Data Sheet
LEVITRA®
Vardenafil tablets, BAYER
name of the MEDICINE
Vardenafil, as vardenafil hydrochloride trihydrate is 2-[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. It is a nearly colourless solid. Vardenafil hydrochloride trihydrate is soluble in 0.1M HCl, very slightly soluble in water, freely soluble in methanol, soluble in ethanol and slightly soluble in acetone.
The empirical formula of vardenafil hydrochloride trihydrate is C23H32N6O4S.HCl.3H2O and its molecular weight is 579.1 g/mol. Its chemical structure is shown in Figure 1. (CAS number: 224785-90-4)
Figure 1.
Description
LEVITRA tablets are available in strengths of:
- 5 mg of vardenafil (5.926 mg of vardenafil hydrochloride trihydrate)
- 10 mg of vardenafil (11.852 mg of vardenafil hydrochloride trihydrate)
- 20 mg of vardenafil (23.705 mg of vardenafil hydrochloride trihydrate).
Besides the active ingredient, LEVITRA tablets also contain the following excipients: crospovidone, magnesium stearate, microcrystalline cellulose, colloidal anhydrous silica, macrogol 400, hypromellose, titanium dioxide (CI77891), iron oxide yellow (CI77492), iron oxide red (CI77491).
Pharmacology
Penile erection is a haemodynamic process based on the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, from nerve ends in the corpus cavernosum nitric oxide (NO) is released, which activates the enzyme guanylate cyclase resulting in an increased level of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. This in turn triggers smooth muscle relaxation, allowing increased inflow of blood into the penis resulting in erection. The actual cGMP level is regulated by the rate of synthesis via the guanylate cyclase on the one hand, and by the rate of degradation via cGMP hydrolyzing phosphodiesterases (PDEs) on the other hand.
The most prominent PDE in the human corpus cavernosum is the cGMP specific phosphodiesterase type 5 (PDE5).
By inhibiting PDE5, the enzyme responsible for cGMP degradation in the corpus cavernosum, vardenafil potently enhances the effect of endogenous NO, locally released in corpus cavernosum upon sexual stimulation. The inhibition of PDE5 by vardenafil leads to increased cGMP levels in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Vardenafil thus potentiates the natural response to sexual stimulation.
In vitro
assays have shown that vardenafil is a selective inhibitor of PDE5, with an IC50 of 0.7 nM for human platelet PDE5.The inhibitory effect of vardenafil is more potent on PDE5 than on 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 vitro, vardenafil causes an elevation of cGMP in the isolated human corpus cavernosum resulting in muscle relaxation.
In the conscious rabbit, vardenafil causes a penile erection which is dependent upon endogenous nitric oxide synthesis and is potentiated by nitric oxide donors.
Effects on Visual Perception
In a specific clinical trial, evaluation of visual function at a vardenafil dose of 40 mg (twice the maximum recommended daily dose) revealed no effects of vardenafil on visual acuity, visual fields, intraocular pressure, ERG latency, fundoscopic and slit lamp findings. A subset of patients was found to have mild and transient impairment of colour discrimination in the blue/green range and in the purple range 1 hour after dosing. These changes had improved by 6 hours and no changes were present at 24 hours. The majority of these patients had no subjective visual symptoms.
In other trials, daily use of vardenafil at doses of 10 mg to 40 mg for 31 days was not associated with changes in visual acuity, intraocular pressure, or findings on fundoscopic or slit lamp examination.
Effects on Blood Pressure
Vardenafil causes mild and transient decreases in blood pressure which, in the majority of the cases, do not translate into clinical effects. The mean maximum decreases in supine systolic blood pressure following 20 mg and 40 mg vardenafil were - 6.9 mmHg with 20 mg and - 4.3 mmHg with 40 mg of vardenafil, when compared to placebo.
Effects on Cardiac Parameters
Single oral doses of vardenafil up to 80 mg (four times the maximum recommended daily dose) did not produce clinically relevant effects on the ECGs of healthy volunteers.
