Propranolol Hydrochloride 1 mg/mL Injection, 10 vials — NDC 0143-9872-10 (Billing 00143-9872-10)

WARNINGS Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta blockade may precipitate more severe failure. Although beta‑blockers should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving additional therapies, including diuretics as needed. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle.

Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema) In general, patients with bronchospastic lung disease should not receive beta blockers. Propranolol should be administered with caution in this setting since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors. Major Surgery The necessity or desirability of withdrawal of beta-blocking therapy prior to major surgery is controversial.

It should be noted, however, that the impaired ability of the heart to respond to reflex adrenergic stimuli in propranolol-treated patients might augment the risks of general anesthesia and surgical procedures. Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension.

Diabetes and Hypoglycemia Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin-dependent diabetics. In these patients, it may be more difficult to adjust the dosage of insulin. Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting, as in preparation for surgery.

Hypoglycemia has been reported after prolonged physical exertion and in patients with renal insufficiency. Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm.

Propranolol may change thyroid-function tests, increasing T 4 and reverse T 3 , and decreasing T 3 . Wolff-Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolff-Parkinson-White syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. In one case this resulted after an initial 5 mg dose of intravenous propranolol.

ADVERSE REACTIONS In a series of 225 patients, there were 6 deaths (see CLINICAL STUDIES ). Cardiovascular events (hypotension, congestive heart failure, bradycardia, and heart block) were the most common. The only other event reported by more than one patient was nausea.

Other adverse events for intravenous propranolol, reported during post-marketing surveillance include cardiac arrest, dyspnea, and cutaneous ulcers. The following adverse events have been reported with use of formulations of sustained- or immediate-release oral propranolol and may be expected with intravenous propranolol. Cardiovascular Bradycardia; congestive heart failure; intensification of AV block; hypotension; paresthesia of hands; thrombocytopenic purpura; arterial insufficiency, usually of the Raynaud type.

Central Nervous System Light-headedness; mental depression manifested by insomnia, lassitude, weakness, fatigue; reversible mental depression progressing to catatonia; visual disturbances; hallucinations; vivid dreams; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. For immediate‑release formulations, fatigue, lethargy, and vivid dreams appear dose-related. Gastrointestinal Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis.

Allergic Pharyngitis and agranulocytosis; erythematous rash, fever combined with aching and sore throat; laryngospasm, and respiratory distress. Respiratory Bronchospasm. Hematologic Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.

Autoimmune In extremely rare instances, systemic lupus erythematosus has been reported. Miscellaneous Alopecia, LE-like reactions, psoriaform rashes, dry eyes, male impotence, and Peyronie’s disease have been reported rarely. Oculomucocutaneous reactions involving the skin, serous membranes and conjunctivae reported for a beta-blocker (practolol) have not been associated with propranolol.

To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drug Interactions Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes Because propranolol’s metabolism involves multiple pathways in the cytochrome P-450 system (CYP2D6, 1A2, 2C19), administration of propranolol with drugs that are metabolized by, or affect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see PRECAUTIONS, Drug Interactions ). Substrates or Inhibitors of CYP2D6 Blood levels of propranolol may be increased by administration of propranolol with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavirdine, fluoxetine, paroxetine, quinidine, and ritonavir.

No interactions were observed with either ranitidine or lansoprazole. Substrates or Inhibitors of CYP1A2 Blood levels of propranolol may be increased by administration of propranolol with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan. Substrates or Inhibitors of CYP2C19 Blood levels of propranolol may be increased by administration of propranolol with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, teniposide, and tolbutamide.

No interaction was observed with omeprazole. Inducers of Hepatic Drug Metabolism Blood levels of propranolol may be decreased by administration of propranolol with inducers such as rifampin and ethanol. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 100% the clearance of propranolol, resulting in decreased plasma concentrations.

Cardiovascular Drugs Antiarrhythmics The AUC of propafenone is increased by more than 200% with co-administration of propranolol. The metabolism of propranolol is reduced by co-administration of quinidine, leading to a 2- to 3-fold increased blood concentrations and greater beta-blockade. The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations.

Calcium Channel Blockers The mean C max and AUC of propranolol are increased respectively, by 50% and 30% by co-administration of nisoldipine and by 80% and 47%, by co-administration of nicardipine. The mean values of C max and AUC of nifedipine are increased by 64% and 79%, respectively, by co-administration of propranolol. Propranolol does not affect the pharmacokinetics of verapamil and norverapamil.

Verapamil does not affect the pharmacokinetics of propranolol. Non-Cardiovascular Drugs Migraine Drugs Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and C max by 37%) or rizatriptan (the AUC and C max were increased by 67% and 75%, respectively). Theophylline Co-administration of theophylline with propranolol decreases theophylline clearance by 33% to 52%.

Benzodiazepines Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol. The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol.

Neuroleptic Drugs Co-administration of propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 50% to 370% and increased thioridazine metabolites concentrations ranging from 33% to 210%. Co-administration of chlorpromazine with propranolol resulted in increased plasma levels of both drugs (70% increase in propranolol concentrations). Anti-Ulcer Drugs Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol concentrations by about 40%.

Co‑administration with aluminum hydroxide gel (1200 mg) resulted in a 50% decrease in propranolol concentrations. Co-administration of metoclopramide with propran… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General Propranolol should be used with caution in patients with impaired hepatic or renal function. Propranolol is not indicated for the treatment of hypertensive emergencies. Beta-adrenergic receptor blockade can cause reduction of intraocular pressure.

Patients should be told that propranolol might interfere with the glaucoma screening test. Withdrawal may lead to a return of elevated intraocular pressure. 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. Angina Pectoris There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy.

Therefore, when discontinuance of propranolol is planned, the dosage should be gradually reduced over at least a few weeks, and the patient should be cautioned against interruption or cessation of therapy without a physician’s advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it is usually advisable to reinstitute propranolol therapy and take other measures appropriate for the management of angina pectoris. Since coronary artery disease may be unrecognized, it may be prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease who are given propranolol for other indications.

Clinical Laboratory Tests In patients with hypertension, use of propranolol has been associated with elevated levels of serum potassium, serum transaminases and alkaline phosphatase. In severe heart failure, the use of propranolol has been associated with increases in Blood Urea Nitrogen. Drug Interactions Caution should be exercised when propranolol is administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways.

Co-administration of such drugs with propranolol may lead to clinically relevant drug interactions and changes in its efficacy and/or toxicity (see CLINICAL PHARMACOLOGY, Drug Interactions ). Cardiovascular Drugs Antiarrhythmics Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol. Quinidine increases the concentration of propranolol and produces a greater degree of clinical beta-blockade and may cause postural hypotension.

Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects and has been associated with severe bradycardia, asystole and heart failure when administered with propranolol. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with propranolol. The clearance of lidocaine is reduced when administered with propranolol.

Lidocaine toxicity has been reported following co-administration with propranolol. Caution should be exercised when administering propranolol with drugs that slow A-V nodal conduction, e.g., digitalis, lidocaine and calcium channel blockers. Calcium Channel Blockers Caution should be exercised when patients receiving a beta-blocker are administered a calcium-channel-blocking drug with negative inotropic and/or chronotropic effects.

Both agents may depress myocardial contractility or atrioventricular conduction. There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta‑blockers. Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high degree heart block, and heart failure.

ACE Inhibitors When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction. ACE inhibitors have been reported to increase bronchial hyperreactivity when admin… [Excerpted — this section continues on DailyMed.]