Inderal®-LA

Propranolol HCl

Beta-adrenergic Receptor Blocking Agent

Wyeth Canada

http://www.wyeth.com/

Inderal-LA Monograph PDF download here.

 

CPS:PIS_m262000

 

 

 

Pharmacology

Propranolol is a non-selective beta-adrenergic receptor blocking drug. It has no other autonomic nervous system activity. Propranolol is a competitive antagonist which specifically competes with beta-adrenergic receptor stimulating agents for available beta-receptor sites. When access to beta-adrenergic receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately.

     Beta-adrenergic blockade is useful in some clinical conditions in which sympathetic activity is excessive or inappropriate, and therefore, detrimental to the patient. Sympathetic stimulation is however, vital in some situations (e.g. in patients with AV block or with a severely damaged heart) and should be preserved. The basic objective of beta-adrenergic blockade is to decrease adverse sympathetic stimulation but not to the degree that impairs necessary sympathetic support. Beta-blockade may result in bronchial constriction by interfering with endogenously or exogenously induced bronchodilation (see Contraindications and Warnings).

     The mechanism of the antihypertensive effects of propranolol has not been established. Among the factors that may be involved are decreased cardiac output, inhibition of renin release by the kidneys, and diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. It has been suggested, but not established, that propranolol may achieve a better antihypertensive effect in patients with normal or elevated plasma renin activity (PRA) than those with low PRA.

     Propranolol may reduce the oxygen requirement of the heart at any level of effort by blocking catecholamine induced increases in the heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. On the other hand, propranolol may increase oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection period. When the net effect is beneficial in anginal patients, it manifests itself during exercise or stress by delaying the onset of pain and reducing the incidence and severity of anginal attacks.

     Propranolol exerts antiarrhythmic effects in concentrations producing beta-adrenergic blockade, which appears to be its principal antiarrhythmic mechanism of action. Beta-adrenergic blockade is of unique importance in the management of arrhythmias caused by increased levels of circulating catecholamines or enhanced sensitivity of the heart to catecholamines (arrhythmias associated with pheochromocytoma, thyrotoxicosis, exercise).

     Mechanisms of the antimigraine and antitremor effects of propranolol have not been established. The antimigraine effect may be due to inhibition of vasodilatation or arteriolar spasms over the cortex. Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain. The antitremor effects may be exerted through both peripheral and central sites of action. The mechanism by which propranolol reduces the incidence of cardiovascular mortality in post-myocardial infarct patients is unknown.

     Inderal-LA is a special formulation of propranolol HCl consisting of capsules filled with spheroids of the active drug that have a sustained-release coating.

     Propranolol from Inderal-LA capsules is almost completely absorbed from the gastrointestinal tract. A large part of the absorbed drug is lost from the systemic circulation due to first-pass metabolism in the liver. The first-pass metabolism is saturable. Steady-state plasma propranolol concentrations from Inderal-LA are proportional to the dose over the range of 60 to 160 mg/day although there is considerable intersubject variation. In healthy volunteers steady state was achieved after 2 or 3 days administration of Inderal-LA.

     Peak blood levels following administration of Inderal-LA capsules occur at about 6 hours and the apparent plasma half-life has been reported to be between 10 and 12 hours i.e. 2 to 3 times that of the conventional tablet formulation.

     When measured at steady state over a 24-hour period the areas under the propranolol plasma concentration-time curve (AUCs) for the LA-capsules are approximately 60 to 65% of the AUCs for a comparable divided daily dose of propranolol tablets. The lower AUCs for the Inderal-LA capsules are due to greater hepatic metabolism of propranolol because of slower absorption. Over a 24-hour period, blood levels are fairly constant for about 12 hours, then decline exponentially.

 

Indications

For maintenance therapy in the treatment of hypertension and prophylaxis of angina pectoris.

     As for Inderal, the combination of Inderal-LA with thiazide-like diuretics and/or peripheral vasodilators has been shown to be compatible and generally more effective than Inderal-LA alone. Experience with most commonly used antihypertensive agents has not suggested evidence of incompatibility.

     Treatment must always be initiated and individual titration of dosage carried out using the conventional tablets. The long-acting formulation may be used for maintenance provided the dosage requirement is suitable.

     Not indicated for the emergency treatment of hypertensive crises.

 

Contraindications

Bronchospasm, including bronchial asthma; allergic rhinitis during the pollen season; sinus bradycardia and greater than first degree block; cardiogenic shock; right ventricular failure secondary to pulmonary hypertension; congestive heart failure (see Warnings) unless the failure is secondary to a tachyarrhythmia treatable with propranolol.