Effects on Exercise Performance in Patients with Coronary Artery Disease
In a two-period, placebo-controlled, cross-over trial, 10 mg vardenafil did not alter the total treadmill exercise time compared to placebo in 39 male patients aged 48-77 years with coronary artery disease and exercise induced ischaemia. The total time to angina was not altered compared to placebo; however, the total time to 1 mm or greater ST-segment depression was prolonged 15% in the vardenafil group compared to the placebo group (p<0.001). All patients who entered the trial completed the exercise treadmill tests without significant drug-related side effects.
Pharmacokinetics
Absorption
Vardenafil is rapidly absorbed after oral administration. Cmax is reached as early as 15 minutes, in 90% of the time Cmax is reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state.
There is extensive first-pass metabolism of vardenafil, resulting in considerable inter-subject and intra-subject variability in the observed pharmacokinetic parameters. The mean absolute bioavailability is approximately 15% after a 10 mg dose. After oral dosing of vardenafil, AUC and Cmax increase almost dose proportionally over the recommended dose range (5 mg - 20 mg).
When vardenafil was taken with a high fat meal (~57% fat), the rate of absorption (mean Cmax) was reduced by approximately 20%, median tmax was delayed by approximately 1 hour, and mean AUC was not affected. After a 'normal meal' (~30% fat) pharmacokinetic parameters were not significantly affected. Based on these results vardenafil can be taken with or without food.
Distribution
The mean steady state volume of distribution (Vss) for vardenafil is about 2.5 L/kg, indicating distribution into the tissues.
Vardenafil and its major circulating metabolite (M1) are highly bound to plasma proteins (about 95% for parent drug or M1). This protein binding is reversible and independent of total drug concentrations.
Based upon measurements of vardenafil in semen of healthy subjects 90 minutes after dosing, not more than 0.00012% of the administered dose may appear in the semen of patients.
Metabolism
Vardenafil is metabolised predominantly by hepatic enzymes via CYP3A4, with some contribution from CYP3A5 and CYP2C9 isoforms. Mean terminal elimination half-life from plasma is approximately 4-5 hours.
In humans, the major circulating metabolite (M1) results from desethylation at the piperazine moiety of vardenafil, and is subject to further metabolism. The terminal plasma elimination half-life of the metabolite M1 is approximately 4 hours, comparable to the parent drug. M1 is also present in its glucuronide-conjugated (glucuronic acid) form in systemic circulation. The plasma concentration of non-glucuronidated M1 is about 26% that of the parent compound. The metabolite M1 shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 of approximately 28% compared to vardenafil, resulting in an efficacy contribution of about 7%.
Excretion
The total body clearance of vardenafil is 56 L/hour with a resultant terminal half-life of about 4-5 hours.
After oral administration, vardenafil is excreted as metabolites predominantly in the faeces (approximately 91 - 95% of administered oral dose) and to a lesser extent in the urine (approximately 2 - 6% of administered oral dose).
Pharmacokinetics in special populations
Elderly
Vardenafil half life in healthy elderly volunteers (65 years or over) was not significantly reduced as compared to volunteers of younger age (45 years and below). On average, elderly males had a 52% higher AUC than younger males which is within the variability observed in clinical trials. No overall differences in safety or effectiveness were observed between elderly and younger subjects in placebo controlled clinical trials. Dosage adjustments are not required in elderly patients.
Renal insufficiency
In patients with mild (CLcr > 50 - 80 mL/min) to moderate (CLcr > 30 - 50 mL/min) renal impairment, vardenafil pharmacokinetics were similar to that of a normal renal function control group. In volunteers with severe renal impairment (CLcr < 30 mL/min) the mean AUC was increased by 21% and the mean Cmax decreased by 23%, compared to volunteers with no renal impairment. No statistically significant correlation between creatinine clearance and vardenafil plasma exposure (AUC and Cmax) was observed. Based on these data, no dose adjustment is needed in patients with impaired renal function.
The pharmacokinetics of vardenafil have not been studied in patients requiring dialysis and vardenafil should not be used in this situation.
