Drug Name

Levitra (Vardenafil)

Generic Name

Vardenafil (var-DEN-a-fil)

Looks like

Vardenafil is available with a prescription under the brand name Levitra. Other brand or generic formulations may also be available. Ask your pharmacist any questions you have about this medication, especially if it is new to you.

• Levitra 2.5 mg-orange, film-coated round tablets with debossed "BAYER" cross on one side and "2.5" on the other side equivalent to 2.5 mg of Levitra
• Levitra 5 mg-orange, film-coated round tablets with debossed "BAYER" cross on one side and "5" on the other side equivalent to 5 mg of Levitra
• Levitra 10 mg-orange, film-coated round tablets with debossed "BAYER" cross on one side and "10" on the other side equivalent to 10 mg of Levitra
• Levitra 20 mg-orange, film-coated round tablets with debossed "BAYER" cross on one side and "20" on the other side equivalent to 20 mg of Levitra

Dosage Form

Tablets

Route Of Administration

ORAL

Imprint Code

BAYER 2.5 / BAYER 5 / BAYER 10 / BAYER 20

Size

6mm / 6mm / 7mm / 8mm

Alternatives

Impotence
Viagra, Cialis, Yohimbe, Muse, Yohimbine, Alprostadil

Drug Uses

Levitra is an oral drug for male impotence. It works by dilating blood vessels in the penis, allowing the inflow of blood needed for an erection.

Drug class

Levitra is a phosphodiesterase inhibitor that works by helping the blood flow into the penis to achieve and maintain an erection.

Contains

Levitra is available as orange, film-coated round tablets with debossed "BAYER" cross on one side and "2.5", "5", "10", and "20" on the other side equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of Levitra, respectively.

Chemical formula

Levitra is an oral therapy for the treatment of erectile dysfunction. This monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
Vardenafil HCl is designated chemically 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.
In addition to the active ingredient, vardenafil HCl, each tablet contains microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide.

Mechanism of Action

Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMP-specific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual stimulation.
In vitro studies have shown that Levitra is a selective inhibitor of PDE5. The inhibitory effect of Levitra is more selective on PDE5 than for other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10).

How Taken

Take levitra exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water.

Levitra can be taken with or without food.

Levitra is usually taken when needed. Generally, it is taken about 1 hour before sexual activity. The medication can help achieve an erection when sexual stimulation occurs. An erection will not occur just by taking a pill. Follow your doctor's instructions.

Levitra should not be taken with grapefruit or grapefruit juice. Levitra can interact with grapefruit and grapefruit juice, and the interaction may have dangerous effects. You should discuss the use of grapefruit and grapefruit juice with your doctor.
Do not take levitra more than once a day. In some cases, use of levitra may be restricted to once every 72 hours (3 days). Follow your doctor's instructions.

If you develop dizziness, nausea, or angina (pain, tightness, discomfort, numbness, or tingling in the chest, arms, neck, or jaw) during sexual activity, refrain from further sexual activity and notify your doctor.

Contact your doctor or seek emergency medical attention for any erection that lasts longer than 4 hours. A sustained erection can damage the penis.
Store this medication at room temperature away from moisture and heat.

Dosage and Administration

For most patients, the recommended starting dose of Levitra is 10 mg, taken orally 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. Levitra can be taken with or without food. Sexual stimulation is required for a response to treatment.

Geriatrics
A starting dose of 5 mg Levitra should be considered in patients ≥65 years of age.

Hepatic Impairment
For patients with mild hepatic impairment (Child-Pugh A), no dose adjustment of Levitra is required. Levitra clearance is reduced in patients with moderate hepatic impairment (Child-Pugh B), and a starting dose of 5 mg Levitra is recommended. The maximum dose in patients with moderate hepatic impairment should not exceed 10 mg. Levitra has not been evaluated in patients with severe hepatic impairment (Child-Pugh C).

