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Levitra vardenafil 20mg tablets

CLASSES

Erectile Dysfunction Products

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

HOW SUPPLIED

Levitra 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.
NOTE: Vardenafil 10 mg orally disintegrating tablets provide higher systemic exposure compared to vardenfil 10 mg film-coated tablets. Therefore, these dosage forms are not interchangeable.

Oral dosage (oral tablet)

Adult males

The recommended starting dose is 10 mg PO approximately 60 minutes before sexual activity. The dose may be increased to a maximum recommended dose of 20 mg or decreased to 5 mg based on efficacy and side effects. The maximum recommended dosing frequency is once per day. 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 certain CYP3A4 inhibitors are also given). Single doses ranging from 5 to 40 mg PO have been evaluated in clinical studies of men with mild-to-severe ED for at least 6 months and diabetic men. Doses of 10 mg PO and 20 mg PO were the most effective. The 40 mg PO dose was no more effective than the 20 mg dose. See Other Dosage Adjustments below.
   -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.

Geriatric males

Initially, consider a starting dose of 5 mg PO approximately 60 minutes before sexual activity. The maximum recommended dosing frequency is once per day.

Oral dosage (orally disintegrating tablets)

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).
   -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, 20 mg/day PO when not given with certain CYP3A4 inhibitors; 2.5 mg/day PO when given with indinavir, atazanavir, saquinavir, clarithromycin, ketoconazole 400 mg daily, or itraconazole 400 mg daily; 5 mg/day PO when given with erythromycin, ketoconazole 200 mg daily, or itraconazole 200 mg daily; 2.5 mg/72-hours PO when given with ritonavir. For orally disintegrating tablets, 10 mg/day PO.

Elderly

For regular tablets, 20 mg/day PO when not given with certain CYP3A4 inhibitors; 2.5 mg/day PO when given with indinavir, atazanavir, saquinavir, clarithromycin, ketoconazole 400 mg daily, or itraconazole 400 mg daily; 5 mg/day PO when given with erythromycin, ketoconazole 200 mg daily, or itraconazole 200 mg daily; 2.5 mg/72-hours PO when given with ritonavir. For orally disintegrating tablets, 10 mg/day PO.

Adolescents

Safety and efficacy has not been established.

Children

Safety and efficacy has not been established.

Infants

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Hepatic Impairment

For patients with mild hepatic impairment (Child-Pugh class A), no dose adjustment is required. For regular vardenafil tablets, clearance is reduced in patients with moderate hepatic impairment (Child-Pugh class B) and a starting dose of 5 mg/day PO is recommended; the maximum dose should not exceed 10 mg/day PO. Vardenafil has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Do not use vardenafil orally disintegrating tablets in patients with moderate or severe hepatic impairment as this dosage form provides higher systemic exposure than the regular tablets.

Renal Impairment

No dosage adjustments are needed in patients with varying degrees of renal impairment.
 
Hemodialysis
The pharmacokinetics of vardenafil have not been studied in patients requiring dialysis. Do not administer vardenfil orally disintegrating tablets in patients on hemodialysis.

