Combigan 0.2%/0.5%

Because of the brimonidine tartrate 0.2% component, COMBIGAN (brimonidine tartrate 0.2%/timolol maleate as timolol 0.5%) ophthalmic solution may reduce pulse and blood pressure. Caution in the concomitant use of drugs such as antihypertensives and/or cardiac glycosides is advised.

Interactions with food have not been established.

Close observation of the patient is recommended when timolol maleate is administered to patients receiving oral calcium channel blockers, catecholamine-depleting drugs such as reserpine, or beta-adrenergic blocking agents. The potential exists for additive effects and the production of hypotension, atrioventricular conduction disturbances, left ventricular failure and/or marked bradycardia.

Interactions with laboratory tests have not been established.

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.

Although specific drug interaction studies have not been conducted with COMBIGAN, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered.

Mydriasis resulting from concomitant use of timolol maleate and epinephrine has been reported occasionally.

Interactions with herbal products have not been established.

Although specific drug interaction studies have not been conducted with COMBIGAN, the possibility of an additive or potentiating effect with CNS depressants such as alcohol exists.

Patients who are receiving a beta-adrenergic blocking agent orally and COMBIGAN should be observed for potential additive effects of beta-blockade, both systemically and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended.

Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol maleate, possibly because quinidine inhibits the metabolism of timolol maleate via the P-450 enzyme, CYP2D6.

Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with COMBIGAN can lead to an interference in IOP lowering effect.

No data are available on the level of circulating catecholamines after COMBIGAN is instilled. Caution, however, is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

The recommended dose is one drop of COMBIGAN (brimonidine tartrate 0.2%/timolol maleate as timolol 0.5%) ophthalmic solution in the affected eye(s) twice daily (doses taken approximately 12 hours apart).

As with any eye drops, it is recommended that the lachrymal sac be compressed at the medial canthus (punctual occlusion) for one minute, to reduce possible systemic absorption. This should be performed immediately following the instillation of each drop.

If more than one topical ophthalmic product is to be used, the different products should be instilled at least 10 minutes apart.

The preservative in COMBIGAN, benzalkonium chloride, may be absorbed by soft (hydrophilic) contact lenses. Patients wearing soft contact lenses should be instructed to wait at least 15 minutes after instilling COMBIGAN to insert soft contact lenses.

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. If handled improperly, ocular solutions can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

A missed dose should be applied as soon as the patient remembers. The regular dosing schedule should then be resumed with the next dose.

visual acuity worsened, conjunctival oedema, follicular conjunctivitis, allergic belpharitis, conjunctivitis, vitreous floater, asthenopia, photophobia, papillary hypertrophy, eyelid pain, conjunctival blanching, corneal oedema, corneal infiltrates, vitreous detachment.

taste perversion.

To date, there has not been any serious, unexpected adverse drug reactions related to treatment with COMBIGAN during post-marketing use.

Additional adverse events that have been reported with one of the components and may be potential adverse reactions for COMBIGAN are:

Common: Liver function tests abnormal.

rhinitis, nasal dryness.

Adverse reactions reported in clinical experience with oral timolol maleate may be considered potential side effects of ophthalmic timolol maleate.

Clinically important changes in standard laboratory parameters were rarely associated with the administration of systemic timolol maleate. Slight increases in blood urea nitrogen, serum potassium and serum uric acid and triglycerides, and slight decreases in hemoglobin and hematocrit and HDL-cholesterol occurred, but were not progressive or associated with clinical manifestations.

For other detailed information, please consult the Product Monograph for timolol maleate.

The following adverse reactions have been reported but a causal relationship to therapy with timolol maleate has not been established: aphakic cystoid macular edema, nasal congestion, anorexia, CNS effects (e.g., behavioral changes including confusion, hallucinations, anxiety, disorientation, nervousness, somnolence, and other psychic disturbances), hypertension, retroperitoneal fibrosis and pseudopemphigoid.

Adverse events reported in ≥1% and <8% of patients receiving ALPHAGAN (brimonidine tartrate) ophthalmic solution 0.2% include: Dizziness, upper respiratory symptoms, gastrointestinal symptoms, abnormal taste, nasal dryness, photophobia, tearing, conjunctival edema, conjunctival blanching, conjunctival papillae, and abnormal vision.