Renal Impairment
For patients with mild (CLcr = 50-80 ml/min), moderate (CLcr = 30-50 ml/min), or severe (CLcr<30 ml/min) renal impairment, no dose adjustment is required. Levitra has not been evaluated in patients on renal dialysis.

Concomitant Medications
The dosage of Levitra may require adjustment in patients receiving potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, atazanavir, and clarithromycin as well as in other patients receiving moderate CYP3A4 inhibitors such as erythromycin. For ritonavir, a single dose of 2.5 mg Levitra should not be exceeded in a 72-hour period. For indinavir, saquinavir, atazanavir, ketoconazole 400 mg daily, itraconazole 400 mg daily, and clarithromycin, a single dose of 2.5 mg Levitra should not be exceeded in a 24-hour period. For ketoconazole 200 mg daily, itraconazole 200 mg daily, and erythromycin, a single dose of 5 mg Levitra should not be exceeded in a 24-hour period. For alpha-blockers, caution is advised when PDE5 inhibitors, including Levitra, are used concomitantly with alpha-blockers because of the potential for an additive effect on blood pressure. In some patients, concomitant use of these two drug classes can lower blood pressure significantly. Concomitant treatment should be initiated only if the patient is stable on his alpha blocker therapy. In those patients who are stable on alpha-blocker therapy, Levitra should be initiated at a dose of 5 mg.

Usual Starting Dose

The recommended starting dose of Levitra is 10 mg, taken orally approximately 60 minutes before sexual activity.

Missed Dose

Levitra is used as needed, so you are not likely to miss a dose.

Overdose

Seek emergency medical attention if you think you have used too much of this medicine. Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center ( http://www.aapcc.org/findyour.htm ), or emergency room immediately.
Symptoms of a cialis overdose are not known.

Storage

Store Levitra at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Levitra out of the reach of children and away from pets.

How Supplied

Levitra (vardenafil HCl) is formulated as orange, film-coated round tablets with debossed "BAYER" cross on one side and "2.5", "5", "10", and "20" on the other side equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of Levitra, respectively.

What is the most important information I should know about Levitra (Vardenafil)?

A small number of patients have lost eyesight in one eye after taking levitra. This type of vision loss is called non-arteritic anterior ischemic optic neuropathy (NAION). NAION causes a sudden loss of eyesight because blood flow is blocked to the optic nerve. It is not clear at this time if levitra causes NAION. NAION also happens in patients who do not take this medicine. People who have a higher chance for NAION include those who:

• have heart disease;
• are over 50 years old;
• have diabetes;
• have high blood pressure;
• have high cholesterol;
• smoke; or
• have certain eye problems.

Stop using levitra if you have any loss in your eyesight and seek medical help right away.
Do not take levitra if you are taking any of the following medicines:

• a nitrate such as nitroglycerin (Nitrostat, Nitrolingual, Nitro-Dur, Nitro-Bid, Minitran, Deponit, Transderm-Nitro, others), isosorbide dinitrate (Dilatrate-SR, Isordil, Sorbitrate), isosorbide mononitrate (Imdur, ISMO, Monoket), and others;
• a recreational drug such as amyl nitrate or nitrite ("poppers"); or
• an alpha blocker such as doxazosin (Cardura), guanadrel (Hylorel), prazosin (Minipress), terazosin (Hytrin), alfuzosin (Uroxatral), tamsulosin (Flomax), and others.

Taking levitra with any of these medications may cause very low blood pressure, possibly resulting in dizziness, fainting, stroke, or heart attack.
Contact your doctor or seek emergency medical attention for any erection that lasts longer than 4 hours. A sustained erection can damage the penis.
Refrain from further sexual activity and notify your doctor it you develop dizziness, nausea, or angina (pain, tightness, discomfort, numbness, or tingling in the chest, arms, neck, or jaw) during sexual activity.
Do not take levitra more than once a day. In some cases, use of levitra may be restricted to once every 72 hours (3 days). Follow your doctor's instructions.

What should I discuss with my doctor before taking Levitra (Vardenafil)?

