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    Phosphodiesterase Inhibitors for ED

    DEA CLASS

    Rx

    DESCRIPTION

    Phosphodiesterase type 5 (PDE5) inhibitor similar to sildenafil and tadalafil
    Used for the treatment of erectile dysfunction (ED)
    Achieves maximum plasma concentration sooner than sildenafil and tadalafil; may result in a faster onset of action

    COMMON BRAND NAMES

    Levitra, Staxyn

    HOW SUPPLIED

    Levitra/Staxyn/Vardenafil/Vardenafil Hydrochloride Oral Tab: 2.5mg, 5mg, 10mg, 20mg
    Staxyn Oral Tab Orally Dis: 10mg

    DOSAGE & INDICATIONS

    For the treatment of erectile dysfunction (ED) including ED associated with diabetes or after radical prostatectomy.
    Oral dosage (oral tablet; e.g., Levitra)
    Adult males

    Initially, 10 mg PO approximately 60 minutes before sexual activity. For males 65 years of age or older, consider a lower starting dose of 5 mg PO. The maximum dosing frequency is once per day. May titrate based on efficacy and side effects. Max: 20 mg/day PO. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or vardenafil dosage adjustments may be necessary; review drug interactions. Vardenafil dosage reductions are required in patients taking moderate or potent CYP3A4 inhibitors. If coadministering with an alpha-blocker, patients should be stable on alpha blocker therapy before starting vardenafil, and the initial vardenafil dose should be reduced to 5 mg (or 2.5 mg if given with certain CYP3A4 inhibitors).
    PDE5 inhibitors are first-line agents for ED according to guidelines. Although associated with high rates of success, approximately 35% of ED patients fail to respond to PDE5 inhibitor therapy. A course of an alternate PDE5 inhibitor may be considered if a patient does not respond to a PDE5 inhibitor trial; a treatment failure may be deemed after at least 4 unsuccessful trials. Patients refractory to PDE5 inhibitors should be counseled on appropriate use, potentially modifiable factors (e.g. hormonal abnormalities, food or drug interactions, lack of adequate sexual stimulation, heavy alcohol use, and the patient's relationship with his partner), and the risks and benefits of other therapies. Second-line treatment options include intracavernous injection and intra-urethral therapy. Follow-up visits for ED patients, regardless of therapy, are necessary to determine whether therapy continues to be effective and whether cardiovascular health has significantly changed.

    Adult males taking ritonavir

    A single dose of 2.5 mg PO should not be exceeded in a 72-hour period.

    Adult males taking indinavir, atazanavir, saquinavir, clarithromycin, ketoconazole 400 mg daily, or itraconazole 400 mg daily

    A single dose of 2.5 mg PO should not be exceeded in a 24-hour period.

    Adult males taking erythromycin, ketoconazole 200 mg daily, or itraconazole 200 mg daily

    A single dose of 5 mg PO should not be exceeded in a 24-hour period. If the patient is also taking an alpha-blocker, the initial dose should be 2.5 mg PO.

    Oral dosage (orally disintegrating tablets; e.g., Staxyn)
    Adult males

    10 mg PO, taken approximately 60 minutes before sexual activity (Max dose: 10 mg/day PO). Patients requiring a lower dose of vardenafil should use the film-coated tablets. Do not use the orally disintegrating tablets with concomitant moderate or potent CYP3A4 inhibitors (e.g., ritonavir, indinavir, atazanavir, saquinavir, clarithromycin, ketoconazole, itraconazole, erythromycin). Vardenafil 10 mg orally disintegrating tablets provide higher systemic exposure compared to vardenfil 10 mg film-coated tablets, and these dosage forms are not interchangeable.
    PDE5 inhibitors are first-line agents for ED according to guidelines. Although associated with high rates of success, approximately 35% of ED patients fail to respond to PDE5 inhibitor therapy. A course of an alternate PDE5 inhibitor may be considered if a patient does not respond to a PDE5 inhibitor trial; a treatment failure may be deemed after at least 4 unsuccessful trials. Patients refractory to PDE5 inhibitors should be counseled on appropriate use, potentially modifiable factors (e.g. hormonal abnormalities, food or drug interactions, lack of adequate sexual stimulation, heavy alcohol use, and the patient's relationship with his partner), and the risks and benefits of other therapies. Second-line treatment options include intracavernous injection and intra-urethral therapy. Follow-up visits for ED patients, regardless of therapy, are necessary to determine whether therapy continues to be effective and whether cardiovascular health has significantly changed.

    MAXIMUM DOSAGE

    Adults

    For regular tablets (e.g., Levitra), 20 mg/day PO. For orally disintegrating tablets (e.g., Staxyn), 10 mg/day PO.

    Geriatric

    For regular tablets (e.g., Levitra), 20 mg/day PO. For orally disintegrating tablets (e.g., Staxyn), 10 mg/day PO.

    Adolescents

    Safety and efficacy has not been established.

    Children

    Safety and efficacy has not been established.

    Infants

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Patients with mild hepatic impairment (Child-Pugh class A): No dose adjustment is required.
    Patients with moderate hepatic impairment (Child-Pugh class B): Decrease starting dose to 5 mg/day PO using the regular tablets; the maximum dose should not exceed 10 mg/day PO. Do not use vardenafil orally disintegrating tablets in patients with moderate hepatic impairment.
    Patients with severe hepatic impairment (Child-Pugh class C): Do not use.

    Renal Impairment

    CrCl 30 mL/minute or more: No dosage adjustments are needed.
     
    Hemodialysis
    Do not use vardenafil in patients requiring dialysis; vardenafil has not been studied in these patients.

    ADMINISTRATION

    Oral Administration

    Vardenafil is administered orally approximately 1 hour before expected intercourse. May be administered with or without food.
    Orally disintegrating tablets: Place on tongue where tablet will disintegrate. Do not administer with any liquids. Administer immediately upon removal from blister packaging.

    STORAGE

    Levitra:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Staxyn:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Vardenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet. The safety and efficacy of combinations of vardenafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
     
    The safe and effective use of vardenafil in combination with other agents for treating erectile dysfunction has not been studied. Therefore, the use of such combinations is not recommended.

    Nitrate/nitrite therapy

    Vardenafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Consistent with its known effects on the nitric oxide/cGMP pathway, vardenafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive vardenafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once vardenafil has been administered. A suitable time interval following vardenafil dosing for safe administration of nitrates or nitric oxide donors has not been determined.

    Hepatic disease, renal disease, renal failure, renal impairment

    Vardenafil tablets are not recommended in patients with severe hepatic disease (Child-Pugh class C) or end stage renal disease requiring dialysis (severe renal impairment or renal failure). There are no controlled clinical studies on the safety and efficacy of vardenafil in these patients; therefore, vardenafil use is not recommended until further information is available. Patients with moderate hepatic impairment require a reduction in the starting dose of the regular tablets and a lower maximum dosage (see Indications/Dosage). Patients with mild hepatic impairment or mild to moderate renal impairment do not require adjustments in the vardenafil regular tablet dosage. The concomitant use of certain potent hepatic cytochrome P450 3A4 inhibitors may result in a requirement to adjust the vardenafil dosage (see Dosage and Drug Interactions). Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, the orally disintegrating tablets should not be used in patients with moderate or severe hepatic disease (Child-Pugh class B or C) or in patients on hemodialysis. Patients who require lower doses of vardenafil should use the regular tablets.

