Levitra Data

Levitra Doctor Information

Vardenafil (CAS number: 224785-90-4) in the form of vardenafil hydrochloride trihydrate. The empirical formula of vardenafil hydrochloride trihydrate: C23H32N6O4S.HCI.3H2O. Molecular weight: 579.1 g/mol.

Vardenafil hydrochloride trihydrate, a nearly colorness solid, is 2-[ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one hydrochloride trihydrate. Vardenafil hydrochloride trihydrate is soluble in 0.1M HCI and ethanol, freely soluble in methanol, and only slightly soluble in water and acetone.

LEVITRA comes in varying strength:

• 20 mg of vardenafil (23.705 mg of vardenafil hydrochloride trihydrate)
• 10 mg of vardenafil (11.852 mg of vardenafil hydrochloride trihydrate)
• 5 mg of vardenafil (5.926 mg of vardenafil hydrochloride trihydrate)

The above are LEVITRA’S active ingredients, the tablets also contain: crospoyidone, colloidal anhydrous silica, microcrystalline cellulose, magnesium stearate, macrogol 400, titanium dioxide (CI77891), iron oxide red (CI77491), iron oxide yellow (CI77492).

The haemodynamic process of erecting a penis is grounded in the relaxation of smooth muscle in the corpus cavernosum and its allied arterioles. Nitric oxide (NO) is released from the corpus cavernosum’s nerve ends during sexual arousal. This triggers the enxyme guanylate cyclase causing the corpus cavernosum’s cyclic guanosine monophosphate (cGMP) levels to increase. This is what causes relaxation in the smooth muscle and allows freer blood flow into the penis, causing an erect penis. The rate of degradation via cGCP hydrolyzing phosphodiesterases (PDEs) and the rate of synthesis via the guanylate cyclase are the two factors that actually regulates the cGMP level. The cGMP specific phosphodiesterase type 5 (PDE5) is the main PDE in the corpus cavernosum of a human.

Vardenafil powerfully improves the effect of endogenous Nitric Oxide, which the corpus cavernosum unleashes during sexual arousal, by regulating PDE5. PDE5 is the enzyme that causes cGMP degradation in the corpus caverosum. The levels of cGMP are boosted in the corpus as a result of the PDE5 inhibition, causing smooth muscle relaxation and freer blood flow to the corpus cavernosum. This is how vardenafil creates the potential for men to respond naturally to sexual stimulation.

Quantitative analysis, outside of a living organism, display vardenafil as a selective inhibitor of PDE5. It has an IC50 of 0.7 nM for human platelet PDE5.

Vardenafils inhibitory effects are powerful on powerful on PDE5 than any other known phosphodiesterases (>1,000-fold more than PDE2, 3, 4, 7, 8, 9, and 10, >300-fold more than PDE11, >130-fold more than PDE1). In the isolated human corpus cavernosum, vardenafil causes a rise of cGMP causing muscle relaxation, as tested in vitro.

Vardenafil gives the conscious rabbit an erect penis, but it depends on endogenous nitric oxide synthesis and is potentiate by nitric oxide donors.

In one particular clinical trial, Visual fields, visual acuity, ERG latency, intraocular pressure, fundoscopic, nor slit lamp findings showed signs of being effected when visual functions were tested after a 40mg dose of vardenafil (two times the maximum recommended daily dosage). A minor group of patients spoke of color distortions in the blue/green and purple range, occurring one hour post dosing. After 6 hours the color distortions had been restored and did not return at 24 hours. There were no records of subjective visual symptoms on a majority of these patients. In separate trial, no association was made with dysfunction in intraocular pressure, visual acuity, or findings or slit lamp or fundoscopic examinations and once a day use of 10mg to 40mg doses of vardenafil over a 31 day period.

A slight, temporary drop in blood pressure has been attributed to taking vardenafil, but not, in most cases, to the extent of clinical concern. Supine systolic blood pressure had the maximum decrease, when being compared to placebo, of 6,9mmHg after 20 mg of vardenafil and 4.3 mmHg after 40 mg of vardenafil.