Before taking levitra, tell your doctor if you

• currently have or have ever had a heart attack, stroke, irregular heartbeats, angina (chest pain), or congestive heart failure;
• have high or low blood pressure;
• have a personal or family history of a rare heart condition known as prolongation of the QT interval (long QT syndrome);
• have liver problems;
• have kidney problems;
• have ever had blood problems, including sickle cell anemia, multiple myeloma, or leukemia;
• have a bleeding or blood clotting disorder;
• have a stomach ulcer;
• a family history of degenerative eye disease (e.g., retinitis pigmentosa); or
• have a physical deformity of the penis such as Peyronie's disease.

You may not be able to take levitra, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

Although levitra is not indicated for use by women, it is in the FDA pregnancy category B. This means that levitra is not expected to be harmful to an unborn baby. Levitra should not be taken by women.
It is not known whether levitra passes into breast milk. Levitra should not be taken by women.

If you are over 65 years of age, you may be more likely to experience side effects from levitra. Your doctor may prescribe a lower dose of the medication.

Absorption

Vardenafil is rapidly absorbed with absolute bioavailability of approximately 15%. Maximum observed plasma concentrations after a single 20 mg dose in healthy volunteers are usually reached between 30 minutes and 2 hours (median 60 minutes) after oral dosing in the fasted state. Two food-effect studies were conducted which showed that high-fat meals caused a reduction in Cmax by 18%-50%.

Distribution

The mean steady-state volume of distribution (Vss) for vardenafil is 208 L, indicating extensive tissue distribution. Vardenafil and its major circulating metabolite, M1, are highly bound to plasma proteins (about 95% for parent drug and M1). This protein binding is reversible and independent of total drug concentrations.
Following a single oral dose of 20 mg Levitra in healthy volunteers, a mean of 0.00018% of the administered dose was obtained in semen 1.5 hours after dosing.

Metabolism and Excretion

Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 and CYP2C isoforms. The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 is subject to further metabolism. The plasma concentration of M1 is approximately 26% that of the parent compound. This metabolite shows a phosphodiesterase selectivity profile similar to that of Levitra and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. Therefore, M1 accounts for approximately 7% of total pharmacologic activity.

The total body clearance of vardenafil is 56 L/h, and the terminal half-life of vardenafil and its primary metabolite (M1) is approximately 4-5 hours. After oral administration, vardenafil is excreted as metabolites predominantly in the feces (approximately 91-95% of administered oral dose) and to a lesser extent in the urine (approximately 2-6% of administered oral dose).

Special Populations

Geriatric

In a healthy volunteer study of elderly males (≥65 years) and younger males (18-45 years), mean Cmax and AUC were 34% and 52% higher, respectively, in the elderly males. Consequently, a lower starting dose of Levitra (5 mg) in patients ≥65 years of age should be considered.

Pediatric

Levitra trials were not conducted in the pediatric population.

Race

Pharmacokinetic data among various ethnic groups are not available.

Renal Insufficiency

In volunteers with mild renal impairment (CLcr = 50-80 ml/min), the pharmacokinetics of vardenafil were similar to those observed in a control group with normal renal function. In the moderate (CLcr = 30-50 ml/min) or severe (CLcr<30 ml/min) renal impairment groups, the AUC of vardenafil was 20-30% higher compared to that observed in a control group with normal renal function (CLcr>80 ml/min). Vardenafil pharmacokinetics have not been evaluated in patients requiring renal dialysis.

Hepatic Impairment

In volunteers with mild hepatic impairment (Child-Pugh A), the Cmax and AUC following a 10 mg vardenafil dose were increased by 22% and 17%, respectively, compared to healthy control subjects. In volunteers with moderate hepatic impairment (Child-Pugh B), the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects. Consequently, a starting dose of 5 mg is recommended for patients with moderate hepatic impairment, and the maximum dose should not exceed 10 mg. Levitra has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment.

Possible side effects

The most common side effects with Levitra are headache, flushing, stuffy or runny nose, indigestion, upset stomach, or dizziness. These side effects usually go away after a few hours. Call your doctor if you get a side effect that bothers you or one that will not go away.