    Geriatric

    Lower starting doses of vardenafil regular tablets should be considered for geriatric patients (>= 65 years) because elderly patients have higher plasma concentrations than younger males (18—45 years) (see Indications/Dosage). In phase III clinical trials of the regular tablets, 834 elderly patients participated and there was no difference in safety or effectiveness compared to younger patients. In trials with the orally disintegrating tablets, the vardenafil AUC in elderly patients (>= 65 years) was increased by 39% and the Cmax was increased by 21% as compared to patients <= 45 years; however, no differences in safety and efficacy were observed between elderly patients and those < 65 years old in placebo-controlled trials. Elderly patients may potentially have renal and hepatic impairment which can increase vardenafil plasma concentrations. Because higher plasma concentrations may increase the incidence of adverse reactions, the regular tablet starting dose should be reduced in these patients. Patients who require lower doses of vardenafil should use the regular tablets and not the orally disintegrating tablets.

    Alcoholism, angina, aortic stenosis, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, hypotension, idiopathic hypertrophic subaortic stenosis, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, stroke, thyroid disease

    There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. In particular, caution should be used if vardenafil is prescribed in the following patient groups: patients who have suffered a myocardial infarction, stroke, or life-threatening cardiac arrhythmias in the last 6 months; patients with resting hypotension (BP < 90/50) or resting hypertension (BP > 170/110); patients with cardiac disease, severe heart failure or coronary artery disease (CAD) which causes unstable angina including those with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis). Based on recommendations for sildenafil by the American College of Cardiology, it is recommended that vardenafil be used with caution in the following: patients with active coronary ischemia who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status; patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of vardenafil. Vardenafil is contraindicated in patients currently on nitrate/nitrite therapy. In a double-blind, crossover, single-dose study of patients with stable CAD, vardenafil did not cause any impairment in exercise capabilities at levels equivalent to or greater than that achieved during sexual intercourse. The effects of vardenafil on QT prolongation were evaluated in 59 healthy males using moxifloxacin (400 mg) as an active control. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced similar increases in QTc interval (e.g., 4—6 msec calculated by individual QT correction) as moxifloxacin. 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. The manufacturer recommends that vardenafil not be used in patients with congenital long QT syndrome and those taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs. Further, use vardenafil with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.

    Leukemia, multiple myeloma, penile structural abnormality, polycythemia, priapism, sickle cell disease

    Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Vardenafil and other agents for the treatment of erectile dysfunction should be used with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism).

    Human immunodeficiency virus (HIV) infection

    Patients should be reminded that vardenafil offers no protection against sexually transmitted disease. Counseling of patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, should be considered.

    Non-arteritic anterior ischemic optic neuropathy, retinitis pigmentosa, visual disturbance

    Advise patients to stop use of all phosphodiesterase 5 (PDE5) inhibitors, including vardanafil, and seek medical attention for evaluation in the event of a sudden visual disturbance in 1 or both eyes. Postmarketing reports with PDE5 inhibitors have included cases of visual disturbances including retinal vein occlusion, visual field defects, reduced visual acuity, and loss of vision (temporary or permanent). Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve; this can cause permanent loss of vision; discontinue vardenafil if there is visual loss in 1 or both eyes. Patients with a history of NAION are at increased risk for recurrence. Only use a PDE5 inhibitor in these individuals if the anticipated benefit outweighs the risk. Patients with low cup to disc ratio ('crowded disc') are also at increased risk; however, this condition is uncommon, and there is insufficient evidence to support screening of prospective users of a PDE5 inhibitor. Vardenafil use is not recommended in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa. A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. Vardenafil use is not recommended in these patients until further information is available.

    Pregnancy

    Vardenafil is not indicated for use in females. There are no adequate and well-controlled trials of vardenafil in humans during pregnancy. In animal reproduction studies, no adverse developmental outcomes were observed during organogenesis at exposures for unbound vardenafil and its major metabolite at 100 and 29 times, respectively, the maximum recommended human dose (MRHD) of 20 mg.

    Breast-feeding

    Vardenafil is not indicated for use in females and is therefore not recommended during breast-feeding. There is no information on the presence of vardenafil and its major metabolite in human milk, the effects on the breast-fed infant, or the effects on milk production. Vardenafil is excreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma; following a single oral dose of 3 mg/kg, 3.3% of the administered dose was excreted into the milk within 24 hours.

    Children, infants, neonates

    There is no known indication for the use of vardenafil in neonates, infants, or children. Vardenafil should not be prescribed to these populations.

    Gastroesophageal reflux disease (GERD), hiatal hernia

    Vardenafil should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Like sildenafil, vardenafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.

    Coagulopathy, peptic ulcer disease

    Vardenafil should be administered to patients with coagulopathy only after careful benefit vs. risk assessment. Vardenafil alone does not prolong the bleeding time nor does its use in combination with aspirin cause any additive prolongation of the bleeding time. However, vardenafil has not been studied or administered to patients with bleeding disorders or significant active peptic ulcer disease. Therefore administer to these patients after careful benefit-risk assessment.

    Hearing impairment, tinnitus

    Patients with a sudden decrease or loss of hearing (hearing impairment) should stop taking vardenafil and seek prompt medical attention. Hearing loss, which may be accompanied by tinnitus and dizziness, has been reported in temporal association with the intake of PDE5 inhibitors, including vardenafil; however, it is unknown if the hearing loss is directly related to PDE5 inhibitors or to other factors.

    Phenylketonuria

    The vardenafil orally disintegrating tablets contain aspartame, which is a source of phenylalanine. This may be harmful for people with phenylketonuria. Each tablet contains 1.01 mg of phenylalanine.

    Hereditary fructose intolerance

    The vardenafil orally disintegrating tablets contain sorbitol. Patients with hereditary fructose intolerance should not take the orally disintegrating tablets.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / 0-2.0
    laryngeal edema / Rapid / 0-2.0
    angioedema / Rapid / 0-2.0
    seizures / Delayed / 0-2.0
    ventricular tachycardia / Early / 0-2.0
    myocardial infarction / Delayed / 0-2.0
    visual impairment / Early / 0-2.0
    hearing loss / Delayed / 0-2.0
    non-arteritic anterior ischemic optic neuropathy / Delayed / Incidence not known

    Moderate

    erythema / Early / 0-2.0
    amnesia / Delayed / 0-2.0
    hypertonia / Delayed / 0-2.0
    esophagitis / Delayed / 0-2.0
    gastritis / Delayed / 0-2.0
    dysphagia / Delayed / 0-2.0
    angina / Early / 0-2.0
    hypertension / Early / 0-2.0
    sinus tachycardia / Rapid / 0-2.0
    orthostatic hypotension / Delayed / 0-2.0
    chest pain (unspecified) / Early / 0-2.0
    hypotension / Rapid / 0-2.0
    palpitations / Early / 0-2.0
    dyspnea / Early / 0-2.0
    ejaculation dysfunction / Delayed / 0-2.0
    conjunctivitis / Delayed / 0-2.0
    photophobia / Early / 0-2.0
    blurred vision / Early / 0-2.0
    hyperemia / Delayed / 0-2.0
    elevated hepatic enzymes / Delayed / 0-2.0
    priapism / Early / Incidence not known
    QT prolongation / Rapid / Incidence not known

