Levitra (vardenafil) Side Effects, Warnings, and Drug Interactions

Levitra (vardenafil) is a phosphodiesterase inhibitor (PDE-5 inhibitor) used to treat impotence (or erectile dysfunction, ED, the inability to attain or maintain a penile erection). 

Penile erection is caused by the engorgement of the penis with blood, which occurs when the blood vessels delivering blood to the penis increase in size and increase delivery of blood to the penis. At the same time, blood vessels carrying blood away from the penis decrease in size and decrease removal of blood from the penis. 

Sexual stimulation that leads to the engorgement and erection causes the production and release of nitric oxide in the penis. Nitric oxide activates the enzyme, guanylate cyclase, to produce cyclic guanosine monophosphate (cGMP). The cGMP is primarily responsible for increasing and decreasing the size of the blood vessels carrying blood to and from the penis. 

Levitra prevents an enzyme called phosphodiesterase-5 (PDE-5) from destroying cGMP so that cGMP persists longer. The longer cGMP persists, the more prolonged the engorgement of the penis. 

Common side effects of Levitra include:

• facial flushing (reddening),
• headaches,
• stomach upset,
• diarrhea,
• flu-like symptoms, and
• nausea. 

Serious side effects of Levitra include:

• chest pain,
• low blood pressure,
• blurred vision and changes in color vision,
• abnormal ejaculation and painful erection lasting more than 6 hours (priapism).

Rare cases of sudden loss of hearing have been reported with phosphodiesterase inhibitors such as Levitra, sometimes associated with ringing in the ears and dizziness. 

Drug interactions of Levitra include:

• erythromycin,
• clarithromycin,
• ketoconazole,
• itraconazole,
• indinavir,
• ritonavir,
• atazanavir,
• grapefruit juice, which increase the concentration of Levitra in the blood and can lead to increased side effects.

Levitra reduces the effect of ritonavir and indinavir. Levitra increases heart rate and also exaggerates blood pressure lowering effects of nitrates. 

In patients with chest pain (angina), Levitra can cause chest pain by increasing heart rate and lowering blood pressure. Levitra also exaggerates the blood pressure lowering effects of alpha-blockers. Levitra also adds to the blood pressure reducing effect of other medications. 

Levitra is not approved for use in women so is unlikely to be used during pregnancy or while breastfeeding.

The most common side effects of vardenafil are:

• facial flushing (reddening),
• headaches,
• stomach upset,
• diarrhea,
• flu-like symptoms, and
• nausea.

Vardenafil also may cause:

• chest pain,
• low blood pressure,
• blurred vision and changes in color vision,
• abnormal ejaculation and
• priapism (painful erection lasting more than 6 hours).

Patients should seek immediate medical help if they experience an erection lasting more than 4 hours.

Rare cases of sudden loss of hearing have been reported with phosphodiesterase inhibitors such as vardenafil, sometimes associated with ringing in the ears and dizziness. If changes in hearing occur, patients should discontinue their vardenafil and seek immediate medical attention.

The following serious adverse reactions with the use of Levitra (vardenafil) are discussed elsewhere in the labeling:

• Cardiovascular Effects
• Priapism
• Effects on Eye
• Sudden Hearing Loss
• QT Prolongation

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Levitra was administered to over 4430 men (mean age 56, range 18-89 years; 81% White, 6% Black, 2% Asian, 2% Hispanic and 9% Other) during controlled and uncontrolled clinical trials worldwide. Over 2200 patients were treated for 6 months or longer and 880 patients were treated for at least 1 year.

In placebo-controlled clinical trials, the discontinuation rate due to adverse events was 3.4% for Levitra compared to 1.1% for placebo.

When Levitra was taken as recommended in placebo-controlled clinical 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 Flexible^a Dose Randomized, Controlled Trials of 5 mg, 10 mg, or 20 mg Vardenafil

Back pain was reported in 2.0% of patients treated with Levitra and 1.7% of patients on placebo

Placebo-controlled trials suggested a dose effect in the incidence of some adverse reactions (headache, flushing, dyspepsia, nausea, and rhinitis) over the 5 mg, 10 mg, and 20 mg doses of Levitra.

All Vardenafil Studies

Levitra film-coated tablets and vardenafil orally disintegrating tablets have been administered to over 17,000 men (mean age 54.5, range 18.89 years; 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other) during controlled and uncontrolled clinical trials worldwide. The number of patients treated for 6 months or longer was 3357, and 1350 patients were treated for at least 1 year.

In the placebo-controlled clinical trials for Levitra film-coated tablets and vardenafil orally disintegrating tablets, the discontinuation rate due to adverse events was 1.9% for vardenafil compared to 0.8% for placebo.

