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It can be expected that concomitant administration of CYP3A4 enzyme-inducers, like the rifamycins, will decrease plasma levels of vardenafil. Rifamycins: (Minor) Vardenafil is metabolized by cytochrome P450 3A4.

It can be expected that concomitant administration of CYP3A4 enzyme-inducers, like the rifamycins, will decrease plasma levels of vardenafil. Rifapentine: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, like the rifamycins, will decrease plasma levels of vardenafil. Rilpivirine: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vardenafil. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.

Riociguat: (Severe) Coadministration of riociguat and vardenafil is contraindicated due to the risk of hypotension. Risperidone: (Moderate) Use risperidone and vardenafil together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Ritonavir: (Major) Coadministration of ritonavir with vardenafil results in a 20% decrease in ritonavir AUC and a 49-fold increase in vardenafil AUC. Substantially increased vardenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.

If coadministered, use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, use of the orally disintegrating tablets with ritonavir is not recommended. In addition, both ritonavir and vardenafil are associated with QT prolongation; concomitant use increases the risk of QT prolongation.

Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with vardenafil as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Sapropterin: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation.

Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors.

When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies.

The additive effect of these agents has not been studied in humans. Saquinavir: (Major) Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving saquinavir as there is an increased risk for serious adverse effects. Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as vardenafil, if possible. Coadministration of saquinavir, especially when 'boosted' with ritonavir, with vardenafil is expected to substantially increase vardenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.

In addition, saquinavir boosted with ritonavir increases the QT and PR intervals in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP).

Although it is best to avoid this drug combination if possible, if no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy (see Contraindications), and use vardenafil at reduced doses of no more than 2.5 mg, every 24 hours when used with saquinavir or every 72 hours when used with ritonavir-'boosted' saquinavir, with increased monitoring for adverse reactions.

The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as saquinavir.

Sertraline: (Moderate) Use caution and monitor patients for QT prolongation when administering vardenafil with sertraline. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.

Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).

Short-acting beta-agonists: (Minor) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).

The effect of vardenafil on the QT interval should be considered when prescribing the drug.

Drugs with a possible risk for QT prolongation that should be used cautiously with vardenafil include the beta agonists.

Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.

Silodosin: (Moderate) Due to the potential cvs sildenafil coupon for symptomatic hypotension, patients should be stable on silodosin therapy before initiating therapy with the lowest dose of vardenafil. Conversely, patients already receiving an optimized dose of vardenafil should be started on the lowest dose of silodosin; increases in the alpha-blocker dose should be done in a stepwise fashion. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of vardenafil and silodosin. Simeprevir: (Moderate) Coadministration of vardenafil with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in vardenafil plasma concentrations. No dose adjustments are required when treating erectile dysfunction. Siponimod: (Major) Avoid coadministration of siponimod and vardenafil due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study.

Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Solifenacin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering solifenacin with vardenafil.

Solifenacin has been associated with dose-dependent prolongation of the QT interval; TdP has been reported during post-marketing use, although causality was not determined. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Sorafenib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of sorafenib with vardenafil is necessary; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs.

Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.

Sorafenib has also been associated with QT prolongation. Sotalol: (Major) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).

The effect of vardenafil on the QT interval should be considered when prescribing the drug. The manufacturer recommends that vardenafil be avoided in patients taking sotalol.

Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.

Sparfloxacin

: (Moderate) Sparfloxacin is associated with an established risk for QT prolongation and torsades de pointes. This risk my be increased if combined with other drugs that may prolong the QT interval, such as vardenafil.

Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with vardenafil. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.

Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with vardenafil. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Tadalafil: (Major) The safety and efficacy of tadalafil administered concurrently with any other phosphodiesterase (PDE5) inhibitors, such as vardenafil, has not been studied.

The manufacturer of tadalafil recommends to avoid the use of tadalafil with any other PDE5 inhibitors. Tamoxifen: (Moderate) Caution is advised with the concomitant use of tamoxifen and vardenafil due to an increased risk of QT prolongation.

Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Vardenafil is also associated with QT prolongation.

Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Tamsulosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on tamsulosin therapy before initiating therapy with the lowest dose of vardenafil.

Conversely, patients already receiving an optimized dose of vardenafil should be started on the lowest dose of tamsulosin; increases in the alpha-blocker dose should be done in a stepwise fashion.

Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of vardenafil and tamsulosin. Telaprevir: (Major) Close clinical monitoring is advised when administering vardenafil with telaprevir due to an increased potential for vardenafil-related adverse events, such as QT interval prolongation.

During coadministration, do not exceed a maximum vardenafil dosage of 2.5 mg in 72 hours. If vardenafil dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment.

Predictions about the interaction can be made based on the metabolic pathways of vardenafil. Vardenafil is a substrate of the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme.

When used in combination, the plasma concentrations of vardenafil may be elevated.

Telavancin: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with vardenafil. Telavancin has been associated with QT prolongation.

Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil also produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). Telithromycin: (Major) Do not use vardenafil orally disintegrating tablets with telithromycin.

Decrease the dose of vardenafil oral tablets if administered with telithromycin. Coadministration may increase vardenafil exposure and the risk of QT prolongation.