    Mild

    headache / Early / 14.4-15.0
    flushing / Rapid / 7.6-11.0
    rhinitis / Early / 9.0-9.0
    dyspepsia / Early / 2.8-4.0
    nasal congestion / Early / 3.1-3.1
    sinusitis / Delayed / 3.0-3.0
    dizziness / Early / 2.0-2.3
    hyperhidrosis / Delayed / 0-2.0
    photosensitivity / Delayed / 0-2.0
    rash / Early / 0-2.0
    pruritus / Rapid / 0-2.0
    paresthesias / Delayed / 0-2.0
    dysesthesia / Delayed / 0-2.0
    asthenia / Delayed / 0-2.0
    diarrhea / Early / 0-2.0
    xerostomia / Early / 0-2.0
    gastroesophageal reflux / Delayed / 0-2.0
    nausea / Early / 2.0-2.0
    abdominal pain / Early / 0-2.0
    vomiting / Early / 2.0-2.0
    muscle cramps / Delayed / 0-2.0
    back pain / Delayed / 2.0-2.0
    arthralgia / Delayed / 0-2.0
    myalgia / Early / 0-2.0
    vertigo / Early / 0-2.0
    drowsiness / Early / 0-2.0
    insomnia / Early / 0-2.0
    syncope / Early / 0-2.0
    pharyngitis / Delayed / 0-2.0
    epistaxis / Delayed / 0-2.0
    ocular pain / Early / 0-2.0
    lacrimation / Early / 0-2.0
    tinnitus / Delayed / 0-2.0