 

Warnings

Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure; therefore, inhibition by means of beta-adrenergic blockade is a potential hazard as it may further depress myocardial contractility and precipitate cardiac failure. Propranolol acts selectively without completely abolishing the inotropic action of digitalis on the heart muscle (i.e., that of supporting the strength of myocardial contractions). In patients already receiving digitalis, the positive inotropic action of digitalis may be reduced by propranolol's negative inotropic effect. The effects of propranolol and digitalis are additive in depressing AV conduction.

Patients without a History of Cardiac Failure: Continued depression of the myocardium over a period of time can, in some patients, lead to cardiac failure. In rare instances, this has been observed during propranolol therapy. Therefore, at the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic, and the response observed closely: a) if cardiac failure continues, despite adequate digitalization and diuretic therapy, propranolol should be withdrawn immediately; b) if tachyarrhythmia is being controlled, patients should be maintained on combined therapy and closely followed until threat of cardiac failure is over.

Abrupt Cessation of Therapy in Angina Pectoris: Severe exacerbation of angina and the occurrence of myocardial infarction have been reported in some patients with angina pectoris following abrupt discontinuation of propranolol therapy. Therefore, when discontinuation of propranolol is planned in patients with angina pectoris, the dosage should be gradually reduced over a period of about 2 weeks and the patient should be carefully observed. For patients receiving propranolol tablets, the same frequency of administration should be maintained. For patients on Inderal-LA, discontinuation can be achieved by substituting Inderal-LA 60, 80, 120 and 160 mg by the equivalent dosage of conventional propranolol tablets spread throughout the day, and then gradually reducing the dose. In situations of greater urgency, propranolol dosage should be reduced stepwise, in 4 days under close observation. If angina markedly worsens, or acute coronary insufficiency develops, it is recommended that treatment with propranolol be reinstituted promptly, at least temporarily. In addition, patients with angina pectoris should be warned against abrupt discontinuation of propranolol.

Oculomucocutaneous Syndrome: Various skin rashes and conjunctival xerosis have been reported in patients treated with beta-blockers including propranolol. A severe oculomucocutaneous syndrome, whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the long-term use of one beta-adrenergic blocking agent. This syndrome has not been observed with propranolol, however, physicians should be alert to the possibility of such reactions and discontinue treatment if they occur.

Patients with Thyrotoxicosis: Possible deleterious effects from long-term use of propranolol have not yet been adequately appraised. Special consideration should be given to propranolol's potential for aggravating congestive heart failure. Propranolol may mask the clinical signs of developing or continuing hyperthyroidism or its complications, and give a false impression of improvement. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. This may be another instance where propranolol should be withdrawn slowly by reducing dosage. Propranolol does not distort thyroid function tests.

Patients with Wolff-Parkinson-White Syndrome: Propranolol should be used with caution since several cases have been reported in which, after propranolol treatment, the tachycardia was replaced by a severe bradycardia requiring a demand pacemaker. In one patient, this occurred after an initial dose of 5 mg of propranolol.

Patients Undergoing Elective or Emergency Surgery: The management of patients with angina, being treated with beta-blockers and undergoing elective or emergency surgery, is controversial because beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli, but abrupt discontinuation of therapy with propranolol may be followed by severe complications (see Warnings). Some patients receiving beta-adrenergic blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported.

     For these reasons, in patients with angina undergoing elective surgery, propranolol should be withdrawn gradually (see Warnings). According to available evidence, all clinical and physiologic effects of beta-blockade are no longer present 48 hours after cessation of medication.

     In emergency surgery, since propranolol is a competitive inhibitor of beta-adrenergic receptor agonists, its effects may be reversed, if necessary, by sufficient doses of such agonists as isoproterenol or dobutamine.

     Anesthesia with agents which maintain cardiac contractility by virtue of their effect on catecholamine release (e.g. ether) should be avoided in patients on propranolol therapy.

Patients prone to nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema, bronchiectasis): Propranolol should be administered with caution since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-adrenergic receptors.

Patients with Diabetes and in those subject to Hypoglycemia: Because of its beta-adrenergic blocking activity, propranolol may block premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia. This is especially important to keep in mind in patients with labile diabetes. Hypoglycemic attacks may be accompanied by a precipitous elevation of blood pressure. Acute increases in blood pressure have occurred after insulin-induced hypoglycemia in subjects on propranolol.

     Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol (see Adverse Effects).

Skin Reactions: Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of propranolol (see Adverse Effects).

Pregnancy

The safe use of propranolol in pregnancy has not been established. Use of any drug in pregnancy or in women of childbearing potential requires that the possible risk to mother and/or fetus be weighed against the expected therapeutic benefit. Perinatal complications, such as small placenta and intrauterine growth retardation, have been reported in a few cases where the mother took propranolol during pregnancy. Some infants born to mothers treated with propranolol were reported to have hypoglycemia and/or bradycardia.

