Description for Levitra
LEVITRA (vardenafil hydrochloride) is prescribed orally for treating erectile dysfunction. Formulated as a monohydrochloride salt, vardenafil acts as a selective inhibitor targeting cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), crucial in managing the physiological processes underlying erectile function.
Chemically, vardenafil hydrochloride is defined as piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-, monohydrochloride, exhibiting the following structural formula:
LEVITRA® (vardenafil hydrochloride) Structural Formula Illustration
Vardenafil HCl is an almost colorless, solid compound, possessing a molecular weight of 579.1 g/mol, with a solubility of approximately 0.11 mg/mL in water, making it suitable for pharmaceutical formulations.
LEVITRA is available in the form of orange, round, film-coated tablets marked with “BAYER” on one side and dosage strengths of “2.5”, “5”, “10”, and “20” on the other, indicating the respective content of vardenafil in each tablet. Apart from the active ingredient vardenafil HCl, the formulation includes inactive components such as microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide.
Uses for Levitra
LEVITRA® is specifically indicated for the management of erectile dysfunction.
Dosage for Levitra
General Dose Information
For most patients, the advised starting dosage of LEVITRA is 10 mg, administered orally as needed, approximately 60 minutes before engaging in sexual activity. The dose may be suitably adjusted to a maximum of 20 mg or reduced to 5 mg based on efficacy and tolerability, with the maximum dosing frequency capped at once per day. Notably, sexual stimulation remains essential for effective treatment response.
Use With Food
LEVITRA can be ingested with or without food, providing flexibility in administration timing.
Use In Specific Populations
Geriatrics
A cautious initiation of 5 mg of LEVITRA should be considered in patients aged 65 years and older [see Use In Specific Populations].
Hepatic Impairment
Patients with moderate hepatic impairment (Child-Pugh B) should begin treatment with a dose of 5 mg LEVITRA, ensuring that the maximum dosage does not exceed 10 mg.
LEVITRA is contraindicated in patients experiencing severe hepatic impairment (Child-Pugh C) [see WARNINGS AND PRECAUTIONS, Use In Specific Populations, and CLINICAL PHARMACOLOGY].
Renal Impairment
LEVITRA is not to be administered to patients on renal dialysis [refer to WARNINGS AND PRECAUTIONS, Use In Specific Populations, and CLINICAL PHARMACOLOGY].
Concomitant Medications
Nitrates
Concomitant use of nitrates and nitric oxide donors in any form is strictly prohibited [refer to CONTRAINDICATIONS].
Guanylate Cyclase (GC) Stimulators, Such As riociguat
This combination is contraindicated [see CONTRAINDICATIONS].
CYP3A4 Inhibitors
Dosage adjustments may be necessary for patients receiving strong CYP3A4 inhibitors, including ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, atazanavir, cobicistat, and clarithromycin, as well as those on moderate inhibitors, such as erythromycin [see DRUG INTERACTIONS].
In instances of strong CYP3A4 inhibitors, the following dosage recommendations apply:
- Ritonavir: Max 2.5 mg within a 72-hour time frame
- Indinavir, saquinavir, atazanavir, ketoconazole (400 mg daily), itraconazole (400 mg daily), clarithromycin: Max 2.5 mg within 24 hours
- Ketoconazole (200 mg daily), itraconazole (200 mg daily), erythromycin: Max 5 mg within 24 hours.
- Cobicistat: Max 2.5 mg within a 72-hour duration.
Alpha-Blockers
In patients stabilized on alpha-blocker therapy, PDE5 inhibitors should be started at the lowest recommended dose. Concomitant treatments should only be initiated if the patient has shown stability on alpha-blocker therapy. A stepwise increase in alpha-blocker dosage may lead to additional reductions in blood pressure among patients taking PDE5 inhibitors, including vardenafil. For those patients with stable alpha-blocker therapy, LEVITRA should be commenced at 5 mg (or 2.5 mg when used alongside certain CYP3A4 inhibitors) [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
It is prudent to account for a suitable time interval between doses when prescribing Levitra in conjunction with alpha-blocker therapy [see CLINICAL PHARMACOLOGY].
HOW SUPPLIED
Dosage Forms And Strengths
LEVITRA is formulated as orange, round, film-coated tablets, with debossed “BAYER” on one side and “2.5”, “5”, “10”, and “20” on the other side corresponding to the respective dosages of vardenafil.