Vardenafil is a sensitive CYP3A4 substrate that can produce an increase in QTc interval at both therapeutic and supratherapeutic doses. Telithromycin is a strong CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP).

Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of vardenafil in healthy volunteers by 10-fold and 4-fold, respectively. Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and vardenafil is necessary, as the systemic exposure of vardenafil may be decreased resulting in reduced efficacy.

If these drugs are used together, monitor patients for suboptimal efficacy of vardenafil; consider increasing the dose of vardenafil if necessary. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Terazosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alpha-blocker therapy before initiating therapy with the lowest dose of vardenafil.

Conversely, patients already receiving an optimized dose of vardenafil should be started on the lowest dose of the alpha-blocker; increases in the alpha-blocker dose should be done in a stepwise fashion. Other variables, such as intravascular volume depletion, concurrent antihypertensive therapy, or evidence of hemodynamic instability with alpha-blocker monotherapy, may affect the safety of concomitant use of vardenafil and an alpha-blocker. Tetrabenazine: (Major) Tetrabenazine causes a small increase in sildenafil soft tabs the corrected QT interval.

Caution is advisable during concurrent use of other agents associated with a possible risk for QT prolongation and TdP including vardenafil.

Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. The effect of vardenafil on the QT interval should be considered when prescribing the drug. Thiethylperazine: (Major) Concomitant administration of thiethylperazine with vardenafil may cause additive QT prolongation and should be used cautiously. Thioridazine: (Severe) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP).

Thioridazine is considered contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Because of the potential for TdP, use of vardenafil with thioridazine is contraindicated. Tipranavir: (Major) Concurrent use of tipranavir boosted with ritonavir and varadenafil is expected to substantially increase vardenafil plasma concentrations and may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection.

During coadministration, use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.

Tolterodine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with vardenafil.

Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil also produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).

Toremifene: (Major) Avoid coadministration of vardenafil with toremifene if possible due to the risk of additive QT prolongation.

If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene.

Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.

Vardenafil is associated with QT prolongation at both therapeutic and supratherapeutic doses.

Trandolapril; Verapamil: (Moderate) Vardenafil is metabolized by hepatic CYP3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4, such as verapamil, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. Patients taking moderate CYP3A4 inhibitors, such as verapamil, may need to have their vardenafil dose decreased to 5 mg PO in a 24-hour period. Antihypertensives, when used with vardenafil, additionally have additive effects on blood pressure. In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing.

Trazodone: (Major) Avoid coadministration of vardenafil and trazodone. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).

When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed.

Trazodone can prolong the QT/QTc interval at therapeutic doses.

In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.

Tricyclic antidepressants: (Minor) Use vardenafil with caution in combination with tricyclic antidepressants (TCAs) as concurrent use may increase the risk of QT prolongation.

Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose

prescription

therapy (elevated serum concentrations).

Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Trifluoperazine: (Minor) Use vardenafil with caution in combination with trifluoperazine as concurrent use may increase the risk of QT prolongation.

Trifluoperazine is associated with a possible risk for QT prolongation.

Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.

Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving vardenafil as concurrent use may increase the risk of QT prolongation.

Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.

Androgen deprivation therapy may cvs sildenafil coupon also prolong the QT/QTc interval.

Vandetanib: (Major) Avoid coadministration of vandetanib with vardenafil due to an increased risk of QT prolongation and torsade de pointes (TdP).

If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration.

An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation.

Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib.

Both therapeutic and supratherapeutic doses of vardenafil also produce an increase in QTc interval. Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation.

If vemurafenib and another drug, such as vardenafil, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, vardenafil is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate/inducer.

Therefore concentrations of vardenafil may be decreased with concomitant use.

Venlafaxine: (Moderate) Use vardenafil with caution in combination with venlafaxine due to increased risk of QT prolongation.

Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc

interval

.

Venlafaxine administration is also associated with a possible risk of QT prolongation; torsade de pointes has been reported with postmarketing use.

Verapamil: (Moderate) Vardenafil is metabolized by hepatic CYP3A4 and to a lesser extent CYP2C9.

Inhibitors of CYP3A4, such as verapamil, can reduce vardenafil clearance.

Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.

Patients taking moderate CYP3A4 inhibitors, such as verapamil, may need to have their vardenafil dose decreased to 5 mg PO in a 24-hour period.

Antihypertensives, when used with vardenafil, additionally have additive effects on blood pressure.

In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute.

The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Vigabatrin: (Major) Vigabatrin should not be used with phosphodiesterase inhibitors, which is associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks. Voriconazole: (Major) Caution is advised when administering voriconazole with vardenafil due to the potential for additive effects on the QT interval and increased exposure to vardenafil. If these drugs must be administered together, consider use of a lower vardenafil dose. However, because vardenafil orally disintegrating tablets (ODTs) provide increased exposure as compared to the regular tablets, concurrent use of vardenafil ODTs and voriconazole should be avoided. In addition, because both vardenafil and voriconazole are associated with QT prolongation, coadministration may increase the risk irregular heartbeats. If these drugs are given together, closely monitor for prolongation of the QT interval.

Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.

Vorinostat: (Moderate) Use vardenafil with caution in combination with vorinostat due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Vorinostat therapy is also associated with a risk of QT prolongation.



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