Betoptic S

1 INDICATIONS AND USAGE BETOPTIC S ® (betaxolol hydrochloride ophthalmic suspension) 0.25% is indicated for the treatment of elevated intraocular pressure (IOP) in patients with chronic open-angle glaucoma or ocular hypertension. BETOPTIC S is a beta-adrenergic receptor inhibitor indicated for the treatment of elevated intraocular pressure (IOP) in patients with chronic open-angle glaucoma or ocular hypertension.

Instill one drop of BETOPTIC S in the affected eye(s) twice daily. Shake well before using. BETOPTIC S may be used alone or in combination with other IOP lowering medications. Advise patients requiring concomitant topical ophthalmic medications to administer these at least 10 minutes before instilling BETOPTIC S. Instill one drop in the affected eye(s) twice daily.

Systemic Absorption : Same adverse reactions found with systemic administration of beta-adrenergic receptor inhibitors may occur with topical ophthalmic administration. Cardiac Failure : Discontinue treatment at the first signs of cardiac failure. Diabetes Mellitus : Beta-adrenergic receptor inhibitors may mask the signs and symptoms of acute hypoglycemia. Administer with caution in diabetic patients subject to hypoglycemia. Thyrotoxicosis : Beta-adrenergic receptor inhibitors may mask certain clinical signs (e.g., tachycardia) or hyperthyroidism.

5.1Systemic Absorption As with

many topically applied ophthalmic drugs, this drug is absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic receptor inhibitors may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and death due to cardiac failure, have been reported with topical application of beta-adrenergic receptor inhibitors.

5.2Cardiac Failure

BETOPTIC S has been shown to have a minor effect on heart rate and blood pressure in clinical studies. Caution should be used in treating patients with a history of cardiac failure or heart block. Treatment with BETOPTIC S should be discontinued at the first signs of cardiac failure.

5.3Diabetes Mellitus Beta-adrenergic

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

5.4Thyrotoxicosis Beta-adrenergic

receptor inhibitors 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 receptor inhibitors, which might precipitate a thyroid storm.

5.5Muscle Weakness Beta-adrenergic

receptor inhibitors have been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness).

5.6Surgical Anesthesia The

necessity or desirability of withdrawal of beta-adrenergic receptor inhibitors prior to major surgery is controversial. Beta-adrenergic receptor inhibitors impair 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 inhibitors have experienced protracted, severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. In patients undergoing elective surgery, consider gradual withdrawal of beta-adrenergic receptor inhibitors.

If necessary during surgery, the effects of beta-adrenergic receptor inhibitors may be reversed by sufficient doses of adrenergic agonists.

5.7Bronchospasm and Obstructive Pulmonary Disease Caution

should be exercised in the treatment of glaucoma patients with excessive restriction of pulmonary function. There have been reports of asthmatic attacks and pulmonary distress during betaxolol treatment. Although rechallenges of some such patients with ophthalmic betaxolol has not adversely affected pulmonary function test results, the possibility of adverse pulmonary effects in patients sensitive to beta-adrenergic receptor inhibitors cannot be ruled out.

5.8Atopy/Anaphylaxis While

taking beta-adrenergic receptor inhibitors, 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. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

5.9Angle-Closure Glaucoma In

patients with angle-closure glaucoma, the immediate treatment objective is to reopen the angle. This may require constricting the pupil. Betaxolol has little or no effect on the pupil and should not be used alone in the treatment of angle-closure glaucoma.

5.10Vascular Insufficiency Because of

potential effects of beta-adrenergic receptor inhibitors on blood pressure and pulse, these inhibitors should be used with caution in patients with vascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow or Raynaud’s phenomenon develop following initiation of therapy with BETOPTIC S, alternative therapy should be considered.

5.11Bacterial Keratitis Bacterial

keratitis may occur with use of multiple dose containers of topical ophthalmic products when these containers are inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. Instruct patients on appropriate instillation techniques .

5.12Choroidal Detachment Choroidal

detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy.

5.13Contact Lens Wear The

preservative in BETOPTIC S, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of BETOPTIC S but may be reinserted 15 minutes after instillation .

4 CONTRAINDICATIONS BETOPTIC S is contraindicated in patients with: sinus bradycardia greater than a first degree atrioventricular (AV) block cardiogenic shock patients with overt cardiac failure hypersensitivity to any component of this product Hypersensitivity to any component of this product. Sinus bradycardia, second or third degree atrioventricular (AV) block, overt cardiac failure, and cardiogenic shock.