    DRUG INTERACTIONS

    Abarelix: (Major) Avoid use of vardenafil in patients taking abarelix therapy. Abarelix has been associated with QT prolongation and torsade de pointes. Vardenafil is also associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Acetaminophen; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Alfuzosin: (Moderate) Due to the potential for symptomatic hypotension, patients should be stable on alfuzosin therapy before initiating therapy with the lowest starting dose of vardenafil. Conversely, patients already receiving an optimized dose of vardenafil should be started on the lowest dose of alfuzosin; 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 alfuzosin. Concurrent use of these medications may also increase the risk for QT prolongation. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Alfuzosin may prolong the QT interval in a dose-dependent manner.
    Alpha-blockers: (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.
    Amiodarone: (Major) Do not use vardenafil orally disintegrating tablets with amiodarone due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; amiodarone is a moderate CYP3A4 inhibitor. Use of vardenafil with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold. There may be an increased risk of QT prolongation or other side effects. Therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Do not use vardenafil orally disintegrating tablets with clarithromycin due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; clarithromycin is a strong CYP3A4 inhibitor. Use of vardenafil with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to16-fold. Use of these drugs together may increase the risk for QT prolongation or vardenafil-related side effects. Clarithromycin has an established risk of QT prolongation and torsade de pointes. Vardenafil may produce an increase in QTc interval at both therapeutic and supratherapeutic doses.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Do not use vardenafil orally disintegrating tablets with clarithromycin due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; clarithromycin is a strong CYP3A4 inhibitor. Use of vardenafil with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to16-fold. Use of these drugs together may increase the risk for QT prolongation or vardenafil-related side effects. Clarithromycin has an established risk of QT prolongation and torsade de pointes. Vardenafil may produce an increase in QTc interval at both therapeutic and supratherapeutic doses.
    Amyl Nitrite: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Anagrelide: (Major) Coadministration of vardenafil and anagrelide increases the risk for QT prolongation and torsade de pointes. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Anagrelide may cause QT prolongation, and TdP and ventricular tachycardia have been reported postmarketing. Consider the potential for additive QT effects if vardenafil is given with anagrelide. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in the QTc interval.
    Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with vardenafil since concurrent use may increase the risk of QT prolongation. Vardenafil is also associated with QT prolongation at both therapeutic and supratherapeutic doses. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Aprepitant, Fosaprepitant: (Major) Do not use vardenafil orally disintegrating tablets with aprepitant, fosaprepitant due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; aprepitant is a moderate CYP3A4 inhibitor when administered as a 3-day oral regimen (125 mg/80 mg/80 mg). Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold. Fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. Monitor for an increase in vardenafil-related adverse effects for several days after administration of a multi-day aprepitant regimen.
    Aripiprazole: (Moderate) Use caution when administering aripiprazole with vardenafil due to increased risk of QT prolongation. Vardenafil is associated with an increase in QTc interval at both therapeutic and supratherapeutic doses. QT prolongation has also occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Coadministration of vardenafil and arsenic trioxide should be avoided since there is an increased risk for QT prolongation and torsade de pointes. Drugs that are known to prolong the QT interval should be discontinued if possible prior to initiating arsenic trioxide therapy. Consider if an alternative to vardenafil would be appropriate. If use with arsenic trioxide is unavoidable, frequently monitor the electrocardiogram (ECG). QT prolongation should be expected with the administration of arsenic trioxide, and torsade de pointes (TdP) and complete atrioventricular block have been reported. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in the QTc interval.
    Artemether; Lumefantrine: (Major) Concurrent use of vardenafil and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if vardenafil must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil have also produced increases in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
    Asenapine: (Major) Avoid use of vardenafil in combination with asenapine due to the potential for QT prolongation. Asenapine and vardenafil are associated with QT prolongation. Consider the potential for additive effects on the QT interval. Therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
    Atazanavir: (Major) Do not use vardenafil orally disintegrating tablets with atazanavir due to increased vardenafil exposure. Use reduced doses of no more than 2.5 mg every 72 hours of vardenafil oral tablets with increased monitoring for adverse reactions. Vardenafil is primarily metabolized by CYP3A4/5; atazanavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to16-fold.
    Atazanavir; Cobicistat: (Major) Do not use vardenafil orally disintegrating tablets with atazanavir due to increased vardenafil exposure. Use reduced doses of no more than 2.5 mg every 72 hours of vardenafil oral tablets with increased monitoring for adverse reactions. Vardenafil is primarily metabolized by CYP3A4/5; atazanavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to16-fold. (Major) Do not use vardenafil orally disintegrating tablets with cobicistat due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to 16-fold.
    Atomoxetine: (Moderate) Consider the potential for additive QT effects if vardenafil is administered with atomoxetine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Azithromycin: (Major) Avoid coadministration of azithromycin with vardenafil due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Bedaquiline: (Major) If possible, avoid the use of vardenafil with bedaquiline due to the risk of QT prolongation. Monitor ECGs if bedaquiline is used in patients receiving other drugs that prolong the QTc interval, such as vardenafil. Also monitor serum electrolytes. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or if a QTcF interval greater than 500 ms occurs. Both therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produce an increase in the QTc interval.
    Bepridil: (Severe) Concomitant administration of bepridil and vardenafil may cause additive QT prolongation and an increased risk of torsades de pointes (TdP).
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Consider the potential for additive effects on QT prolongation if vardenafil is administered with metronidazole. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Consider the potential for additive effects on QT prolongation if vardenafil is administered with metronidazole. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Boceprevir: (Major) Do not use vardenafil orally disintegrating tablets with boceprevir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; boceprevir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    Brompheniramine; Carbetapentane; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Buprenorphine: (Major) Buprenorphine should be used cautiously and with close monitoring with vardenafil. If these drugs are used together, consider the potential for additive effects on the QT interval. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval, such as vardenafil. Therapeutic and supratherapeutic doses of vardenafil produce an increase in the QTc interval.
    Buprenorphine; Naloxone: (Major) Buprenorphine should be used cautiously and with close monitoring with vardenafil. If these drugs are used together, consider the potential for additive effects on the QT interval. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval, such as vardenafil. Therapeutic and supratherapeutic doses of vardenafil produce an increase in the QTc interval.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbetapentane; Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbetapentane; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbetapentane; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbetapentane; Phenylephrine; Pyrilamine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbinoxamine; Hydrocodone; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Carbinoxamine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Ceritinib: (Major) Do not use vardenafil orally disintegrating tablets with ceritinib due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; ceritinib is a strong CYP3A4 inhibitor. Use of vardenafil with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to 16-fold. There may also be an increased potential for QT prolongation. Vardenafil can produce an increase in QTc interval at both therapeutic and supratherapeutic doses. Ceritinib has been reported to cause concentration-dependent QT prolongation. Periodically monitor ECGs and electrolytes during concurrent use of ceritinib and vardenafil oral tablets.
    Chlophedianol; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Chloramphenicol: (Major) Do not use vardenafil orally disintegrating tablets with chloramphenicol due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to 16-fold.
    Chloroquine: (Major) Avoid coadministration of chloroquine with vardenafil due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Chlorpheniramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Chlorpromazine: (Major) In general, avoid use of vardenafil and chlorpromazine together if possible due to a potential increased risk of QT prolongation and torsade de pointes (TdP). Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP. Consider the potential for additive QT effects if vardenafil is administered with chlorpromazine. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Ciprofloxacin: (Major) Do not use vardenafil orally disintegrating tablets with ciprofloxacin due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; ciprofloxacin is a moderate CYP3A4 inhibitor. Use of vardenafil with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold. There is also a potential increased risk for QT prolongation and torsade de pointes (TdP). Rare cases of QT prolongation and TdP have been reported with ciprofloxacin during postmarketing surveillance. Both therapeutic and supratherapeutic doses of vardenafil can produce and increase in QTc interval.
    Cisapride: (Severe) Because of the potential for QT prolongation and torsade de pointes (TdP), use of cisapride with vardenafil is contraindicated. Cisapride has a known potential to cause QT prolongation and has been associated with torsade de pointes (TdP). Therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Citalopram: (Major) Concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. Citalopram causes dose-dependent QT interval prolongation. If concurrent therapy is considered essential, ECG monitoring is recommended. Vardenafil has been associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
    Clarithromycin: (Major) Do not use vardenafil orally disintegrating tablets with clarithromycin due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; clarithromycin is a strong CYP3A4 inhibitor. Use of vardenafil with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to16-fold. Use of these drugs together may increase the risk for QT prolongation or vardenafil-related side effects. Clarithromycin has an established risk of QT prolongation and torsade de pointes. Vardenafil may produce an increase in QTc interval at both therapeutic and supratherapeutic doses.
    Class IA Antiarrhythmics: (Major) Vardenafil should be avoided in patients taking Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsade de pointes (TdP). Therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. The effect of vardenafil on the QT interval should be considered when prescribing the drug.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with vardenafil. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Clozapine: (Moderate) Use vardenafil with caution in combination with clozapine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Treatment with clozapine has also been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Cobicistat: (Major) Do not use vardenafil orally disintegrating tablets with cobicistat due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to 16-fold.
    Codeine; Phenylephrine; Promethazine: (Moderate) Use vardenafil with caution in combination with promethazine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Codeine; Promethazine: (Moderate) Use vardenafil with caution in combination with promethazine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Conivaptan: (Major) Concomitant use of conivaptan with vardenafil should be avoided. Vardenafil is primarily metabolized by CYP3A4/5; conivaptan is a strong CYP3A4 inhibitor. Coadministration of conivaptan with other primary CYP3A substrates increased the mean AUC values 1- to 3-fold. In studies of vardenafil with strong CYP3A4 inhibitors, the AUC of vardenafil was increased by 10- to 16-fold. According to the manufacturer of conivaptan, treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Major) Do not use vardenafil orally disintegrating tablets with crizotinib due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold. In addition, vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil may produce an increase in QTc interval. Crizotinib has also been associated with concentration-dependent QT prolongation. Monitor ECGs and electrolytes if crizotinib and vardenafil oral tablets are used together.
