Duo-Medihaler™
(isoproterenol hydrochloride and
phenylephrine bitartrate)

Inhalation Aerosol

PHARMACIST: Tear off ‘Patient Instructions for Use” and dispense with product.

DUO-MEDIHALER (isoproterenol hydrochloride and phenylephrine bitartrate) is a combination of two sympathomimetics administered by oral inhalation for the treatment of bronchoconstriction. Each metered dose of the aerosol delivers through the oral adapter 0.16 mg isoproterenol hydrochloride and 0.24 mg phenylephrine bitartrate of appropriate particle size (the majority less than 5 μ). This drug product also cortains cetylpyridinium chloride, dichloro­difluoromethane, dichlorotetrafluoroethane, sorbitan trioleate, and trichloromonofluoromethane. Chemically, isoproterenol hydrochlo­ride is 4-[1-hydroxy-2-[(1-methytethyl)amino]ethyl]-1,2-benzene­diol hydrochloride and phenylephrine bitartrate is (-)-m-hydroxy­-a-[(methylamino) methyl]benzyl alcohol bitartrate.

Structural formulae:

Isoproterenol acts directly on beta-adrenergic receptors and phenylephrine acts directly on alpha-adrenergic receptors. The beta-adrenergic effects stem from the release of cyclic AMP following activation of the enzyme adenyl cyclase. Alpha-adren­ergic effects probably result from inhibition of adenyl cyclase. Isoproterenol produces bronchodilatation, systemic vasodilation, mild hypotension, and tachycardia. Phenylephrine produces mild bronchodilatation, systemic vasoconstriction, mild hypertension, and bradycardia. These two drugs appear to act synergistically to allow the expression of each product's ability to relax bronchial smooth muscle. The vasoconstrictor effect of phenylephrine reduces bronchiolar blood flow thereby producing a decongestant effect, promotes retention of the drug in the bronchial mucosa, and blocks the tachycardia of isoproterenol. After oral inhalation of the combination, the pulmonary effects occur within a few minutes and persist up to three hours.

Studies demonstrate that the ventilatory effects of isoproterenol­phenylephrine are superior to those obtained with the administration of isoproterenol alone. Because isoproterenol is a potent vasodilator that lowers blood pressure and acts upon the heart to increase cardiac output and pulse rate, its combination with phenylephrine results in a product with fewer cardiovascular effects. Studies have shown the absence of tachycardia and hypotension.

Isoproterenol alone often lowers arterial blood oxygen (PO₂). Several studies have shown that the combination of isoproterenol and phenylephrine rarely produces a significant drop in arterial oxygen tension while usually producing an increase in P_aO₂ in asthmatic patients.

DUO-MEDIHALER is indicated for the treatment of bronchospasm associated with acute and chronic asthma and reversible broncho­spasm which may be associated with chronic bronchitis or emphysema.

DUO-MEDIHALER must not be used by patients with known hyper­sensitivity to sympathomimetics. The use of isoproterenol in patients with pre-existing cardiac arrhythmias associated with tachycardia is contraindicated because the cardiac stimulant effects of the drug may aggravate such disorders.

Excessive use of an adrenergic aerosol should be discouraged, as it may lose effectiveness. Occasional patients have been reported to develop severe paradoxical airway resistance with repeated, excessive use of isoproterenol inhalation preparations (see ADVERSE REACTIONS). The cause of this is unknown. It is advis­able that in such instances the use of this preparation be discon­tinued immediately and alternative therapy instituted, since in the reported cases the patients did not respond to other forms of therapy until the drug was withdrawn. Deaths have been reported following excessive use of isoproterenol inhalation preparations, and the exact cause is unknown. Cardiac arrest was noted in several instances (see ADVERSE REACTIONS).

The following adverse effects, uled by organ system in decreasing frequency have been associated with the use of DUO-MEDIHALER and are similar to those produced by other sympathomimetic agents:

Drug abuse and dependence have not been reported with DUO­-MEDIHALER.

Before each use, remove dust cap and inspect mouthpiece for foreign objects. Shake DUO-MEDIHALER.

• Breathe out fully and place mouthpiece well into the mouth aimed at the back of the throat.
• As you begin to breathe in deeply, press the vial firmly down into the adapter with the index finger. This releases one dose.
• Release pressure on vial and remove unit from mouth. Hold your breath as long as possible, then breathe out slowly.

Replace dust cap after each use.

DUO-MEDIHALER is an aerosol device which delivers 0.16 mg of isoproterenol hydrochloride and 0.24 mg of phenylephrine bitar­trate through the oral adapter with each depression of the valve.

15-ml vial and oral adapter, containing 21.0 gm, a minimum of 300 actuations

NDC 0089-0735-21).

15-ml refill vial only, containing 21.0 gm, a minimum of 300 actu­ations (NDC 0089-0735-11).

Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manu­factured with chlorofluorocarbons (CFC's).

Federal law prohibits dispensing without prescription. CONTENTS UNDER PRESSURE. Do not puncture or incinerate container Store at controlled room temperature between 15°C and 30°C. (59°F and 86°F). KEEP OUT OF THE REACH OF CHILDREN.

3M Pharmaceuticals
Northridge, CA 91324
DUO-20
NOVEMBER 1993
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