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 levitra vardenafil 20mg tablets 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 (unspecified) / 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) Concomitant administration of vardenafil and abarelix may cause additive QT prolongation and should be used together cautiously.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Alpha-blockers: (Major) Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Vardenafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the lowest recommended dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. In general, patients should not be initiated on the orally disintegrating vardenafil tablets while on alpha-blocker therapy; however, if patients have previously used the film-coated tablets, this may be changed to the orally disintegrating tablets upon the advice of the healthcare provider. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers. Studies have been conducted to determine the effects of vardenafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers terazosin and tamsulosin. When vardenafil 10 or 20 mg was administered to healthy subjects taking terazosin (10 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of terazosin on standing systolic blood pressure. In contrast, coadministration of a single 10 or 20 mg dose of vardenafil to healthy subjects taking 0.4 mg once daily of tamsulosin, a selective antagonist of alpha-1a receptors, resulted in no significant decreases in blood pressure.
Amiodarone: (Major) The concomitant use of amiodarone and vardenafil should only be done after careful assessment of risks versus benefits, especially when the coadministered agent might decrease the metabolism of amiodarone. If possible, avoid coadministration. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction) The effect of vardenafil on the QT interval should be considered when prescribing the drug. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. In addition, vardenafil is a substrate for CYP3A4. Amiodarone is an inhibitor of CYP3A4 and can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.
Amoxicillin; Clarithromycin; Lansoprazole: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Clarithromycin is also a known inhibitor of the hepatic cytochrome isozyme CYP3A4. Vardenafil is also associated with potential QT prolongation and is primarily metabolized by CYP3A4. The manufacturer of clarithromycin recommends against concomitant use. However, if coadministered, use vardenafil at reduced doses of 2.5 mg, every 24 hours when used with clarithromycin or every 72 hours when used with ritonavir-'boosted' clarithromycin, with increased monitoring for adverse reactions. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as clarithromycin
Amoxicillin; Clarithromycin; Omeprazole: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Clarithromycin is also a known inhibitor of the hepatic cytochrome isozyme CYP3A4. Vardenafil is also associated with potential QT prolongation and is primarily metabolized by CYP3A4. The manufacturer of clarithromycin recommends against concomitant use. However, if coadministered, use vardenafil at reduced doses of 2.5 mg, every 24 hours when used with clarithromycin or every 72 hours when used with ritonavir-'boosted' clarithromycin, with increased monitoring for adverse reactions. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as clarithromycin
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) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include vardenafil.
Apomorphine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering vardenafil with apomorphine. 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). Limited data indicate that QT prolongation is also possible with apomorphine administration. The change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines; however, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
Aprepitant, Fosaprepitant: (Moderate) Use caution if vardenafil and aprepitant, fosaprepitant are used concurrently and monitor for an increase in vardenafil-related adverse effects for several days after administration of a multi-day aprepitant regimen. Vardenafil is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of vardenafil. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. 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. Aripiprazole should be used cautiously and with close monitoring with vardenafil.
Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide 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).
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) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug 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). 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.
Atazanavir: (Major) Particular caution should be used when prescribing vardenafil to patients receiving atazanavir. Coadministration of atazanavir with vardenafil is expected to substantially increase vardenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered, use vardenafil for erectile dysfunction at reduced doses of 2.5 mg, every 24 hours when used with atazanavir or every 72 hours when used with ritonavir-'boosted' atazanavir, with increased monitoring for adverse reactions. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as atazanavir.
Atazanavir; Cobicistat: (Major) Coadministration of vardenafil with cobicistat is expected to substantially increase the plasma concentrations of vardenafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. (Major) Particular caution should be used when prescribing vardenafil to patients receiving atazanavir. Coadministration of atazanavir with vardenafil is expected to substantially increase vardenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered, use vardenafil for erectile dysfunction at reduced doses of 2.5 mg, every 24 hours when used with atazanavir or every 72 hours when used with ritonavir-'boosted' atazanavir, with increased monitoring for adverse reactions. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as atazanavir.
Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include vardenafil.
Azithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering vardenafil with azithromycin. Azithromycin has been associated with post-marketing reports of QT prolongation and TdP. Vardenafil, at therapeutic (10 mg) and supratherapeutic (80 mg) doses, produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
Barbiturates: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as barbiturates, will decrease plasma levels of vardenafil.
Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with vardenafil. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. 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).
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: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include vardenafil.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include vardenafil.
Boceprevir: (Moderate) Close clinical monitoring is advised when administering vardenafil with boceprevir due to an increased potential for vardenafil-related adverse events, such as hypotension, syncope, visual disturbances, and priapism. During coadministration, do not exceed a maximum vardenafil dosage of 2.5 mg in 24 hours. If vardenafil dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Predictions about the interaction can be made based on the metabolic pathways of vardenafil. Vardenafil is a substrate of the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. When used in combination, the plasma concentrations of vardenafil may be elevated.
Bosentan: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of bosentan, a CYP3A4 enzyme-inducer, will decrease plasma levels of vardenafil, however, no interaction studies have been performed.
Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Buprenorphine: (Major) Buprenorphine should be used cautiously and with close monitoring with vardenafil. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as 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 (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. If these drugs are used together, consider the potential for additive effects on the QT interval.
Buprenorphine; Naloxone: (Major) Buprenorphine should be used cautiously and with close monitoring with vardenafil. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval, such as 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 (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. If these drugs are used together, consider the potential for additive effects on the QT interval.
Carbamazepine: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as carbamazepine, will decrease plasma levels of vardenafil, however, no interaction studies have been performed.
Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Carbetapentane; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Carbinoxamine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Ceritinib: (Major) Avoid coadministration of ceritinib with vardenafil due to increased vardenafil exposure; additive QT prolongation may also occur. If coadministration is unavoidable, monitor for vardenafil-related adverse reactions; a dosage adjustment may be necessary. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval; the extent of CYP3A4 inhibition is unknown. Vardenafil is primarily metabolized by CYP3A4 and is also associated with QT prolongation at both therapeutic and supratherapeutic doses. Coadministration with various strong CYP3A4 inhibitors increased the AUC of vardenafil by 10-fold to 49-fold, and the Cmax by 4-fold to 13-fold. Coadministration with a moderate CYP3A4 inhibitor increased the AUC and Cmax of vardenafil by 4-fold and 3-fold, respectively.