Levitra may uncommonly cause:

• an erection that won't go away (priapism). If you get an erection that lasts more than 4 hours, get medical help right away. Priapism must be treated as soon as possible or lasting damage can happen to your penis including the inability to have erections.
• color vision changes, such as seeing a blue tinge to objects or having difficulty telling the difference between the colors blue and green.

In rare instances, men taking PDE5 inhibitors (oral erectile dysfunction medicines, including Levitra) reported a sudden decrease or loss of vision in one or both eyes. It is not possible to determine whether these events are related directly to these medicines, to other factors such as high blood pressure or diabetes, or to a combination of these. If you experience sudden decrease or loss of vision, stop taking PDE5 inhibitors, including Levitra, and call a doctor right away.
Sudden loss or decrease in hearing, sometimes with ringing in the ears and dizziness, has been rarely reported in people taking PDE5 inhibitors, including Levitra. It is not possible to determine whether these events are related directly to the PDE5 inhibitors, to other diseases or medications, to other factors, or to a combination of factors. If you experience these symptoms, stop taking Levitra and contact a doctor right away.
These are not all the side effects of Levitra. For more information, ask your doctor or pharmacist.

What other drugs will affect Levitra (Vardenafil)?

Do not take levitra if you are taking any of the following medicines::

• a nitrate such as nitroglycerin (Nitrostat, Nitrolingual, Nitro-Dur, Nitro-Bid, Minitran, Deponit, Transderm-Nitro, others), isosorbide dinitrate (Dilatrate-SR, Isordil, Sorbitrate), isosorbide mononitrate (Imdur, ISMO, Monoket), and others;
• a recreational drug such as amyl nitrate or nitrite ("poppers"); or
• an alpha blocker such as doxazosin (Cardura), guanadrel (Hylorel), prazosin (Minipress), terazosin (Hytrin), alfuzosin (Uroxatral), tamsulosin (Flomax), and others.

Taking levitra with any of these medications may cause very low blood pressure, possibly resulting in dizziness, fainting, stroke, or heart attack. Before taking levitra, tell your doctor if you are taking any of the following medications:

• any other drug used to treat impotence, such as alprostadil (Caverject, Muse, Edex) or yohimbine (Yocon, Yodoxin, others);
• the antibiotic drug erythromycin (E-Mycin, Eryc, Ery-Tab, others);
• an antifungal medication such as itraconazole (Sporanox) or ketoconazole (Nizoral);
• a medication used to treat irregular heartbeats such as quinidine (Quinaglute, Quinidex, Quin-Release), procainamide (Procan SR, Procanbid, Pronestyl), amiodarone (Cordarone, Pacerone), or sotalol (Betapace, Sorine); or
• the HIV medications indinavir (Crixivan) or ritonavir (Norvir).

You may not be able to take Levitra, or you may require a dosage adjustment or special monitoring during treatment if you are taking any of the medicines listed above.
Drugs other than those listed here may also interact with Levitra or affect your condition. Talk to your doctor or pharmacist before taking any prescription or over-the-counter medicines, including vitamins, minerals, and herbal products.

What should I avoid while taking Levitra (Vardenafil)?

Do not take any other drug used to treat impotence, such as alprostadil (Caverject, Muse, Edex) or yohimbine (Yocon, Yodoxin, others), without first talking to your doctor.
Levitra should not be taken with grapefruit or grapefruit juice. Levitra can interact with grapefruit and grapefruit juice, and the interaction may have dangerous effects. You should discuss the use of grapefruit and grapefruit juice with your doctor.

Contraindications

Nitrates
Administration of Levitra with nitrates (either regularly and/or intermittently) and nitric oxide donors is contraindicated. Consistent with the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine monophosphate pathway, PDE5 inhibitors may potentiate the hypotensive effects of nitrates. A suitable time interval following Levitra dosing for the safe administration of nitrates or nitric oxide donors has not been determined.

