Drug Interaction Report

MONITOR: Concomitant use of multiple vasodilator drugs for the treatment of erectile dysfunction (ED) may increase the risk of additive adverse effects, including hypotension, dizziness, syncope, prolonged erection, or priapism. However, available data are conflicting. For example, approximately 4.9% and 7.1% of people in selected studies using single ingredient intracavernosal injections (ICIs) of papaverine reported experiencing painful/prolonged erections and priapism, respectively. Conversely, selected studies of people using ICIs containing papaverine and phentolamine reported an increase in the average rate of prolonged/painful erections to approximately 8.9%, but a reduction in the average rate of priapism to approximately 5.5%. Additionally, 1 case series reported an increase in dizziness and syncope when patients used both oral agents and ICIs to treat ED. Clinical data are not available for all possible combinations. The route of administration and amount of medication absorbed systemically may affect the clinical significance and severity of this interaction.

MANAGEMENT: Most clinical guidelines advise caution and closer clinical monitoring for patients on erectile dysfunction (ED) regimens that include multiple vasodilative agents due to the potential for additive adverse effects. Some drug manufacturers recommend avoiding combinations due to the potential risks and a lack of established data on safety. However, some of these medications are available as combinations (either commercially or via compounding) and some ED guidelines indicate that combination therapy may be appropriate in certain situations. Healthcare providers should refer to the product labeling and appropriate treatment guidelines for the most up to date information and recommendations; as well as, counsel patients on potential adverse effects and what to do should they occur.

MONITOR: Concomitant use of multiple vasodilator drugs for the treatment of erectile dysfunction (ED) may increase the risk of additive adverse effects, including hypotension, dizziness, syncope, prolonged erection, or priapism. However, available data are conflicting. For example, approximately 4.9% and 7.1% of people in selected studies using single ingredient intracavernosal injections (ICIs) of papaverine reported experiencing painful/prolonged erections and priapism, respectively. Conversely, selected studies of people using ICIs containing papaverine and phentolamine reported an increase in the average rate of prolonged/painful erections to approximately 8.9%, but a reduction in the average rate of priapism to approximately 5.5%. Additionally, 1 case series reported an increase in dizziness and syncope when patients used both oral agents and ICIs to treat ED. Clinical data are not available for all possible combinations. The route of administration and amount of medication absorbed systemically may affect the clinical significance and severity of this interaction.

MANAGEMENT: Most clinical guidelines advise caution and closer clinical monitoring for patients on erectile dysfunction (ED) regimens that include multiple vasodilative agents due to the potential for additive adverse effects. Some drug manufacturers recommend avoiding combinations due to the potential risks and a lack of established data on safety. However, some of these medications are available as combinations (either commercially or via compounding) and some ED guidelines indicate that combination therapy may be appropriate in certain situations. Healthcare providers should refer to the product labeling and appropriate treatment guidelines for the most up to date information and recommendations; as well as, counsel patients on potential adverse effects and what to do should they occur.

MONITOR: Concurrent use of a phosphodiesterase-5 (PDE5) inhibitor with phentolamine may result in additive adverse effects resulting from both medications acting as vasodilators. Additional factors may affect the severity of this interaction including the route of administration, dosing regimen, amount of each medication absorbed systemically, presence of intravascular depletion, and use of other medications with hypotensive effects. Reductions of systolic BP ranging from 2.5 mmHg to greater than 30 mmHg from baseline have been reported with alfuzosin, doxazosin, tamsulosin and/or terazosin. However, data are not available for all formulations of phentolamine. There are studies which evaluate the combination of intracavernosal injections (ICIs) containing phentolamine with an oral PDE5 inhibitor for erectile dysfunction (ED). In one case series, 93 patients were treated for ED with sildenafil monotherapy or sildenafil in combination with ICI triple-therapy after failing a trial of ICI (monotherapy or triple therapy). Those who received sildenafil in combination with ICI triple-therapy (n=41) reported an increase in adverse effects (e.g., dizziness, syncope) when compared to monotherapy (49% with combination therapy vs. 31% with ICI alone and 37% with sildenafil alone).

MANAGEMENT: Caution and clinical monitoring for adverse effects (e.g., hypotension, dizziness, syncope, priapism) are advised if phentolamine is used in combination with a PDE5 inhibitor. Some manufacturers (both of PDE5 inhibitors as well as of phentolamine) advise against combining treatments for ED due to a lack of safety and efficacy data. However, there are guidelines specific to the treatment of ED which contain guidance for using an oral PDE5 inhibitor with ICIs containing phentolamine (though this may be an off-label indication for phentolamine). The severity of this interaction may be affected by additional factors listed above. In general, most product labeling recommends stabilizing a patient on either alpha-blocker therapy or PDE5 inhibitor therapy first and then initiating the other medication with the knowledge that increases in dosage may result in further lowering of blood pressure. If combination therapy is used, consultation with product labeling and relevant treatment guidelines as well as counseling the patient on potential adverse effects is recommended.

GENERALLY AVOID: Coadministration with grapefruit juice may slightly increase the oral bioavailability and delay the onset of action of sildenafil. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In a randomized, crossover study with 24 healthy male volunteers, ingestion of 250 mL of grapefruit juice one hour before and concurrently with a 50 mg dose of sildenafil increased the mean area under the plasma concentration-time curve (AUC) of sildenafil and its pharmacologically active N-desmethyl metabolite by 23% and 24%, respectively, compared to water. Peak plasma concentrations (Cmax) were unaltered, but the time to reach sildenafil Cmax was prolonged by 0.25 hour. The observed increase in sildenafil bioavailability is unlikely to be of clinical significance in most individuals. However, pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability and may be significant in the occasional susceptible patient. Indeed, one subject in the study had a 2.6-fold increase in sildenafil concentrations.

MANAGEMENT: It may be advisable to avoid administration of sildenafil with grapefruit juice to prevent potential toxicity and delay in onset of action.

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients should also avoid driving or operating hazardous machinery until they know how the medications affect them.

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients should also avoid driving or operating hazardous machinery until they know how the medications affect them.