 )

7.1 Oral Carbonic Anhydrase Inhibitors 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.

7.2 High-Dose Salicylate Therapy 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).

7.3 Beta-Adrenergic Blocking Agents 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.

7.4 Calcium Antagonists 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.

7.5 Catecholamine-Depleting Drugs 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.

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

7.7 CYP2D6 Inhibitors 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.

7.8 Clonidine 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.

Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) 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 )

4.1 Asthma, COPD 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>.

4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.

4.3 Hypersensitivity 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span>.

AND PRECAUTIONS 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 )

5.1 Potentiation of Respiratory Reactions Including Asthma 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 <span class="opacity-50 text-xs">[see Contraindications (4.1) and Patient Counseling Information (17.1) ]</span>.

5.2 Cardiac Failure 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 <span class="opacity-50 text-xs">[see Contraindications (4.2) and Patient Counseling Information (17.2) ]</span>.

5.3 Sulfonamide Hypersensitivity 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 <span class="opacity-50 text-xs">[see Contraindications (4.3) and Patient Counseling Information (17.3) ]</span>.

5.4 Obstructive Pulmonary Disease 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) <span class="opacity-50 text-xs">[see Contraindications (4.1) and Patient Counseling Information (17.1) ]</span>.

5.5 Increased Reactivity to Allergens 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.

5.6 Potentiation of Muscle Weakness 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.

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

5.8 Masking of Thyrotoxicosis 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.

5.9 Renal and Hepatic Impairment Dorzolamide has not been studied in patients with severe renal impairment (CrCl &lt;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.

5.10 Impairment of Beta-Adrenergically Mediated Reflexes During Surgery 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