DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Inderal XL (Propranolol Hydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

INDERAL XL contains propranolol hydrochloride, a nonselective, beta-adrenergic receptor-blocking agent for oral administration, as an extended- release product. INDERAL XL is available as 80 mg and 120 mg capsules which contain sustained-release beads. Each of the beads contains propranolol hydrochloride and is coated with dual membranes. These membranes are designed to retard release of propranolol hydrochloride for several hours after ingestion followed by the sustained release of propranolol.

The active ingredient in INDERAL XL is a synthetic beta-adrenergic receptor-blocking agent chemically described as 1‑(Isopropylamino)‑3-(1‑naphthyloxy)‑2‑propanol hydrochloride. Its structural formula is:

Propranolol hydrochloride is a stable, white, crystalline solid, which is readily soluble in water and ethanol. Its molecular weight is 295.81. Each capsule for oral administration contains sugar spheres, ethylcellulose, povidone, hypromellose phthalate, diethyl phthalate, hypromellose, polyethylene glycol, gelatin, titanium dioxide. The ink contains FD&C Blue #2 Aluminum Lake. In addition, INDERAL XL 120 mg capsules contain yellow iron oxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of the antihypertensive effect of propranolol has not been established. Among factors that contribute to the antihypertensive action are: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use. Effects of propranolol on plasma volume appear to be minor and somewhat variable.

Pharmacodynamics

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. Of the 2 enantiomers of propranolol, the S-enantiomer blocks beta-adrenergic receptors. When access to beta‑receptor sites is blocked by propranolol, 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.

Pharmacokinetics

Absorption: Propranolol is highly lipophilic and is 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.

A single-dose, food-effect study in 36 healthy subjects showed that a high fat meal administered with INDERAL XL at 10 p.m., increased the lag time from 3 to 5 hours and the time to reach the maximum concentration from 11.5 to 15.4 hours, with no effect on the AUC.

Following multiple-dose administration of INDERAL XL at 10 p.m. under fasting conditions, the steady state lag time was between 4 and 5 hours and propranolol peak plasma concentrations were reached approximately 12 to 14 hours after dosing. Propranolol trough levels were achieved 24 to 27 hours after dosing, and persisted for 3 to 5 hours after the next dose.

The plasma levels of propranolol showed dose-proportional increases after single and multiple administration of 80, 120, and 160mg of INDERAL XL.

At steady state, the bioavailability of a 160 mg dose of INDERAL XL and propranolol hydrochloride long-acting capsules did not differ significantly.

Distribution: Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha1 acid glycoprotein). The binding is enantiomer-selective. The S‑isomer is preferentially bound to alpha1 glycoprotein and the R‑isomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters.

Metabolism and Elimination: Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through 3 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 4 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 for 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 to 4‑hydroxy propranolol was significantly higher and to naphthyloxylactic acid was significantly lower in EMs than PMs.

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.

The elimination half-life of propranolol was approximately 8 hours.

Specific Populations

Pediatric: The pharmacokinetics of INDERAL XL have not been investigated in patients younger than 18 years of age.

Geriatric: The pharmacokinetics of INDERAL XL have not been investigated in patients older than 65 years. In a study of 12 elderly (62 to 79 years old) and 12 young (25 to 33 years old) healthy subjects administered immediate-release propranolol, the clearance of the S-enantiomer of propranolol was decreased in the elderly. Additionally, the half-lives of both R- and S-propranolol were prolonged in the elderly compared with the young (11 hours versus 5 hours).

Gender: In a dose-proportionality study, the pharmacokinetics of INDERAL XL were evaluated in 22 male and 14 female healthy volunteers. Following single doses under fasting conditions, the mean AUC and Cmax were about 49% and 16% higher for females across the dosage range. The mean elimination half-life was longer in females than in males (11 hours versus 7.5 hours).

Race: A study conducted in 12 white and 13 African-American male subjects taking immediate-release propranolol showed, that at steady state, the clearance of R- and S-propranolol were about 76% and 53% higher in African-Americans than in whites, respectively.

Renal Impairment: The pharmacokinetics of propranolol after administration of INDERAL XL have not been evaluated in patients with renal impairment. 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 3- to 5-fold (161±41 ng/mL) 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.

Chronic renal failure has been associated with a decrease in drug metabolism via down regulation of hepatic cytochrome P450 activity.

Propranolol is not significantly dialyzable.