Several serious adverse reactions have been reported in association with the administration of brimonidine tartrate ophthalmic solution 0.2% to infants in the age range of 28 days to 3 months. These reactions included: bradycardia, hypotension, hypothermia, hypotonia, apnea, dyspnoea, hypoventilation, cyanosis and lethargy resulting in hospitalisation. Upon discontinuation of brimonidine tartrate 0.2% the infants recovered without sequelae.

For other detailed information, please consult the Product Monograph for brimonidine tartrate.

Based on 12 month clinical data, the most commonly reported adverse drug reactions were conjunctival hyperaemia (approximately 15% of patients) and burning sensation in the eye (approximately 11% of patients). The majority of cases were mild and led to discontinuation rates of only 3.4% and 0.5% respectively.

allergic contact dermatitis.

Adverse events reported with timolol maleate include: Cardiovascular: Aggravation or precipitation of certain cardiovascular, pulmonary, and other disorders presumably related to effects of systemic beta-blockade (see Contraindications, Warnings and Precautions), including bradycardia; arrhythmia; hypotension; syncope; heart block; cerebrovascular accident; cerebral ischemia; palpitation; cardiac arrest; edema; claudication; Raynaud’s phenomenon; cold hands and feet; congestive heart failure. Endocrine: masked symptoms of hypoglycaemia in insulindependent diabetics. Respiratory: bronchospasm (predominantly in patients with pre-existing bronchospastic disease); respiratory failure; dyspnea; cough. Body as a whole: chest pain; fatigue. Nervous System/Psychiatric: increase in signs and symptoms of myasthenia gravis; paresthesia; insomnia; nightmares; memory loss. Skin: alopecia; psoriasiform rash or exacerbation of psoriasis. Hypersensitivity: signs and symptoms of allergic reactions including angioedema, urticaria, localized and generalized rash. Immunologic: systemic lupus erythematous. Digestive: nausea; diarrhea, dyspepsia. Special Senses: decreased corneal sensitivity; visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases); diplopia; ptosis; choroidal detachment following filtration surgery; tinnitus. Urogenital: decreased libido, Peyronie’s disease.

dizziness, syncope.

congestive heart failure, palpitations.

Not recommended for paediatric use. The safety and efficacy of COMBIGAN in paediatric patients have not been established in clinical trials.

Based on evidence from clinical studies and experience, use in the geriatric population is not associated with any differences in safety or effectiveness. Use as is for adult patients.

Results from pivotal trials indicate that the mean change from baseline IOP was significantly lower (p <0.001) with COMBIGAN than with either brimonidine tartrate alone or timolol maleate alone for both patients with diabetes and those without diabetes. See Warnings and Precautions for considerations during use in this population.

Results from pivotal trials indicate that the mean change from baseline IOP was significantly lower (p <0.001) with COMBIGAN than with either brimonidine tartrate alone or timolol maleate alone for both patients treated with systemic beta-blockers and those who were not. Topical beta-blockers are known to be less effective in patients on systemic beta-blockers. See Drug Interactions. This analysis shows that this is not the case with COMBIGAN, despite having timolol as one of the ingredients.

Use atropine sulfate intravenously in a dosage of 0.25 to 2 mg to induce vagal blockade. If bradycardia persists, intravenous isoproterenol hydrochloride should be administered cautiously. In refractory cases the use of a transvenous cardiac pacemaker may be considered.

Use isoproterenol hydrochloride. Additional therapy with aminophylline may be considered.

Conventional therapy with digitalis, diuretics and oxygen should be instituted immediately. In refractory cases the use of intravenous aminophylline is suggested. This may be followed if necessary by glucagon hydrochloride which has been reported to be useful.

Use isoproterenol hydrochloride or a transvenous cardiac pacemaker.

If ingested.

Use sympathomimetic pressor drug therapy, such as dopamine, dobutamine or levarterenol. In refractory cases the use of glucagon hydrochloride has been reported to be useful.