Storage And Handling
LEVITRA (vardenafil HCl) is supplied as orange, film-coated round tablets, featuring debossed “BAYER” on one side and the dosage strengths on the other side.
Store at a temperature of 25°C (77°F); excursions may range between 15-30°C (59-86°F) [according to USP Controlled Room Temperature guidelines].
Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981. Revised: Mar 2023.
Side Effects for Levitra
The following serious adverse reactions associated with LEVITRA (vardenafil) are further elaborated elsewhere in the labeling:
- Cardiovascular Effects [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
- Priapism [see WARNINGS AND PRECAUTIONS]
- Effects on Eye [see WARNINGS AND PRECAUTIONS]
- Sudden Hearing Loss [see WARNINGS AND PRECAUTIONS]
- QT Prolongation [see WARNINGS AND PRECAUTIONS]
Clinical Studies Experience
Given the varying conditions under which clinical trials are conducted, adverse reaction rates observed with a drug in clinical trials cannot be directly compared to rates from trials of another drug, nor can they represent rates likely found in practice.
LEVITRA was administered to over 4,430 male patients (mean age of 56 years, ranging from 18-89 years; with 81% White, 6% Black, 2% Asian, 2% Hispanic, and 9% Other) during both controlled and uncontrolled clinical trials globally. Over 2,200 patients underwent treatment for six months or longer, and 880 patients were treated for at least a year.
During placebo-controlled clinical trials, the discontinuation rate due to adverse events was recorded at 3.4% for LEVITRA in comparison to 1.1% for the placebo group.
When LEVITRA was administered as directed during placebo-controlled trials, the following adverse reactions were reported (see Table 1):
Table 1: Adverse Reactions Reported By ≥2% of Patients Treated with LEVITRA and More Frequent on Drug than Placebo in Fixed and Flexiblea Dose Randomized, Controlled Trials of 5 mg, 10 mg, or 20 mg Vardenafil
| Adverse Reaction | Percentage of Patients Reporting Reactions | |
| Placebo N = 1199 | LEVITRA N = 2203 | |
| Headache | 4% | 15% |
| Flushing | 1% | 11% |
| Rhinitis | 3% | 9% |
| Dyspepsia | 1% | 4% |
| Accidental Injuryb | 2% | 3% |
| Sinusitis | 1% | 3% |
| Flu Syndrome | 2% | 3% |
| Dizziness | 1% | 2% |
| Increased Creatine Kinase | 1% | 2% |
| Nausea | 1% | 2% |
| a) Flexible dose studies started all patients at LEVITRA 10 mg and allowed decrease in dose to 5 mg or increase in dose to 20 mg based on side effects and efficacy. b) All events listed above were regarded as adverse drug reactions, except accidental injury. | ||
Back pain was reported in 2.0% of patients treated with LEVITRA as opposed to 1.7% among those receiving the placebo.
The placebo-controlled trials suggested a dose-dependent effect in the incidence of certain adverse reactions (headache, flushing, dyspepsia, nausea, and rhinitis) across the 5 mg, 10 mg, and 20 mg dosages of LEVITRA.
All Vardenafil Studies
LEVITRA film-coated tablets and vardenafil orally disintegrating tablets have been administered to over 17,000 men (mean age of 54.5 years, range 18–89 years; comprising 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other) during both controlled and uncontrolled clinical trials globally. A total of 3,357 patients were treated for 6 months or longer, with 1,350 patients undergoing treatment for at least one year.
In placebo-controlled clinical trials related to LEVITRA film-coated tablets and vardenafil orally disintegrating tablets, the discontinuation rate due to adverse events was noted at 1.9% for vardenafil compared to 0.8% for placebo.
The subsequent section provides information on additional, less common adverse reactions reported during the clinical development of LEVITRA film-coated tablets and vardenafil orally disintegrating tablets. This list excludes infrequent and minor adverse reactions that can be seen without medication, along with events not plausibly associated with the medication:
Body as a Whole: allergic edema, angioedema, feelings of unwellness, allergic reactions, chest pain
Auditory: tinnitus, vertigo
Cardiovascular: palpitations, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension
Digestive: nausea, gastrointestinal and abdominal discomfort, dry mouth, diarrhea, gastroesophageal reflux disease, gastritis, vomiting, increase in transaminases
Musculoskeletal: increase in creatine phosphokinase (CPK), increased muscle tone and cramping, myalgia
Nervous: paresthesia, dysesthesia, somnolence, sleep disorders, syncope, amnesia, seizure
Respiratory: dyspnea, sinus congestion
Skin and Appendages: erythema, rash
Ophthalmologic:visual disturbances, ocular hyperemia, visual color distortions, eye pain and discomfort, photophobia, increased intraocular pressure, conjunctivitis
Urogenital:increased erection, priapism
Postmarketing Experience
Adverse reactions identified during post-approval usage of LEVITRA include:
Ophthalmologic
Non-arteritic anterior ischemic optic neuropathy (NAION), which can lead to vision loss including permanent impairment, has been sporadically reported in conjunction with the use of PDE5 inhibitors, including vardenafil. Many affected patients had pre-existing anatomical or vascular risk factors, although not all conditions are necessarily correlated [refer to WARNINGS AND PRECAUTIONS and PATIENT INFORMATION].
