Extended Duration of Efficacy of Vardenafil When Taken 8 Hours Before Intercourse: A Randomized, Double-Blind, Placebo-Controlled Study

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.

Vardenafil has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment.

Renal Impairment: In male volunteers with ClCr= 50-80 mL/min, the pharmacokinetics of vardenafil were similar to those observed in a control group with ClCr >80 mL/min.

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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). Pediatrics: Vardenafil is not indicated for use in pediatric patients. Vardenafil trials were not conducted in the pediatric population. 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. 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 male volunteers with ClCr = 30-50 mL/min or ClCr <30 mL/min renal impairment groups, the AUC of vardenafil was 20-30% higher compared to that observed in a control group with ClCr >80 mL/min).

• Patients should be aware of potential low blood pressure from vardenafil.
• Pregnancy or breastfeeding concerns should be discussed with a healthcare provider.
• The medication may cause dizziness; avoid driving if affected.
• Adjustments in diet or lifestyle may enhance vardenafil effectiveness.

Vardenafil pharmacokinetics have not been evaluated in patients requiring renal dialysis.

Advise patients of the contraindication of vardenafil with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of vardenafil with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.

Latest CME

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 vardenafil in healthy volunteers, a mean of 0.00018% of the administered dose pills for womens libido was obtained in semen 1.5 hours after dosing. Metabolism: Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 and CYP2C isoforms.

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The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. The plasma concentration of M1 is approximately 26% that of the parent compound. This metabolite shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. Therefore, M1 accounts for approximately 7% of total pharmacologic activity. Elimination: 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. Inform patients of the potential cardiac risk of sexual activity for patients with preexisting cardiovascular risk factors.

Vardenafil side effects

Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose- related impairment of color discrimination (blue/green) using the Farnsworth-Munsell 100-hue test and reductions in electroretinogram (ERG) b-wave amplitudes, with peak effects near the time of peak plasma levels. These findings are consistent with the inhibition of PDE6 in rods and cones, which is involved in phototransduction in the retina. The findings were most evident one hour after administration, diminishing but still present 6 hours after administration. In a single dose study in 25 normal males, vardenafil 40 mg, twice the maximum daily recommended dose, did not alter visual acuity, intraocular pressure, fundoscopic and slit lamp findings. In another double blind, placebo controlled clinical trial, at least 15 doses of 20 mg vardenafil were administered over 8 weeks versus placebo to 52 males.

Other Interactions

Thirty-two (32) males (62%) of the patients completed the trial. Retinal function was measured by ERG and FM-100 test 2, 6 and 24 hours after dosing. The trial was designed to detect changes in retinal function that might occur in more than 10% of patients. Vardenafil did not produce clinically significant ERG or FM-100 effects in healthy men compared to placebo. Two patients on vardenafil in the trial reported episodes of transient cyanopsia (objects appear blue).

3.3 Efficacy

There was no effect on sperm motility or morphology after single 20 mg oral doses of vardenafil in healthy volunteers. The pharmacokinetics of vardenafil are approximately dose proportional over the recommended dose range. Absorption: premature ejaculation pills 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%. Inform patients that in some patients concomitant use of PDE5 inhibitors, including vardenafil, with alpha-blockers can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting).

Before Using

Instances of outlier blood pressure values (defined as standing SBP <85 mmHg and/ or a decrease from baseline of standing SBP >30 mmHg) were observed in 9/24 subjects receiving tamsulosin and 19/29 receiving terazosin. The incidence of subjects with standing SBP <85 mmHg given vardenafil and terazosin to achieve simultaneous Tmax led to early termination of that arm of the study. In most (7/8) of these subjects, instances of standing SBP <85 mmHg were not associated with symptoms. Among subjects treated with terazosin, outlier values were observed more frequently when vardenafil and terazosin were given to achieve simultaneous Tmax than when dosing was administered to separate Tmax by 6 hours. There were 3 cases of dizziness observed with concomitant administration of terazosin and vardenafil.

What should I tell my healthcare provider before taking vardenafil?