COMBIGAN has not been studied in patients with renal impairment; caution should be exercised in treating such patients. In patients with severe renal impairment on dialysis, treatment with timolol maleate has been associated with pronounced hypotension.

The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or levarterenol.

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

COMBIGAN contains the preservative benzalkonium chloride, which may be deposited in soft contact lenses; therefore, COMBIGAN should not be administered while wearing these lenses. The lenses should be removed before application of the drops and not be reinserted earlier than 15 minutes after use.

Choroidal detachment after filtration procedures has been reported with administration of aqueous suppressant therapy (e.g., timolol maleate, acetazolamide). Management of eyes with chronic or recurrent choroidal detachment should include stopping all forms of aqueous suppressant therapy and treating endogenous inflammation vigorously.

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.

There are no adequate and well-controlled studies of COMBIGAN in pregnant women. Because animal reproduction studies are not always predictive of human response, COMBIGAN should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

There has been no experience with exposure during pregnancy in clinical trials.

COMBIGAN should be used with caution in patients with depression.

COMBIGAN has not been studied in patients with hepatic impairment; caution should be exercised in treating such patients.

Beta-adrenergic blockade has been reported to increase muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis and generalized weakness). Timolol maleate has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

Note: COMBIGAN is a combination of brimonidine tartrate 0.2% and timolol 0.5% as timolol maleate. When COMBIGAN is prescribed, the relevant Product Monographs for brimonidine tartrate and/or timolol maleate should be consulted.

For topical ophthalmic use only.

If signs of serious reactions or hypersensitivity occur, discontinue use of this preparation.

As with many topically applied ophthalmic drugs, this drug is absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration of COMBIGAN (brimonidine tartrate 0.2%/timolol maleate as timolol 0.5%) ophthalmic solution. 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. See Contraindications.

Patients prescribed IOP-lowering medication should be routinely monitored for IOP.

Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycaemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycaemia agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycaemia.

Beta-adrenergic blocking agents may mask certain clinical signs of hyperthyroidism (e.g., tachycardia). Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm.

The use of COMBIGAN in pediatric patients is currently not recommended. Several serious adverse reactions have been reported in association with the administration of brimonidine tartrate ophthalmic solution 0.2% to infants in the age range of 28 days to 3 months. (See Adverse Reactions.)

COMBIGAN, as with other similar medications, can potentially cause fatigue and/or drowsiness in some patients. Patients who engage in hazardous activities should be cautioned of the potential for a decrease in mental alertness.

Because of the brimonidine tartrate component COMBIGAN should be used with caution in patients with known hypersensitivity to other alpha-adrenoceptor agonists.

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. These patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions since timolol maleate may blunt the beta agonist effect of epinephrine. In such cases, alternatives to epinephrine should be considered.

Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. It is not known whether brimonidine tartrate is excreted in human milk, although in animal studies, brimonidine tartrate has been shown to be excreted in breast milk. Because of the potential for serious adverse reactions from timolol maleate or brimonidine tartrate in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Because of the timolol maleate component, cardiac failure should be adequately controlled before beginning therapy with COMBIGAN. In patients with a history of severe cardiac disease, signs of cardiac failure should be watched for and pulse rates should be checked.

Caution should be exercised in treating patients with severe cardiovascular disease.

Use with caution in patients with cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension or thromboangiitis obliterans.

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 COMBIGAN, alternative therapy should be considered.

Plasma brimonidine tartrate and timolol maleate concentrations were determined in 16 healthy subjects dosed with COMBIGAN, ALPHAGAN (brimonidine tartrate) ophthalmic solution 0.2%, or TIMOPTIC (timolol maleate) ophthalmic solution USP 0.5%, each BID for seven days in a three-period, complete crossover study. There were no statistically significant differences in brimonidine tartrate or timolol maleate AUC between COMBIGAN and the respective monotherapy treatments. Mean plasma brimonidine tartrate C_max values from the COMBIGAN and ALPHAGAN 0.2% groups were 0.0327±0.0150 (N=15) and 0.0347±0.0226 ng/mL (N=16), respectively, indicating no apparent difference. Mean plasma timolol maleate C_max values from the COMBIGAN and TIMOPTIC USP 0.5% treatment groups were 0.406±0.216 (N=15) and 0.507±0.269 ng/mL (N=14), respectively. Although the C_max of timolol maleate was approximately 20% lower in the COMBIGAN treatment, the difference was not statistically significant (p=0.088).