Chlophedianol; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Chloroquine: (Major) Chloroquine administration is associated with an increased risk of QT prolongation and torsades de pointes (TdP). The need to coadminister chloroquine with drugs known to prolong the QT interval should be done with a careful assessment of risks versus benefits and should be avoided when possible. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with chloroquine 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).
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Chlorpheniramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Chlorpromazine: (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 chlorpromazine. Phenothiazines have been associated with a risk of QT prolongation and/or torsade de pointes TdP. This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine. Agents that prolong the QT interval could lead to torsade de pointes when combined with a phenothiazine, and therefore are generally not recommended for combined use.
Cimetidine: (Major) Phosphodiesterase inhibitors are metabolized principally by cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Cimetidine is a known inhibitor of hepatic CYP enzymes. Cimetidine (800 mg) caused a 56% increase in plasma sildenafil concentrations when coadministered with sildenafil 50 mg to healthy volunteers. Population data from patients in clinical trials also indicate a reduction in sildenafil clearance when it was coadministered with cimetidine. If possible, cimetidine use should be avoided in patients who take phosphodiesterase inhibitors
Ciprofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering ciprofloxacin with vardenafil. Ciprofloxacin has been associated with a possible risk for QT prolongation and TdP. Vardenafil, at therapeutic (10 mg) and supratherapeutic (80 mg) doses, produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effects of these drugs on the QT interval should be considered when prescribing the drug.
Cisapride: (Severe) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. Because of the potential for torsade de pointes (TdP), use of cisapride with vardenafil is contraindicated.
Citalopram: (Major) Citalopram causes dose-dependent QT interval prolongation. According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with citalopram 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).
Clarithromycin: (Major) Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes (TdP). Clarithromycin is also a known inhibitor of the hepatic cytochrome isozyme CYP3A4. Vardenafil is also associated with potential QT prolongation and is primarily metabolized by CYP3A4. The manufacturer of clarithromycin recommends against concomitant use. However, if coadministered, use vardenafil at reduced doses of 2.5 mg, every 24 hours when used with clarithromycin or every 72 hours when used with ritonavir-'boosted' clarithromycin, with increased monitoring for adverse reactions. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as clarithromycin
Class IA Antiarrhythmics: (Major) The manufacturer recommends that vardenafil be avoided in patients taking Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (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) The effect of vardenafil on the QT interval should be considered when prescribing the drug.
Clozapine: (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 and with close monitoring with vardenafil include clozapine.
Cobicistat: (Major) Coadministration of vardenafil with cobicistat is expected to substantially increase the plasma concentrations of vardenafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.
Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Coadministration of vardenafil with cobicistat is expected to substantially increase the plasma concentrations of vardenafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.
Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of vardenafil with cobicistat is expected to substantially increase the plasma concentrations of vardenafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.
Codeine; Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include vardenafil. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Codeine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include vardenafil.
Conivaptan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as vardenafil, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with vardenafil. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. Treatment with vardenafil may be initiated no sooner than 1 week after completion of conivaptan therapy.
Crizotinib: (Major) Crizotinib has been associated with QT prolongation. If crizotinib and another drug, such as vardenafil, that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Crizotinib is also a CYP3A4 substrate and inhibitor, while vardenafil is a CYP3A4 substrate. Therefore increased serum concentrations of vardenafil may occur with concomitant administration. Monitor patients for increased toxicity.
Cyclobenzaprine: (Major) Because both vardenafil and cyclobenzaprine have a possible risk for QT prolongation and torsade de pointes (TdP), caution is advisable during concurrent use. 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. Cyclobenzaprine is structurally similar to tricyclic antidepressants (TCAs). TCAs have been reported to prolong the QT interval, especially when given in excessive doses (or in overdosage settings). Cyclobenzaprine is associated with a possible risk of QT prolongation and torsade de pointes (TdP), particularly in the event of acute overdose.
Darunavir: (Major) Coadministration of darunavir with vardenafil is expected to substantially increase vardenafil plasma concentrations and may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.
Darunavir; Cobicistat: (Major) Coadministration of darunavir with vardenafil is expected to substantially increase vardenafil plasma concentrations and may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. (Major) Coadministration of vardenafil with cobicistat is expected to substantially increase the plasma concentrations of vardenafil and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of ritonavir with vardenafil results in a 20% decrease in ritonavir AUC and a 49-fold increase in vardenafil AUC. Substantially increased vardenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered, use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, use of the orally disintegrating tablets with ritonavir is not recommended. No change in ritonavir dose is required. In addition, both ritonavir and vardenafil are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Dasatinib: (Major) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. In addition, vardenafil is a substrate for CYP3A4. Inhibitors of CYP3A4 can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. Therefore, it is advisable to closely monitor for adverse events when vardenafil is coadministered with drugs that inhibit CYP3A4 and prolong the QT interval, including dasatinib.
Daunorubicin: (Major) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported during anthracycline therapy.
Degarelix: (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 degarelix.
Delavirdine: (Major) If used together, the vardenafil tablet dose should not exceed 2.5 mg in a 24-hour period; advise patients to promptly report adverse events such as dizziness, faintness on standing, or prolonged erection. Vardenafil orally disintegrating tablets (ODT) provide increased exposure as compared to the regular tablets; therefore, use with potent CYP3A4 inhibitors such as delavirdine is not recommended. Delavirdine is expected to substantially increase vardenafil plasma concentrations and may result in vardenafil-related adverse events including hypotension, visual changes, and priapism.
Deutetrabenazine: (Major) Avoid coadministration of deutetrabenazine with vardenafil. Clinically relevant QT prolongation may occur with deutetrabenazine. 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).
Dexamethasone: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as dexamethasone, will decrease plasma levels of vardenafil.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Dextromethorphan; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include vardenafil.
Dextromethorphan; Quinidine: (Major) The manufacturer recommends that vardenafil be avoided in patients taking Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (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) The effect of vardenafil on the QT interval should be considered when prescribing the drug.
Diltiazem: (Moderate) Vardenafil is metabolized by hepatic cytochrome P450 3A4. Inhibitors of CYP3A4, such as diltiazem, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.
Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Diphenhydramine; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Disopyramide: (Major) The manufacturer recommends that vardenafil be avoided in patients taking Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (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) The effect of vardenafil on the QT interval should be considered when prescribing the drug.
Dofetilide: (Severe) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Because of the potential for TdP, use of vardenafil with dofetilide is contraindicated.
Dolasetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dolasetron and vardenafil should be used together cautiously. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. 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). Concurrent use may increase the risk for QT prolongation.
Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include vardenafil.
Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include vardenafil.
