Inderal La Information
Inderal la (Propranolol)
Inderal la (Propranolol) Description
Inderal (propranolol hydrochloride) is a synthetic beta-adrenergic receptor-blocking agent chemically described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride,(±)-. Its molecular and structural formulae are:
CHNO · HCl
Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.80.
Inderal la (Propranolol) is formulated to provide a sustained release of propranolol hydrochloride. Inderal la (Propranolol) is available as 60 mg, 80 mg, 120 mg, and 160 mg capsules for oral administration.
The inactive ingredients contained in Inderal la (Propranolol) capsules are: cellulose, ethylcellulose, gelatin capsules, hypromellose, and titanium dioxide. In addition, Inderal la (Propranolol) 60 mg, 80 mg, and 120 mg capsules contain D&C Red No. 28 and FD&C Blue No. 1; Inderal la (Propranolol) 160 mg capsules contain FD&C Blue No. 1.
These capsules comply with USP Dissolution Test 1.
Inderal la (Propranolol) Clinical Pharmacology
Propranolol is a nonselective, beta-adrenergic receptor-blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor-stimulating agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately. At dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.
Inderal la (Propranolol) should not be considered a simple mg-for-mg substitute for conventional propranolol and the blood levels achieved do not match (are lower than) those of two to four times daily dosing with the same dose (see ). When changing to Inderal la (Propranolol) from conventional propranolol, 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 (Propranolol) has been therapeutically equivalent to the same mg dose of conventional Inderal 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 (Propranolol) Pharmacokinetics And Drug Metabolism
Propranolol is highly lipophilic and almost completely absorbed after oral administration. However, it undergoes high first pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. Inderal la (Propranolol) Capsules (60, 80, 120, and 160 mg) release propranolol HCl at a controlled and predictable rate. Peak blood levels following dosing with Inderal la (Propranolol) occur at about 6 hours.
The effect of food on Inderal LA bioavailability has not been investigated.
Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha‑1-acid glycoprotein). The binding is enantiomer-selective. The S(–)-enantiomer is preferentially bound to alpha-1-glycoprotein and the R(+)-enantiomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters/kg.
Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk.
Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N‑dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been estimated that the percentage contributions of these routes to total metabolism are 42%, 41% and 17%, respectively, but with considerable variability between individuals. The four major metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol.
In-vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6.
Propranolol is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter, p‑glycoprotein (p-gp). Studies suggest however that p-gp is not dose-limiting for intestinal absorption of propranolol in the usual therapeutic dose range.
In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial clearance of 4-hydroxy propranolol was significantly higher and naphthyloxyactic acid was significantly lower in EMs than PMs.
When measured at steady state over a 24-hour period the areas under the propranolol plasma concentration-time curve (AUCs) for the Inderal la (Propranolol) capsules are approximately 60% to 65% of the AUCs for a comparable divided daily dose of Inderal Tablets. The lower AUCs for the Inderal la (Propranolol) capsules are due to greater hepatic metabolism of propranolol, resulting from the slower rate of absorption of propranolol. Over a twenty-four (24) hour period, blood levels are fairly constant for about twelve (12) hours, then decline exponentially. The apparent plasma half-life is about 10 hours.
Inderal la (Propranolol) Pharmacodynamics And Clinical Effects
In a retrospective, uncontrolled study, 107 patients with diastolic blood pressure 110 to 150 mmHg received propranolol 120 mg t.i.d. for at least 6 months, in addition to diuretics and potassium, but with no other hypertensive agent. Propranolol contributed to control of diastolic blood pressure, but the magnitude of the effect of propranolol on blood pressure cannot be ascertained.
Four double-blind, randomized, crossover studies were conducted in a total of 74 patients with mild or moderately severe hypertension treated with Inderal la (Propranolol) 160 mg once daily or propranolol 160 mg given either once daily or in two 80 mg doses. Three of these studies were conducted over a 4-week treatment period. One study was assessed after a 24-hour period. Inderal la (Propranolol) was as effective as propranolol in controlling hypertension (pulse rate, systolic and diastolic blood pressure) in each of these trials.
In a double-blind, placebo-controlled study of 32 patients of both sexes, aged 32 to 69 years, with stable angina, propranolol 100 mg t.i.d. was administered for 4 weeks and shown to be more effective than placebo in reducing the rate of angina episodes and in prolonging total exercise time.
