Adverse events occurring at a rate of =3%, excluding those reported more commonly in placebo encountered in the InnoPran XL placebo-controlled hypertension trials and are plausibly related to treatment are shown in Table 1.

Table 1. Treatment Emergent Adverse Events Reported In = 3% of Subjects

The following adverse events were observed and have been reported with use of formulations of sustained- or immediate-release 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, psoriasiform 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.

Caution should be exercised when InnoPran XL 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 on its efficacy and/or toxicity (see DRUG INTERACTIONS in CLINICAL PHARMACOLOGY).

Cardiovascular Drugs

ACE Inhibitors

When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infraction.

Certain ACE inhibitors have been reported to increase bronchial hyperreactivity when administered with propranolol.

The antihypertensive effects of clonidine may be antagonized by beta-blockers. InnoPran XL should be administered cautiously to patients withdrawing from clonidine.

Alpha Blockers

Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-blockers.

Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin.

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 greater degrees 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 with administration of propranolol. Lidocaine toxicity has been reported following coadministration with propranolol.

Caution should be exercised when administering InnoPran XL 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 is 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.

Digitalis Glycosides

Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Inotropic Agents

Patients on long term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation. Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE).

Isoproterenol and Dobutamine

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. Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia.

Reserpine

Patients receiving catecholamine-depleting drugs, such as reserpine and InnoPran XL, should be closely observed for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension. Administration of reserpine with propranolol may also potentiate depression.

Non-Cardiovascular Drugs

Anesthetic Agents

Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol.

Antidepressants

The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta-blocking activity of propranolol.

Neuroleptic Drugs

Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.

Non-Steroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents.

Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate.

Thyroxine

Thyroxine may result in a lower than expected T3 concentration when used concomitantly with propranolol.

Warfarin

Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored.

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