Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension contains betaxolol hydrochloride, a cardiovascular (beta) adrenoceptor antagonist and pilocarpine hydrochloride, a cholinergic parasympathomimetic agent.

Betaxolol hydrochloride is a white, crystalline powder. Its chemical name is (±)-1[p-(cyclopropylmethoxy)ethyl]phenoxy]-3-(isopropylamino)-2-propanol hydrochloride with an empirical formula of CHNOHCl and a molecular weight of 343.89. The chemical structure of betaxolol hydrochloride is as follows:

Pilocarpine hydrochloride is a white powder. Its chemical name is 2(3H)-furanone, 3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl)-methyl]-, monohydrochloride, (3S-cis)- with an empirical formula of CHNOHCl and a molecular weight of 244.72. The chemical structure of pilocarpine hydrochloride is as follows:

Each mL of Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension contains the following:

Active: Betaxolol hydrochloride 2.8 mg equivalent to 2.5 mg betaxolol base and pilocarpine hydrochloride 17.5 mg;

Preservative: Benzalkonium chloride 0.01%.

Inactive: Mannitol, poly(styrene-divinyl benzene) sulfonic acid, carbomer 934P, boric acid, edetate disodium, sodium hydroxide and/or hydrochloric acid to adjust to a pH 6.0-8.0 and purified water.

Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension is provided as a two-part unit for combination by the Pharmacist. It consists of the following components: Part I – a glass syringe containing pilocarpine hydrochloride 8.75%, sodium hydroxide and/or hydrochloric acid (pH 5.0 ± 0.2) and purified water to 1.6 mL; and Part II – a DROP-TAINER containing betaxolol 0.313%, poly(styrene-divinyl benzene) sulfonic acid, carbomer 934P, boric acid, mannitol, edetate disodium, benzalkonium chloride, sodium hydroxide (pH 8.0 ± 0.2) and purified water to 6.4 mL.

Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension is prepared by affixing a one-inch, blunt, 27 gauge cannula (supplied) to the syringe containing the pilocarpine hydrochloride solution and adding the entire contents of the syringe through the opening in the dropper tip to the DROP-TAINER containing the betaxolol suspension and mixing well. The final pH of the combination suspension is 6.0 to 8.0

Betaxolol hydrochloride, a cardioselective (beta) adrenoceptor antagonist, does not have significant membrane-stabilizing (local anesthetic) activity and is devoid of intrinsic sympathomimetic action. Orally administered beta-adrenergic blocking agents reduce cardiac output in healthy subjects and subjects with heart disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor antagonists may inhibit the sympathetic stimulatory effect necessary to maintain adequate cardiac function.

Pilocarpine is a direct acting cholinergic parasympathomimetic agent which acts through direct stimulation of muscarinic neuroreceptors and smooth muscle such as the iris and secretory glands. Each of these compounds lowers elevated intraocular pressure (IOP) by different mechanisms of action. Betaxolol lowers IOP predominately by decreasing aqueous humor production. Pilocarpine lowers IOP predominantly by increasing the outflow of aqueous humor from the eye.

The efficacy and safety of Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension dosed TID was evaluated in two prospective, multicenter, controlled clinical trials. In both controlled studies, Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension dosed TID provide up to an additional 1-3 mmHg IOP lowering from the Betoptic (Betaxolol hydrochloride) -S BID baseline. Betoptic (Betaxolol hydrochloride) Pilo has not been shown to be superior to any other beta-blocker aside from Betoptic (Betaxolol hydrochloride) -S.

The potential for systemic absorption was evaluated following topical use of Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension TID. After five and eight days of dosing with Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension TID, plasma levels of betaxolol were below the level of quantification (2.0 ng/mL) indicating that TID dosing results in a low systemic exposure to the drug. Plasma concentrations of pilocarpine were higher following topical ocular administration of Pilocarpine HCl Solution 4% QID than after dosing with Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension TID.

Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension is indicated for the reduction of elevated intraocular pressure in patients with primary open-angle glaucoma and ocular hypertension who are insufficiently responsive to Betoptic (Betaxolol hydrochloride) -S (failed to achieve target IOP determined after multiple measurements over time).

It is known whether Betoptic (Betaxolol hydrochloride) Pilo is equivalent in IOP lowering efficacy to the administration of Betoptic (Betaxolol hydrochloride) -S 0.25% and pilocarpine 1.75% dosed separately. It is known whether Betoptic (Betaxolol hydrochloride) Pilo is equivalent to other beta-blockers given in combination with pilocarpine.

Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension is contraindicated in patients with sinus bradycardia, greater than a first degree atrioventricular heart block, cardiogenic shock or patients with overt cardiac failure.

Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension is also contraindicated in conditions where miosis is undesirable (e.g., peripheral anterior synechia, trauma, acute inflammatory disease of the anterior chamber, glaucoma occurring or persisting after extracapsular cataract extraction when posterior synechia may occur, and papillary block glaucoma).

Hypersensitivity to any component of this product.

Topically applied beta-adrenergic blocking agents may be absorbed systemically. 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 with topical application of beta-adrenergic blocking agents.

Betaxolol 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. Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension should be discontinued at the first signs of cardiac failure.

Ocular.
In patients with angle-closure glaucoma, the immediate treatment objective is to re-open the angle by constriction of the pupil with a miotic agent. Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension contains pilocarpine HCl 1.75%, a miotic, which, while having an effect on the pupil, is to be sufficient to effectively treat an angle closure event.

Diabetes Mellitus.
Thyrotoxicosis.
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Risk from Anaphylactic Reaction.
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 disruption of the ocular epithelial surface.

The preservative in Betoptic (Betaxolol hydrochloride) Pilo, benzalkonium chloride, may be absorbed by soft contact lenses. Betoptic (Betaxolol hydrochloride) Pilo should not be administered while wearing soft contact lenses.

Patients who are receiving a beta-adrenergic blocking agent orally and Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension should be observed for a potential additive effect on the intraocular pressure or on the known systemic effects of beta blockade.

Close observation of the patient is recommended when a beta blocker is administered to patients receiving catecholamine-depleting drugs (e.g., reserpine) or calcium-channel blockers because of possible additive effects and the production of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Betaxolol is an adrenergic blocking agent; therefore, caution should be exercised in patients using concomitant adrenergic psychotropic drugs.

Lifetime studies with betaxolol hydrochloride have been completed in mice at oral doses of 6, 20, or 60 mg/kg/day and in rats at 3, 12, or 48 mg/kg/day; betaxolol hydrochloride demonstrated no carcinogenic effect. Higher dose levels were not tested. In a variety of bacterial and mammalian cell assays, betaxolol hydrochloride was nonmutagenic.

There have been no long-term studies done using pilocarpine in animals to evaluate carcinogenic potential.

In multi-center controlled clinical trials of Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension the adverse events reported in an approximately 5 to 20% incidence of patients were: headaches, blurred vision, dim vision, abnormal vision, and vitreous disorder.

In the 3-month controlled clinical trials, 12% of patients enrolled on Betoptic (Betaxolol hydrochloride) Pilo treatment discontinued the therapy within the first two weeks of treatment because of intolerance due to adverse reactions. In a 24-month long-term safety study, by Month-12, 20% of patients had discontinued and by the Month-24 endpoint, 55% of patients had discontinued Betoptic (Betaxolol hydrochloride) Pilo therapy.

The following adverse events were reported at an incidence of 1 to 4% of patients: bronchitis, browache, constipation, dizziness, hyperemia, ocular discomfort, nausea, and pain.

The following adverse events were reported in less than 1% of the patients: abnormal dreams, asthenia, asthma, blepharitis, conjunctival edema, lid erythema, lid margin crusting, lid spasm, palpitation, periorbital edema, photophobia, scotoma, synechiae, and tearing.

In addition, the following adverse events have been associated with ophthalmic formulations containing betaxolol or pilocarpine:

Additional ocular events reported with other formulations of betaxolol or pilocarpine include allergic reactions, decreased corneal sensitivity, edema, anisocoria, lacrimation, and superficial keratitis (corneal granularity).

No information is available on overdosage of Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension in humans. The symptoms which might be expected with an overdose of a systemically administered beta-1-adrenergic blocking agent are bradycardia, hypotension and acute cardiac failure. Symptoms associated with pilocarpine toxicity include sweating, salivation, gastrointestinal over activity (nausea, vomiting, diarrhea), tremors, bradycardia, hypotension, atrioventricular block, mental status changes, and bronchial constriction (in asthmatic patients).

One or two drops of Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension should be instilled in the affected eye(s) three-times daily.

Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension is supplied as two parts requiring mixing before dispensing. Part I consists of a glass syringe containing pilocarpine hydrochloride sealed in a sterile blister pack also containing a sterile, one inch, blunt, 27 gauge cannula. Part II consists of a DROP-TAINER containing betaxolol hydrochloride ophthalmic suspension. Once Part I is added into Part II and mixed, the resulting Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension is to be used for no longer than two (2) weeks. At this time, the reconstituted Betoptic (Betaxolol hydrochloride) Pilo Ophthalmic Suspension should be replaced.

Storage: Store at 4 – 30°C (40 – 86°F). Shake well before using. Discard reconstituted suspension two (2) weeks after combining.

U.S. Patent No’s.: 4,252,984; 4,311,708; 4,342,783; and 4,911,920

March 26, 1997

Alcon

Alcon Laboratories, Inc.

Fort Worth, Texas 76134