INDICATIONS AND USAGE: COMBIGAN® (brimonidine
tartrate/timolol maleate ophthalmic solution) 0.2%/0.5% is an alpha-adrenergic receptor
agonist with a beta‐adrenergic receptor inhibitor indicated for the reduction of
elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension
who require adjunctive or replacement therapy due to inadequately controlled IOP;
the IOP‐lowering of COMBIGAN® dosed twice a day was slightly less
than that seen with the concomitant administration of 0.5% timolol maleate ophthalmic
solution dosed twice a day and 0.2% brimonidine tartrate ophthalmic solution dosed
three times per day.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS: COMBIGAN® is contraindicated
in patients with bronchial asthma; a history of bronchial asthma; severe chronic
obstructive pulmonary disease; in patients with sinus bradycardia; second or third
degree atrioventricular block; overt cardiac failure; in neonates and infants (under
the age of 2 years); in patients with a hypersensitivity reaction to any component
of COMBIGAN® in the past.
WARNINGS AND PRECAUTIONS: COMBIGAN®
contains timolol maleate. COMBIGAN® is administered topically, but
can be absorbed systemically. The adverse reactions with systemic administration
of beta‐adrenergic blocking agents may occur with topical use (eg, severe respiratory
reactions including death due to bronchospasm in patients with asthma have been
reported with systemic or ophthalmic administration of timolol maleate).
Sympathetic stimulation may be essential to support the circulation in patients
with diminished myocardial contractility and its inhibition by beta‐adrenergic receptor
blockade may precipitate more severe failure. In patients with no history of cardiac
failure, continued depression of the myocardium with beta-blocking agents over time
can lead to cardiac failure. Discontinue COMBIGAN® at the first sign
or symptom of cardiac failure.
Patients with chronic obstructive pulmonary disease (eg, chronic bronchitis, emphysema)
of mild or moderate severity, bronchospastic disease, or a history of bronchospastic
disease should not receive beta‐blocking agents, including COMBIGAN®.
COMBIGAN® may potentiate syndromes associated with vascular insufficiency.
Use caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s
phenomenon, orthostatic hypotension, or thromboangiitis obliterans.
Patients taking beta-blockers with a history of atopy or 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 can potentiate muscle weakness with myasthenic symptoms
(eg, diplopia, ptosis, and generalized weakness). Although rare, timolol can increase
muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.
Beta‐adrenergic receptor blocking agents may mask the signs and symptoms of acute
hypoglycemia and clinical signs (eg, tachycardia) of hyperthyroidism. Use caution
in patients subject to spontaneous hypoglycemia or to diabetic patients (especially
those with labile diabetes) who are receiving insulin or oral hypoglycemic agents.
Carefully manage patients that may develop thyrotoxicosis to avoid abrupt withdrawal
of beta‐adrenergic blocking agents that might precipitate a thyroid storm.
Ocular hypersensitivity has occurred with brimonidine tartrate ophthalmic solutions
0.2% (eg, increase in IOP).
Some authorities recommend gradual withdrawal of beta‐adrenergic receptor blocking
agents due to impairment of beta-adrenergically mediated reflexes during surgery.
If necessary during surgery, the effects of beta‐adrenergic blocking agents may
be reversed by sufficient doses of adrenergic agonists.
ADVERSE REACTIONS: The most frequent reactions with
COMBIGAN® in about 5% to 15% of patients included: allergic conjunctivitis,
conjunctival folliculosis, conjunctival hyperemia, eye pruritus, ocular burning,
DRUG INTERACTIONS: COMBIGAN® may reduce
blood pressure. Use caution in patients on antihypertensives and/or cardiac glycosides.
Observe patients receiving a beta‐adrenergic blocking agent orally and COMBIGAN®
for additive effects of beta‐blockade, both systemic and on intraocular pressure.
Concomitant use of two topical beta‐adrenergic blocking agents is not recommended.
Use caution in the co‐administration of beta‐adrenergic blocking agents (eg, COMBIGAN®)
and oral or intravenous calcium antagonists due to possible atrioventricular conduction
disturbances, left ventricular failure, and hypotension. Avoid co-administration
in patients with impaired cardiac function.
Observe patients closely when a beta‐blocker is administered to patients receiving
catecholamine‐depleting drugs (eg, reserpine) due to possible additive effects and
the production of hypotension and/or marked bradycardia, which may result in vertigo,
syncope, or postural hypotension.
Specific drug interaction studies have not been conducted with COMBIGAN®,
but consider the possibility of an additive or potentiating effect with CNS depressants
(alcohol, barbiturates, opiates, sedatives, or anesthetics).
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 (eg, decreased heart rate, depression) has been
reported with combined use of CYP2D6 inhibitors (eg, quinidine, SSRIs) and timolol.
Tricyclic antidepressants (TCAs) can blunt the hypotensive effect of systemic clonidine.
It is not known whether the concurrent use of TCAs with COMBIGAN®
in humans can interfere with the IOP‐lowering effect. Caution is advised in patients
taking TCAs, which can affect the metabolism and uptake of circulating amines.
Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism
of brimonidine and potentially increase systemic side effect such as hypotension.
Use caution in patients taking MAO inhibitors, which can affect the metabolism and
uptake of circulating amines.
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