Inducers of Hepatic Drug Metabolism

Blood levels of propranolol may be decreased by administration of InnoPran XL with inducers such as rifampin and ethanol. Cigarette smoking also induces hepatic metabolism and has been show to increase up to 100% the clearance of propranolol, resulting in decrease plasma concentrations.

Cardiovascular Drugs

Antiarrhythmics

The concomitant administration of propranolol and propafenone increased propranolol average steady-state plasma concentrations (213%), AUC (113%), Cmax (83%), Tmax (55%), and T½ (30%), and significantly decreased plasma levels of 4-hydroxy-propranolol. Co-administration of propranolol and propafenone did not produce any significant change in propafenone pharmacokinetics. While the therapeutic range for propranolol is wide, a reduction in dosage may be necessary during concomitant administration with propafenone.

The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two-three fold increase in blood concentrations 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.

Calcium channel blockers

The mean Cmax and 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 Cmax and 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.

Non-Cardiovascular Drugs

Anti-Ulcer Drugs

Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol concentrations by about 40%. Co-administration with aluminum hydroxide gel (1200 mg) resulted in a 50% decrease in propranolol concentrations.

Co-administration of metoclopramide with propranolol did not have a significant effect on propranolol's pharmacokinetics.

Benzodiazepines

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.

Lipid Lowering Drugs

Co-administration of cholesteramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations.

Co-administration of propranolol with lovastatin or pravastatin decreased 20% to 25% the AUC of both, but did not alter their pharmacodynamics. Propranolol did not have an effect on the pharmacokinetics of fluvastatin.

Migraine Drugs

Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and Cmax by 37%) or rizatriptan (the AUC and Cmax were increased by 67% and 75%, respectively).

Neuroleptic Drugs

Co-administration of propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 50% to 370% and increased thioridazine metabolites concentrations ranging from 33% to 210%.

Co-administration of chlopromazine with propranolol resulted in increased plasma levels of both drugs (70% increase in propranolol concentrations).

Theophylline

Co-administration of theophylline with propranolol decreases theophylline oral clearance by 33% to 52%.

Warfarin

Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time.

Pharmacodynamics And Clinical Effects

Hypertension

In a double-blind, parallel dose-response study in patients with mild-to-moderate hypertension (n=434), doses of InnoPran XL from 80 to 640 mg were taken once daily at approximately 10PM. InnoPran 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 were -3.0 and -4.0 mm Hg, respectively. Higher doses of InnoPran XL (160, 640 mg) had no additional blood pressure lowering effect when compared with 120 mg. The antihypertensive effects of InnoPran XL were seen in the elderly (greater than or equal to 65 years old) and men and women. There were too few non-White patients to assess the efficacy of InnoPran XL in these patients.

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