Hypersensitivity
Levitra is contraindicated for patients with a known hypersensitivity to any component of the tablet.

Warnings

Cardiovascular effects
General: Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. In men for whom sexual activity is not recommended because of their underlying cardiovascular status, any treatment for erectile dysfunction, including Levitra, generally should not be used.
Left Ventricular Outflow Obstruction: Patients with left ventricular outflow obstruction, e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis, can be sensitive to the action of vasodilators including Type 5 phosphodiesterase inhibitors.
Blood Pressure Effects: Levitra has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 7 mmHg systolic and 8 mmHg diastolic). While this normally would be expected to be of little consequence in most patients, prior to prescribing Levitra, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.

Effect of Co-administration of Potent CYP3A4 Inhibitors
Long-term safety information is not available on the concomitant administration of Levitra with HIV protease inhibitors. Concomitant administration with ritonavir or indinavir substantially increases plasma concentrations of Levitra. Because ritonavir prolongs Levitra elimination half-life (5 to 6-fold), no more than a single 2.5 mg dose of Levitra should be taken in a 72-hour period by patients also taking ritonavir. Patients taking indinavir, saquinavir, atazanavir or other potent CYP3A4 inhibitors such as clarithromycin, ketoconazole 400 mg daily, or itraconazole 400 mg daily should not exceed a dose of Levitra 2.5 mg once daily. For patients taking ketoconazole 200 mg daily or itraconazole 200 mg daily, a single dose of 5 mg Levitra should not be exceeded in a 24-hour period.

Other Effects
There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds, including Levitra. In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

Patient Subgroups Not Studied in Clinical Trials
There are no controlled clinical data on the safety or efficacy of Levitra in the following patients; and therefore its use is not recommended until further information is available.

• unstable angina; hypotension (resting systolic blood pressure of <90 mmHg); uncontrolled hypertension (>170/110 mmHg); recent history of stroke, life-threatening arrhythmia, or myocardial infarction (within the last 6 months); severe cardiac failure;
• severe hepatic impairment (Child-Pugh C);
• end stage renal disease requiring dialysis;
• known hereditary degenerative retinal disorders, including retinitis pigmentosa.

Precautions

The evaluation of erectile dysfunction should include a determination of potential underlying causes, a medical assessment, and the identification of appropriate treatment.
Before prescribing Levitra, it is important to note the following:

Alpha-blockers
Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Phosphodiesterase Type 5 (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. In some patients, concomitant use of these two drug classes can lower blood pressure significantly eading to symptomatic hypotension (e.g., fainting). Consideration should be given to the following:

• Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
• In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose.
• In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor.
• Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

Hepatic Insufficiency
n volunteers with moderate impairment (Child-Pugh B), the Cmax and AUC following a 10 mg vardenafil dose were increased 130% and 160%, respectively, compared to healthy control subjects. Consequently, a starting dose of 5 mg is recommended for patients with moderate hepatic impairment and the maximum dose should not exceed 10 mg. Levitra has not been evaluated in patients with severe hepatic impairment (Child-Pugh C).
Congenital or Acquired QT Prolongation: In a study of the effect of Levitra on QT interval in 59 healthy males, therapeutic (10 mg) and supratherapeutic (80 mg) doses of Levitra and the active control moxifloxacin (400 mg) produced similar increases in QTc interval. A postmarketing study evaluating the effect of combining Levitra with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone. These observations should be considered in clinical decisions when prescribing Levitra to patients with known history of QT prolongation or patients who are taking medications known to prolong the QT interval. Patients taking Class 1A (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications or those with congenital QT prolongation, should avoid using Levitra.

