Metipranolol

Metipranolol is part of the drug class:

• Beta blocking agents

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Eye irritation.
• Blurred eyesight.
• More tears.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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.

Metipranolol ophthalmic solution 0.3% is a sterile solution that contains Metipranolol, a non-selective beta-adrenergic receptor blocking agent. Metipranolol is a white, odorless, crystalline powder. The chemical name of Metipranolol is (±)-1-(4-Hydroxy-2, 3,5-trimethylphenoxy)-3-(isopropylamino)-2-propanol-4-acetate.

The chemical structural of Metipranolol is:

Each mL of Metipranolol ophthalmic solution, for ophthalmic administration, contains 3 mg Metipranolol. INACTIVES: povidone, glycerol, hydrochloric acid, sodium chloride, edetate disodium, and purified water. Sodium Hydroxide may be added to adjust pH. PRESERVATIVE ADDED: Benzalkonium chloride 0.004%.              DM-00

General

Because of potential effects of beta-adrenergic receptor blocking agents relative to 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 Metipranolol ophthalmic solution, alternative therapy should be considered.

Some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents in patients undergoing elective surgery. If necessary during surgery, the effects of beta-adrenergic receptor blocking agents may be reversed by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or levarterenol.

While Metipranolol ophthalmic solution has demonstrated a low potential for systemic effect, it should be used with caution in patients with diabetes (especially labile diabetes) because of possible masking of signs and symptoms of acute hypoglycemia.

Beta-adrenergic receptor blocking agents may mask certain signs and symptoms of hyperthyroidism, and their abrupt withdrawal might precipitate a thyroid storm.

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

Risk of anaphylactic reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

Information for Patients

Patients should be instructed to avoid allowing the tip of the dispensing containers to contact the eye or surrounding structures. Patients should be advised that Metipranolol contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following Metipranolol administration.

Drug Interactions

Metipranolol ophthalmic solution should be used with caution in patients who are receiving a beta-adrenergic blocking agent orally, because of the potential for additive effects on systemic beta-blockade.

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 bradycardia.

Caution should be used in the coadministration of beta-adrenergic receptor blocking agents, such as Metipranolol, and oral or intravenous calcium channel antagonists, because of possible precipitation of left ventricular failure, and hypotension. In patients with impaired cardiac function, who are receiving calcium channel antagonists, coadministration should be avoided.

The concomitant use of beta-adrenergic receptor blocking agents with digitalis and calcium channel antagonists may have additive effects, prolonging atrioventricular conduction time.

Caution should be used in patients using concomitant adrenergic psychotropic drugs.

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. Metipranolol ophthalmic solution has little or no effect on the pupil, therefore, when it is used to reduce intraocular pressure in angle-closure glaucoma, it should be used only with concomitant administration of a miotic agent.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lifetime studies with Metipranolol have been conducted in mice at oral doses of 5, 50 and 100 mg/kg/day and in rats at oral doses of up to 70 mg/kg/day. Metipranolol demonstrated no carcinogenic effect. In the mouse study, female animals receiving the low, but not the intermediate or high dose, had an increased number of pulmonary adenomas. The significance of this observation is unknown. In a variety of in vitro and in vivo bacterial and mammalian cell assays, Metipranolol was nonmutagenic.

Reproduction and fertility studies of Metipranolol in rats and mice showed no adverse effect on male fertility at oral doses of up to 50 mg/kg/day, and female fertility at oral doses of up to 25 mg/kg/day.

Pregnancy

Teratogenic Effects

Pregnancy Category C: No drug related effects were reported for the segment II teratology study in fetal rats after administration, during organogenesis, to dams of up to 50 mg/kg/day. Metipranolol ophthalmic solution has been shown to increase fetal resorption, fetal death, and delayed development when administered orally to rabbits at 50 mg/kg/day during organogenesis.

There are no adequate and well-controlled studies in pregnant women. Metipranolol ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether Metipranolol ophthalmic solution is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Metipranolol ophthalmic solution is administered in nursing women.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

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

Elevated intraocular pressure: Treatment elevated intraocular pressure in patient with chronic open-angle glaucoma or ocular hypertension

Refer to adult dosing.

There are no dosage adjustments provided in manufacturer's labeling. However, dosage adjustment unlikely due to low systemic absorption.

Alpha-/Beta-Agonists (Direct-Acting): Beta-Blockers may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Some beta-adrenoceptor mediated effects of Alpha-/Beta-Agonists (Direct-Acting), including anti-anaphylactic effects of epinephrine, may be diminished by Beta-Blockers. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Exceptions: Dipivefrin. Consider therapy modification

Anilidopiperidine Opioids: May enhance the bradycardic effect of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Beta2-Agonists: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Bupivacaine: Beta-Blockers may increase the serum concentration of Bupivacaine. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Cholinergic Agonists: Beta-Blockers may enhance the adverse/toxic effect of Cholinergic Agonists. Of particular concern are the potential for cardiac conduction abnormalities and bronchoconstriction. Management: Administer these agents in combination with caution, and monitor for conduction disturbances. Avoid methacholine with any beta blocker due to the potential for additive bronchoconstriction. Monitor therapy

Dronedarone: May enhance the bradycardic effect of Beta-Blockers. Dronedarone may increase the serum concentration of Beta-Blockers. This likely applies only to those agents that are metabolized by CYP2D6. Management: Use lower initial beta-blocker doses; adequate tolerance of the combination, based on ECG findings, should be confirmed prior to any increase in beta-blocker dose. Consider therapy modification

Ergot Derivatives: Beta-Blockers may enhance the vasoconstricting effect of Ergot Derivatives. Exceptions: Nicergoline. Consider therapy modification

Fingolimod: Beta-Blockers may enhance the bradycardic effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and beta-blockers if possible. If coadministration is necessary, patients should have overnight continuous ECG monitoring conducted after the first dose of fingolimod. Monitor patients for bradycardia. Consider therapy modification

Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. Avoid combination

Grass Pollen Allergen Extract (5 Grass Extract): Beta-Blockers may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). More specifically, Beta-Blockers may inhibit the ability to effectively treat severe allergic reactions to Grass Pollen Allergen Extract (5 Grass Extract) with epinephrine. Some other effects of epinephrine may be unaffected or even enhanced (e.g., vasoconstriction) during treatment with Beta-Blockers. Consider therapy modification

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Lidocaine (Systemic): Beta-Blockers may increase the serum concentration of Lidocaine (Systemic). Monitor therapy

Lidocaine (Topical): Beta-Blockers may increase the serum concentration of Lidocaine (Topical). Monitor therapy

Mepivacaine: Beta-Blockers may increase the serum concentration of Mepivacaine. Monitor therapy

Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Avoid combination

Methoxyflurane: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Midodrine: Beta-Blockers may enhance the bradycardic effect of Midodrine. Monitor therapy

NIFEdipine: May enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers. Monitor therapy

Regorafenib: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Reserpine: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Rivastigmine: May enhance the bradycardic effect of Beta-Blockers. Avoid combination

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Theophylline Derivatives: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Theophylline Derivatives. Consider therapy modification

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Adverse events were observed in some animal reproduction studies. The same adverse effects observed with systemic administration of beta-blockers may occur following ophthalmic use of metipranolol. If ophthalmic agents are needed for the treatment of glaucoma during pregnancy, the minimum effective dose should be used in combination with punctal occlusion to decrease potential exposure to the fetus (Johnson 2001; Salim 2014; Samples 1988).