TIMOLOL Drug Interactions: What You Need to Know

INTERACTIONS

• Concomitant use with systemic beta-blockers may potentiate systemic beta-blockade. ( 7.1 )
• Oral or intravenous calcium antagonists may cause atrioventricular conduction disturbances, left ventricular failure, and hypotension. ( 7.2 )
• Catecholamine-depleting drugs may have additive effects and produce hypotension and/or marked bradycardia. ( 7.3 )
• Digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. ( 7.4 )
• Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol. ( 7.5 )

7.1 Beta-Adrenergic Blocking Agents Patients who are receiving a beta-adrenergic blocking agent orally and Timolol Maleate Ophthalmic Solution 0.5% should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended.

7.2 Calcium Antagonists Caution should be used in the co-administration of beta-adrenergic blocking agents, such as Timolol Maleate Ophthalmic Solution 0.5%, and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided.

7.3 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.

7.4 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.

7.5 CYP2D6 Inhibitors Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine) and timolol.

7.6 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.

7.1 Beta-Adrenergic Blocking Agents Patients who are receiving a beta-adrenergic blocking agent orally and Timolol Maleate Ophthalmic Solution 0.5% should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended.

7.2 Calcium Antagonists Caution should be used in the co-administration of beta-adrenergic blocking agents, such as Timolol Maleate Ophthalmic Solution 0.5%, and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided.

7.3 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.

7.4 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.

7.5 CYP2D6 Inhibitors Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine) and timolol.

7.6 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.

4 CONTRAINDICATIONS

• Bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease ( 4.1 , 5.1 , 5.3 )
• Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, cardiogenic shock ( 4.2 , 5.2 )
• Hypersensitivity to any component of this product ( 4.3 )

4.1 Asthma, COPD Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients with bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.3 )]</span>.

4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients with sinus bradycardia; second or third degree atrioventricular block; overt cardiac failure; cardiogenic shock <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> .

4.3 Hypersensitivity Reactions Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this product in the past.

4.1 Asthma, COPD Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients with bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.3 )]</span>.

4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients with sinus bradycardia; second or third degree atrioventricular block; overt cardiac failure; cardiogenic shock <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> .

4.3 Hypersensitivity Reactions Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this product in the past.

AND PRECAUTIONS Potentiation of Respiratory Reactions Including Asthma ( 5.1 )

Cardiac

Failure ( 5.2 )

Obstructive Pulmonary

Disease ( 5.3 )

Increased

Reactivity to Allergens ( 5.4 ) Potentiation of Muscle Weakness ( 5.5 ) Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus ( 5.6 ) Masking of Thyrotoxicosis ( 5.7 )

5.1 Potentiation of Respiratory Reactions Including Asthma Timolol Maleate Ophthalmic Solution contains timolol maleate; and although administered topically, it can be absorbed systemically. Therefore, the same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac 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 )]</span>.

5.2 Cardiac Failure Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition of 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, Timolol Maleate Ophthalmic Solution should be discontinued <span class="opacity-50 text-xs">[see Contraindications ( 4.2 )]</span>.

5.3 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 Timolol Maleate Ophthalmic Solution is contraindicated] should, in general, not receive beta-blocking agents, including Timolol Maleate Ophthalmic Solution <span class="opacity-50 text-xs">[see Contraindications ( 4.1 )]</span>.

5.4 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.

5.5 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.

5.6 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.

5.7 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.

5.8 Contamination of Topical Ophthalmic Products After Use 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 <span class="opacity-50 text-xs">[see Patient Counseling Information ( 17 )]</span>.

5.9 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.

5.10 Angle-Closure Glaucoma In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This may require constricting the pupil. Timolol maleate has little or no effect on the pupil.

Timolol Maleate Ophthalmic

Solution should not be used alone in the treatment of angle-closure glaucoma.

5.11 Cerebrovascular Insufficiency Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Timolol Maleate Ophthalmic Solution, alternative therapy should be considered.

5.12 Choroidal Detachment Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol).

5.13 Contact Lens Use Timolol Maleate Ophthalmic Solution contains benzalkonium chloride, an anti-microbial preservative 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 Timolol Maleate Ophthalmic Solution administration.

5.1 Potentiation of Respiratory Reactions Including Asthma Timolol Maleate Ophthalmic Solution contains timolol maleate; and although administered topically, it can be absorbed systemically. Therefore, the same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac 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 )]</span>.

5.2 Cardiac Failure Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition of 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, Timolol Maleate Ophthalmic Solution should be discontinued <span class="opacity-50 text-xs">[see Contraindications ( 4.2 )]</span>.

5.3 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 Timolol Maleate Ophthalmic Solution is contraindicated] should, in general, not receive beta-blocking agents, including Timolol Maleate Ophthalmic Solution <span class="opacity-50 text-xs">[see Contraindications ( 4.1 )]</span>.

5.4 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.

5.5 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.

5.6 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.

5.7 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.

5.8 Contamination of Topical Ophthalmic Products After Use 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 <span class="opacity-50 text-xs">[see Patient Counseling Information ( 17 )]</span>.

5.9 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.

5.10 Angle-Closure Glaucoma In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This may require constricting the pupil. Timolol maleate has little or no effect on the pupil.

Timolol Maleate Ophthalmic

Solution should not be used alone in the treatment of angle-closure glaucoma.

5.11 Cerebrovascular Insufficiency Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Timolol Maleate Ophthalmic Solution, alternative therapy should be considered.

5.12 Choroidal Detachment Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol).