Combigan

Combigan is a prescription medication used to reduce elevated pressure in patients with glaucoma or ocular hypertension (higher than normal blood pressure inside the eye).

It is a single product containing two medications: brimonidine and timolol. Brimonidine belongs to a group of drugs called alpha-adrenergic agonists. These work by decreasing the amount of fluid produced in the eyes, which reduces overall pressure within the eye. Timolol belongs to a group of drugs called beta-blockers. These work by decreasing the amount of fluid produced in the eyes, which reduces overall pressure within the eye.

Combigan is available in eye drop form and is typically administered twice a day.

Common side effects of Combigan include itchy eyes, eye redness, and burning or stinging of the eyes.

Combigan can cause blurred vision, drowsiness, and dizziness. Do not drive or operate heavy machinery until you know how Combigan affects you.

Before taking Combigan, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Combigan or to any of its ingredients
• are planning to administer this medication to a child under 2 years of age
• have depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension, or thromboangiitis obliterans
• have heart disease
• have or have recently had an eye infection
• have or have a history of bronchial asthma
• have severe chronic obstructive pulmonary disease
• have sinus bradycardia
• have second or third-degree atrioventricular block
• have heart failure
• have major surgery coming up
• have hyperthyroidism
• have diabetes
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Brimonidine and timolol ophthalmic (eye) drops are used to treat increased pressure in the eye caused by glaucoma or a condition called hypertension of the eye. Both conditions are caused by high pressure in your eye and can lead to pain from pressure in your eye and then can eventually harm your vision. This medicine can help you keep your sight by reducing the pressure in your eye and stopping eye pain.

This medicine is available only with your doctor's prescription.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Burning, dry, or itching eyes
• discharge or excessive tearing
• redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid
• stinging in the eyes
• tiny bumps on lining of the eyelid

• Blurred or loss of vision
• disturbed color perception
• dizziness
• double vision
• feeling of having something in the eye
• halos around lights
• headache
• nervousness
• night blindness
• pounding in the ears
• sensitivity of the eyes to light
• slow, fast, or irregular heartbeat
• tunnel vision
• watery eyes

Get emergency help immediately if any of the following symptoms of overdose occur:

• Chest pain or discomfort
• cough
• difficulty breathing
• lightheadedness, dizziness or fainting
• no blood pressure or pulse
• noisy breathing
• stopping of heart
• tightness in the chest
• unconsciousness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Dry mouth
• feeling sad or empty
• irritability
• lack of appetite
• lack or loss of strength
• loss of interest or pleasure
• sleepiness or unusual drowsiness
• trouble concentrating
• trouble sleeping

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Combigan or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Combigan. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

The recommended dose is one drop of Combigan® in the affected eye(s) twice daily approximately 12 hours apart. If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart.

Antihypertensives/Cardiac Glycosides

Because Combigan® may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with Combigan® is advised.

Beta-adrenergic Blocking Agents

Patients who are receiving a beta-adrenergic blocking agent either orally or intravenously and Combigan® 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.

Calcium Antagonists

Caution should be used in the co-administration of beta-adrenergic blocking agents, such as Combigan®, 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.

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.

CNS Depressants

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.

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.

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.

Tricyclic Antidepressants

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® in humans can lead to resulting interference with the IOP-lowering effect. Caution, however, is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

Monoamine Oxidase Inhibitors

Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine and potentially result in an increased systemic side effect such as hypotension. Caution, however, is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

Pregnancy

Teratogenicity studies have been performed in animals. Brimonidine tartrate was not teratogenic when given orally during gestation days 6 through 15 in rats and days 6 through 18 in rabbits. The highest doses of brimonidine tartrate in rats (2.5 mg/kg/day) and rabbits (5 mg/kg/day) achieved AUC exposure values 580 and 37-fold higher, respectively, than similar values estimated in humans treated with Combigan®, 1 drop in both eyes twice daily.

Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day [4,200 times the maximum recommended human ocular dose of 0.012 mg/kg/day on a mg/kg basis (MRHOD)] demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 mg/kg/day (83,000 times the MRHOD) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses 8,300 times the MRHOD without apparent maternotoxicity.

There are no adequate and well-controlled studies in pregnant women; however, in animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. 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.

Nursing Mothers

Timolol 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 Combigan® 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.

Pediatric Use

Combigan® is contraindicated in children under the age of 2 years [see Contraindications (4.3)]. During post-marketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine. The safety and effectiveness of brimonidine tartrate and timolol maleate have not been studied in children below the age of 2 years.

The safety and effectiveness of Combigan® have been established in the age groups 2 – 16 years of age. Use of Combigan® in these age groups is supported by evidence from adequate and well-controlled studies of Combigan® in adults with additional data from a study of the concomitant use of brimonidine tartrate ophthalmic solution 0.2% and timolol maleate ophthalmic solution in pediatric glaucoma patients (ages 2 to 7 years). In this study, brimonidine tartrate ophthalmic solution 0.2% was dosed three times a day as adjunctive therapy to beta-blockers. The most commonly observed adverse reactions were somnolence (50%-83% in patients 2 to 6 years) and decreased alertness. In pediatric patients 7 years of age or older (>20 kg), somnolence appears to occur less frequently (25%). Approximately 16% of patients on brimonidine tartrate ophthalmic solution discontinued from the study due to somnolence.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

Mechanism of Action

Combigan® is comprised of two components: brimonidine tartrate and timolol. Each of these two components decreases elevated intraocular pressure, whether or not associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous field loss and optic nerve damage.

Combigan® is a relatively selective alpha-2 adrenergic receptor agonist with a non-selective beta-adrenergic receptor inhibitor. Both brimonidine and timolol have a rapid onset of action, with peak ocular hypotensive effect seen at two hours post-dosing for brimonidine and one to two hours for timolol.

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

Timolol maleate is a beta1 and beta2 adrenergic receptor inhibitor that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity.

Pharmacokinetics

Absorption

Systemic absorption of brimonidine and timolol was assessed in healthy volunteers and patients following topical dosing with Combigan®. Normal volunteers dosed with one drop of Combigan® twice daily in both eyes for seven days showed peak plasma brimonidine and timolol concentrations of 30 pg/mL and 400 pg/mL, respectively. Plasma concentrations of brimonidine peaked at 1 to 4 hours after ocular dosing. Peak plasma concentrations of timolol occurred approximately 1 to 3 hours post-dose.

In a crossover study of Combigan®, brimonidine tartrate 0.2%, and timolol 0.5% administered twice daily for 7 days in healthy volunteers, the mean brimonidine area-under-the-plasma-concentration-time curve (AUC) for Combigan® was 128 ± 61 pg•hr/mL versus 141 ± 106 pg•hr/mL for the respective monotherapy treatments; mean Cmax values of brimonidine were comparable following Combigan® treatment versus monotherapy (32.7 ± 15 pg/mL versus 34.7 ± 22.6 pg/mL, respectively). Mean timolol AUC for Combigan® was similar to that of the respective monotherapy treatment (2919 ± 1679 pg•hr/mL versus 2909 ± 1231 pg•hr/mL, respectively); mean Cmax of timolol was approximately 20% lower following Combigan® treatment versus monotherapy.

In a parallel study in patients dosed twice daily with Combigan®, twice daily with timolol 0.5%, or three times daily with brimonidine tartrate 0.2%, one-hour post dose plasma concentrations of timolol and brimonidine were approximately 30-40% lower with Combigan® than their respective monotherapy values. The lower plasma brimonidine concentrations with Combigan® appears to be due to twice-daily dosing for Combigan® versus three-times dosing with brimonidine tartrate 0.2%.

Distribution

The protein binding of timolol is approximately 60%. The protein binding of brimonidine has not been studied.

Metabolism

In humans, brimonidine is extensively metabolized by the liver. Timolol is partially metabolized by the liver.

Excretion

In the crossover study in healthy volunteers, the plasma concentration of brimonidine declined with a systemic half-life of approximately 3 hours. The apparent systemic half-life of timolol was about 7 hours after ocular administration.

Urinary excretion is the major route of elimination of brimonidine and its metabolites. Approximately 87% of an orally-administered radioactive dose of brimonidine was eliminated within 120 hours, with 74% found in the urine. Unchanged timolol and its metabolites are excreted by the kidney.

Special Populations

Combigan® has not been studied in patients with hepatic impairment.

Combigan® has not been studied in patients with renal impairment.

A study of patients with renal failure showed that timolol was not readily removed by dialysis. The effect of dialysis on brimonidine pharmacokinetics in patients with renal failure is not known.

Following oral administration of timolol maleate, the plasma half-life of timolol is essentially unchanged in patients with moderate renal insufficiency.

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Do not use other eye medications unless your doctor tells you to.