Twelve male patients with moderately severe angina pectoris were studied in a double-blind, crossover study. Patients were randomized to either Inderal la (Propranolol) 160 mg daily or conventional propranolol 40 mg four times a day for 2 weeks. Nitroglycerine tablets were allowed during the study. Blood pressure, heart rate and ECG's were recorded during serial exercise treadmill testing. Inderal la (Propranolol) was as effective as conventional propranolol for exercise heart rate, systolic and diastolic blood pressure, duration of anginal pain and ST-segment depression before or after exercise, exercise duration, angina attack rate and nitroglycerine consumption.
In another double-blind, randomized, crossover trial, the effectiveness of propranolol LA 160 mg daily and conventional propranolol 40 mg four times a day were evaluated in 13 patients with angina. ECG's were recorded while patients exercised until angina developed. Inderal la (Propranolol) was as effective as conventional propranolol for amount of exercise performed, ST-segment depression, number of anginal attacks, amount of nitroglycerine consumed, systolic and diastolic blood pressures and heart rate at rest and after exercise.
Inderal la (Propranolol) Contraindications
Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first-degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to propranolol hydrochloride.
Inderal la (Propranolol) Warnings
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 the physician's advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it usually is advisable to reinstitute propranolol therapy and take other measures appropriate for the management of unstable 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.
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol (see ).
Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of propranolol (see ).
In Patients without a History of Heart Failure,
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 may 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.
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 when given to infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion and in patients with renal insufficiency.
Inderal la (Propranolol) Precautions
Propranolol should be used with caution in patients with impaired hepatic or renal function. Inderal la (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 Inderal la (Propranolol) may interfere with the glaucoma screening test. Withdrawal may lead to a return of increased intraocular pressure.
Caution should be exercised when Inderal la (Propranolol) is administered with drugs that have an affect 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 in ).
Alcohol
In a series of reproductive and developmental toxicology studies, propranolol was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose). No evidence of embryo or neonatal toxicity was noted.
There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy. Neonates whose mothers are receiving propranolol at parturition have exhibited bradycardia, hypoglycemia and/or respiratory depression. Adequate facilities for monitoring such infants at birth should be available. Inderal la (Propranolol) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Safety and effectiveness of propranolol in pediatric patients have not been established.
Bronchospasm and congestive heart failure have been reported coincident with the administration of propranolol therapy in pediatric patients.
Inderal la (Propranolol) Adverse Reactions
The following adverse events were observed and have been reported in patients using propranolol.
Inderal la (Propranolol) Overdosage
Propranolol is not significantly dialyzable. In the event of overdosage or exaggerated response, the following measures should be employed:
The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be monitored. Isoproterenol and aminophylline may be used for bronchospasm.
Inderal la (Propranolol) Dosage And Administration
Starting with 80 mg Inderal la (Propranolol) once daily, dosage should be gradually increased at three- to seven-day intervals until optimal response is obtained. Although individual patients may respond at any dosage level, the average optimal dosage appears to be 160 mg once daily. In angina pectoris, the value and safety of dosage exceeding 320 mg per day have not been established.
If treatment is to be discontinued, reduce dosage gradually over a period of a few weeks (see ).
Inderal la (Propranolol) How Supplied
Inderal la (Propranolol) Capsules (propranolol hydrochloride)
Each white/light-blue capsule, identified by 3 narrow bands, 1 wide band, and “INDERAL LA 60,” contains 60 mg of propranolol hydrochloride in bottles of 100 (NDC 0046‑0470‑81).
Each light-blue capsule, identified by 3 narrow bands, 1 wide band, and “Inderal la (Propranolol) 80,” contains 80 mg of propranolol hydrochloride in bottles of 100 (NDC 0046-0471-81).
Each light-blue/dark-blue capsule, identified by 3 narrow bands, 1 wide band, and “Inderal la (Propranolol) 120,” contains 120 mg of propranolol hydrochloride in bottles of 100 (NDC 0046-0473-81).
Each dark-blue capsule, identified by 3 narrow bands, 1 wide band, and “Inderal la (Propranolol) 160,” contains 160 mg of propranolol hydrochloride in bottles of 100 (NDC 0046-0479-81).
The appearance of these capsules is a registered trademark of Wyeth Pharmaceuticals.
Wyeth Pharmaceuticals Inc.Philadelphia, PA 19101
W10478C009ET01Rev 11/07