Volunteers, in fit physical condition, who swallowed a single dose of 80mg of vardenafil (four times the maximum prescribed day to day dose) showed no effects on their ECGs of clinical relevance.

The amount of treadmill exercise time compared to placebo, in a total of 39 males, between the ages of 48-77, with exercise induced ischaemia and coronary artery disease, were not altered in a placebo-controlled, two-period, cross-over trial after taking 10mg of vardenafil. The sum time of angina, compared to placebo, did not change. In the vardenafil group, the sum time of 1mm or more ST-segment depression was extended 15% in comparison to the placebo group (p<0.001). No patient was marked with any serious drug-related side effects during or after the trial.

After being applied orally, Vardenafil is quickly absorbed. 90% of patients reach Cmax, on an empty stomach, between 30 to 120 mins (median 1 hour) after oral dosing, but Cmax has been achieved as soon as 15 minutes in others.

Observed pharmacokinetic parameters have a substantial intra-subject and inter-subject variability caused by vardenafil’s ample first-pass metabolism. A 10mg dose of vardenafil has a mean absolute bioavailability of about 15%. Within the recommended dose range of 5mg-20mg of vardenafil, there almost a proportional increase of Cmax and AUC, after oral dosing.

Though the mean AUC went unaffected, the mean Cmax (rate of absorption) suffered an approximate 20% reduction and there was an approximate 60min delay in median tmax when vardenafil was taken with a high fat meal of approximately 57% fat. Pharmacokinetic parameters were not notably affected after consuming a ‘regular meal’ of approximately 30% fat. These results should prove that food is not required to take vardenafil.

Vardenafil’s mean steady state volume of distribution (Vss) is ~2.5 L/kg, referring to tissue distribution.

Plasma proteins are strongly bound to both vardenafil and it main circulating metabolite (M1) (~95% for M1 or parent drug). Total drug concentration is not dependent on this reversable protein binding. A maximum of only 0.0002% of a given dose of vardenafil is traceable in patient’s semen. This was taken from healthy subjects, an hour and a half post dosing.

Hepatic enzymes via CYP3A4 mostly metabolize vardenafil, but CYP3A5 and CYP2C9 isoforms make a few contributions. It takes about from 4 to 5 hours for the mean terminal elimination half-life from plasma.

The desethylation at the piperazine moiety of vardenafil produces human beings main circulating metabolite, M1, which may undergo further metabolism. The metabolite M1 has a terminal plasma elimination half-life of ~4 hours, equivalent to the parent drug. M1 appears in systemic circulation as it glucuronide-conjugated form (glucuronic acid). Non-glucuronidated M1 has a plasma concentration of only 26% of the parent compound. M1 has an efficacy contribution of about 7%, which means it has almost the same phosphodiesterase selectivity profile as vardenafil and an in vitro inhibitory potency for PDE5 of ~28%, in comparison to vardenafil.

Vardenafil has a 56 L/hour total body clearance, giving it a terminal half-life of between 4 and 5 hours. Vardenafil is mostly excreted in the fecal matter (about 91 – 95% of given oral dose) and partially during urination (only about 2 – 6 % of given oral dose).

In healthy elderly volunteers, 65 years +, vardenafil’s half-life did not suffer a notable reduction from that or younger voulunteers (45 years and younger). There is a 52% higher AUC in the average elderly male than that of a younger male, that is within a clinical trials observed variability. Placebo monitored clinical trials produced no signs of an overall safety or effectiveness difference between older and younger volunteers.

A control group of patients with an average renal function had comparable vardenafil pharmacokinetics to that of patients with severe (CLcr < 30 mL/min), moderate (CLcr 30 – 50 mL/min), or mild (CLcr 50 – 80 mL/min) renal impairment. Vardenafil plasma exposure and creatinine clearance (Cmax and AUC) depicted no apparent statistical correlation of significance. This data shows that renal function imparment is not grounds for dose adjustment.