Doxazosin: (Major) Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Vardenafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the lowest recommended dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. In general, patients should not be initiated on the orally disintegrating vardenafil tablets while on alpha-blocker therapy; however, if patients have previously used the film-coated tablets, this may be changed to the orally disintegrating tablets upon the advice of the healthcare provider. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers. Studies have been conducted to determine the effects of vardenafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers terazosin and tamsulosin. When vardenafil 10 or 20 mg was administered to healthy subjects taking terazosin (10 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of terazosin on standing systolic blood pressure. In contrast, coadministration of a single 10 or 20 mg dose of vardenafil to healthy subjects taking 0.4 mg once daily of tamsulosin, a selective antagonist of alpha-1a receptors, resulted in no significant decreases in blood pressure.
Doxorubicin: (Major) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported during anthracycline therapy.
Dronedarone: (Severe) Concomitant use of dronedarone and vardenafil is contraindicated.Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
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: (Major) Since the symptoms of orthostasis (e.g., postural hypotension, dizziness and vertigo) are reported more frequently in tamsulosin-treated vs. placebo patients, there is a theoretical risk of enhanced hypotensive effects in individual patients when tamsulosin co-administered with vasodilatory agents such as phosphodiesterase inhibitors. Concurrent use of PDE5 inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. When sildenafil (25 mg) was simultaneously administered with doxazosin (4 mg) to patients with BPH, mean additional reductions in supine blood pressure of 7 mmHg systolic and 7 mmHg diastolic were observed. When higher doses of sildenafil were administered with doxazosin (4 mg), symptomatic postural hypotension within 1 to 4 hours was reported in some patients. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers. The manufacturers for tadalafil and vardenafil state that patients should be stabilized on alpha blocker therapy prior to starting either tadalafil or vardenafil, or if already vardenafil receiving optimum dose of tadalafil or vardenafil, alpha blocker therapy should be started at the lowest possible dose.
Efavirenz: (Major) Although data are limited, coadministration of efavirenz and vardenafil may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. 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). In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as vardenafil.
Efavirenz; Emtricitabine; Tenofovir: (Major) Although data are limited, coadministration of efavirenz and vardenafil may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. 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). In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as vardenafil.
Elbasvir; Grazoprevir: (Moderate) Administering vardenafil with elbasvir; grazoprevir may result in elevated vardenafil plasma concentrations. Vardenafil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eliglustat: (Major) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with eliglustat include vardenafil.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with 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). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with 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). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Epirubicin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering vardenafil with epirubicin. 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). Acute cardiotoxicity can also occur during administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
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) It may be prudent to avoid the use of vardenafil in patients being treated with erythromycin. If these drugs must be used together, do so with extreme caution. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as erythromycin. Erythromycin is generally considered by experts to have an established risk for QT prolongation and torsades de pointes (TdP). Vardenafil, at therapeutic (10 mg) and supratherapeutic (80 mg) doses, produces increases in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). Coadministration could lead to the risk of additive QT prolongation. Additionally, erythromycin inhibits CYP3A4. Vardenafil is metabolized by CYP3A4. Coadministration of erythromycin (500 mg tid) increased the AUC and Cmax of vardenafil 4-fold and 3-fold, respectively; increased vardenafil concentrations further increase the risk for serious side effects.
Erythromycin; Sulfisoxazole: (Major) It may be prudent to avoid the use of vardenafil in patients being treated with erythromycin. If these drugs must be used together, do so with extreme caution. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as erythromycin. Erythromycin is generally considered by experts to have an established risk for QT prolongation and torsades de pointes (TdP). Vardenafil, at therapeutic (10 mg) and supratherapeutic (80 mg) doses, produces increases in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). Coadministration could lead to the risk of additive QT prolongation. Additionally, erythromycin inhibits CYP3A4. Vardenafil is metabolized by CYP3A4. Coadministration of erythromycin (500 mg tid) increased the AUC and Cmax of vardenafil 4-fold and 3-fold, respectively; increased vardenafil concentrations further increase the risk for serious side effects.
Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as vardenafil, should be done with caution and close monitoring.
Etravirine: (Moderate) Etravirine is an inducer of CYP3A4; coadministration may result in decreased vardenafil concentrations. Dosage adjustments may be needed based on clinical efficacy.
Ezogabine: (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 ezogabine.
Fingolimod: (Major) Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). 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. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fingolimod 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). When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed.
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). Fluconazole is an inhibitor of CYP3A4, an 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. Additionally, fluconazole has been associated with prolongation of the QT interval; do not use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as vardenafil.
Fluoxetine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. Vardenafil is metabolized by hepatic cytochrome P450 3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4, such as fluoxetine, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.
Fluoxetine; Olanzapine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. Vardenafil is metabolized by hepatic cytochrome P450 3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4, such as fluoxetine, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. (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 olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
Fluphenazine: (Minor) 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 that should be used cautiously with vardenafil include fluphenazine.
Fluvoxamine: (Major) Caution should be used when prescribing vardenafil in patients receiving fluvoxamine. Coadministration may substantially increase vardenafil plasma concentrations and result in vardenafil-related adverse events including hypotension, visual changes, and priapism. If used together, vardenafil dosage adjustment may be necessary. The manufacturer of vardenafil tablets recommends not exceeding a single 2.5 to 5 mg dose in a 24-hour period when used with certain potent CYP3A4 inhibitors (e.g., ketoconazole, indinavir); advise patients to promptly report adverse events such as prolonged erection. Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, use with moderate or potent CYP3A4 inhibitors is not recommended. Fluvoxamine is a potent inhibitor of CYP3A4 in vitro and a mild inhibitor of CYP2C9. Vardenafil is metabolized by CYP3A4 and to a lesser extent CYP2C9.
Fosamprenavir: (Major) Coadministration of vardenafil with fosamprenavir, especially when 'boosted' with ritonavir, is expected to substantially increase vardenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Use vardenafil at reduced doses of no more than 2.5 mg, every 24 hours when used with fosamprenavir or every 72 hours when used with ritonavir-'boosted' fosamprenavir, with increased monitoring for adverse reactions.
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.
Fosphenytoin: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as fosphenytoin, will decrease plasma levels of vardenafil.
Gemifloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering vardenafil with gemifloxacin. 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). Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Goserelin: (Major) Vardenafil should be used cautiously and with close monitoring with goserelin. 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. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
Granisetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), granisetron and vardenafil should be used together cautiously. 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 (e.g., 4 to 6 msec calculated by individual QT correction).
Grapefruit juice: (Moderate) Vardenafil is metabolized via the CYP3A4 isozyme. Grapefruit juice has been reported to decrease the metabolism of drugs metabolized via this enzyme. Grapefruit juice contains a compound that inhibits CYP3A4 in enterocytes in the GI tract. Vardenafil levels may increase; it is possible that vardenafil-induced side effects could also be increased in some individuals.
Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
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) Halogenated anesthetics should be used cautiously and with close monitoring with vardenafil. Halogenated anesthetics can prolong the QT interval. 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.
Haloperidol: (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 haloperidol. 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. In addition, haloperidol is a substrate for CYP2D6. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and inhibitors of CYP2D6. Vardenafil is a CYP2D6 inhibitor. Monitor closely.
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: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and vardenafil. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. 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).
Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include vardenafil.
Ibutilide: (Major) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. The manufacturer recommends that vardenafil be avoided in patients ibutilide. Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Idarubicin: (Major) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction) The effect of vardenafil on the QT interval should be considered when prescribing the drug. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, and idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported during anthracycline therapy.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with vardenafil, a CYP3A substrate, as vardenafil toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
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, STI-571: (Major) Imatinib is a potent inhibitor of CYP3A4. Vardenafil is metabolized by hepaticCYP3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4 can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. In vivo studies report that several strong CYP3A4 inhibitors can significantly increase the AUC and Cmax of vardenafil when coadministered with vardenafil. Vardenafil dose adjustments are required when vardenafil is administered with such agents. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as erythromycin. Other potent CYP3A4 inhibitors such as, imatinib, STI-571, would be expected to have effects on vardenafil clearance when coadministered.
Indinavir: (Major) Particular caution should be used when prescribing vardenafil in patients receiving indinavir. Coadministration is expected to substantially increase vardenafil plasma concentrations and may result in vardenafil-related adverse events including hypotension, visual changes, and priapism. In addition, indinavir exposure may be reduced. If used together, the vardenafil dose should not exceed 2.5 mg in a 24-hour period; advise patients to promptly report adverse events such as prolonged erection. Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, use with potent CYP3A4 inhibitors such as indinavir is not recommended. Coadministration of indinavir (800 mg every 8 hours) with a single dose of vardenafil (10 mg) altered the pharmacokinetics of vardenafil with a 16-fold increase in AUC, a 7-fold increase in Cmax, and a 2-fold increase in half-life. Conversely, vardenafil reduced the AUC and Cmax of indinavir by 30% and 40%, respectively.
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: (Moderate) Concomitant use of isavuconazonium with vardenafil may result in increased serum concentrations of vardenafil. Vardenafil is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring for adverse events, including hypotension, syncope, visual changes, and prolonged erection, are advised if these drugs are used together.
Isoniazid, INH: (Major) Vardenafil is metabolized by hepatic cytochrome P450 3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4, such as isoniazid, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. In vivo studies report that several strong CYP3A4 inhibitors can significantly increase the AUC and Cmax of vardenafil when coadministered with vardenafil. Vardenafil dose adjustments are required when vardenafil is administered with such agents
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Vardenafil is metabolized by hepatic cytochrome P450 3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4, such as isoniazid, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. In vivo studies report that several strong CYP3A4 inhibitors can significantly increase the AUC and Cmax of vardenafil when coadministered with vardenafil. Vardenafil dose adjustments are required when vardenafil is administered with such agents (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, like the rifamycins, will decrease plasma levels of vardenafil.
Isoniazid, INH; Rifampin: (Major) Vardenafil is metabolized by hepatic cytochrome P450 3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4, such as isoniazid, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. In vivo studies report that several strong CYP3A4 inhibitors can significantly increase the AUC and Cmax of vardenafil when coadministered with vardenafil. Vardenafil dose adjustments are required when vardenafil is administered with such agents (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, like the rifamycins, will decrease plasma levels of vardenafil.
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) Caution is advised when administering itraconazole with vardenafil due to the potential for additive effects on the QT interval and increased exposure to vardenafil. Both itraconazole and vardenafil have been associated with QT prolongation; coadministration may increase this risk. If these drugs must be administered together, a lower dose of vardenafil is required. The vardenafil orally disintegrating tablets (ODTs) provide increased exposure as compared to the regular tablets; therefore, use of the vardenafil ODTs with potent CYP3A4 inhibitors should be avoided. For patients receiving itraconazole 200 mg daily, the maximum single vardenafil dose is 5 mg every 24 hours. For patients receiving itraconazole 400 mg daily, the maximum single vardenafil dose is 2.5 mg every 24 hours.
Ivacaftor: (Moderate) Use caution when administering ivacaftor and vardenafil concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as vardenafil, can increase vardenafil exposure leading to increased or prolonged therapeutic effects and adverse events.
Ketoconazole: (Major) Caution is advised when administering ketoconazole with vardenafil due to the potential for additive effects on the QT interval and increased exposure to vardenafil. Both ketoconazole and vardenafil have been associated with QT prolongation; coadministration may increase this risk. If these drugs must be administered together, a lower dose of vardenafil is required. The vardenafil orally disintegrating tablets (ODTs) provide increased exposure as compared to the regular tablets; therefore, use of the vardenafil ODTs with potent CYP3A4 inhibitors should be avoided. For patients receiving ketoconazole 200 mg daily, the maximum single vardenafil dose is 5 mg every 24 hours. For patients receiving ketoconazole 400 mg daily, the maximum single vardenafil 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.
Lapatinib: (Major) In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. If lapatinib will be coadministered with a CYP3A4 substrate, exercise caution and consider dose reduction of the concomitant substrate drug, especially for drugs that have a narrow therapeutic index. Several CYP3A4 substrates can prolong the QT interval, and lapatinib can also prolong the QT interval. Use lapatinib with extreme caution, if at all, in patients taking CYP3A4 substrates that also have potential to induce QT prolongation such as vardenafil.
Lenvatinib: (Major) Vardenafil should be used cautiously and with close monitoring with lenvatinib. 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). The effect of vardenafil on the QT interval should be considered when prescribing the drug. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of vardenafil; monitor for potential reduction in efficacy. Vardenafil is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Leuprolide: (Major) 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 another drug that is known to cause QT prolongation, an additive effect on the QT interval was observed. The effect of vardenafil on the QT interval should be considered when prescribing the drug. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Use leuprolide and vardenafil together with caution and with close clinical monitoring if use together is not avoidable.
Leuprolide; Norethindrone: (Major) 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 another drug that is known to cause QT prolongation, an additive effect on the QT interval was observed. The effect of vardenafil on the QT interval should be considered when prescribing the drug. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Use leuprolide and vardenafil together with caution and with close clinical monitoring if use together is not avoidable.
Levofloxacin: (Major) Concurrent use of vardenafil and levofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. 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).
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: (Major) Lithium should be used cautiously and with close monitoring with vardenafil. Lithium has been associated with QT prolongation. 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.
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) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. Drugs with a possible risk for QT prolongation that should be used cautiously with vardenafil include the beta agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