Visual disturbances including temporary or permanent vision loss, such as visual field defects or reduced visual acuity, have also been reported infrequently during postmarketing experience. Determining the direct relationship of these occurrences to vardenafil usage remains challenging.
Neurologic
Reports of seizures, seizure recurrence, and transient global amnesia have also surfaced postmarketing in correlation with vardenafil usage.
Otologic
Rare instances of sudden hearing loss or decreases in hearing have been documented postmarketing in relation to PDE5 inhibitors, including vardenafil. Specific conditions or factors contributing to these events have been identified in some cases, while limited follow-up data restrict definitive conclusions regarding direct associations to vardenafil or its use.
Drug Interactions for Levitra
Potential For Pharmacodynamic Interactions With LEVITRA
Nitrates
Concomitant administration of LEVITRA and nitrates or nitric oxide donors is contraindicated due to the potential for serious hypotension. The blood pressure-lowering effects of sublingual nitrates (0.4 mg) taken one and four hours after vardenafil are significantly potentiated when administered alongside a 20 mg dose of LEVITRA in healthy volunteers. There is no established safe interval for administering nitrates or nitric oxide donors following LEVITRA dosages [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].
Alpha-Blockers
Heightened caution is essential when PDE5 inhibitors are coadministered with alpha-blockers. Both classes of medications have vasodilatory properties that can cause a combined blood pressure-lowering effect. Clinical pharmacology studies demonstrate the possibility of significant hypotension, particularly in patients taking the alpha-blockers terazosin, tamsulosin, or alfuzosin alongside vardenafil [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
Antihypertensives
LEVITRA may enhance the blood pressure-lowering effects of antihypertensive agents. One study indicated that a single 20 mg dose of vardenafil resulted in a mean maximum decrease of 7 mmHg systolic and 8 mmHg diastolic blood pressure, in comparison to placebo, during the peak effect period. Similar blood pressure responses were observed with extended dosing periods of LEVITRA [see DRUG INTERACTIONS].
Alcohol
LEVITRA (20 mg) failed to enhance the hypotensive effects of alcohol when administered concurrently in healthy subjects [see WARNINGS AND PRECAUTIONS].
Effect Of Other Drugs On Vardenafil
In Vitro studies
Studies using human liver microsomes reveal that vardenafil is predominantly metabolized by the cytochrome P450 (CYP) isoforms 3A4 and 5, with minor contributions from CYP2C9. Accordingly, the presence of inhibitors for these enzymes would likely reduce the clearance of vardenafil [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
In Vivo studies
Strong CYP3A4 inhibitorsKetoconazole (200 mg once daily) has been shown to produce a tenfold increase in vardenafil AUC and a fourfold increase in maximum concentration (Cmax) when administered in conjunction with LEVITRA (5 mg). As such, maximum doses of LEVITRA should not exceed 5 mg in a 24-hour timeframe when combined with ketoconazole (200 mg once daily). Higher doses of ketoconazole may necessitate further reductions in LEVITRA dosage [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Indinavir (800 mg t.i.d.) co-administered with LEVITRA (10 mg) resulted in a sixteenfold increase in vardenafil AUC, necessitating a maximum single dose of 2.5 mg within a 24-hour period.
Ritonavir (600 mg b.i.d.) co-administration escalated vardenafil AUC by forty-nine times and Cmax by thirteen times, thereby restricting the maximum single dose of LEVITRA to 2.5 mg within a 72-hour duration due to the substantial inhibition of hepatic metabolism.
The combination of cobicistat and LEVITRA may yield increased plasma concentrations, suggesting a necessity for restricting to a maximum of 2.5 mg in a 72-hour period.