Seven subjects experienced dizziness mainly occurring with simultaneous Tmax administration of tamsulosin. The effect of 10 mg and 80 mg vardenafil on QT interval was evaluated in a single- dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) crossover study in 59 healthy males (81% White, 12% Black, 7% Hispanic) aged 45-60 years. The QT interval was measured at one-hour post dose because this time point approximates the average time of peak vardenafil concentration. The 80 mg dose of vardenafil (four times the highest recommended dose) was chosen because this dose yields plasma concentrations covering those observed upon co-administration of a low-dose of vardenafil (5 mg) and 600 mg BID of ritonavir. Of the CYP3A4 inhibitors that have been studied, ritonavir causes the most significant drug-drug interaction with vardenafil.

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No single correction method is known to be more valid than the other. In this study, the mean increase in heart rate associated with a 10 mg dose of vardenafil compared to placebo was 5 beats/minute and with an 80 mg dose the mean increase was 6 beats/minute. Therapeutic and supratherapeutic doses of vardenafil and the active control moxifloxacin produced similar increases in QTc interval. This study, however, was not designed to make direct statistical comparisons between the drug or the dose levels. The clinical impact of these QTc changes is unknown. Patients prescribed vardenafil who are taking alpha-blockers should be started on the lowest recommended starting dose.

Vardenafil Interactions

In a separate post-marketing study of 44 healthy volunteers, single doses of 10 mg vardenafil resulted in a placebo-subtracted mean change from baseline of QTcF (Fridericia correction) of 5 msec (90% CI: 2,8). Single doses of gatifloxacin 400 mg resulted in a placebo-subtracted mean change from baseline QTcF of 4 msec (90% CI: 1,7). When vardenafil 10 mg and gatifloxacin 400 mg were co-administered, the mean QTcF change from baseline was additive when compared to either drug alone and produced a mean QTcF change of 9 msec from baseline (90% CI: 6,11). The clinical impact of these QT changes is unknown. Effects on Exercise Treadmill Test in Patients with Coronary Artery Disease (CAD): In vardenafil pills two independent trials that assessed 10 mg (n=41) and 20 mg (n=39) vardenafil, respectively, vardenafil did not alter the total treadmill exercise time compared to placebo.

Other Examples of PDE5 Inhibitors

The patient population included men aged 40-80 years with stable exercise- induced angina documented by at least one of the following: 1) prior history of myocardial infarction (MI), coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA), or stenting (not within 6 months); 2) positive coronary angiogram showing at least 60% narrowing of the diameter of at least one major coronary artery; or 3) a positive stress echocardiogram or stress nuclear perfusion study. Results of these studies showed that vardenafil did not alter the total treadmill exercise time compared to placebo (10 mg vardenafil vs. placebo: 433±109 and 426±105 seconds, respectively; 20 mg vardenafil vs. placebo: 414±114 and 411±124 seconds, respectively). The total time to angina was not altered by vardenafil when compared to placebo (10 mg vardenafil vs.

Does vardenafil interact with foods or drinks?

placebo: 291±123 and 292±110 seconds; 20 mg vardenafil vs. placebo: 354±137 and 347±143 seconds, respectively). The total time to 1 mm or greater ST-segment depression was similar to placebo in both the 10 mg and the 20 mg vardenafil groups (10 mg LEVITRA vs. placebo: 380±108 and 334±108 seconds; 20 mg vardenafil vs. placebo: 364±101 and 366±105 seconds, respectively). Patients should be advised of the possible occurrence of symptoms related to postural hypotension and appropriate countermeasures. Patients should be advised to contact the prescribing physician if other anti-hypertensive drugs or new medications that may interact with vardenafil are prescribed by another healthcare provider.

• Clinical studies demonstrate improved ability to achieve and maintain erection.
• The drug's molecular structure differs slightly from sildenafil and tadalafil.
• Patients should avoid taking it with other vasodilators.
• May cause a small, temporary decrease in blood pressure.
• Sexual activity may pose cardiac risk for those with pre-existing heart disease.
• The tablet should be swallowed whole with a glass of water.