Hepatic insufficiency
In patients with mild to moderate hepatic impairment (Child-Pugh A and B), vardenafil clearance was reduced in proportion to the degree of hepatic impairment.
In patients with mild hepatic impairment (Child-Pugh A), vardenafil AUC and Cmax were increased 1.2-fold (AUC by 17% and Cmax by 22%) following a 10 mg vardenafil dose, compared to healthy control subjects. No dose adjustment is required in patients with mild hepatic impairment.
In patients with moderate hepatic impairment (Child-Pugh B), vardenafil AUC was increased 2.6-fold (an increase of 160%) and Cmax was increased 2.3-fold (an increase of 130%), compared to healthy control subjects. Therefore, in patients with moderate hepatic impairment, a 5 mg starting dose should be used, which may subsequently be increased to 10 mg based on tolerability and efficacy.
The pharmacokinetics of vardenafil have not been studied in patients with severe hepatic impairment (Child-Pugh C) and vardenafil should not be used in this situation.
Clinical Studies
In a placebo-controlled Rigiscan study, LEVITRA (vardenafil) 20 mg produced erections sufficient for penetration (≥ 60% rigidity by Rigiscan) in some men as early as 15 minutes. The overall response of these subjects to vardenafil became statistically significant compared to placebo at 25 minutes post dosing.
Vardenafil demonstrated clinically meaningful and statistically significant improvement of erectile function compared to placebo in all major efficacy trials including special populations.
Across all trials, vardenafil was administered to over 3750 men with erectile dysfunction (ED) aged 18 to 89 years, many of whom had multiple other medical conditions. Over 1630 patients were treated with vardenafil for 6 months or longer.
In all major efficacy trials, including studies in post-prostatectomy patients and patients with diabetes, vardenafil 10 mg and 20 mg produced statistically significant and clinically meaningful improvements, compared to placebo, in the International Index of Erectile Function (IIEF) erectile function domain score, the percentage of patients achieving successful penetration and maintenance of erections, and the percentage of patients who rated their erections as improved (Tables 1 and 2).
Table 1. IIEF erectile function domain score and global assessment at Week 12 (Intention-to-treat population).*
| Study Population | IIEF erectile function domain score | Percentage of patients rating erections as improved | ||||
|---|---|---|---|---|---|---|
| Placebo | Vardenafil 10 mg | Vardenafil 20 mg | Placebo | Vardenafil 10 mg | Vardenafil 20 mg | |
| General | 15.0 | 20.6 | 21.4 | 30% | 72% | 78% |
| General | 13.2 | 20.9 | 21.5 | 19% | 73% | 73% |
| Diabetic | 12.6 | 17.1 | 19.0 | 13% | 54% | 70% |
| Prostatectomy | 9.2 | 15.3 | 15.3 | 9% | 58% | 60% |
* Last available observation used in patients with no data at Week 12.
Table 2. Percentage of patients achieving successful penetration and maintenance of erection at Week 12 (Intention-to-treat population). *
| Study Population | Penetration | Maintenance of erection | ||||
|---|---|---|---|---|---|---|
| Placebo | Vardenafil 10 mg | Vardenafil 20 mg | Placebo | Vardenafil 10 mg | Vardenafil 20 mg | |
| General | 52% | 76% | 81% | 32% | 65% | 65% |
| General | 45% | 76% | 80% | 25% | 62% | 64% |
| Diabetic | 36% | 61% | 64% | 23% | 49% | 54% |
| Prostatectomy | 22% | 47% | 48% | 10% | 37% | 34% |
* Last available observation used in patients with no data at Week 12.
In a randomised, double blind, placebo controlled, fixed dose trial in 749 patients, based on a global assessment question (GAQ), vardenafil improved erections in 56%, 77%, and 81% of the patients on 5 mg, 10 mg, and 20 mg, respectively, at 6 months compared to 23% on placebo.
