Inderal La (Propranolol Hydrochloride)
Dosage & administration
Inderal LA provides propranolol hydrochloride in a sustained-release capsule for administration once daily. If patients are switched from Inderal Tablets to Inderal LA Capsules, care should be taken to assure that the desired therapeutic effect is maintained. Inderal LA should not be considered a simple mg-for-mg substitute for Inderal. Inderal LA has different kinetics and produces lower blood levels. Retitration may be necessary, especially to maintain effectiveness at the end of the 24-hour dosing interval.
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Inderal LA prescribing information
Inderal LA is indicated in the management of hypertension. It may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic. Inderal LA is not indicated in the management of hypertensive emergencies.
Inderal LA provides propranolol hydrochloride in a sustained-release capsule for administration once daily. If patients are switched from Inderal Tablets to Inderal LA Capsules, care should be taken to assure that the desired therapeutic effect is maintained. Inderal LA should not be considered a simple mg-for-mg substitute for Inderal. Inderal LA has different kinetics and produces lower blood levels. Retitration may be necessary, especially to maintain effectiveness at the end of the 24-hour dosing interval.
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.
The following adverse events were observed and have been reported in patients using propranolol.
Caution should be exercised when Inderal LA 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
All drug interaction studies were conducted with propranolol. There are no data on drug interactions with Inderal LA capsules.
Because propranolol's metabolism involves multiple pathways in the Cytochrome P-450 system (CYP2D6, 1A2, 2C19), co-administration 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
Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole.
Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan.
Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction was observed with omeprazole.
Blood levels of propranolol may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in decreased plasma concentrations.
The AUC of propafenone is increased by more than 200% by co-administration of propranolol.
The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two to three fold increased blood concentration and greater degrees of clinical beta-blockade.
The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations.
The mean Cmaxand 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 Cmaxand 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.
Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and Cmaxby 37%) or rizatriptan (the AUC and Cmaxwere increased by 67% and 75%, respectively).
Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%.
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.
Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%.
Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level.
Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and Cmaxby 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations.
Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol's pharmacokinetics.
Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations.
Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin.
Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time.
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 Capsules (60, 80, 120, and 160 mg) release propranolol HCl at a controlled and predictable rate. Peak blood levels following dosing with Inderal LA 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.
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 naphthyloxylactic 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 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 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.
Propranolol is a racemic mixture of two enantiomers, R(+) and S(-). The S(-)-enantiomer is approximately 100 times as potent as the R(+)-enantiomer in blocking beta-adrenergic receptors. In normal subjects receiving oral doses of racemic propranolol, S(-)-enantiomer concentrations exceeded those of the R(+)-enantiomer by 40 to 90% as a result of stereoselective hepatic metabolism. Clearance of the pharmacologically active S(-)-propranolol is lower than R(+)-propranolol after intravenous and oral doses.
The pharmacokinetics of Inderal LA have not been investigated in patients over 65 years of age.
In a study of 12 elderly (62 to 79 years old) and 12 young (25 to 33 years old) healthy subjects, the clearance of S-enantiomer of propranolol was decreased in the elderly. Additionally, the half-life of both the R- and S-propranolol were prolonged in the elderly compared with the young (11 hours vs. 5 hours).
Clearance of propranolol is reduced with aging due to decline in oxidation capacity (ring oxidation and side chain oxidation). Conjugation capacity remains unchanged. In a study of 32 patients age 30 to 84 years given a single 20-mg dose of propranolol, an inverse correlation was found between age and the partial metabolic clearances to 4-hydroxypropranolol (40HP ring oxidation) and to naphthoxylactic acid (NLA-side chain oxidation). No correlation was found between age and the partial metabolic clearance to propranolol glucuronide (PPLG conjugation).
In a study of 9 healthy women and 12 healthy men, neither the administration of testosterone nor the regular course of the menstrual cycle affected the plasma binding of the propranolol enantiomers. In contrast, there was a significant, although non-enantioselective diminution of the binding of propranolol after treatment with ethinyl estradiol. These findings are inconsistent with another study, in which administration of testosterone cypionate confirmed the stimulatory role of this hormone on propranolol metabolism and concluded that the clearance of propranolol in men is dependent on circulating concentrations of testosterone. In women, none of the metabolic clearances for propranolol showed any significant association with either estradiol or testosterone.
A study conducted in 12 Caucasian and 13 African-American male subjects taking propranolol, showed that at steady state, the clearance of R(+)- and S(-)-propranolol were about 76% and 53% higher in African-Americans than in Caucasians, respectively.
Chinese subjects had a greater proportion (18% to 45% higher) of unbound propranolol in plasma compared to Caucasians, which was associated with a lower plasma concentration of alpha-1-acid glycoprotein.