8.1Pregnancy Risk Summary There

are no adequate and well-controlled studies of BETOPTIC S administration in pregnant women to inform a drug-associated risk. There are limited data with the use of betaxolol eye drops in pregnant women. Epidemiological studies have not revealed malformative effects but show a risk for intrauterine growth retardation when beta-blockers are administered by the oral route.

In animal reproductive studies, no drug-induced maternal toxicity or teratogenicity was observed at clinically relevant doses . Because animal reproductive studies are not always predictive of human response, BETOPTIC S should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data In a rat embryo-fetal development (EFD) study, oral administration of 4, 40, or 400 mg/kg/day betaxolol on gestational days 6 through 18, the period of organogenesis, resulted in marked embryo-fetal lethality, increased incidence of skeletal and visceral abnormalities, and decreased fetal weights at the maternally toxic dose of 400 mg/kg/day (7785 times higher than the maximum recommended human ophthalmic dose [MRHOD] of 0.0083 mg/kg/day, on a mg/m 2 basis).

The no-observed-adverse-effect-level (NOAEL) for maternal or embryo-fetal toxicity was 40 mg/kg/day (778 times higher than the MRHOD, on a mg/m 2 basis). In a rabbit EFD study, oral administration of 1, 4, 12, and 36 mg/kg/day betaxolol on gestational days 6 through 18, the period of organogenesis, resulted in a marked increase in embryo-fetal lethality at 36 mg/kg/day (1400 times higher than the MRHOD, on a mg/m 2 basis). No maternal toxicity was reported in this study.

In a perinatal and postnatal development study in rats, oral administration of 4, 32, and 256 mg/kg/day betaxolol during late gestation through lactation resulted in a marked decrease in offspring survival within 4 days postpartum at the highest dose (4982 times higher than the MRHOD, on a mg/m 2 basis). In surviving F 1 offspring, growth/development and reproductive function were also affected. The NOAEL was 32 mg/kg/day (623 times higher than the MRHOD, on a mg/m 2 basis).

In a prenatal and postnatal development study in rats, an oral betaxolol dose of 150 mg/kg/day (2920 times higher than the MRHOD, on mg/m 2 basis) administered throughout the entire gestation period and lactation, resulted in maternal and developmental toxicity in F 1 offspring, including decreased offspring survival, body weight and growth/development and functional deficits in surviving offspring. No NOAEL for developmental or maternal toxicity was established in this study. Oral administration of 4, 32, and 256 mg/kg/day betoxolol to rats prior to mating and through late gestation, or until weaning, produced embryo-fetal lethality, neonatal mortality, decreased mean fetal weight, growth/development and functional deficits in surviving offspring at 256 mg/kg/day (4982 times higher than the MRHOD, on a mg/m 2 basis).

At 32 mg/kg/day (623 higher than the MRHOD, on a mg/m 2 basis), decreased mean fetal weight on Gestation Day 20, and pup weight at birth and on Day 4 postpartum were observed. At 4 mg/kg/day (78 times higher than the MRHOD, on a mg/m 2 basis), a slight decrease in mean fetal weight was observed on Gestation Day 20.

The most frequent adverse reaction is transient ocular discomfort. To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, the most frequent adverse reaction associated with the use of BETOPTIC S has been transient ocular discomfort. The following other adverse reactions have been reported in small numbers of patients: Ocular: blurred vision, corneal punctate keratitis, foreign body sensation, photophobia, tearing, itching, dryness of eyes, erythema, inflammation, discharge, ocular pain, decreased visual acuity, and crusty lashes.

Systemic Adverse Reactions Include : Cardiovascular: Bradycardia, heart block, and congestive failure. Pulmonary: Pulmonary distress characterized by dyspnea, bronchospasm, thickened bronchial secretions, asthma, and respiratory failure. Central Nervous System: Insomnia, dizziness, vertigo, headaches, depression, lethargy, and increase in signs, and symptoms of myasthenia gravis.

Other: Hives, toxic epidermal necrolysis, hair loss and glossitis. Perversions of taste and smell have been reported. In a 3-month, double-masked, active-controlled, multicenter study in pediatric patients, the adverse reaction profile of BETOPTIC S was comparable to that seen in adult patients.

6.2Additional Potential Adverse Reactions Associated

With Betaxolol Additional medical events reported with other formulations of betaxolol include allergic reactions, decreased corneal sensitivity, corneal punctate staining which may appear in dendritic formation, edema, and anisocoria.