Patients using dialysis should not use vardenafil, as the pharmacokinetics of vardenafil have yet to be observed in such a situation.

Vardenafil clearance, in patients with a mild to modest hepatic handicap (Child-Pugh A and B), was reduced in accordance.

Vardenafil Cmax and AUC were multiplied 1.2 times (Cmax by 22% and AUC by 17%) more than a healthy controlled subject after patients with a mild hepatic handicap took a 10mg dose. Adjusting dosage for mild hepatic impairments is not required. Vardenafil Cmax multiplied 2.3 times (a 130% increase) and AUC multiplied 2.6 times (a 160% increase) more than a healthy controlled subject did after patients with a moderate hepatic handicap took a 10mg dose. Based on this a 5mg starting dose, which might eventually be upped to 10 or 20 mg, depending largely on efficacy and tolerability, should be utilized in patients with a moderate hepatic handicap. Individuals with a serious hepatic impairment (Child-Pugh C) should refrain from using vardenafil, as the pharmacokinetics of such a situation has yet to be researched.

In a few patients, a 20 mg dose of LEVITRA (vardenafil) produced an erection firm enough for sexual penetration (=60% rigidity) in only fifteen minutes during a placebo controlled Rigiscan study. 25 minutes after taking vardenafil, the statistical significance compared to placebo of the patients overall response became evident.

In every major efficacy trial, Vardenafil produced clinically substantial as well as statistically important improvement to erectile function compared to placebo, even including special population.

Vardenafil was issued to more than 3750 men battling with erectile dysfuction (ED) over the course of all trials. The men were aged between 18 and 89 years and a good number of them possessed multiple other medical conditions. More than 1630 patients took vardenafil for at least 6 months.

The International Index of Erectile Function (IIEF) erectile function domain score captured that vardenafil 10 mg and 20 mg created clinically substantial as well as statistically important improvements compared to placebo in every major efficacy trial; this includes patients battling diabetes and post-prostatectomy patients. The percentage has improved with both patients rating their erections and the amount of patients who gain and maintain erections. (Tables 1 and 2).

* Last available observation used in patients with no data at Week 12.

*Last available observation used in patients with no data at Week 12.

At the 6 month mark, 81%, 77%, and 56% of patients had improved erections aftertaking 5 mg, 10 mg, and 20 mg doses of vardenafil, respectively compared to 23% with placebo. These statistics are derived from a placebo controlled, randomized, double blind, fixed dose trial using 749 patients. It was based on a GAQ (Global Assessment Question).

The major efficacy trial’s combined data, including data taken from studies on special population, showed the patients who achieved an erection firm enough for penetration upon first dose were 70% for 20 mg, 68% for 10 mg, and 37% on placebo. A three month study period showed that, on average, patients whose first dose gave them a penetrating erection, 86% of the time for those taking 10 mg of vardenafil and 90% of the time for those taking 20 mg, continued to have successful responses afterward. Factors such as prior term of erectile dysfunction, baseline severity, aetiology (psychogenic, organic, and/or mixed), ethnicity and age, as concluded during subgroup analysis, had no effect on vardenafil’s effectiveness. A double blind, fixed dose, placebo controlled trial of vardenafil in post-prostatectomy patients, vardenafil produced clinically important and statistically significant erectile function improvements. The rate of achieving an erection firm enough for sexual penetration, the rate of maintaining such an erection to complete sexual relations, erectile funciton domain score, and firmness of each erection improved dramatically as opposed to placebo for doses of 10 mg and 20 mg. There was a 57% improvement on 10 mg, 60% on 20 mg, as opposed to 9% on placebo, to erectile function response rates as based on GAQ. As based on the GAQ, over a three month period, the patients that fell into the bilateral nerve-sparing prostatectomy subcategory had a response rate of 61% for 10 mg and 66% for 20 mg, as opposed to placebo’s 8%.