    Cyclosporine: (Major) Do not use vardenafil orally disintegrating tablets with cyclosporine due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
    Danazol: (Major) Do not use vardenafil orally disintegrating tablets with danazol due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; danazol is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
    Darunavir: (Major) Do not use vardenafil orally disintegrating tablets with darunavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    Darunavir; Cobicistat: (Major) Do not use vardenafil orally disintegrating tablets with cobicistat due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to 16-fold. (Major) Do not use vardenafil orally disintegrating tablets with darunavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Do not use vardenafil orally disintegrating tablets with cobicistat due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to 16-fold. (Major) Do not use vardenafil orally disintegrating tablets with darunavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Do not use vardenafil orally disintegrating tablets with ritonavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 72-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; ritonavir is a strong CYP3A4 inhibitor. Coadministration of ritonavir with vardenafil resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax. Concomitant use may increase the risk of vardenafil-related adverse effects, such as prolonged erection or QT prolongation.
    Dasatinib: (Moderate) Monitor for evidence of QT prolongation during concurrent use of dasatinib and vardenafil. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving vardenafil as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Delavirdine: (Major) Do not use vardenafil orally disintegrating tablets with delavirdine due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; delavirdine is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    Deutetrabenazine: (Moderate) Use vardenafil with caution in combination with deutetrabenazine as concurrent use may increase the risk of QT prolongation. For patients taking a deutetrabenazine dosage more than 24 mg/day with vardenafil, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Dextromethorphan; Promethazine: (Moderate) Use vardenafil with caution in combination with promethazine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Dextromethorphan; Quinidine: (Major) Vardenafil should be avoided in patients taking Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsade de pointes (TdP). Therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. The effect of vardenafil on the QT interval should be considered when prescribing the drug.
    Diltiazem: (Major) Do not use vardenafil orally disintegrating tablets with diltiazem due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; diltiazem is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold. Additive effects on blood pressure are also possible.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Diphenhydramine; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Disopyramide: (Major) Vardenafil should be avoided in patients taking Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsade de pointes (TdP). Therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. The effect of vardenafil on the QT interval should be considered when prescribing the drug.
    Dofetilide: (Major) Coadministration of dofetilide and vardenafil is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Dolasetron: (Moderate) Administer dolasetron with caution in combination with vardenafil as concurrent use may increase the risk of QT prolongation. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vardenafil. Vardenafil is associated with QT prolongation. 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.
    Donepezil: (Moderate) Use donepezil with caution in combination with vardenafil as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with vardenafil as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Doxazosin: (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.
    Dronedarone: (Severe) Use of dronedarone with vardenafil is contraindicated due to an increased risk for QT prolongation and torsade de pointes. Increased vardenafil exposure may occur due to dronedarone inhibition of CYP3A4. An increase in vardenafil-related adverse effects, such as prolonged erection, hypotension, or QT prolongation, is possible. Dronedarone is associated with a dose-related increase in the QTc interval. Coadministration of other drugs that also prolong the QT interval may result in additive QT prolongation. Vardenafil is associated with QT prolongation. Therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval. Dronedarone is a moderate inhibitor of CYP3A4, the primary isoenzyme responsible for the metabolism of vardenafil. Increased systemic vardenafil exposure may occur.
    Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include 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).
    Dutasteride; 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.
    Duvelisib: (Major) Do not use vardenafil orally disintegrating tablets with duvelisib due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; duvelisib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
    Efavirenz: (Moderate) Consider the potential for additive QT effects if vardenafil is administered with efavirenz. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider the potential for additive QT effects if vardenafil is administered with efavirenz. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider the potential for additive QT effects if vardenafil is administered with efavirenz. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. QTc prolongation has been observed with the use of efavirenz.
    Eliglustat: (Moderate) Use vardenafil with caution in combination with eliglustat due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Do not use vardenafil orally disintegrating tablets with cobicistat due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to 16-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not use vardenafil orally disintegrating tablets with cobicistat due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to 16-fold.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vardenafil. Vardenafil is associated with QT prolongation. 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.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vardenafil. Vardenafil is associated with QT prolongation. 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.
    Encorafenib: (Major) Avoid coadministration of encorafenib and vardenafil due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
    Entrectinib: (Major) Avoid coadministration of entrectinib with vardenafil due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Eribulin: (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). 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. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vardenafil include eribulin. ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erythromycin: (Major) Do not use vardenafil orally disintegrating tablets with erythromycin due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; erythromycin is a moderate CYP3A4 inhibitor. Use of vardenafil 5 mg with erythromycin (500 mg three times/day) increased the AUC and Cmax of vardenafil 4-fold and 3-fold, respectively. Concurrent use may also increase the risk for QT prolongation. Erythromycin has an established risk for QT prolongation and torsade de pointes (TdP). Both therapeutic and supratherapeutic doses of vardenafil produce increases in the QTc interval.
    Erythromycin; Sulfisoxazole: (Major) Do not use vardenafil orally disintegrating tablets with erythromycin due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; erythromycin is a moderate CYP3A4 inhibitor. Use of vardenafil 5 mg with erythromycin (500 mg three times/day) increased the AUC and Cmax of vardenafil 4-fold and 3-fold, respectively. Concurrent use may also increase the risk for QT prolongation. Erythromycin has an established risk for QT prolongation and torsade de pointes (TdP). Both therapeutic and supratherapeutic doses of vardenafil produce increases in the QTc interval.
    Escitalopram: (Moderate) Use escitalopram with caution in combination with vardenafil as concurrent use may increase the risk of QT prolongation. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP). Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Ezogabine: (Moderate) Use vardenafil with caution in combination with ezogabine due to increased risk of QT prolongation as concurrent use may increase the risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Ezogabine has also been associated with QT prolongation.
    Fedratinib: (Major) Do not use vardenafil orally disintegrating tablets with fedratinib due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; fedratinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
    Fingolimod: (Moderate) Use vardenafil with caution in combination with fingolimod due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with flecainide include 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).
    Fluconazole: (Severe) Concurrent use of fluconazole and vardenafil is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Both fluconazole and vardenafil have been associated with QT prolongation. Also, fluconazole is an inhibitor of CYP3A4, the primary isoenzyme responsible for the metabolism of vardenafil. These drugs used in combination may result in elevated vardenafil plasma concentrations, causing an increased risk for vardenafil-related adverse events, such as QT prolongation.
    Fluoxetine: (Moderate) Use fluoxetine with caution in combination with vardenafil. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Fluoxetine; Olanzapine: (Moderate) Caution is advised when administering olanzapine with vardenafil as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in the QTc interval. (Moderate) Use fluoxetine with caution in combination with vardenafil. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Fluphenazine: (Minor) Use vardenafil with caution in combination with fluphenazine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Fluphenazine is also associated with a possible risk for QT prolongation.
    Fluvoxamine: (Major) Do not use vardenafil orally disintegrating tablets with fluvoxamine due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold. There may also be an increased risk for QT prolongation and torsade de pointes (TdP) during coadministration. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in the QTc interval.
    Fosamprenavir: (Major) Do not use vardenafil orally disintegrating tablets with fosamprenavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as vardenafil. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Vardenafil is also associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Gemifloxacin: (Moderate) Use vardenafil with caution in combination with gemifloxacin due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and vardenafil together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and vardenafil is necessary. Gilteritinib has been associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Glasdegib: (Major) Avoid coadministration of glasdegib with vardenafil due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) 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 also prolong the QT/QTc interval.
    Granisetron: (Moderate) Use granisetron with caution in combination with vardenafil due to the risk of QT prolongation. Granisetron has been associated with QT prolongation. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Grapefruit juice: (Major) Grapefruit and grapefruit juice should be avoided during treatment with vardenafil orally disintegrating tablets due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; grapefruit juice is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
    Guaifenesin; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Halofantrine: (Major) Halofantrine is considered to have a well-established risk for QT prolongation and torsades de pointes. Halofantrine should be avoided in patients receiving drugs which may induce QT prolongation including vardenafil.
    Halogenated Anesthetics: (Major) Coadministration of halogenated anesthetics and vardenafil may increase the risk for QT prolongation and torsade de pointes. Halogenated anesthetics can prolong the QT interval. Consider the potential for additive QT prolongation. Therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
    Haloperidol: (Moderate) Consider the potential for additive effects on QT prolongation if vardenafil is administered with haloperidol. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) 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 also prolong the QT/QTc interval.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Hydrocodone; Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Hydroxychloroquine: (Major) Avoid coadministration of vardenafil and hydroxychloroquine due to an increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with vardenafil due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Ibutilide: (Major) Avoid use of these drugs together. Ibutilide can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. Monitor the electrocardiogram (ECG) as directed during ibutilide administration. The potential for proarrhythmia may increase when giving ibutilide to patients treated with drugs that prolong the QT interval, such as vardenafil. Therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Idelalisib: (Major) Do not use vardenafil orally disintegrating tablets with idelalisib due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; idelalisib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as 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).
