ISOPROTERENOL: 311 Adverse Event Reports & Safety Profile

Isoproterenol hydrochloride injection, USP is 3,4-Dihydroxy-α-[(isopropylamino)methyl] benzyl alcohol hydrochloride, a synthetic sympathomimetic amine that is structurally related to epinephrine but acts almost exclusively on beta receptors. Isoproterenol hydrochloride is white to practically white, crystalline powder and the molecular formula is C 11 H 17 NO 3 · HCl. It has a molecular weight of 247.72 and the following structural formula: Isoproterenol hydrochloride, USP is a racemic compound. Each milliliter of the sterile solution contains: Isoproterenolhydrochloride,USP (equivalent to Isoproterenol 0.17 mg) 0.2 mg Edetate Disodium (EDTA) 0.2 mg Sodium Citrate Dihydrate 2.07 mg Citric Acid, Anhydrous 2.5 mg Sodium Chloride 7 mg Water for Injection qs 1 mL The pH is adjusted between 2.5 and 4.5 with hydrochloric acid and/or sodium hydroxide. The sterile solution is nonpyrogenic clear, colorless or practically colorless liquid free from visible particles and can be administered by the intravenous route. isoproterenol-str

INDICATIONS AND USAGE Isoproterenol hydrochloride injection is indicated: For mild or transient episodes of heart block that do not require electric shock or pacemaker therapy. For serious episodes of heart block and Adams-Stokes attacks (except when caused by ventricular tachycardia or fibrillation). (See CONTRAINDICATIONS.) For use in cardiac arrest until electric shock or pacemaker therapy, the treatments of choice, is available. (See CONTRAINDICATIONS.) For bronchospasm occurring during anesthesia. As an adjunct to fluid and electrolyte replacement therapy and the use of other drugs and procedures in the treatment of hypovolemic and septic shock, low cardiac output (hypoperfusion) states, congestive heart failure, and cardiogenic shock. (See WARNINGS.)

DOSAGE AND ADMINISTRATION Start isoproterenol hydrochloride injection at the lowest recommended dose and increase the rate of administration gradually if necessary while carefully monitoring the patient. The usual route of administration is by intravenous infusion or bolus intravenous injection. In dire emergencies, the drug may be administered by intracardiac injection. If time is not of the utmost importance, initial therapy by intramuscular or subcutaneous injection is preferred. Recommended dosage for adults with heart block, Adams-Stokes attacks, and cardiac arrest : Route of Administration Preparation of Dilution Initial Dose Subsequent Dose Range* Bolus intravenous injection Dilute 1 mL (0.2 mg) in 9 mL of Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP 0.02 mg to 0.06 mg (1 mL to 3 mL of diluted solution) 0.01 mg to 0.2 mg (0.5 mL to 10 mL of diluted solution) Intravenous infusion Dilute 10 mL (2 mg) in 500 mL of 5% Dextrose Injection, USP 5 mcg/min. (1.25 mL of diluted solution per minute)

Intramuscular Use

Solution undiluted 0.2 mg (1 mL) 0.02 mg to 1 mg (0.1 mL to 5 mL)

Subcutaneous Use

Solution undiluted 0.2 mg (1 mL) 0.15 mg to 0.2 mg (0.75 mL to 1 mL)

Intracardiac Use

Solution undiluted 0.02 mg (0.1 mL) * Subsequent dosage and method of administration depend on the ventricular rate and the rapidity with which the cardiac pacemaker can take over when the drug is gradually withdrawn. There are no well-controlled studies in children to establish appropriate dosing; however, the American Heart Association recommends an initial infusion rate of 0.1 mcg/kg/min, with the usual range being 0.1 mcg/kg/min to 1 mcg/kg/min. Recommended dosage for adults with shock and hypoperfusion states: Route of Administration Preparation of Dilution † Infusion Rate †† Intravenous infusion Dilute 5 mL (1 mg) in 500 mL of 5% Dextrose Injection, USP 0.5 mcg to 5 mcg per minute(0.25 mL to 2.5 mL of diluted solution) † Concentrations up to 10 times greater have been used when limitation of volume is essential. †† Rates over 30 mcg per minute have been used in advanced stages of shock. The rate of infusion should be adjusted on the basis of heart rate, central venous pressure, systemic blood pressure, and urine flow. If the heart rate exceeds 110 beats per minute, it may be advisable to decrease or temporarily discontinue the infusion. Recommended dosage for adults with bronchospasm occurring during anesthesia: Route of Administration Preparation of Dilution Initial Dose Subsequent Dose Bolus intravenous injection Dilute 1 mL (0.2 mg) in 9 mL of Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP 0.01 mg to 0.02 mg (0.5 mL to 1 mL of diluted solution) The initial dose may be repeated when necessary Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Such solution should not be used.

Isoproterenol hydrochloride injection is contraindicated in patients with:

• tachycardia
• ventricular arrhythmias
• angina pectoris Isoproterenol hydrochloride injection is contraindicated in patients with:
• Tachycardia ( 4 )
• Ventricular arrhythmias ( 4 )
• Angina pectoris ( 4 )

6.

Adverse Reactions

The following adverse reactions have been associated with use of isoproterenol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Nervous system disorders: Nervousness, headache, dizziness, visual blurring Cardiovascular: Tachycardia, tachyarrhythmias, palpitations, angina, ventricular arrhythmias, Adams-Stokes attacks, pulmonary edema Respiratory: Dyspnea Other: Flushing of the skin, sweating, mild tremors, pallor, nausea Common adverse reactions with isoproterenol include tachycardia and palpitations ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lambda Therapeutics Limited at 1-855-642-2594 or email: [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

AND PRECAUTIONS

• Cardiac arrhythmias and ischemia may be induced by isoproterenol hydrochloride injection ( 5.1 )
• Sulfite: Isoproterenol hydrochloride injection contains metabisulfite, which may cause allergic reaction ( 5.2 ) 5.1.

