Health and Prostate

Clinically Relevant Drug­-Drug Interactions With the 5-Alpha-Reductase Inhibitors

Neither dutasteride nor finasteride have any clinically significant pharmacodynamic or pharmacokinetic adverse drug interactions. Studies show that the 5-alpha-reductase inhibitors do not affect the CYP 450 enzyme system. However, agents that inhibit the CYP 450 3A4 may, in theory, interfere with metabolism of these medications. Therefore, until more data are available, cautious monitoring should follow the concurrent administration of a 5-alpha-reductase inhibitor with an agent known to alter the activity of the hepatic mixed function oxidase enzyme system.

Pharmacodynamic Drug-Drug Interactions With PDE-5 Inhibitors

Pharmacodynamic drug interactions leading to precipitous hypotension and MI are clinically relevant with PDE-5 inhibitors. All selective inhibitors of cyclic GMP-specific PDE-5 are prone to clinically significant pharmacodynamic interactions with agents that produce vasodilation. The concurrent use of nitrate preparations is a contraindication to treatment with selective inhibitors of cyclic GMP-specific PDE-5. The selective inhibitors of cyclic GMP-specific PDE-5 differ with regard to the warning against concurrent use of with alpha-1-adrenergic blockers. For example, sildenafil in doses above 25 mg should not be used within four hours after ingestion of an alpha-1-adrenergic blocker. Vardenafil is contraindicated in patients treated with alpha-1-adrenergic blockers. Tadalafil is contraindicated in patients receiving an alpha-1-adrenergic blocker, with the exception of those taking tamsulosin 0.4 mg once daily. Extreme caution should be employed when any PDE-5 inhibitors are used in patients receiving antihypertensive medications (e.g., nitroprusside, nitroglycerin, phentolamine, amyl nitrate, ACE inhibitors, angiotensin receptor blockers, hydralazine, and nitrates) because the vasoactive effects of the combination may be exaggerated. Lastly, the concurrent administration of PDE-5 inhibitors and opiates (e.g., dihydrocodeine) results in exaggerated release of cyclic GMP and has been reported to produce priapism. An increased risk of cardiac events has been suspected with these agents when given concurrently with vasoactive agents that may steal blood from the cardiac collateral circulation.

Pharmacokinetic Drug­-Drug Interactions With PDE-5 Inhibitors

There are increasing numbers of patients with ED who are taking concurrent medications that can affect the metabolism of PDE-5 inhibitors. Medications that inhibit CYP3A4 (e.g., protease inhibitors, azole antifungals, erythromycin, and grapefruit juice) will significantly alter the metabolism and raise the bioavailability of PDE-5 inhibitors. These clinically significant pharmacokinetic interactions require that the dose or dosage interval of the PDE-5 inhibitor be modified to prevent drug accumulation and precipitous hypotension. Table 4 lists the drugs that may produce potentially life-threatening drug­drug interactions if used concurrently with a PDE-5 inhibitor.Although medications that induce CYP3A4 may increase the metabolism of PDE-5 inhibitors, no specific dosage adjustments are required. Lastly, studies show that PDE-5 inhibitors may be given safely with theophylline, digoxin, warfarin, antacids, glyburide, tolbutamide, and ranitidine.

Table 4. Drugs that May Produce Clinically Significant Pharmacokinetic Drug­Drug Interactions With PDE-5 Inhibitors
Sildenafil plus	Mechanism	Effect
Cimetidine 800 mg	CYP3A4 inhibition	56% increase in sildenafil’s Cp
Erythromycin 500 mg BID	CYP3A4 inhibition	182% increase in sildenafil’s AUC
Saquinavir 1.2 g BID	CYP3A4 inhibition	210% increase in sildenafil’s AUC
Indinavir 800 mg TID	CYP3A4 inhibition	340% increase in sildenafil’s AUC
Ritonavir 500 mg BID	CYP3A4 inhibition	1,000% increase in sildenafil’s AUC
Tadalafil plus	Mechanism	Effect
Ketoconazole 400 mg/d	CYP3A4 inhibition	312% increase in tadalafil’s AUC
Ritonavir 200 mg BID	CYP3A4 inhibition	124% increase in tadalafil’s AUC
Rifampin 600 mg/d	CYP3A4 induction	88% reduction in tadalafil’s AUC
Theophylline	CYP1A2 substrate	Pharmacokinetics were unchanged
Vardenafil plus	Mechanism	Effect
Cimetidine 400 mg BID	CYP3A4 inhibition	No effect on vardenafil’s AUC
Erythromycin 500 mg BID	CYP3A4 inhibition	Fourfold increase in vardenafil’s AUC
Ketoconazole 200 mg/d	CYP3A4 inhibition	Tenfold increase in vardenafil’s AUC
Indinavir 800 mg TID	CYP3A4 inhibition	16-fold increase in vardenafil’s AUC
Ritonavir 600 mg BID	CYP3A4 inhibition	49-fold increase in vardenafil’s AUC

Conclusions

Currently, the scientific literature is skewed in its content of useful information regarding potential drug interactions with alpha-1-adrenergic blockers and PDE-5 inhibitors. Most of the information on drug­drug interactions is with the older non­prostate-selective alpha-1-adrenergic blockers. The limited data available with tamsulosin and alfuzosin show that these agents are less likely to have pharmacodynamic interactions with alpha-1-adrenergic blockers than doxazosin or terazosin. Regarding pharmacokinetic interactions, tamsulosin has the lowest potential for clinically significant interactions because it undergoes minimal hepatic metabolism and is primarily eliminated via the kidneys. Fortunately, neither dutasteride nor finasteride have any clinically significant pharmacodynamic or pharmacokinetic adverse drug interactions. Because clinicians see an increasing number of patients being prescribed PDE-5 inhibitors who also have cardiovascular disease, clinicians must be vigilant about the potential for clinically significant pharmacodynamic interactions with medications that produce vasodilation or increase the release of NO. Furthermore, PDE-5 inhibitors are prime targets for clinically important drug interactions with agents that inhibit CYP3A4. Currently, there is insufficient information with which to judge the pharmacodynamic drug interaction liability of alfuzosin and of tamsulosin relative to PDE-5 inhibitors. Until such data are available, patients receiving alfuzosin or tamsulosin should be advised about the potential dangers of concomitant therapy with any of the PDE-5 inhibitors.

Tags: Alfuzosin, Digoxin, Doxazosin, Dutasteride, Erythromycin, Finasteride, Glyburide, Indinavir, Ketoconazole, Ranitidine, Ritonavir, Sildenafil, Tadalafil, Tamsulosin, Terazosin, Vardenafil, Warfarin
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