    Imatinib: (Major) Do not use vardenafil orally disintegrating tablets with imatinib due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; imatinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
    Indinavir: (Major) Do not use vardenafil orally disintegrating tablets with indinavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; indinavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with vardenafil due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
    Isavuconazonium: (Major) Do not use vardenafil orally disintegrating tablets with isavuconazonium due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; isavuconazoniium is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
    Isosorbide Dinitrate, ISDN: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Isosorbide Mononitrate: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Itraconazole: (Major) Do not use vardenafil orally disintegrating tablets with itraconazole due to increased vardenafil exposure. Vardenafil is primarily metabolized by CYP3A4/5; itraconazole is a strong CYP3A4 inhibitor. If coadministration of itraconazole and vardenafil oral tablets is required, the maximum single vardenafil dose is 5 mg every 24 hours in patients receiving itraconazole 200 mg daily; for patients receiving itraconazole 400 mg daily, the maximum single vardenafil dose is 2.5 mg every 24 hours. In addition, both itraconazole and vardenafil have been associated with QT prolongation; coadministration may increase this risk.
    Ivosidenib: (Major) Avoid use of vardenafil during ivosidenib therapy due to a possible increased risk of QT prolongation. Ivosidenib has been associated with prolongation of the QTc interval and ventricular arrhythmias. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs.
    Ketoconazole: (Major) Do not use vardenafil orally disintegrating tablets with ketoconazole due to increased vardenafil exposure. Vardenafil is primarily metabolized by CYP3A4/5; ketoconazole is a strong CYP3A4 inhibitor. If concurrent use of ketoconazole and vardenafil oral tablets is required, the maximum single vardenafil oral tablet dose is 5 mg every 24 hours for patients receiving ketoconazole 200 mg daily. For patients receiving ketoconazole 400 mg daily, the maximum single vardenafil oral tablet dose is 2.5 mg every 24 hours. In one study, health subjects receiving ketoconazole 200 mg PO daily with a single 5 mg vardenafil dose experienced a 10-fold increase in the AUC and a 4-fold increase in the Cmax of vardenafil. Both ketoconazole and vardenafil have been associated with QT prolongation; coadministration may increase this risk.
    Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with vardenafil. Vardenafil is associated with QT prolongation at both therapeutic and supratherapeutic doses. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Lefamulin: (Major) Coadministration of lefamulin tablets is contraindicated with vardenafil due to increased vardenafil exposure which may result in QT prolongation and torsade de pointes (TdP). Avoid use of lefamulin injection with vardenafil; however, if coadministration of lefamulin injection cannot be avoided, ECG monitoring is recommended during treatment. Vardenafil is a primary CYP3A4 substrate that is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval. Lefamulin is a moderate CYP3A4 inhibitor that has a concentration-dependent QTc prolongation effect. Coadministration of vardenafil with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with vardenafil due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Vardenafil is associated with QT prolongation at both therapeutic and supratherapeutic doses.
    Letermovir: (Major) Do not use vardenafil orally disintegrating tablets with letermovir due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; letermovir is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
    Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) 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 also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) 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 also prolong the QT/QTc interval.
    Levofloxacin: (Moderate) Levofloxacin should be used cautiously with other agents, such as vardenafil, that may prolong the QT interval or increase the risk of torsade de pointes (TdP). Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Levofloxacin has been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Levomethadyl: (Severe) Concomitant administration of levomethadyl and vardenafil may cause additive QT prolongation and/or torsades de pointes. Levomethadyl is contraindicated in combination with other agents that may prolong the QT interval.
    Lithium: (Moderate) Lithium should be used cautiously and with close monitoring with vardenafil as concurrent use may increase the risk of QT prolongation. Lithium has been associated with QT prolongation. Vardenafil is also associated with QT prolongation. 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).
    Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with vardenafil due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Lomefloxacin: (Moderate) Lomefloxacin has been associated with QT prolongation and infrequent cases of arrhythmia. Other medications which may prolong the QT interval, such as vardenafil, should be used cautiously when given concurrently with lomefloxacin.
    Long-acting beta-agonists: (Moderate) Coadministration of vardenafil and long-acting beta-agonists may increase the risk of QT prolongation. Vardenafil has been associated with QT prolongation. Therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loperamide: (Moderate) Consider the potential for additive QT effects if vardenafil is administered with loperamide. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Moderate) Consider the potential for additive QT effects if vardenafil is administered with loperamide. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with vardenafil due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Both drugs are associated with QT prolongation. (Major) Do not use vardenafil orally disintegrating tablets with ritonavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 72-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; ritonavir is a strong CYP3A4 inhibitor. Coadministration of ritonavir with vardenafil resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax. Concomitant use may increase the risk of vardenafil-related adverse effects, such as prolonged erection or QT prolongation.
    Lorcaserin: (Moderate) Lorcaserin is a serotonin 2C receptor agonist, and priapism is a potential effect of 5-HT2C receptor agonism. Because there is little experience with the combination of lorcaserin and medications indicated for erectile dysfunction (e.g., phosphodiesterase inhibitors), combined use should be approached with caution.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as vardenafil. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Maprotiline: (Moderate) Use vardenafil with caution in combination with maprotiline due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving vardenafil as concurrent use may increase the risk of QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Meperidine; Promethazine: (Moderate) Use vardenafil with caution in combination with promethazine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Mesoridazine: (Major) Concomitant administration of mesoridazine with vardenafil may cause additive QT prolongation and should be used cautiously.
    Methadone: (Major) The need to coadminister methadone with drugs that can prolong the QT interval, such as vardenafil, should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain, with large multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Vardenafil is associated with QT prolongation. Therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
    Metronidazole: (Moderate) Consider the potential for additive effects on QT prolongation if vardenafil is administered with metronidazole. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Midostaurin: (Major) The concomitant use of midostaurin and vardenafil may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Both therapeutic and supratherapeutic doses of vardenafil produced an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
    Mifepristone: (Major) Do not use vardenafil orally disintegrating tablets with mifepristone due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; mifepristone is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold. There may also be an increased risk of QT prolongation and torsade de pointes (TdP) during coadministration of vardenfil and mifepristone. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval. Mifepristone has been associated with dose-dependent prolongation of the QT interval.
    Mirtazapine: (Moderate) Use caution when using mirtazapine in combination with vardenafil as concurrent use may increase the risk of QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Moxifloxacin: (Major) Concurrent use of vardenafil and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Moxifloxacin has been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil have also produced increases in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
    Nefazodone: (Major) Do not use vardenafil orally disintegrating tablets with nefazodone due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; nefazodone is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    Nelfinavir: (Major) Do not use vardenafil orally disintegrating tablets with nelfinavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; nelfinavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Do not use vardenafil orally disintegrating tablets with netupitant due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; netupitant is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
    Nicardipine: (Moderate) Vardenafil is metabolized by hepatic cytochrome P450 3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4, such as nicardipine, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.
    Nifedipine: (Moderate) Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors). The patient should be monitored carefully and the dosage should be adjusted based on clinical response. For example, in patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 3 to 4 mmHg (age group 65 to 69 years) and 5 to 6 mmHg (age group 70 to 80 years) compared to placebo.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib with other agents known to prolong the QT interval, such as vardenafil. Sudden death and QT prolongation have occurred in patients receiving nilotinib therapy. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval. Also, nilotinib is a moderate CYP3A4 inhibitor and vardenafil is a primary CYP3A4 substrate; administering these drugs together may result in increased vardenafil concentrations. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold. Do not use vardenafil orally disintegrating tablets with nilotinib due to increased vardenafil exposure. If use of nilotinib and vardenafil oral tablets is required, do not exceed a single vardenafil oral tablet dose of 5 mg per 24-hour period.
    Nitrates: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Nitroglycerin: (Severe) Coadministration of phosphodiesterase inhibitors with organic nitrates or nitrites in any dosage formulation is contraindicated. Consistent with their known effects on the nitric oxide/cGMP pathway, concomitant use of phosphodiesterase inhibitors and nitrates can cause severe hypotension, syncope, or myocardial infarction. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina.
    Nitroprusside: (Moderate) The hypotensive effects of nitroprusside may be augmented by phosphodiesterase inhibitors. Monitor blood pressure when co-administering phosphodiesterase inhibitors and blood pressure lowering medications, like nitroprusside. Phosphodiesterase inhibitors have vasodilatory properties, and nitroprusside is a potent vasodilator. In addition, phosphodiesterase type-5 (PDE5) is found in platelets, and PDE5 inhibitors may potentiate the nitric oxide-mediated platelet anti-aggregatory activity of nitroprusside.
    Norfloxacin: (Moderate) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering vardenafil with norfloxacin. 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). Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Octreotide: (Moderate) Use octreotide with caution in combination with vardenafil. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Moderate) Ofloxacin should be used cautiously with vardenafil as concurrent use may increase the risk of QT prolongation. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) Caution is advised when administering olanzapine with vardenafil as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in the QTc interval.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Do not use vardenafil orally disintegrating tablets with ritonavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 72-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; ritonavir is a strong CYP3A4 inhibitor. Coadministration of ritonavir with vardenafil resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax. Concomitant use may increase the risk of vardenafil-related adverse effects, such as prolonged erection or QT prolongation.
    Ondansetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and vardenafil should be used together cautiously. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
    Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with vardenafil as concurrent use may increase the risk of QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Osimertinib: (Major) Avoid coadministration of vardenafil with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Vardenafil is associated with QTc prolongation at both therapeutic and supratherapeutic doses.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of vardenafil with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Vardenafil is associated with QT prolongation at both therapeutic and supratherapeutic doses. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking vardenafil due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as 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). If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include vardenafil.
    Pasireotide: (Moderate) Pasireotide should be used cautiously and with close monitoring with vardenafil as coadministration may have additive effects on the prolongation of the QT interval. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. QT prolongation has also occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval, such as vardenafil, is not advised; pazopanib has been reported to prolong the QT interval. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval. If pazopanib and vardenafil are coadministered, closely monitor the patient for QT interval prolongation.
    Pentamidine: (Major) Pentamidine has been associated with QT prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with pentamidine include vardenafil. 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 was given with prescriptive doses of another agent known to prolong the QT interval, an additive effect on the QT interval was observed.
    Perphenazine: (Minor) Use vardenafil with caution in combination with perphenazine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Perphenazine is associated with a possible risk for QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Use vardenafil with caution in combination with perphenazine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Perphenazine is associated with a possible risk for QT prolongation.
    Phenoxybenzamine: (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.
    Phentolamine: (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.
    Phenylephrine: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Phenylephrine; Promethazine: (Moderate) Use vardenafil with caution in combination with promethazine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval. Vardenafil is associated with QT prolongation. 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. The effect of vardenafil on the QT interval should be considered when prescribing the drug. Coadministration may increase the risk for QT prolongation.
    Pimozide: (Severe) Because of the potential for torsade de pointes (TdP), use of vardenafil with pimozide is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and TdP. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
    Pitolisant: (Major) Avoid coadministration of pitolisant with vardenafil as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Posaconazole: (Severe) The concurrent use of posaconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as vardenafil, is contraindicated. Posaconazole is associated with QT prolongation, and vardenafil may cause QT prolongation at both therapeutic and supratherapeutic doses. Also, posaconazole may inhibit the metabolism of vardenafil. Posaconazole is a potent CYP3A4 inhibitor. Elevated plasma concentrations of vardenafil may also increase the risk for other vardenafil-related adverse events, such as prolonged erection or potential for syncope.
    Prazosin: (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.
    Primaquine: (Moderate) Due to the potential for QT interval prolongation with primaquine, caution is advised with vardenafil and other drugs that prolong the QT interval. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Procainamide: (Major) Vardenafil should be avoided in patients taking Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsade de pointes (TdP). Therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. The effect of vardenafil on the QT interval should be considered when prescribing the drug.
    Prochlorperazine: (Minor) Use vardenafil with caution in combination with prochlorperazine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Prochlorperazine is also associated with a possible risk for QT prolongation.
    Promethazine: (Moderate) Use vardenafil with caution in combination with promethazine due to increased risk of QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Propafenone: (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). 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. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vardenafil include propafenone. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Quetiapine: (Major) Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. According to the manufacturer, use of quetiapine should be avoided in combination with drugs known to increase the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with quetiapine include 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).
    Quinidine: (Major) Vardenafil should be avoided in patients taking Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsade de pointes (TdP). Therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. The effect of vardenafil on the QT interval should be considered when prescribing the drug.
    Quinine: (Major) Concurrent use of quinine and vardenafil should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Vardenafil is associated with QT prolongation. Therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
    Ranolazine: (Major) Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, such as vardenafil, concurrent use may result in additive QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
    Ribociclib: (Major) Concurrent use of vardenafil orally disintegrating tablets with ribociclib should be avoided due to increased vardenafil exposure. If use of vardenafil oral tablets and ribociclib is required, do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Ribociclib is a strong CYP3A4 inhibitor and vardenafil is a primary CYP3A4 substrate. Also, coadministration of ribociclib with vardenafil should be avoided if possible due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Vardenafil is associated with QT prolongation. Vardenafil can produce QT prolongation at both therapeutic and supratherapeutic doses.
    Ribociclib; Letrozole: (Major) Concurrent use of vardenafil orally disintegrating tablets with ribociclib should be avoided due to increased vardenafil exposure. If use of vardenafil oral tablets and ribociclib is required, do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Ribociclib is a strong CYP3A4 inhibitor and vardenafil is a primary CYP3A4 substrate. Also, coadministration of ribociclib with vardenafil should be avoided if possible due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Vardenafil is associated with QT prolongation. Vardenafil can produce QT prolongation at both therapeutic and supratherapeutic doses.
    Rilpivirine: (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vardenafil. Vardenafil is associated with QT prolongation. 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) Use of vardenafil with riociguat and other guanylate cyclase (GC) stimulators is contraindicated. PDE5 inhibitors, including vardenafil, may potentiate the hypotensive effects of riociguat.
    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. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Ritonavir: (Major) Do not use vardenafil orally disintegrating tablets with ritonavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 72-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; ritonavir is a strong CYP3A4 inhibitor. Coadministration of ritonavir with vardenafil resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax. Concomitant use may increase the risk of vardenafil-related adverse effects, such as prolonged erection or 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. Vardenafil is associated with QT prolongation. 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: (Severe) Coadministration of saquinavir boosted with ritonavir is contraindicated with other drugs that may prolong the QT interval and which are primary CYP3A4 substrates, such as vardenafil. Saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor that increases the QT interval in a dose-dependent fashion. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
    Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with vardenafil is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Consider the potential for additive QT effects if vardenafil is administered with selpercatinib.
    Sertraline: (Moderate) Use caution and monitor patients for QT prolongation when administering vardenafil with sertraline. Vardenafil is associated with QT prolongation. 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) Coadministration of vardenafil and short-acting beta-agonists may increase the risk of QT prolongation. Vardenafil has been associated with QT prolongation. Therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval. 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 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.
    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. Vardenafil is associated with QT prolongation. 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. Vardenafil is associated with QT prolongation. 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) Patients taking sotalol, a Class III antiarrhythmic, should avoid using vardenafil, as use together may increase the risk for QT prolongation and torsade de pointes. Proarrhythmic events should be anticipated after initiation of sotalol therapy and after each upward dosage adjustment. Consider the potential for adverse effects on the QT interval during use of vardenafil with sotalol. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    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. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. Sunitinib can prolong the QT 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) Do not use vardenafil orally disintegrating tablets with telaprevir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; telaprevir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    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 due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; telithromycin is a strong CYP3A4 inhibitor. Use of vardenafil with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to 16-fold. Concurrent use may also increase the risk of QT prolongation. Telithromycin is associated with QT prolongation and torsade de pointes (TdP). Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in the QTc interval.
    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 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) Because of the potential for torsades de pointes (TdP), use of vardenafil with thioridazine is contraindicated. Thioridazine is associated with a well-established risk of QT prolongation and TdP. Thioridazine is considered contraindicated for use along with agents that may prolong the QT interval and increase the risk of TdP. Vardenafil has a possible risk for QT prolongation and TdP. 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).
    Tipranavir: (Major) Do not use vardenafil orally disintegrating tablets with tipranavir boosted with ritonavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 72-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; ritonavir is a strong CYP3A4 inhibitor. Coadministration of ritonavir with vardenafil resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil Cmax.
    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: (Major) Do not use vardenafil orally disintegrating tablets with verapamil due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; verapamil is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold. Antihypertensives, when used with vardenafil, may have additive effects on blood pressure reduction.
    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) since 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). Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can 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. Vardenafil is associated with 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 also prolong the QT/QTc interval.
    Tucatinib: (Major) Do not use vardenafil orally disintegrating tablets with tucatinib due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; tucatinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
    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) Coadministration of vardenafil and vemurafenib may increase the risk for QT prolongation and torsade de pointes. If coadministration is necessary, ECG monitoring is recommended. Vemurafenib and vardenafil have both been associated with QT prolongation; additive effects are possible during coadministration. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in the QTc interval.
    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: (Major) Do not use vardenafil orally disintegrating tablets with verapamil due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; verapamil is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold. Antihypertensives, when used with vardenafil, may have additive effects on blood pressure reduction.
    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) Do not use vardenafil orally disintegrating tablets with voriconazole due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; voriconazole is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold. In addition, voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil can produce an increase in QTc interval.
    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.
    Ziprasidone: (Major) Concomitant use of ziprasidone and vardenafil should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.