The pharmacokinetics of Inderal LA have not been investigated in patients with renal insufficiency.
In a study conducted in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5 healthy subjects, who received a single oral dose of 40 mg of propranolol, the peak plasma concentrations (Cmax) of propranolol in the chronic renal failure group were 2 to 3-fold higher (161±41 ng/mL) than those observed in the dialysis patients (47±9 ng/mL) and in the healthy subjects (26±1 ng/mL). Propranolol plasma clearance was also reduced in the patients with chronic renal failure.
Studies have reported a delayed absorption rate and a reduced half-life of propranolol in patients with renal failure of varying severity. Despite this shorter plasma half-life, propranolol peak plasma levels were 3 to 4 times higher and total plasma levels of metabolites were up to 3 times higher in these patients than in subjects with normal renal function.
Chronic renal failure has been associated with a decrease in drug metabolism via down regulation of hepatic cytochrome P450 activity resulting in a lower "first-pass" clearance.
Propranolol is not significantly dialyzable.
The pharmacokinetics of Inderal LA have not been investigated in patients with hepatic insufficiency.
Propranolol is extensively metabolized by the liver. In a study conducted in 6 patients with cirrhosis and 7 healthy subjects receiving 160 mg of a long-acting preparation of propranolol once a day for 7 days, the steady-state propranolol concentration in patients with cirrhosis was increased 2.5-fold in comparison to controls. In the patients with cirrhosis, the half-life obtained after a single intravenous dose of 10 mg propranolol increased to 7.2 hours compared to 2.9 hours in control (see
All drug interaction studies were conducted with propranolol. There are no data on drug interactions with Inderal LA capsules.
Because propranolol's metabolism involves multiple pathways in the Cytochrome P-450 system (CYP2D6, 1A2, 2C19), co-administration 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
Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole.
Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan.
Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction was observed with omeprazole.
Blood levels of propranolol may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in decreased plasma concentrations.
The AUC of propafenone is increased by more than 200% by co-administration of propranolol.
The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two to three fold increased blood concentration and greater degrees of clinical beta-blockade.
The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations.
The mean Cmaxand 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 Cmaxand 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.
Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and Cmaxby 37%) or rizatriptan (the AUC and Cmaxwere increased by 67% and 75%, respectively).
Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%.
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.
Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%.
Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level.
Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and Cmaxby 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations.
Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol's pharmacokinetics.
Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations.
Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin.
Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time.
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.
Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with β-blockers such as propranolol.
The clearance of lidocaine is reduced with administration of propranolol. Lidocaine toxicity has been reported following co-administration with propranolol.
Caution should be exercised when administering Inderal LA with drugs that slow A-V nodal conduction, e.g., lidocaine and calcium channel blockers.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
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.
When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction.
The antihypertensive effects of clonidine may be antagonized by beta-blockers. Inderal LA should be administered cautiously to patients withdrawing from clonidine.
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.
Patients receiving catecholamine-depleting drugs, such as reserpine 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.
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
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.
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.
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.
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.
Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol.
Propranolol when administered with warfarin increases the concentration of warfarin. Prothrombin time, therefore, should be monitored.
Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.
Thyroxine may result in a lower than expected T3 concentration when used concomitantly with propranolol.
Inderal® LA (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:
C16H21NO2 · HCl
Propranolol hydrochloride USP is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.80.
Inderal LA is formulated to provide a sustained release of propranolol hydrochloride USP. Inderal LA is available as 60 mg, 80 mg, 120 mg, and 160 mg capsules for oral administration.
• Each Inderal LA 60 mg capsule contains 60 mg propranolol hydrochloride USP (equivalent to 52.60 mg of propranolol).• Each Inderal LA 80 mg capsule contains 80 mg propranolol hydrochloride USP (equivalent to 70.14 mg of propranolol).• Each Inderal LA 120 mg capsule contains 120 mg propranolol hydrochloride USP (equivalent to 105.21 mg of propranolol).• Each Inderal LA 160 mg capsule contains 160 mg propranolol hydrochloride USP (equivalent to 140.28 mg of propranolol).
The inactive ingredients contained in Inderal LA capsules are: diethyl phthalate, hypromellose phthalate, ethylcellulose, povidone, polyethylene glycol, corn starch, sucrose, hypromellose, gelatin capsules and titanium dioxide. In addition Inderal LA 60 mg capsules contain D&C Red No. 28 and FD&C Blue No. 1; Inderal LA 80 mg and 120 mg capsules contain FD&C Red No. 3 and FD&C Blue No. 1; Inderal LA 160 mg capsules contain FD&C Blue No. 1.
FDA approved dissolution specifications differ from USP.