Improvements of erectile function on a clinically important and statistically significant level were obtained during a fixed dose, double blind, placebo controlled trial over a term of 3 month with diabetes mellitus patients on vardenafil. Notable improvements in the rate of achieving an erection firm enough for sexual penetration, the rate of maintaining such an erection to complete sexual relations, erectile funciton domain score, and firmness were evident 10 mg and 20 mg of vardenafil was compared to placebo. Every time point during a 3-month treatment period displayed these improvements. The rate of response for erectile function improvements as based on GAQ was 70% for 20 mg and 54% for 10 mg, in this generally more therapy resistant population, over a three month period, as opposed 13% for placebo. A 6-month blind active therapy of vardenafil was continued for patients in the active treatment group. The response rate for these groups was 74% for 20 mg and 66% for 10 mg.

LEVITRA’S indication is to aid adult males suffering with erectile dysfunction, or lacking the capacity to produce or sustain and erect penis capable of completing sexual intercourse.

LEVITRA is not indicated for female use.

Vardenafil’s contraindications are found in patients who are known to be highly sensitive any of the drugs ingredients, active or inactive.

Vardenafil and Nitrates must not be used together. Using vardenafil with nitric oxide donors, organic nitrites, or organic nitrate is contraindicated, whether it is used occasionally of regularly. A list of other drugs than must not be used together with vardenafil, though not a complete list, are: isosorbide salts, amyl nitrite, glyceryl trinitrate (spray, tablets, patches, and injection) sodium nitroprusside, organic nitrates (any form), and nicorandil. In line with the common effect of PDE inhibition on nitric oxide and cGMP, pathway, PDE5 inhibitors may cause encourage the hypotensive nitriate effects.

As warned in PRECAUTIONS, men use cardiovascular condition makes sex a health risk are contraindicated for vardenafil. Men with erectile dysfunction should have themselves checked for any cardiovascular complications they may not be aware of prior too taking vardenafil.

The use of vardenafil is contraindicated for patients with the following health conditions as the effects of vardenafil has yet to be studied in such situations: uncontrolled hypertension, unstable angina, myocardial infraction, resting or orthostatic hypotension (systolic blood pressure less than 90 mmHg), cardiac ischaemia (except stable angina), stroke, uncontrolled arrhythmia, life threatening arrhythmia in the past 6 months, on dialysis for end-stage renal disease, severe hepatic impairment, and known hereditary degenerating retinal complications like reinitis pigmentosa.

There is some element of cardiac risk involved in sexual activity, therefore physicians must take a look their patients cardiovascular condition before prescribing erectile dysfunction treatment.

Patients with anatomically deforming penis conditions (like cavernosal fibrosis, angulation, or Peyronie’s disease) or with condition that might induce priapism (like leukemia, sickle cell anemia, or multiple myeloma) must use agents for treating erectile dysfunction carefully.

Using a combination of vardenafil with other erectile dysfunction treatments (this includes other PDE5 inhibitors) has yet to be studied and is therefore ill-advised.

Patients with significant active peptic ulceration or other bleeding disorders have not yet been given vardenafil therefore should not be given vardenafil until after a serious benefit-risk assessment. Vardenafil has no effect on human bleeding time, alone or with aspirin. Human platelets from in vitro studies showed that platelet aggregation caused by various types of platelet agonists was not inhibited by vardenafil. Studies observed a small concentration-dependent improvement of the antiaggregatory effect fo sodium nitroprusside, a nitric oxide donor, with super-therapeutic concentrations of vardenafil. Though combining heparin and vardenafil has yet to be studied in humans, it did not effect the bleeding time in rats.

Some patients may experience symptomatic hypotension with the conjoined use of alpha-blockers and vardenafil. Conjoining alpha-blockers with vardenafil is ill-advised until more is known about such a combination.