Moderate CYP3A4 inhibitorsIntroducing erythromycin (500 mg t.i.d.) alongside LEVITRA (5 mg) produced a fourfold increase in vardenafil AUC and a threefold increase in Cmax, leading to a recommendation that the maximum single dose should be limited to 5 mg within a 24-hour timeframe [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Though specific interactions have not been examined, other CYP3A4 inhibitors, such as grapefruit juice, may similarly elevate vardenafil levels.
Other Drug InteractionsNo pharmacokinetic interactions were identified between vardenafil and the following medications: glyburide, warfarin, digoxin, an antacid containing magnesium-aluminum hydroxide, and ranitidine. Vardenafil exhibited no effect on prothrombin time or related pharmacodynamic variables in patients using warfarin.
Cimetidine (400 mg b.i.d.) did not influence vardenafil's bioavailability (AUC) or peak concentration (Cmax) when administered with a 20 mg dose of LEVITRA in healthy volunteers.
Effects Of Vardenafil On Other Drugs
In Vitro studies
In vitro studies confirmed that vardenafil and its metabolites had no significant effect on CYP1A2, 2A6, and 2E1. Weak inhibition was observed for other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) but the inhibition constants far exceed plasma concentrations reached following dosing. Most notably, vardenafil metabolite M1 exhibited strong inhibitory activity against CYP3A4 at therapeutic doses.
In vitro data suggests the potential for vardenafil to inhibit P-glycoprotein (P-gp) at therapeutic levels. While vardenafil did not significantly elevate plasma levels of digoxin, a P-gp substrate, the impact on plasma levels of more sensitive P-gp substrates remains undetermined.
In Vivo studies
NifedipineThe combination of a 20 mg dose of vardenafil with nifedipine (30 mg or 60 mg) did not affect the AUC or Cmax of nifedipine. Conversely, when administered together, vardenafil expressed additive effects on blood pressure in patients stabilized on nifedipine for hypertension.
Ritonavir and IndinavirCo-administration of 5 mg of LEVITRA with a 600 mg BID dose of ritonavir resulted in a reduction of approximately 20% in ritonavir’s Cmax and AUC. Similarly, administering 10 mg of LEVITRA with 800 mg TID of indinavir yielded a significant reduction in both Cmax and AUC, with 40% and 30% declines, respectively.
AspirinLEVITRA (10 mg or 20 mg) did not exacerbate the increase in bleeding time induced by therapeutic doses of aspirin (two 81 mg tablets).
Other interactionsLEVITRA did not influence the pharmacodynamics of glyburide or warfarin in terms of glucose, insulin concentrations, and prothrombin time, respectively.
Warnings for Levitra
Included as part of the "PRECAUTIONS" Section
Precautions for Levitra
A comprehensive evaluation of erectile dysfunction is crucial, necessitating a medical assessment to determine potential underlying causes and appropriate treatment strategies.
Prior to prescribing LEVITRA, healthcare professionals must acknowledge the following:
Cardiovascular Effects
General
Physicians should carefully evaluate the cardiovascular condition of their patients, as sexual activity carries an inherent degree of cardiac risk. Therefore, treatment for erectile dysfunction, including LEVITRA, should be avoided in men where sexual activity is contraindicated due to their cardiovascular status.
Data on the safety or efficacy of vardenafil remains limited in patients with conditions such as unstable angina; hypotension (resting systolic blood pressure below 90 mmHg); uncontrolled hypertension (greater than 170/110 mmHg); recent strokes, life-threatening arrhythmias, or myocardial infarctions (within the last 6 months); or severe cardiac failure.
Left Ventricular Outflow Obstruction
Patients exhibiting left ventricular outflow obstruction, such as those with aortic stenosis or idiopathic hypertrophic subaortic stenosis, may be particularly sensitive to the effects of vasodilators including PDE5 inhibitors.
Blood Pressure Effects
LEVITRA has demonstrated systemic vasodilatory activity, which can result in transient drops in supine blood pressure (mean maximum reduction of 7 mmHg systolic and 8 mmHg diastolic) in healthy individuals [see CLINICAL PHARMACOLOGY]. While generally insignificant, clinicians should assess whether patients with cardiovascular disease could be adversely impacted by vasodilatory agents.
Potential For Drug Interactions With Strong Or Moderate CYP3A4 Inhibitors
When co-administered with strong CYP3A4 inhibitors (e.g., ritonavir, indinavir, cobicistat, ketoconazole) or moderate CYP3A4 inhibitors (e.g., eryth