Children

While experience with propranolol in children under 12 is limited, the indications for which this drug is recommended occur infrequently in childhood. Although reports fail to indicate that children respond in a manner different from the adult, physicians are advised to undertake treatment with caution.

 

Precautions

There may be increased difficulty in treating an allergic type reaction in patients on beta-blockers. In these patients, the reaction may be more severe due to pharmacological effects of beta-blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other, these doses can be associated with excessive alpha adrenergic stimulation with consequent hypertension, reflex bradycardia and heart-block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids, and the use of beta agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm, and norepinephrine to overcome hypotension.

     Some slowing of heart due to unopposed vagal activity is usual in patients receiving propranolol; however, occasionally severe bradycardia occurs and may lead to vertigo, syncopal attacks or orthostatic hypotension. Patients, especially those with limited cardiac reserve should be monitored for signs of excessive bradycardia. Should the patient become symptomatic the dose of propranolol should be decreased or, if necessary, the drug should be discontinued. If it is essential to correct the bradycardia i.v. atropine or isoproterenol should be considered.

     It has been reported that administration of propranolol to control cardiac arrhythmias in acute myocardial infarction has caused marked reduction in cardiac output. Therefore, the doses of propranolol should be kept to the minimum in patients with severe myocardial infarction. Caution should be exercised when administering propranolol in such situations, especially when a large portion of the myocardium has been damaged due to coronary occlusion since adequate sympathetic drive should be preserved to maintain ventricular function. Prior administration of other antiarrhythmic cardiac depressant drugs, such as procainamide or quinidine may potentiate the cardiac depressant activity of propranolol. Prior digitalization may be indicated and atropine should be at hand to control bradycardia.

     The combination of propranolol with a thiazide like diuretic and/or peripheral vasodilator produces a greater fall in blood pressure than either drug alone. This occurs regardless of which drug is administered first. The same degree of blood pressure control can be achieved by lower than usual dosages of each drug. Therefore, when using such combined therapy, careful monitoring of the dosages is required until the patient is stabilized.

     Patients receiving catecholamine depleting drugs such as reserpine or guanethidine should be closely observed if propranolol is administered concomitantly. The added catecholamine blocking action of this drug may produce an excessive reduction of the resting sympathetic nervous activity.

     In patients on long-term treatment with propranolol, laboratory determinations should be made at regular intervals. The drug should be used with caution in patients with impaired renal and hepatic functions.

 

Adverse Effects

The most serious adverse effects that may be encountered with propranolol are congestive heart failure and bronchospasm (see Contraindications, Warnings and Precautions).

Gastrointestinal disturbances: (anorexia, nausea, vomiting, diarrhea, abdominal pain) are the most common adverse effects reported. Other less frequently reported adverse effects are: (in descending order) cold extremities and exacerbation of Raynaud's phenomenon; congestive heart failure; sleep disturbances including vivid dreams; dizziness, fatigue and bronchospasm.

     The following adverse reactions have also been reported with the use of propranolol. Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme and urticaria.

     Reported adverse effects, according to organ systems are recorded below.

 

Cardiovascular

congestive heart failure (see Warnings); secondary effects of decreased cardiac output which could include: syncope, vertigo, lightheadedness, decreased renal perfusion and rarely, postural hypotension; intensification of AV block and hypotension; severe bradycardia; claudication and cold extremities, Raynaud's phenomenon; dyspnea; palpitations; precordial pain.

 

CNS

dizziness, lethargy, weakness, drowsiness, headache, insomnia, fatigue, anorexia, anxiety, mental depression, poor concentration, reversible amnesia and catatonia, vivid dreams with or without insomnia, hallucinations, paresthesia, incoordination.

 

Gastrointestinal

nausea, vomiting, epigastric distress, anorexia, bloating, mild diarrhea, constipation.

 

Respiratory

bronchospasm; laryngospasm and respiratory distress (see Contraindications and Warnings).

 

Dermatologic

A few cases of erythematous rashes and increase of facial acneiform lesions have been reported; urticaria; exfoliative psoriasiform eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and erythema multiforme.

Others

reduction or loss of libido; reversible alopecia and rarely: diminution and loss of hearing; tinnitus; visual disturbances; diminished vision, conjunctivitis; thrombocytopenic purpura; pharyngitis and agranulocytosis, fever combined with aching and sore throat; flushing of the face.

 

Allergic

hypersensitivity reactions, including anaphylactic/anaphylactoid reactions.

Clinical Laboratory Test Findings: Elevated blood urea levels in patients with severe heart disease, elevated serum transaminase, alkaline phosphatase, and lactate dehydrogenase have been reported.

