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The maximum recommended dosing frequency is one tablet per day.
Carcinogenesis, Mutagenesis, Impairment Of Fertility. Vardenafil was not carcinogenic in rats and mice when administered daily for 24 months. In these studies systemic drug exposures (AUCs) for unbound (free) vardenafil 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. Vardenafil was not mutagenic as assessed in either the in vitro bacterial Ames assay or the forward mutation assay in Chinese hamster V 79 cells. Vardenafil was not clastogenic as assessed in either the in vitro chromosomal
aberration test or the in vivo mouse micronucleus test.
Vardenafil 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. Pregnancy Category B LEVITRA is not indicated for use in women.
There are no studies of LEVITRA use in pregnant women. 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 online doctor prescription for viagra than the AUC values for unbound vardenafil and its major metabolite in humans given the maximum recommended human dose (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 sildenafil for sale online 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. It is not known if vardenafil is excreted in human breast milk. Vardenafil 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. LEVITRA is not indicated for use in pediatric patients. Safety and efficacy have not been established in this population. Elderly males 65 years of age 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 [see CLINICAL PHARMACOLOGY ].
Dosage adjustment is necessary in patients with moderate hepatic impairment. Do not use LEVITRA in patients with severe hepatic impairment (Child-Pugh C).
Vardenafil has not been evaluated in this patient population.
A starting dose of 5 mg is recommended in patients with moderate hepatic impairment (Child-Pugh B) and the maximum dose should not exceed 10 mg. In volunteers with moderate hepatic impairment, the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects. [See WARNINGS AND PRECAUTIONS and online ed drug DOSAGE AND ADMINISTRATION .] 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.
No dosage adjustment is necessary in patients with mild hepatic impairment.
Do not use LEVITRA in patients on renal dialysis as vardenafil has not been evaluated in such patients. No dosage adjustment is necessary in patients with creatinine clearance (CLcr) of 30–80 mL/min. 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.
In male volunteers with CLcr = 30-50 mL/min or CLcr 80 mL/min.
[See DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS .] OVERDOSE. The maximum dose of LEVITRA for which human data are available is a single 120 mg dose administered to healthy male volunteers. The majority of these subjects experienced reversible back pain/myalgia and/or “abnormal vision.” Single doses up to 80 mg vardenafil and multiple doses up to 40 mg vardenafil administered once daily over 4 weeks were tolerated without producing serious adverse side effects. When 40 mg of vardenafil was administered twice daily, cases of severe back pain were observed.
In cases of overdose, standard supportive measures should be taken as required.
Renal dialysis is not expected to accelerate clearance as vardenafil is highly bound to plasma proteins and not significantly eliminated in the urine. Administration of LEVITRA with nitrates (either regularly and/or intermittently) and nitric oxide donors is contraindicated [see CLINICAL PHARMACOLOGY ]. Consistent with the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine monophosphate pathway, PDE5 inhibitors, including LEVITRA, may potentiate the hypotensive effects of nitrates. A suitable time interval following dosing of LEVITRA for the safe administration of nitrates or nitric oxide donors has not been determined.
Do not use LEVITRA in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including LEVITRA may potentiate the hypotensive effects of GC stimulators. 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 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 [see DRUG INTERACTIONS ].
Effects On Blood Pressure And Heart Rate When LEVITRA Is 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 LEVITRA 20 mg at various times before NTG administration. LEVITRA 20 mg caused an additional time-related reduction in blood pressure and increase in heart rate in association with NTG administration. The blood pressure effects were observed when LEVITRA 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 LEVITRA 20 mg was dosed 24 hours before NTG.
(See Figure 1.) Figure 1: Placebo-subtracted point estimates (with 90% CI) of mean maximal blood pressure and heart rate effects of pre-dosing with vardenafil 20 mg at 24, 8, 4, and 1 hour before 0.4 mg NTG sublingually. 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 [see CONTRAINDICATIONS ].