Therapeutic drug monitoring was conducted in the two Phase 3 trials. Brimonidine tartrate and timolol maleate plasma concentrations from the COMBIGAN BID group were 15-49% lower than their respective monotherapy values. In the case of brimonidine tartrate, the difference appears to be due to BID dosing for COMBIGAN and TID dosing for ALPHAGAN.

The lower timolol maleate plasma concentrations seen with COMBIGAN, as compared to timolol maleate 0.5%, appear to be related to a slower absorption of timolol maleate, which may be due to a difference in the benzalkonium concentrations rather than a drug-drug (brimonidine tartrate-timolol maleate) interaction.

Orally administered timolol maleate is rapidly and nearly completely absorbed (~90% availability). The apparent elimination half-life of timolol maleate in plasma is 4 hours. The half-life is essentially unchanged in patients with moderate renal insufficiency.

COMBIGAN (brimonidine tartrate 0.2%/timolol maleate as timolol 0.5%) ophthalmic solution reduces intraocular pressure (IOP) by reducing aqueous humor production and increasing uveoscleral outflow.

COMBIGAN is a combination product containing brimonidine tartrate and timolol maleate. Individually, each of these components is used to control IOP in humans.

Brimonidine tartrate is a relatively selective alpha adrenergic receptor agonist that in radioligand binding assays and in functional assays, is approximately 1000 times more selective for the alpha-2 adrenoceptor than the alpha-1 adrenoceptor. This selectivity results in the absence of vasoconstriction in microvessels associated with human retinal xenografts.

Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action. Brimonidine tartrate lowers IOP by reducing aqueous humor production and increasing uveoscleral outflow.

Timolol maleate is a general beta-adrenergic receptor blocking agent that combines reversibly with a part of the cell membrane, the beta-adrenergic receptor, and thus inhibits the usual biological response that would occur with stimulation of that receptor. This specific competitive antagonism blocks stimulation of the beta-adrenergic receptors by catecholamines having beta-adrenergic stimulating (agonist) activity, whether these originate from an endogenous or exogenous source. Reversal of this blockade can be accomplished by increasing the concentration of agonist, which will restore the usual biologic response.

The precise mechanism of action of timolol maleate in lowering intraocular pressure is not clearly established at this time, although a fluorescein study and tonography studies indicate that its predominant action may be related to reduced aqueous humor formation.

Both brimonidine tartrate and timolol maleate have a rapid onset of action, with the peak ocular hypotensive effect occurring at approximately two hours post-dosing for brimonidine tartrate and one to two hours for timolol maleate. The duration of effect is 12 hours or greater for brimonidine tartrate and 24 hours for timolol maleate.

The topical administration of brimonidine tartrate 0.2% ophthalmic solution decreases intraocular pressure (IOP) with minimal effect on cardiovascular parameters. Brimonidine tartrate 0.2% has no effect on pulmonary function or exercise-induced tachycardia. The cardiovascular effects of brimonidine tartrate 0.2% during exercise in normal volunteers were found to be limited to a slight suppression of systolic blood pressure, which was clinically insignificant, during the recovery period following a treadmill test.

Timolol maleate is a non-cardioselective beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity.

In humans, brimonidine tartrate is eliminated rapidly via extensive systemic metabolism; there is no marked systemic accumulation after multiple dosing. It is metabolized primarily by the liver. Urinary excretion is the major route of elimination of the drug and its metabolites. Approximately 87% of an orally-administered radioactive dose was eliminated within 120 hours, with 74% found in the urine in the first 96 hours.

Timolol maleate is partially metabolized by the liver and timolol maleate and its metabolites are excreted by the kidney. Timolol maleate is not extensively bound to plasma proteins (~60%). After oral dosing, timolol maleate is subject to moderate first-pass metabolism (~50%). Only a small amount of unchanged drug appears in the urine, along with its metabolites after oral dosing.