 

Overdose

 

 

Symptoms

Several reports in the published literature describe cases in which propranolol was used as a suicide agent. In most cases, other agents, e.g., alcohol, have also been involved. One patient who died was thought to have ingested 3600 mg of propranolol. Survival of patients taking higher single doses has, however, also been reported. The common signs to be expected in overdosage are bradycardia, hypotension, bronchospasm, or acute cardiac failure.

 

 

Treatment

If overdosage occurs, in all cases therapy with propranolol should be discontinued and the patient observed closely. In addition the following therapeutic measures are suggested:

Bradycardia: Administer atropine incrementally in 600 µg (0.6 mg) doses. If there is no response to vagal blockade, administer isoproterenol cautiously.

Cardiac Failure: Digitalization and diuretics.

Hypotension: Vasopressors, e.g., epinephrine or levarterenol. (There is evidence that epinephrine is the drug of choice).

Bronchospasm: Administer isoproterenol and aminophylline.

 

Dosage

Intended for maintenance therapy in those patients requiring doses within the range of 60 to 320 mg/day. Initiation of treatment and individual titration of dosage should be carried out using the conventional tablets. Inderal-LA may be preferred for maintenance because of the convenience of once-daily dosage. Patients with angina or hypertension on a maintenance regimen within the range of 60 to 320 mg/day regular tablets taken in divided doses may be changed to the appropriate number of Inderal-LA capsules taken once daily in the morning or evening.

     However, Inderal-LA should not be considered a simple mg-for-mg substitute for conventional propranolol tablets and blood levels achieved are lower than those of 2 to 4 times daily dosing with the same dose. When changing to Inderal-LA from conventional propranolol tablets, a possible need for retitration upwards should be considered, especially to maintain effectiveness at the end of the dosing interval. In most clinical settings, however, such as hypertension or angina where there is little correlation between plasma levels and clinical effect, Inderal-LA has been shown to be therapeutically equivalent to the same mg dose of conventional propranolol as assessed by 24-hour effects on blood pressure, and on 24-hour exercise responses of heart rate, systolic pressure, and rate pressure product. Inderal-LA can provide effective beta blockade for 24-hour periods.

     When propranolol is combined with another antihypertensive agent which is already being administered, therapy should be initiated with conventional propranolol tablets following usual dosage recommendations. Once adequate blood pressure control has been obtained, Inderal-LA capsules may be used for maintenance provided the dosage requirement is suitable.

     In the treatment of hypertension, if required, further reduction of blood pressure may be attained by the addition of diuretic and/or peripheral vasodilator. Addition of another antihypertensive agent should, however, be gradual, beginning with 50% of the usual recommended starting dose, to avoid excessive reduction of blood pressure.

 

Supplied

60 mg

Each white/light blue, controlled-release capsule, identified by 3 narrow bands, 1 wide band, and INDERAL-LA 60, contains: propranolol HCl 60 mg. Nonmedicinal ingredients: ethylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose; empty capsule: FD&C Blue No. 1, FD&C Red No. 3, gelatin, silicon dioxide, sodium lauryl sulfate and titanium dioxide. Energy: 0.84 kJ (0.2 kcal). Alcohol-, gluten-, lactose-, sodium-, sugar-, sulfites- and tartrazine-free. Bottles of 100.

80 mg

Each light blue, controlled-release capsule, identified by 3 narrow bands, 1 wide band, and INDERAL-LA 80, contains: propranolol HCl 80 mg. Nonmedicinal ingredients: ethylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose; empty capsule: FD&C Blue No. 1, FD&C Red No. 3, gelatin, silicon dioxide, sodium lauryl sulfate and titanium dioxide. Alcohol-, gluten-, lactose-, sodium-, sugar-, sulfites- and tartrazine-free. Energy: 0.84 kJ (0.2 kcal). Bottles 100.

120 mg

Each light blue/dark blue, controlled-release capsule, identified by 3 narrow bands, 1 wide band and INDERAL-LA 120, contains: propranolol HCl 120 mg. Nonmedicinal ingredients: ethylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose; empty capsule: FD&C Blue No. 1, FD&C Red No. 3, gelatin, silicon dioxide, sodium lauryl sulfate and titanium dioxide. Energy: 0.84 kJ (0.2 kcal). Alcohol-, gluten-, lactose-, sodium-, sugar-, sulfites- and tartrazine-free. Bottles of 100.

160 mg

Each dark blue, controlled-release capsule, identified by 3 narrow bands, 1 wide band, and INDERAL-LA 160, contains: propranolol HCl 160 mg. Nonmedicinal ingredients: ethylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose; empty capsule: FD&C Blue No. 1, gelatin and titanium dioxide. Energy: 1.26 kJ (0.3 kcal). Alcohol-, gluten-, lactose-, sodium-, sugar-, sulfites- and tartrazine-free. Bottles of 100.