In pooled data from the major efficacy trials, including special population studies, those patients who had successful penetration on first dose of treatment were 37% on placebo, 68% for 10 mg, and 70% for 20 mg. For those patients who had successful penetration on first dose, on average, patients on vardenafil 10 mg and 20 mg responded successfully in 86% and 90% of all subsequent attempts, respectively, over a 3 month study period. Vardenafil was efficacious in patients regardless of baseline severity, aetiology (organic, psychogenic and mixed), duration of ED, ethnicity and age as determined in subgroup analyses.
Patients with ED after Radical Prostatectomy
In post-prostatectomy patients, vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a 3 month prospective, fixed dose, placebo- controlled, double blind trial. Erectile function domain score, the rate of obtaining an erection sufficient for penetration, the rate of maintaining an erection sufficient for successful intercourse, and hardness were significantly improved compared to placebo for the tested doses of 10 mg and 20 mg at all time points. Improved erectile function response rates as based on GAQ were 57% on 10 mg, and 60% on 20 mg compared to 9% on placebo at 3 months. In the subgroup of patients with bilateral nerve-sparing prostatectomy the response rates as based on GAQ in patients who completed at 3 months were 61% for 10 mg, and 66% for 20 mg, compared to 8% for placebo.
Patients with ED and Diabetes Mellitus
In patients with diabetes mellitus, vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a 3 month prospective, fixed dose, placebo-controlled, double blind trial. Significant improvements were shown in the erectile function domain score, the rate of obtaining an erection sufficient for penetration, the rate of maintaining an erection sufficient for successful intercourse, and hardness, when 10 mg and 20 mg vardenafil doses were compared to placebo. These improvements were seen at all time points during three months of treatment. In this population, which is typically more resistant to therapy, response rates for improvement of erection as based on GAQ were 54% on 10 mg, and 70% on 20 mg vardenafil compared to 13% on placebo for patients who completed three months of the trial. Patients in the active treatment group were continued on blinded active therapy of vardenafil for a total of 6 months. These patients demonstrated response rates of 66% and 74% for 10 mg and 20 mg, respectively.
Patients with Spinal Cord Injury
In patients with ED secondary to traumatic spinal cord injury, vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a placebo-controlled, double blind, flexible dose clinical trial. Significant improvements were shown in the erectile function domain score, the ability to obtain and maintain an erection long enough for successful intercourse and penile rigidity compared to placebo. The number of patients who returned to a normal IIEF domain score (≥ 26) were 53% on vardenafil compared to 9% on placebo. The response rates for the ability to obtain and maintain an erection were 76% and 59% on vardenafil compared to 41% and 22% on placebo for patients who completed 3 months treatment which were clinically and statistically significant (p<0.001). In this population, which is typically more resistant to therapy, response rates for improvement of erection as based on GAQ were 83% on vardenafil compared to 26% on placebo for patients who completed 3 months of the trial.
QT prolongation
In a separate postmarketing study of 44 healthy volunteers, single doses of 10 mg vardenafil or 50 mg sildenafil were co-administered concomitantly with 400 mg gatifloxacin, a drug with comparable QT effect. Both vardenafil and sildenafil showed an additive Fridericia QTc effect (vardenafil: 4 msec, sildenafil: 5 msec) when compared to either drug alone. The clinical impact of these QT changes is unknown (see PRECAUTIONS).
Effects on vision
In a specific clinical trial, evaluation of visual function at a vardenafil dose of 40 mg (twice the maximum recommended daily dose) revealed no effects of vardenafil on visual acuity, visual fields, intraocular pressure, ERG latency, fundoscopic and slit lamp findings. A subset of patients was found to have mild and transient impairment of colour discrimination in the blue/green range and in the purple range 1 hour after dosing. These changes had improved by 6 hours and no changes were present at 24 hours. The majority of these patients had no subjective visual symptoms.
In another double blind placebo controlled clinical trial, at least 15 doses of 20 mg vardenafil were administered over 8 weeks versus placebo. Retinal function was measured by ERG and FM-100 test 2, 6 and 24 hours after dosing. Vardenafil did not produce clinically significant retinal effects in healthy men compared to placebo.
