Betoptic Pilo

BETOPTIC PILO- betaxolol hydrochloride and pilocarpine hydrochloride
Alcon Laboratories, Inc.

DESCRIPTION

Betoptic^® Pilo Ophthalmic Suspension contains betaxolol hydrochloride, a cardiovascular (beta₁ ) 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 C₁₈ H₂₉ NO₃ HCl 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 C₁₁ H₁₆ N₂ O₂ HCl and a molecular weight of 244.72. The chemical structure of pilocarpine hydrochloride is as follows:

Each mL of Betoptic^® 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^® 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^® 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

Remove Cap from DropTainer	Add Contents of Syringe through Orifice in DropTainer	Cap and Mix Well. Label with a 2-Week Expiry Period

ADD CONTENTS OF PART I TO PART II AND MIX WELL IMMEDIATELY PRIOR TO DISPENSING AND LABEL WITH A TWO (2) WEEK EXPIRATION DATE

CLINICAL PHARMACOLOGY

Betaxolol hydrochloride, a cardioselective (beta₁ ) 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^® Pilo Ophthalmic Suspension dosed TID was evaluated in two prospective, multicenter, controlled clinical trials. In both controlled studies, Betoptic^® Pilo Ophthalmic Suspension dosed TID provide up to an additional 1-3 mmHg IOP lowering from the BETOPTIC^® -S BID baseline. Betoptic^® Pilo has not been shown to be superior to any other beta-blocker aside from Betoptic^® -S.

The potential for systemic absorption was evaluated following topical use of Betoptic^® Pilo Ophthalmic Suspension TID. After five and eight days of dosing with Betoptic^® 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^® Pilo Ophthalmic Suspension TID.

Betoptic Pilo Indications and Usage

Betoptic^® 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^® -S (failed to achieve target IOP determined after multiple measurements over time).

It is not known whether Betoptic^® Pilo is equivalent in IOP lowering efficacy to the administration of Betoptic^® -S 0.25% and pilocarpine 1.75% dosed separately. It is not known whether Betoptic^® Pilo is equivalent to other beta-blockers given in combination with pilocarpine.

CONTRAINDICATIONS

Betoptic^® 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^® 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.

WARNINGS

NOT FOR INJECTION OR ORAL ADMINISTRATION. FOR TOPICAL OPHTHALMIC USE ONLY. COMBINE PARTS I AND II PRIOR TO DISPENSING AND LABEL WITH A TWO (2) WEEK EXPIRATION DATE

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^® Pilo Ophthalmic Suspension should be discontinued at the first signs of cardiac failure.

PRECAUTIONS

General

Ocular. Pilocarpine-induced miosis may cause difficulty in dark adaptation. Patients should be advised to exercise caution in night driving and hazardous tasks performed in poor illumination.

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^® Pilo Ophthalmic Suspension contains pilocarpine HCl 1.75%, a miotic, which, while having an effect on the pupil, is unlikely to be sufficient to effectively treat an angle closure event.

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

Thyrotoxicosis. Beta-adrenergic blocking agents 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 blocking agents, which might precipitate a thyroid storm.

Muscle Weakness. Beta-adrenergic blockage has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis and generalized weakness).

Major Surgery. Consideration should be given to the gradual withdrawal of beta-adrenergic blocking agents prior to general anesthesia because of reduced ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli.

Pulmonary. 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 such patients with ophthalmic betaxolol have not adversely affected pulmonary function test results, the possibility of adverse pulmonary effects in patients sensitive to beta blockers cannot be ruled out.

Risk from Anaphylactic Reaction. 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. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.