Loperamide: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Drugs with a possible risk for QT prolongation and TdP, like vardenafil, should be used cautiously and with close monitoring with loperamide.
Loperamide; Simethicone: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Drugs with a possible risk for QT prolongation and TdP, like vardenafil, should be used cautiously and with close monitoring with loperamide.
Lopinavir; Ritonavir: (Major) Coadministration of ritonavir with vardenafil results in a 20% decrease in ritonavir AUC and a 49-fold increase in vardenafil AUC. Substantially increased vardenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered, use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, use of the orally disintegrating tablets with ritonavir is not recommended. No change in ritonavir dose is required. In addition, both ritonavir and vardenafil are associated with QT prolongation; concomitant use increases the risk of QT prolongation. (Major) Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving lopinavir; ritonavir (Kaletra). Coadministration of lopinavir; ritonavir (Kaletra) with these drugs is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered, use vardenafil at reduced doses of 2.5 mg every 72 hours with increased monitoring for adverse reactions. In addition, QT prolongation in patients taking lopinavir; ritonavir has been reported. Coadministration of lopinavir; ritonavir with other drugs that prolong the QT interval, such as vardenafil, may result in additive QT prolongation.
Lorcaserin: (Major) 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.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of vardenafil by decreasing its systemic exposure. Vardenafil is primarily metabolized by CYP3A4, and lumacaftor is a strong CYP3A inducer.
Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and vardenafil concurrently. Ivacaftor is an inhibitor of CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as vardenafil, can increase vardenafil exposure leading to increased or prolonged therapeutic effects and adverse events.
Maprotiline: (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 maprotiline.
Mefloquine: (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 mefloquine.
Meperidine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include vardenafil.
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 known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with inhibitors of these enzymes may result in increased serum concentrations of methadone. Drugs with a possible risk for QT prolongation and TdP that inhibit CYP2D6 include vardenafil.
Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include vardenafil.
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, RU-486: (Major) Due to an increased risk of QT prolongation and torsade de pointes (TdP), vardenfil and mifepristone should be used together carefully. 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). Mifepristone has been associated with dose-dependent prolongation of the QT interval. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used.
Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and vardenafil. Coadminister with caution. 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). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
Mitotane: (Moderate) Use caution if mitotane and vardenafil are used concomitantly, and monitor for decreased efficacy of vardenafil and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and vardenafil is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of vardenafil.
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: (Moderate) Vardenafil is metabolized by hepatic cytochrome P450 3A4 and inhibitors of CYP3A4, such as nefazodone, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.
Nelfinavir: (Major) Particular caution should be used when prescribing vardenafil to patients receiving nelfinavir. Coadministration is expected to substantially increase vardenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. When used with nelfinavir, administer vardenafil at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions.
Nevirapine: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as nevirapine, will decrease plasma levels of vardenafil.
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 that prolong the QT interval, such as vardenafil. Additionally, nilotinib is a moderate CYP3A4 inhibitor and vardenafil is a CYP3A4 substrate; administering these drugs together may result in increased vardenafil levels. If the use of vardenafil is required, hold nilotinib therapy. If the use of nilotinib and vardenafil cannot be avoided, a vardenafil dose reduction may be necessary; close monitoring of the QT interval is recommended.
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: (Major) 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: (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 octreotide. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy warranting more cautious monitoring during octreotide administration in higher risk patients with cardiac disease. Since bradycardia is a risk factor for development of 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: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering vardenafil with ofloxacin. 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). Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
Olanzapine: (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 olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of ritonavir with vardenafil results in a 20% decrease in ritonavir AUC and a 49-fold increase in vardenafil AUC. Substantially increased vardenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered, use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, use of the orally disintegrating tablets with ritonavir is not recommended. No change in ritonavir dose is required. In addition, both ritonavir and vardenafil are associated with QT prolongation; concomitant use increases the risk of 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).
Oritavancin: (Minor) Vardenafil is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of vardenafil may be reduced if these drugs are administered concurrently.
Osimertinib: (Major) Periodically monitor ECGs and electrolytes if coadministration of osimertinib with vardenafil is necessary due to the risk of QT prolongation and torsade de pointes (TdP). Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). Concentration-dependent QTc prolongation has been suggested at the recommended dosing of osimertinib in a pharmacokinetic/pharmacodynamic analysis. Concomitant use may increase the risk of QT prolongation.
Oxaliplatin: (Major) Use caution if coadministration of oxaliplatin with vardenafil is necessary, and closely monitor for possible QT 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). QT prolongation and ventricular arrhythmias including fatal torsade de pointes (TdP) have also been reported with oxaliplatin use in post-marketing experience. Coadministration may result in additive effects on the QT interval.
Palbociclib: (Moderate) Monitor for an increase in vardenafil-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A and vardenafil is a sensitive CYP3A4 substrate. Coadministration with a moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold and the Cmax by 3-fold. It is possible that a weak CYP3A4 inhibitor like palbociclib may also increase vardenafil exposure.
Paliperidone: (Major) Paliperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. 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 considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, then 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: (Major) Pasireotide should be used cautiously and with close monitoring with vardenafil as coadministration may have additive effects on the prolongation of the QT interval. 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.
Pazopanib: (Major) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. In addition, vardenafil is a substrate for CYP3A4. Inhibitors of CYP3A4 can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. Therefore, it is advisable to closely monitor for adverse events when vardenafil is coadministered with drugs that inhibit CYP3A4 and prolong the QT interval, including pazopanib.
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) 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 perphenazine.
Perphenazine; Amitriptyline: (Minor) 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 perphenazine.
Phenoxybenzamine: (Major) Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Vardenafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the lowest recommended dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. In general, patients should not be initiated on the orally disintegrating vardenafil tablets while on alpha-blocker therapy; however, if patients have previously used the film-coated tablets, this may be changed to the orally disintegrating tablets upon the advice of the healthcare provider. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers. Studies have been conducted to determine the effects of vardenafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers terazosin and tamsulosin. When vardenafil 10 or 20 mg was administered to healthy subjects taking terazosin (10 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of terazosin on standing systolic blood pressure. In contrast, coadministration of a single 10 or 20 mg dose of vardenafil to healthy subjects taking 0.4 mg once daily of tamsulosin, a selective antagonist of alpha-1a receptors, resulted in no significant decreases in blood pressure.