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. 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.
Following simultaneous administration of vardenafil 5 mg and tamsulosin, two patients had a 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 30 mmHg. There were no severe adverse events related to hypotension reported during the study. Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1) Alpha-Blocker Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted Terazosin Standing SBP -3 (-6.7, 0.1) -4 (-7.4, -0.5) 5 or 10 mg daily Supine SBP -4 (-6.7, -0.5) -4 (-7.1, -0.7) Tamsulosin Standing SBP -6 (-9.9, -2.1) -4 (-8.3, -0.5) 0.4 mg daily Supine SBP -4 (-7, -0.8) -5 (-7.9, -1.7) Blood pressure effects (standing SBP) in normotensive men on stable dose of tamsulosin 0.4 mg
following simultaneous administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo separated by 6 online ed drug hours are shown in Figure 2. Blood pressure effects (standing SBP) in normotensive men on stable dose terazosin (5 or 10 mg) following simultaneous administration of vardenafil 5 mg or placebo, or following administration of vardenafil 5 mg or placebo separated by 6 hours, are shown in Figure 3.
Figure 2: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 1) Figure 3: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous or 6 hr separation administration of vardenafil 5 mg or placebo with stable dose terazosin (5 or 10 mg) in normotensive BPH patients (Study 1) 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 placebo was given simultaneously with tamsulosin.
Blood pressure and pulse were evaluated over the 6hour interval after vardenafil dosing.
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 30 online ed drug mmHg). Three patients reported dizziness following vardenafil 20 mg.
Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2) Vardenafil 10 mg Placebo-subtracted
Vardenafil 20 mg Placebo-subtracted Standing SBP -4 (-6.8, -0.3) -4 (-6.8, -1.4) Supine SBP -5 (-8.2, -0.8) -4 (-6.3, -1.8) Blood pressure effects (standing SBP) in normotensive men on stable dose of tamsulosin 0.4 mg following simultaneous administration of vardenafil 10 mg, vardenafil 20 mg or placebo are shown in Figure 4. Figure 4: Mean change from baseline in standing systolic blood pressure (mmHg) over 6 hour interval following simultaneous administration of vardenafil 10 mg (Stage 1), vardenafil 20 mg (Stage 2), or placebo with stable dose tamsulosin 0.4 mg in normotensive BPH patients (Study 2) 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, 3period 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. Table 4: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 and 10 mg in BPH patients on stable alpha-blocker therapy with alfuzosin 10 mg daily (Study 3) Vardenafil 5 mg Placebo-subtracted Vardenafil 10 mg Placebo-subtracted Standing SBP -2 (-5.8, 1.2) -5 (-8.8, -1.6) Supine SBP -1 (-4.1, 2.1) -6 (-9.4, -2.8) 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. 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), online ed drug 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. Instances of outlier blood pressure values (defined as standing SBP 30 mmHg) were observed in 9/24 subjects receiving tamsulosin and 19/29 receiving terazosin.
The incidence of subjects with standing SBP Alpha-Blocker Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours Simultaneous dosing of Vardenafil and Alpha-Blocker Vardenafil 10 mg Placebo-Subtracted Vardenafil 20 mg Placebo-Subtracted Vardenafil 10 mg Placebo-Subtracted Vardenafil 20 mg Placebo-Subtracted Terazosin 10 mg daily Standing SBP -7 (-10, -3) -11 (-14, -7) -23 (-31, 16) a
-14 (-33, 11) a Supine SBP -5 (-8, -2) -7 (-11, -4) -7 (-25, 19) a -7 (-31, 22) a Tamsulosin 0.4 mg daily Standing SBP -4 (-8, -1) -8 (-11, -4) -8 (-14, -2) -8 (-14, -1) Supine SBP -4 (-8, 0) -7 (-11, -3) -5 (-9, -2) -3 (-7, 0) a) Due to the sample size, confidence intervals may not be an accurate measure for these data.
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