    PREGNANCY AND LACTATION

    Pregnancy

    Vardenafil is not indicated for use in females. There are no adequate and well-controlled trials of vardenafil in humans during pregnancy. In animal reproduction studies, no adverse developmental outcomes were observed during organogenesis at exposures for unbound vardenafil and its major metabolite at 100 and 29 times, respectively, the maximum recommended human dose (MRHD) of 20 mg.

    Vardenafil is not indicated for use in females and is therefore not recommended during breast-feeding. There is no information on the presence of vardenafil and its major metabolite in human milk, the effects on the breast-fed infant, or the effects on milk production. Vardenafil is excreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma; following a single oral dose of 3 mg/kg, 3.3% of the administered dose was excreted into the milk within 24 hours.

    MECHANISM OF ACTION

    Mechanism of Action: Vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Vardenafil enhances the effect of NO by inhibiting PDE5, thereby raising concentrations of cGMP in the corpus cavernosum. Vardenafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. Vardenafil has a greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Sildenafil, another PDE inhibitor, has a lower selectivity for PDE5 vs PDE6 and is associated with abnormalities related to color vision with higher doses or plasma concentrations of the drug.Phosphodiesterase type 5 is also abundant in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in pulmonary vasodilation which can be effective in treating pulmonary hypertension. Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Dyspepsia is one of the more common adverse reactions associated with PDE inhibitor therapy.

    PHARMACOKINETICS

    Vardenafil is administered orally. 
     
    Vardenafil is extensively distributed throughout the body. Protein binding is approximately 95%. Clearance is primarily via the hepatic cytochrome P450 isoenzyme CYP3A4 with minor metabolism by CYP3A5 and CYP2C. The major metabolite, designated M1, is the result of desethylation at the piperazine moiety of vardenafil and is further metabolized. M1 has phosphodiesterase selectivity similar to that of vardenafil and an in vitro inhibitory potency for phosphodiesterase 5 (PDE5) that is 28% of that of vardenafil. M1 also accounts for about 7% of the total pharmacological activity. Vardenafil is excreted as metabolites predominantly in the feces (approximately 91—95% of an oral dose) and to a lesser extent in the urine (about 2—6% of an oral dose). The elimination half-life of vardenafil and M1 is about 4—5 hours with the use of the film-coated tablets. The elimination half-life of vardenafil is 4—6 hours and the elimination half-life of MI is 3—5 hours with the use of the orally disintegrating tablets.

    Oral Route

    Oral film-coated tablets:
    Vardenafil is well-adsorbed from the gastrointestinal tract. In healthy volunteers, peak plasma concentrations (Cmax) following a single 20 mg oral tablet dose are usually reached between 30 minutes and 2 hours (median 60 minutes) in the fasted state. High-fat meals reduced Cmax by 18—50%. Absolute bioavailability is approximately 15%. The onset of action is within 1 hour of administration.
     
    Orally disintegrating tablets:
    The orally disintegrating vardenafil tablets provide a higher systemic exposure than the film-coated tablets. In a study of patients with erectile dysfunction, the mean AUC was increased by 21—29% and the mean Cmax was decreased by 19% in elderly patients (>=65) and 8% in younger patients (18—45 years) as compared to the 10 mg film-coated tablets. In a study of healthy male volunteers (18—50 years), the mean Cmax was 15% higher and the mean AUC was 44% higher as compared to the 10 mg film-coated tablets. The median time to reach Cmax in a fasted stated was 1.5 h. High fat meals had no effect on vardenafil AUC or Tmax in healthy volunteers, but reduced the Cmax by 35%. When the orally disintegrating vardenafil tablets were administered with water, the vardenafil AUC was reduced by 29% and the median Tmax was shortened by 60 minutes, while Cmax was not affected.