Phentolamine: (Major) Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Vardenafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the lowest recommended dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. In general, patients should not be initiated on the orally disintegrating vardenafil tablets while on alpha-blocker therapy; however, if patients have previously used the film-coated tablets, this may be changed to the orally disintegrating tablets upon the advice of the healthcare provider. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers. Studies have been conducted to determine the effects of vardenafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers terazosin and tamsulosin. When vardenafil 10 or 20 mg was administered to healthy subjects taking terazosin (10 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of terazosin on standing systolic blood pressure. In contrast, coadministration of a single 10 or 20 mg dose of vardenafil to healthy subjects taking 0.4 mg once daily of tamsulosin, a selective antagonist of alpha-1a receptors, resulted in no significant decreases in blood pressure.
Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include vardenafil. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving phosphodiesterase inhibitors. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Phenytoin: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, such as phenytoin, will decrease plasma levels of vardenafil, however, no interaction studies have been performed.
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) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of vardenafil with pimozide is contraindicated.
Posaconazole: (Severe) Concurrent use of posaconazole and vardenafil is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an 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. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as vardenafil.
Prazosin: (Major) Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Vardenafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the lowest recommended dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. In general, patients should not be initiated on the orally disintegrating vardenafil tablets while on alpha-blocker therapy; however, if patients have previously used the film-coated tablets, this may be changed to the orally disintegrating tablets upon the advice of the healthcare provider. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers. Studies have been conducted to determine the effects of vardenafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers terazosin and tamsulosin. When vardenafil 10 or 20 mg was administered to healthy subjects taking terazosin (10 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of terazosin on standing systolic blood pressure. In contrast, coadministration of a single 10 or 20 mg dose of vardenafil to healthy subjects taking 0.4 mg once daily of tamsulosin, a selective antagonist of alpha-1a receptors, resulted in no significant decreases in blood pressure.
Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include vardenafil.
Procainamide: (Major) The manufacturer recommends that vardenafil be avoided in patients taking Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (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) The effect of vardenafil on the QT interval should be considered when prescribing the drug.
Prochlorperazine: (Minor) 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 prochlorperazine. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential.
Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include vardenafil.
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) The manufacturer recommends that vardenafil be avoided in patients taking Class IA antiarrhythmics (disopyramide, procainamide, and quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (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) 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. 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). In addition, concentrations of vardenafil may be increased with concomitant use of quinine. Vardenafil is a CYP3A4 substrate and quinine is a CYP3A4 inhibitor.
Ranolazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, in vitro studies indicate that ranolazine and its metabolite are inhibitors of CYP3A isoenzymes. Drugs that are CYP3A4 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine 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).
Regadenoson: (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 regadenoson.
Ribociclib: (Major) Avoid coadministration of ribociclib with vardenafil due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of vardenafil may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. 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). Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and vardenafil is a CYP3A4 substrate.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with vardenafil due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of vardenafil may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. 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). Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and vardenafil is a CYP3A4 substrate.
Rifabutin: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, like the rifamycins, will decrease plasma levels of vardenafil.
Rifampin: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, like the rifamycins, will decrease plasma levels of vardenafil.
Rifamycins: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, like the rifamycins, will decrease plasma levels of vardenafil.
Rifapentine: (Minor) Vardenafil is metabolized by cytochrome P450 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers, like the rifamycins, will decrease plasma levels of vardenafil.
Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with 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). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Riociguat: (Severe) Coadministration of riociguat and vardenafil is contraindicated due to the risk of hypotension.
Risperidone: (Major) Because both risperidone and vardenafil have been associated with a possible risk for QT prolongation and torsade de pointes (TdP), cautious use is recommended. Patients with known risk factors for cardiac disease or arrhythmias should be closely monitored. 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). Reports of QT prolongation and TdP during risperidone therapy have occurred primarily in the setting of overdose.
Ritonavir: (Major) Coadministration of ritonavir with vardenafil results in a 20% decrease in ritonavir AUC and a 49-fold increase in vardenafil AUC. Substantially increased vardenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered, use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, use of the orally disintegrating tablets with ritonavir is not recommended. No change in ritonavir dose is required. In addition, both ritonavir and vardenafil are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Romidepsin: (Major) Romidepsin has been reported to prolong the QT interval. 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. If romidepsin and vardenafil must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
Sapropterin: (Moderate) Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as phosphodiesterase inhibitors. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase (PDE5) inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not been studied in humans.
Saquinavir: (Major) Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving saquinavir as there is an increased risk for serious adverse effects. Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as vardenafil, if possible. Coadministration of saquinavir, especially when 'boosted' with ritonavir, with vardenafil is expected to substantially increase vardenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. In addition, saquinavir boosted with ritonavir increases the QT and PR intervals in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Although it is best to avoid this drug combination if possible, if no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy (see Contraindications), and use vardenafil at reduced doses of no more than 2.5 mg, every 24 hours when used with saquinavir or every 72 hours when used with ritonavir-'boosted' saquinavir, with increased monitoring for adverse reactions. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as saquinavir.
Sertraline: (Major) There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline; therefore, caution is advisable when using sertraline in patients with risk factors for QT prolongation, including concurrent use of other drugs that prolong the QTc interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sertraline include vardenafil.
Short-acting beta-agonists: (Minor) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. Drugs with a possible risk for QT prolongation that should be used cautiously with vardenafil include the beta agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
Silodosin: (Major) Symptoms of orthostasis (e.g., postural hypotension, dizziness and vertigo) may occur during treatment with alpha-blockers such as silodosin. Enhanced hypotensive effects are possible when alpha-blockers are coadministered with vasodilatory agents such as vardenafil. Patients should be stabilized on alpha blocker therapy prior to starting vardenafil, or if already receiving an optimum dose of vardenafil, alpha blocker therapy should be started at the lowest possible dose.
Simeprevir: (Moderate) Coadministration of vardenafil with simeprevir, an intestinal CYP3A4 inhibitor, may result in mild increases in vardenafil plasma concentrations. No dose adjustments are required when treating erectile dysfunction.
Solifenacin: (Major) 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. 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).