Renal Insufficiency
n patients with moderate (CLcr = 30-50 ml/min) to severe (CLcr<30 ml/min) renal impairment, the AUC of vardenafil was 20 - 30% higher compared to that observed in a control group with normal renal function (CLcr>80 ml/min). Levitra pharmacokinetics have not been evaluated in patients requiring renal dialysis.
General: In humans, Levitra alone in doses up to 20 mg does not prolong the bleeding time. There is no clinical evidence of any additive prolongation of the bleeding time when Levitra is administered with aspirin. Levitra has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore Levitra should be administered to these patients after careful benefit-risk assessment.
Treatment for erectile dysfunction should generally be used with caution by patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease) or by patients who have conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
The safety and efficacy of Levitra used in combination with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Information For Patients

Carcinogenesis/ Mutagenesis/ Impairment of Fertility

Levitra was not carcinogenic in rats and mice when administered daily for 24 months. In these studies systemic drug exposures (AUCs) for unbound (free) Levitra and its major metabolite were approximately 400- and 170-fold for male and female rats, respectively, and 21- and 37-fold for male and female mice, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 20 mg. Levitra was not mutagenic as assessed in either the in vitro bacterial Ames assay or the forward mutation assay in Chinese hamster V79 cells. Levitra was not clastogenic as assessed in either the in vitro chromosomal aberration test or the in vivo mouse micronucleus test. Levitra did not impair fertility in male and female rats administered doses up to 100 mg/kg/day for 28 days prior to mating in male, and for 14 days prior to mating and through day 7 of gestation in females. In a corresponding 1-month rat toxicity study, this dose produced an AUC value for unbound vardenafil 200 fold greater than AUC in humans at the MRHD of 20 mg.
There was no effect on sperm motility or morphology after single 20 mg oral doses of Levitra in healthy volunteers.

Pregnancy, Nursing Mothers and Pediatric Use

Levitra is not indicated for use in women, newborns, or children. Levitra was secreted 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. It is not known if vardenafil is excreted in human breast milk.

Pregnancy Category B

No evidence of specific potential for teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits that received vardenafil at up to 18 mg/kg/day during organogenesis. This dose is approximately 100 fold (rat) and 29 fold (rabbit) greater than the AUC values for unbound vardenafil and its major metabolite in humans given the MRHD of 20 mg. In the rat pre-and postnatal development study, the NOAEL (no observed adverse effect level) for maternal toxicity was 8 mg/kg/day. Retarded physical development of pups in the absence of maternal effects was observed following maternal exposure to 1 and 8 mg/kg possibly due to vasodilatation and/or secretion of the drug into milk. The number of living pups born to rats exposed pre- and postnatally was reduced at 60 mg/kg/day. Based on the results of the pre- and postnatal study, the developmental NOAEL is less than 1 mg/kg/day. Based on plasma exposures in the rat developmental toxicity study, 1 mg/kg/day in the pregnant rat is estimated to produce total AUC values for unbound vardenafil and its major metabolite comparable to the human AUC at the MRHD of 20 mg. There are no adequate and well-controlled trials of vardenafil in pregnant women.

Geriatric Use

Elderly males age 65 years and older have higher vardenafil plasma concentrations than younger males (18 - 45 years), mean Cmax and AUC were 34% and 52% higher, respectively. Phase 3 clinical trials included more than 834 elderly patients, and no differences in safety or effectiveness of Levitra 5, 10, or 20 mg were noted when these elderly patients were compared to younger patients. However, due to increased vardenafil concentrations in the elderly, a starting dose of 5 mg Levitra should be considered in patients ≥65 years of age.

FDA Alert

[Posted 10/18/2007]
FDA informed healthcare professionals of reports of sudden decreases or loss of hearing following the use of PDE5 inhibitors Viagra, Levitra, Cialis for the treatment of erectile dysfunction, and Revatio for the treatment of pulmonary arterial hypertension. In some cases, the sudden hearing loss was accompanied by tinnitus and dizziness. Medical follow-up on these reports was often limited which makes it difficult to determine if the loss of hearing was related to the use of one of the drugs, an underlying medical condition or other risk factors for hearing loss, a combination of these factors or other factors. The PRECAUTIONS and ADVERSE REACTIONS sections of the approved product labeling for Viagra, Levitra, and Cialis were revised. FDA is working with the manufacturer to revise the labeling for Revatio.

References

References and complaints