Expect a notable increase in vardenafil plasma levels with the conjoined use of the potent cytochrome P450 3A4 (CYP 3A4) inhibitors, ritovavir, ketoconazole, indinavir, or itraconazole. Not only will higher levels of plasma increase effectiveness but it will also increase the occurance of conflicting events. If being combined with the usage of erythromycin, ketoconazole, and itraconazole, vardenafil’s dose should not exceed a maximum of 5 mg. Do not use vardenafil with the HIV protease inhibitors ritonavir or indinavir. (See INTERACTION WITH DRUGS).

Before driving or operating machinery patients should take note of their reactions to vardenafil.

Vardenafil was administers orally in doses up to 75 mg/kg/day to male rates and 25 mg/kg/day to female rats also in drinking water to mice at 150 mg/kg/day to males and 193 mg/kg/day and displayed no carcinogenic activity. Systematic exposure (AUC) to vardenafil was associated with the maximum dose in the studies: 25 (mice) or ~300 (rats) multiplied by that expected in a man taking a daily vardenafil dose of 20mg. When tested for gene mutation (forward mutations in Chinese hamsters V79 cells in vitro and reverse mutations in bacterial cells) or chromosomal damage (mouse micronucleus tested in vivo and Chinese hamsters V79 cells in vitro) vardenafil was found to be non-genotoxic.

Sperm morphology, motility, nor a variety or parameters that indicate the function of male reproduction were affected, in an individual clinical trial, after a single oral dose of 20 mg of vardenafil. A maximum of 0.0002% of the given dose appeared in patients semen when measurements were taken of vardenafil in the semen of healthy patients 90 mins post dosing.

Male and female rats issued an oral dose of 100 mg/kg/day had no effects on fertility, reproductive performance, or reproductive organ morphology (systematic exposure is greater than 200 times that expected at a dose of 20 mg, the maximum recommended, based on AUC).

Vardenafil should not be used by women.

Vardenafil and/or its metabolites has seen to cross the placenta and issued to the fetus, according to rat studies. Neither pregnant rats or rabbits, issued vardenafil in oral doses up to 18 mg/kg/day, displayed signs of teratogenicity or embryofetal toxicity. Systematic exposure to vardenafil 7 (rabbit) or 125 (rat) times more than what’s expected at 20 mg, the maximum advised dose, were associated with these doses, based on AUC. Both rats and rabbits experienced increased embryonic resorptions, maternal toxicity, and delayed fetal development when taking higher doses.

Delayed physical development and postnatal pup mortality was a direct result of giving rats a 60 mg/kg/day dose of vardenafil throughout lactation and in late gestation. Systematic exposure ~28 times that expected in a human being 20 mg vardenafil, maximum advised dose, was associated with the "no-effect-dose" of 8 mg/kg/day.

Vardenafil has not been tested and studied in pregnant women.

Vardenafil should not be used by women.

The milk of lactating rats experiences an excretion of vardenafil and/or its metabolites up to 19 times more than the parallel maternal plasma concentration. Rats given an oral vardenafil dose of 60 mg/kg/day during lactation and gestation periods suffered increases in delayed physical development and prenatal and postnatal mortality to offspring.

Human data regarding vardenafil excretion in breast milk or the safty of infants exposed to vardenafil has not been collected.

Fit voluteers experience a increase of 4-fold vardenafil AUC and 3-fold in Cmax when vardenafil (5 mg) was taken with a CYP3A4 inhibitor called Erythromycin (500 mg t.i.d.). Never take more than a 5 mg dose of vardenafil when combining it with the use of erythromycin.

Fit voluteers experience a increase of 10-fold vardenafil AUC and 4-fold in Cmax when vardenafil (5 mg) was taken with a CYP3A4 inhibitor called Ketoconazole (200 mg). Never take more than a 5 mg dose of vardenafil when combining it with the use of ketoconazole.

10 mg of vardenafil was administered along witn 800 mg t.i.d. of the HIV protease inhibitor indinavir. The result was a 7-fold increase in vardenafil Cmax and 16-fold increase in vardenafil AUC. Vardenafil plasma level were about 4% of the maximum Cmax 24 hours after the drugs were administered. It is highly advised to avoid this combination. Never take more than a 5 mg dose of vardenafil when combining it with the use of indinavir.