Sorafenib: (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 sorafenib. If coadministration is necessary, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Sotalol: (Major) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). The effect of vardenafil on the QT interval should be considered when prescribing the drug. The manufacturer recommends that vardenafil be avoided in patients taking sotalol. Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
Sparfloxacin: (Moderate) Sparfloxacin is associated with an established risk for QT prolongation and torsades de pointes. This risk my be increased if combined with other drugs that may prolong the QT interval, such as vardenafil.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sulfamethoxazole; trimethoprim include vardenafil.
Sunitinib: (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 sunitinib.
Tacrolimus: (Major) Tacrolimus causes QT prolongation. Reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval 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).
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: (Major) 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 also been described when tamoxifen is used at lower doses. 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).
Tamsulosin: (Major) Since the symptoms of orthostasis (e.g., postural hypotension, dizziness and vertigo) are reported more frequently in tamsulosin-treated vs. placebo patients, there is a theoretical risk of enhanced hypotensive effects in individual patients when tamsulosin co-administered with vasodilatory agents such as phosphodiesterase inhibitors. Concurrent use of PDE5 inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. When sildenafil (25 mg) was simultaneously administered with doxazosin (4 mg) to patients with BPH, mean additional reductions in supine blood pressure of 7 mmHg systolic and 7 mmHg diastolic were observed. When higher doses of sildenafil were administered with doxazosin (4 mg), symptomatic postural hypotension within 1 to 4 hours was reported in some patients. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers. The manufacturers for tadalafil and vardenafil state that patients should be stabilized on alpha blocker therapy prior to starting either tadalafil or vardenafil, or if already receiving optimum dose of tadalafil or vardenafil, alpha blocker therapy should be started at the lowest possible dose.
Telaprevir: (Major) Close clinical monitoring is advised when administering vardenafil with telaprevir due to an increased potential for vardenafil-related adverse events, such as QT interval prolongation. During coadministration, do not exceed a maximum vardenafil dosage of 2.5 mg in 72 hours. If vardenafil dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Predictions about the interaction can be made based on the metabolic pathways of vardenafil. Vardenafil is a substrate of the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. When used in combination, the plasma concentrations of vardenafil may be elevated.
Telavancin: (Major) 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) Telithromycin is associated with QT prolongation and torsades de pointes (TdP) and is a strong inhibitor of the CYP3A4 isoenzyme. Coadministration with other drugs that prolong the QT interval and are CYP3A4 substrates may result in increased concentrations of those drugs and an increased risk of adverse reactions, such as QT prolongation. Drugs with a possible risk of QT prolongation that are also CYP3A4 substrates that should be used cautiously with telithromycin 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).
Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and vardenafil is necessary, as the systemic exposure of vardenafil may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of vardenafil; consider increasing the dose of vardenafil if necessary. Vardenafil is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
Terazosin: (Major) Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Vardenafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the lowest recommended dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. In general, patients should not be initiated on the orally disintegrating vardenafil tablets while on alpha-blocker therapy; however, if patients have previously used the film-coated tablets, this may be changed to the orally disintegrating tablets upon the advice of the healthcare provider. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers. Studies have been conducted to determine the effects of vardenafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers terazosin and tamsulosin. When vardenafil 10 or 20 mg was administered to healthy subjects taking terazosin (10 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of terazosin on standing systolic blood pressure. In contrast, coadministration of a single 10 or 20 mg dose of vardenafil to healthy subjects taking 0.4 mg once daily of tamsulosin, a selective antagonist of alpha-1a receptors, resulted in no significant decreases in blood pressure.
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) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is considered contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Because of the potential for TdP, use of vardenafil with thioridazine is contraindicated.
Tipranavir: (Major) Concurrent use of tipranavir boosted with ritonavir and varadenafil is expected to substantially increase vardenafil plasma concentrations and may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. During coadministration, use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.
Tizanidine: (Major) Vardenafil should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. 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.
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) 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 toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
Trandolapril; Verapamil: (Moderate) Vardenafil is metabolized by hepatic CYP3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4, such as verapamil, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. Patients taking moderate CYP3A4 inhibitors, such as verapamil, may need to have their vardenafil dose decreased to 5 mg PO in a 24-hour period. Antihypertensives, when used with vardenafil, additionally have additive effects on blood pressure. In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing.
Trazodone: (Major) Avoid coadministration of vardenafil and trazodone. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
Tricyclic antidepressants: (Minor) Tricyclic antidepressants (TCAs) 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). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with amitriptyline 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).
Trifluoperazine: (Minor) 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 trifluoperazine.
Triptorelin: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include vardenafil.
Vandetanib: (Major) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP). 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 produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose.
Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as vardenafil, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, vardenafil is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate/inducer. Therefore concentrations of vardenafil may be decreased with concomitant use. Monitor patients for efficacy.
Venlafaxine: (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 venlafaxine.
Verapamil: (Moderate) Vardenafil is metabolized by hepatic CYP3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4, such as verapamil, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. Patients taking moderate CYP3A4 inhibitors, such as verapamil, may need to have their vardenafil dose decreased to 5 mg PO in a 24-hour period. Antihypertensives, when used with vardenafil, additionally have additive effects on blood pressure. In a clinical pharmacology study of patients with erectile dysfunction, single doses of vardenafil 20 mg caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing.
Vigabatrin: (Major) Vigabatrin should not be used with phosphodiesterase inhibitors, which is associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.
Voriconazole: (Major) Caution is advised when administering voriconazole with vardenafil due to the potential for additive effects on the QT interval and increased exposure to vardenafil. If these drugs must be administered together, consider use of a lower vardenafil dose. However, because vardenafil orally disintegrating tablets (ODTs) provide increased exposure as compared to the regular tablets, concurrent use of vardenafil ODTs and voriconazole should be avoided. In addition, because both vardenafil and voriconazole are associated with QT prolongation, coadministration may increase the risk irregular heartbeats. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Vorinostat: (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. Vorinostat therapy is associated with a risk of QT prolongation. Vorinostat should be used with caution if given with vardenafil.
Zafirlukast: (Minor) Vardenafil is metabolized by CYP3A4. Inhibitors of CYP3A4, such as zafirlukast, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.
Zileuton: (Minor) Vardenafil is metabolized by CYP3A4. Inhibitors of CYP3A4, such as zileuton, can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects.
Ziprasidone: (Severe) According to the manufacturer, ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsades de pointes including vardenafil.

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.


Source: http://www.pdr.net/drug-summary/Levitra-vardenafil-hydrochloride-2275


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