Hepatic Impairment: The pharmacokinetics of propranolol after administration of INDERAL XL have not been evaluated in patients with hepatic impairment. However, propranolol is extensively metabolized by the liver. In a study conducted in 7 patients with cirrhosis and 9 healthy subjects receiving 80 mg oral propranolol every 8 hours for 7 doses, the steady-state unbound propranolol concentration in patients with cirrhosis was 3-fold that of controls. In cirrhosis, the half-life increased to 11 hours compared to 4 hours.

Drug-Drug Interactions

Impact of Propranolol on Other Drugs
The effect of propranolol on exposure to other drugs is shown in Table 2.

Table 2 Impact of propranolol on other drugs
  Other drug   Effect on their exposure
  Amide anesthetics (lidocaine,
  bupivacaine, mepivicaine)
  Increased
  Warfarin   Increased
  Propafenone   Increased >200%
  Nifedipine   Increased 80%
  Verapamil   None
  Pravastatin, lovastatin   Decreased 20%
  Fluvastatin   None
  Zolmitriptan   Increased 60%
  Rizatriptan   Increased 80%
  Thioridazine   Increased 370%
  Diazepam   Increased
  Oxazepam, triazolam,
  lorazepam, alprazolam
  None
  Theophylline   Increased 70%

Impact of Other Drugs on Propranolol
The effect of propranolol on exposure to other drugs is shown in Table 3.

Table 3 Impact of other drugs on exposure to propranolol
  Other drug   Effect on propranolol exposure
  Inhibitors of CYP2D6,
  CYP1A2, or CYP2C19
  Increased
  Inducers of CYP1A2 or
  CYP2C19
  Decreased
  Quinidine   Increased >200%
  Nisoldipine   Increased 50%
  Nicardipine   Increased 80%
  Chlorpromazine   Increased 70%
  Cimetidine   Increased 50%
  Cholestyramine, colestipol   Decreased 50%
  Alcohol   Increased
  Diazepam   None
  Verapamil   None
  Metochlopramide   None
  Ranitidine   None
  Lansoprazole   None
  Omeprazole   None
  Alcohol   Increase acutely or decrease chronically
  Propafenone   Increased 200%
  Quinidine   Increased 200%
  Cimetidine   Increased 40%
  Aluminum hydroxide   Decreased 50%
  Diazepam   None
  Nisoldipine, nicardipine,
  nifedipine
  Increased 50-80%

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In dietary administration studies in which mice and rats were treated with propranolol HCl for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug‑related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is, respectively, about equal to and about twice the MRHD of 640 mg propranolol HCl. In a study in which both male and female rats were exposed to propranolol HCl in their diets at concentrations of up to 0.05% (about 50 mg/kg body weight and less than the MRHD), from 60 days prior to mating and throughout pregnancy and lactation for 2 generations, there were no effects on fertility. Based on differing results from Ames tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol HCl in bacteria (S. typhimurium strain TA 1538).

CLINICAL STUDIES

Hypertension

In a double-blind, parallel dose-response study in patients with mild-to-moderate hypertension (n=434), doses of INDERAL XL from 80 to 640 mg were taken once daily at approximately 10 p.m. INDERAL XL significantly lowered sitting systolic and diastolic blood pressure when measurements were taken approximately 16 hours later. The placebo-subtracted diastolic blood pressure effect for the 80 and 120 mg doses was -3.0 and -4.0 mm Hg, respectively. Higher doses of INDERAL XL (160, 640 mg) had no additional blood-pressure lowering effect when compared with 120 mg. The antihypertensive effects of INDERAL XL were seen in the elderly (≥65 years old) and men and women. There were too few non-white patients to assess the efficacy of INDERAL XL in these patients.

HOW SUPPLIED/STORAGE AND HANDLING

INDERAL XL (propranolol hydrochloride) Extended-Release Capsules are supplied as capsules containing either 80 mg, or 120 mg propranolol hydrochloride imprinted with “Inderal XL”.

Strength
  
Color
  
Bands
  
  NDC 76299-xxx-xx
  Bottle/30   Bottle/100
  80 mg   white opaque   1   420-85 420-88
  120 mg   buff opaque   3   422-85 422-88

Storage: Store at 25ºC (77ºF); excursions permitted to 15º and 30ºC (59º and 86ºF) [see USP Controlled Room Temperature] in a tightly closed container.

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017