Using the CYP 3A4 inhibitors itraconazole and ritonavir with vardenafil will most likely be responsible for plasma levels similar to indinavir and ketoconazole (In Demonstrated Interactions). High plasma levels will not only increase effectiveness but increase occasions of adverse events. Never take more than a 5 mg dose of vardenafil when combining it with the use of itraconazole, ketaconazole, and erythromycin. It is advised to avoid combination use of the HIV protease inhibitors indinavir or ritonavir with vardenafil.

Data concerning the potential hypotensive effects of vardenafil when combined with use of nitrates is limited. Concomitant use is contraindicated due to experience with patients suffering clinically significant hypotension with co-administration of other PDE5 inhibitors. (In CONTRAINDICATIONS).

Avoid using nitrates until no less than 24 hours (~5 half-lives), after the last time you have taken vardenafil. If you have been using concomitant drugs, like CYP3A4 inhibitors, which injure the metabolism of vardenafil, you should observe an extended wash out period.

Information concerning the combined use of antihypertensive agents ant vardenafil is limited. Notable effects of ACE-inhibitors, diuretics, or beta-blockers on vardenafil’s pharmacokinetics were not uncovered by population pharmacokinetic investigations of phase III data. The potential for additive hypotensive effects still remains so, until more is know about the combination, use cautions when co-administering antihypertensive agents with vardenafil.

The relative bioavailability of glibenclamide was not affected with 3.5 mg of glibenclamide was co-administered with 20mg of vardenafil (there was no effect on glibenclamide’s AUC or Cmax).

The co-administration of warfarin with vardenafil did not effect vardenafil’s pharmacokinetics. When 25 mg of warfarin was co-administered with 20 mg of vardenafil no pharmacokinetic or pharmacodynamic (prothrombin time and clotting factor II, VII and X) interactions were identified.

The bioavailability (AUC and Cmax) of nifedipine was not changed when it was co-administered with 20 mg of vardenafil at 30 mg and 60 mg. Co-administration of the two did not stimulate pharmacodynamic interactions (as opposed to placebo, additonal blood pressure reductions of 5.9 mmHg for supine systolic and 5.2 mmHg for diastolic blood pressure we created by vardenafil).

0.375 mg of Digoxin was co-administered daily with 20 mg of vardenafil for 14 days every other day. The end result was an absence of pharmacokinetic interactions.

Vardenafil’s bioavailability (AUC) nor its maximum concentration (Cmax) were affected by a single dose of Mylanta (aluminium hydroxide/magnesium hydroxide).

150 mg b.i.d. of the H-2 antagonists rantidine and 400 mg b.i.d. of the non-specific cytochrome P450 inhibitor cimetidine co-administered with 20 mg of vardenafil did not affect the bioavailability of the latter.

Neither taking it alone or with a mild dose of aspirin (two 81 mg tablets, caused 10 mg of vardenafil to affect bleeding time.

The hypotensive effects of 0.5 g/kg bodyweight of ethanol where not induced by 20 mg og vardenafil. The combination use of vardenafil and ethanol did not notably change pharmacokinetics.

Weak CYP3A4-inhibitors, aspirin, and medications treating diabetes (metformin and sulfonylureas), according to population pharmacokinetic investigators of phase III data, did not alter the pharmacokinetics of vardenafil.

In a clinical, worldwide, trial, vardenafil was issued to more than 3750 patients. More than 730 patients received treatment for one year or more. For most patients the drug was well tolerated, and the nature of any adverse reactions were usually temporary and mild to moderate.

As of November 29, 2001, in placebo controlled clinical trials, the following adverse reactions were reported to appear more frequently with vardenafil than with placebo.

Table 3:

Table 3: Adverse events reported by = 2% of patients treated with vardenafil and more frequent on drug than placebo in fixed dose phase III trials of 5 mg, 10 mg, and 20 mg vardenafil.

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