Dorzolamide HCl and Timolol Maleate

DORZOLAMIDE HCL AND TIMOLOL MALEATE- dorzolamide hydrochloride and timolol maleate solution/ drops
Akorn, Inc.

1 INDICATIONS AND USAGE

Dorzolamide Hydrochloride-Timolol Maleate 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-timolol maleate 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) ].

2 DOSAGE AND ADMINISTRATION

The dose is one drop of Dorzolamide Hydrochloride-Timolol Maleate 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) ].

3 DOSAGE FORMS AND STRENGTHS

Solution containing 20 mg/mL dorzolamide (22.26 mg of dorzolamide hydrochloride) and 5 mg/mL timolol (6.83 mg timolol maleate).

4 CONTRAINDICATIONS

4.1 Asthma, COPD

Dorzolamide hydrochloride-timolol maleate is contraindicated in patients with bronchial asthma, a history of bronchial asthma, or severe chronic obstructive pulmonary disease [see Warnings and Precautions (5.1) ].

4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock

Dorzolamide hydrochloride-timolol maleate 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) ].

4.3 Hypersensitivity

Dorzolamide hydrochloride-timolol maleate is contraindicated in patients who are hypersensitive to any component of this product [see Warnings and Precautions (5.3) ].

5 WARNINGS AND PRECAUTIONS

5.1 Potentiation of Respiratory Reactions Including Asthma

Dorzolamide hydrochloride-timolol maleate 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)].

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 beta-blocking 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-timolol maleate should be discontinued [see Contraindications (4.2) and Patient Counseling Information (17.2)].

5.3 Sulfonamide Hypersensitivity

Dorzolamide hydrochloride-timolol maleate 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-timolol maleate. 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)].

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-timolol maleate is contraindicated) should, in general, not receive beta-blocking agents, including dorzolamide hydrochloride-timolol maleate [see Contraindications (4.1) and Patient Counseling Information (17.1)].

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 <30 mL/min). Because dorzolamide and its metabolite are excreted predominantly by the kidney, dorzolamide hydrochloride-timolol maleate 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 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.

5.11 Corneal Endothelium

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-timolol maleate to this group of patients.

5.12 Bacterial Keratitis

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 Patient Counseling Information (17.4) ].

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