Cardiac

Arrhythmias and Ischemia Isoproterenol may induce cardiac arrhythmias and myocardial ischemia in patients, especially patients with coronary artery disease, or cardiomyopathy.

5.2 Allergic Reactions associated with Sulfite Isoproterenol hydrochloride injection contains sodium metabisulfite, which may cause mild to severe allergic reactions including anaphylaxis or asthmatic episodes, particularly in patients with a history of allergies. However, the presence of metabisulfite in this product should not preclude its use for treatment in emergency situations, even if the patient is sulfite-sensitive, as the alternatives to using isoproterenol in a life threatening situation may not be satisfactory.

PRECAUTIONS General Isoproterenol hydrochloride injection should generally be started at the lowest recommended dose. This may be gradually increased if necessary while carefully monitoring the patient. Doses sufficient to increase the heart rate to more than 130 beats per minute may increase the likelihood of inducing ventricular arrhythmias. Such increases in heart rate will also tend to increase cardiac work and oxygen requirements which may adversely affect the failing heart or the heart with a significant degree of arteriosclerosis. Adequate filling of the intravascular compartment by suitable volume expanders is of primary importance in most cases of shock and should precede the administration of vasoactive drugs. In patients with normal cardiac function, determination of central venous pressure is a reliable guide during volume replacement. If evidence of hypoperfusion persists after adequate volume replacement, isoproterenol hydrochloride injection may be given. In addition to the routine monitoring of systemic blood pressure, heart rate, urine flow, and the electrocardiograph, monitor the response to therapy by frequent determination of the central venous pressure and blood gases. Closely observe patients in shock during isoproterenol hydrochloride injection administration. If the heart rate exceeds 110 beats per minute, it may be advisable to decrease the infusion rate or temporarily discontinue the infusion. Determinations of cardiac output and circulation time may also be helpful. Take appropriate measures to ensure adequate ventilation. Pay attention to acid-base balance and to the correction of electrolyte disturbances.

Drug Interactions

Isoproterenol hydrochloride injection and epinephrine should not be administered simultaneously because both drugs are direct cardiac stimulants and their combined effects may induce serious arrhythmias. The drugs may, however, be administered alternately provided a proper interval has elapsed between doses. Avoid isoproterenol hydrochloride injection when potent inhalational anesthetics such as halothane are employed because of potential to sensitize the myocardium to effects of sympathomimetic amines. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate the carcinogenic potential of isoproterenol hydrochloride have not been done. Mutagenic potential and effect on fertility have not been determined. There is no evidence from human experience that isoproterenol hydrochloride injection may be carcinogenic or mutagenic or that it impairs fertility.

Pregnancy

Category C Animal reproduction studies have not been conducted with isoproterenol hydrochloride. It is also not known whether isoproterenol hydrochloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Isoproterenol hydrochloride should be given to a pregnant woman only if clearly needed.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isoproterenol hydrochloride injection is administered to a nursing woman.

Pediatric Use

Safety and efficacy of isoproterenol in pediatric patients have not been established. Intravenous infusions of isoproterenol in refractory asthmatic children at rates of 0.05 to 2.7 mcg/kg/min have caused clinical deterioration, myocardial necrosis, congestive heart failure and death. The risks of cardiac toxicity appear to be increased by some factors [acidosis, hypoxemia, coadministration of corticosteroids, coadministration of methylxanthines (theophylline, theobromine) or aminophylline] that are especially likely to be present in these patients. If intravenous isoproterenol is used in children with refractory asthma, patient monitoring must include continuous assessment of vital signs, frequent electrocardiography, and daily measurements of cardiac enzymes, including CPK-MB.

Geriatric Use

Clinical studies of isoproterenol hydrochloride injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects in clinical circumstances. There are, however, some data that suggest that elderly healthy or hypertensive patients are less responsive to beta-adrenergic stimulation than are younger subjects. In general, dose selection for elderly patients should usually start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapy.

INTERACTIONS Table 1.

Clinically Relevant

Interactions with Isoproterenol Epinephrine Clinical Impact Both drugs are direct cardiac stimulants, and their combined effects may induce serious arrhythmias upon simultaneous administration.

Intervention

Isoproterenol hydrochloride injection and epinephrine should not be administered simultaneously. Drugs that may potentiate clinical response of Isoproterenol Clinical Impact The effects of isoproterenol may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine.

Intervention

Monitor hemodynamic parameters in patients who concurrently are taking tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium and certain antihistamines. Adjust doses appropriately. Drugs that may reduce clinical response of Isoproterenol Clinical Impact The cardiostimulating and bronchodilating effects of isoproterenol are antagonized by beta-adrenergic blocking drugs, such as propranolol.

Intervention

Monitor for hemodynamic response and relief of bronchospasm and adjust dose appropriately. Do not administer isoproterenol hydrochloride injection and epinephrine simultaneously due to combined effects may induce serious arrhythmias. ( 7 ) Concomitant use of tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium and certain antihistamines; hemodynamic parameters may potentiate a clinical response of isoproterenol. ( 7 ) Beta-adrenergic blocking drugs may reduce cardiostimulating and bronchodilating effects of isoproterenol. ( 7 )

See

17 for PATIENT COUNSELING INFORMATION.