The following section identifies additional, less frequent adverse reactions (<2%) reported during the clinical development of Levitra film-coated tablets and vardenafil orally disintegrating tablets. Excluded from this list are those adverse reactions that are infrequent and minor, those events that may be commonly observed in the absence of drug therapy, and those events that are not reasonably associated with the drug:

Body as a whole: allergic edema and angioedema, feeling unwell, allergic reactions, chest pain

Auditory: tinnitus, vertigo

Cardiovascular: palpitation, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension

Digestive: nausea, gastrointestinal and abdominal pain, 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 and dysesthesia, somnolence, sleep disorder, syncope, amnesia, seizure

Respiratory: dyspnea, sinus congestion

Skin and appendages: erythema, rash

Ophthalmologic: visual disturbance, ocular hyperemia, visual color distortions, eye pain and eye discomfort, photophobia, increase in intraocular pressure, conjunctivitis

Urogenital: increase in erection, priapism

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Levitra. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.

Ophthalmologic

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking.

Visual disturbances including vision loss (temporary or permanent), such as visual field defect, retinal vein occlusion, and reduced visual acuity, have also been reported rarely in postmarketing experience. It is not possible to determine whether these events are related directly to the use of vardenafil.

Neurologic

Seizure, seizure recurrence and transient global amnesia have been reported postmarketing in temporal association with vardenafil.

Otologic

Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including vardenafil. In some cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of vardenafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors.

Potential For Pharmacodynamic Interactions With Levitra

Nitrates

Concomitant use of Levitra and nitrates and nitric oxide donors is contraindicated. The blood pressure lowering effects of sublingual nitrates (0.4 mg) taken 1 and 4 hours after vardenafil and increases in heart rate when taken at 1, 4 and 8 hours after vardenafil were potentiated by a 20 mg dose of Levitra in healthy middle-aged subjects. These effects were not observed when Levitra 20 mg was taken 24 hours before the nitroglycerin (NTG). Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of Levitra and nitrates is contraindicated.

Alpha-Blockers

Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including Levitra and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with co-administration of vardenafil with alfuzosin, terazosin or tamsulosin.

Antihypertensives

Levitra may add to the blood pressure lowering effects of antihypertensive agents. 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. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1.

Alcohol

Levitra (20 mg) did not potentiate the hypotensive effects of alcohol during the 4-hour observation period in healthy volunteers when administered with alcohol (0.5 g/kg body weight, approximately 40 mL of absolute alcohol in a 70 kg person). Alcohol and vardenafil plasma levels were not altered when dosed simultaneously.

Effect Of Other Drugs On Vardenafil

In Vitro Studies

Studies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9. Therefore, inhibitors of these enzymes are expected to reduce vardenafil clearance.

In Vivo Studies

Potent CYP3A4 inhibitors

Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in maximum concentration (Cmax) when co-administered with Levitra (5 mg) in healthy volunteers. A 5-mg Levitra dose should not be exceeded in a 24-hour period when used in combination with 200 mg once daily ketoconazole. Since higher doses of ketoconazole (400 mg daily) may result in higher increases in Cmax and AUC, a single 2.5 mg dose of Levitra should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily.

Indinavir (800 mg t.i.d.) co-administered with Levitra 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil Cmax and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg Levitra dose in a 24-hour period when used in combination with indinavir.

Ritonavir (600 mg b.i.d.) co-administered with Levitra 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13fold increase in vardenafil Cmax. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg Levitra dose in a 72-hour period when used in combination with ritonavir.

Moderate CYP3A4 inhibitors

Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax when co-administered with Levitra 5 mg in healthy volunteers. It is recommended not to exceed a single 5 mg dose of Levitra in a 24-hour period when used in combination with erythromycin.

Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice would likely increase vardenafil exposure.

Other Drug Interactions

No pharmacokinetic interactions were observed between vardenafil and the following drugs: glyburide, warfarin, digoxin, an antacid based on magnesium-aluminum hydroxide, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters.

Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (Cmax) of vardenafil when co-administered with 20 mg Levitra in healthy volunteers.

Effects Of Vardenafil On Other Drugs

In Vitro Studies

Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 micromolar). Weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) were found, but Ki values were in excess of plasma concentrations achieved following dosing. The most potent inhibitory activity was observed for vardenafil metabolite M1, which had a Ki of 1.4 micromolar toward CYP3A4, which is about 20 times higher than the M1 Cmax values after an 80 mg vardenafil dose.

In Vivo Studies

Nifedipine

Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the AUC or Cmax of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of Levitra when taken in combination. In these patients whose hypertension was controlled with nifedipine, Levitra 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo.

Ritonavir and Indinavir

Upon concomitant administration of 5 mg of Levitra with 600 mg BID ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of Levitra with 800 mg TID indinavir, the Cmax and AUC of indinavir were reduced by 40% and 30%, respectively.

Aspirin

Levitra (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).

Other Interactions

Levitra had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).