Drug Interactions between IFE-Bimix 30/1 and vardenafil

MONITOR CLOSELY: Intracoronary administration of papaverine has been associated with QT interval prolongation and torsade de pointes (TdP) arrhythmia. The risk may theoretically increase in patients receiving concomitant medications that can also prolong the QT interval or cause bradycardia. QT interval prolongation has not been reported following systemic or intracavernosal administration of papaverine. The precise mechanism of papaverine-induced ventricular tachyarrhythmias has not been delineated, but may involve inhibition of potassium currents and prolongation of the action potential duration. In a study involving 182 consecutive patients undergoing fractional flow reserve measurements, premature ventricular beats occurred in 15.9% of patients following administration of intracoronary papaverine. TdP occurred in 2.8% of patients, and of those, 1.7% developed ventricular fibrillation. The incidence of intracoronary papaverine-induced ventricular tachyarrhythmias has not been determined, but has ranged between <0.67% and 8.8% following intracoronary administration of 6 mg to 20 mg. Based on numerous reports, female gender, hypokalemia, alkalosis, bradycardia, administration of papaverine into the left coronary artery, and a prior history of drug-induced QT prolongation may be risk factors for papaverine-induced fatal ventricular tachyarrhythmias. Apart from isolated case reports, there are no published data regarding the potential interaction between intracoronary papaverine and its use with other QT-prolonging drugs. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drugs involved and dosages of the drugs.

MANAGEMENT: Caution and close monitoring are advised during intracoronary administration of papaverine, particularly in patients receiving concomitant drugs that can prolong the QT interval or cause bradycardia and in patients with other risk factors described above. Some QT prolonging medications have specific monitoring, dosing, and/or other recommendations present in their labeling to help mitigate or monitor this side effect; therefore, it may be advisable to consult the package labeling of the concomitant medication if coadministration with intracoronary papaverine is being considered or deemed necessary.

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.