No single correction method is known
Study 3: This study was designed to evaluate the effect of single doses of 5 mg vardenafil (stage 1) and 10 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=24) on stable therapy with alfuzosin 10 mg daily for at least four weeks. The design was a randomized, double blind, 3-period cross- over study. Vardenafil or placebo was administered 4 hours after the administration of alfuzosin. Blood pressure and pulse were evaluated over a 10-hour interval after dosing of vardenafil or placebo. One patient experienced decreases from baseline in standing systolic blood pressure >30 mm Hg after administration of vardenafil 5 mg film-coated tablet and vardenafil 10 mg film-coated tablet.
No instances of standing systolic blood pressure <85 mm Hg were observed during this study. Four patients, one dosed with placebo, two dosed with vardenafil 5 mg film-coated tablets and one dosed with vardenafil 10 mg film-coated tablets, reported dizziness. Blood pressure effects (standing SBP) in normotensive men on a stable dose of alfuzosin 10 mg following administration of vardenafil 5 mg, vardenafil 10 mg, or placebo separated by 4 hours Blood pressure effects in normotensive men after forced titration with alpha-blockers: Two randomized, double blind, placebo-controlled clinical pharmacology studies with healthy normotensive volunteers (age range, 45-74 years) were performed after forced titration of the alpha-blocker terazosin to 10 mg daily over 14 days (n=29), and after initiation of tamsulosin 0.4 mg daily for five days (n=24). There were no severe adverse events related to hypotension in either study. Symptoms of hypotension were a cause for withdrawal in 2 subjects receiving terazosin and in 4 subjects receiving tamsulosin. to be more valid than the other.
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In this study, the
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 vardenafil is a selective inhibitor of PDE5. The inhibitory effect of vardenafil 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). 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. Vardenafil may add to the blood pressure lowering effects of antihypertensive agents. Effects on Blood Pressure and Heart Rate when Combined with Nitrates: A study was conducted in which the blood pressure and heart rate response to 0.4 mg nitroglycerin (NTG) sublingually was evaluated in 18 healthy subjects following pretreatment with vardenafil 20 mg at various times before NTG administration. Vardenafil 20 mg caused an additional time-related reduction in blood pressure and increase in heart rate in association with NTG administration. mean increase in heart
rate associated with a
Nursing Mothers: Not indicated for use in women. Renal Impairment: Do not use in patients on renal dialysis; no dosage adjustment necessary in patients with ClCr 30-80 mL/min. Hepatic Impairment: Do not use in patients with severe impairment (Child-Pugh C); dosage adjustment is necessary in patients with moderate impairment. Pediatric Patients: Not indicated for use in pediatric patients; safety and efficacy have not been established in this population. Geriatric Patients: No differences in safety and effectiveness noted between elderly (≥65 years of age) and younger patients.
However, due to increased vardenafil concentrations in the elderly, a starting dose of 5 mg should be considered in the elderly. 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). 10 mg dose of vardenafil
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. compared to placebo was
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. 5 beats/minute and with an
Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a standing SBP of <85 mmHg. A decrease in standing SBP of >30 mmHg was observed in two patients on tamsulosin receiving simultaneous vardenafil and in one patient receiving simultaneous placebo treatment. When tamsulosin and vardenafil 5 mg were separated by 6 hours, two patients had a standing SBP <85 mmHg and one patient had a decrease in SBP of >30 mmHg. There were no severe adverse events related to hypotension reported during the study. Study 2: This study was designed to evaluate the effect of 10 mg vardenafil (stage 1) and 20 mg vardenafil (stage 2) compared to placebo, when administered to a single cohort of BPH patients (n=23) on stable therapy with tamsulosin 0.4 mg or 0.8 mg daily for at least four weeks.
The design was a randomized, double blind, two-period cross- over study. Vardenafil or generic levitra 20 placebo was given simultaneously with tamsulosin. One patient experienced a decrease from baseline in standing SBP of >30 mmHg following vardenafil 10 mg. There were no other instances of outlier blood pressure values (standing SBP <85 mmHg or decrease from baseline in standing SBP of >30 mmHg). Three patients reported dizziness following vardenafil 20 mg. 80 mg dose the
mean increase was 6 beats/minute.
Therapeutic and supratherapeutic doses
| Instruction | Details |
|---|---|
| Take on an empty stomach or with food | Food may delay onset |
| Alcohol consumption | Limit intake for best results |
| Avoid sudden position changes | To reduce dizziness and hypotension |
| Do not exceed prescribed dose | To prevent adverse effects |
of vardenafil and the
The blood pressure effects were observed when vardenafil 20 mg was dosed 1 or 4 hours before NTG and the heart rate effects were observed when 20 mg was dosed 1, 4, or 8 hours before NTG. Additional blood pressure and heart rate changes were not detected when vardenafil 20 mg was dosed 24 hours before NTG. Because the disease state of patients requiring nitrate therapy is anticipated to increase the likelihood of hypotension, the use of vardenafil by patients on nitrate therapy or on nitric oxide donors is contraindicated. Blood Pressure Effects in Patients on Stable Alpha-Blocker Treatment: Three clinical pharmacology studies were conducted in patients with benign prostatic hyperplasia (BPH) on stable-dose alpha-blocker treatment, consisting of alfuzosin, tamsulosin or terazosin. Study 1: This study was designed to evaluate the effect of 5 mg vardenafil compared to placebo when administered to BPH patients on chronic alpha-blocker therapy in two separate cohorts: tamsulosin 0.4 mg daily (cohort 1, n=21) and terazosin 5 or 10 mg daily (cohort 2, n=21).
The design was a randomized, double blind, cross-over study with four treatments: vardenafil 5 mg or placebo administered simultaneously with the alpha-blocker and vardenafil 5 mg or placebo administered 6 hours after the alpha- blocker. Blood pressure and pulse were evaluated over the 6-hour interval after vardenafil dosing. One patient after simultaneous treatment with 5 mg vardenafil and 10 mg terazosin exhibited symptomatic hypotension with standing blood pressure of 80/60 mmHg occurring one hour after administration and subsequent mild dizziness and moderate lightheadedness lasting for 6 hours. For vardenafil and placebo, five and two patients, respectively, experienced a decrease in standing systolic blood pressure (SBP) of >30 mmHg following simultaneous administration of terazosin. Hypotension was not observed when vardenafil 5 mg and terazosin were administered 6 hours apart. active control moxifloxacin produced similar increases in QTc interval.