In other trials, daily use of vardenafil at doses of 10 mg to 40 mg for 31 days was not associated with changes in visual acuity, intraocular pressure, or findings on fundoscopic or slit lamp examination.
Effects on blood pressure and cardiac parameters
In placebo-controlled clinical pharmacology studies with vardenafil 10 mg and 20 mg, the mean maximum decreases in supine systolic and diastolic blood pressure were negligible in comparison to placebo. There was only a small compensatory increase in heart beat per minute.
Single oral doses of vardenafil up to 80 mg (4 times the maximum recommended daily dose) did not produce clinically relevant effects on the ECGs of healthy volunteers.
The effect of 10 mg and 80 mg vardenafil on QT interval was evaluated in a single-dose, double-blind, randomised, placebo- and active-controlled (moxifloxacin 400 mg) cross-over study in 59 healthy males aged 45-60 years. This study also included another drug in the same class in approximately equipotent therapeutic doses (sildenafil 50 mg and 400 mg). The QT interval was measured at 1 hour post dose because this time point approximates the average time of peak vardenafil concentration. The 80 mg dose of LEVITRA (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 LEVITRA (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. The table below summarises the effect on mean uncorrected QT and mean corrected QT interval (QTC) with different methods of correction (Fridericia and a linear individual correction method) at one 1 hour post-dose. No single correction method is known to be more valid than the other.
Mean QT and QTC changes in msec (90% CI) from baseline relative to placebo at 1 hour post-dose with different methodologies to correct for the effect of heart rate
| Drug/Dose | Heart Rate (bpm) | QT Uncorrected (msec) | Fridericia QT Correction (msec) | Individual QT Correction (msec) |
|---|---|---|---|---|
| Vardenafil 10 mg |
5 (4, 6) |
-2 (-4, 0) |
8 (6, 9) |
4 (3, 6) |
| Vardenafil 80 mg |
6 (5, 7) |
-2 (-4, 0) |
10 (8, 11) |
6 (4, 7) |
| Moxifloxacin * 400 mg |
2 (1, 3) |
3 (1, 5) |
8 (6, 9) |
7 (5, 8) |
| Sildenafil † 50 mg |
4 (3, 5) |
-2 (-4, 0) |
6 (5, 8) |
4 (2, 5) |
| Sildenafil † 400 mg |
5 (4, 6) |
-1 (-3, 1) |
9 (8, 11) |
5 (4, 7) |
Moxifloxacin produced the expected 5 - 10 msec prolongation, indicating that the study had the required sensitivity. Therapeutic and supratherapeutic doses of vardenafil and sildenafil produced similar decreases in uncorrected QT but increases in QTC interval. This study, however, was not designed to make direct statistical comparisons between the drugs or the dose levels. The actual clinical impact of these changes is unknown.
Effects on sperm motility or morphology
In a specific clinical trial, single oral doses of 20 mg of vardenafil did not produce any effects on sperm motility or morphology or a variety of parameters indicative for male reproductive function. Based upon measurements of vardenafil in semen of healthy subjects 90 minutes after dosing, not more than 0.00012% of the administered dose appeared in the semen of patients.
There were no clinically relevant effects on sperm concentration, count, motility or morphology in humans in a placebo-controlled study of daily dosing of vardenafil 20 mg for 6 months. In addition, vardenafil had no effect on serum levels of testosterone, luteinizing hormone, or follicle stimulating hormone.
Indications
LEVITRA is indicated for the treatment of erectile dysfunction in adult males (inability to achieve or maintain penile erection sufficient for satisfactory sexual performance).
LEVITRA is not indicated for use by women.
Contraindications
LEVITRA is contraindicated in patients with known hypersensitivity to any of the drug's components (active or inactive ingredients).
Nitrates and vardenafil must not be used concomitantly. Co-administration of vardenafil with nitric oxide donors, organic nitrates, or organic nitrites in any form either regularly or intermittently is contraindicated. Drugs which must not be used concomitantly include, but are not limited to, glyceryl trinitrate (injection, tablets, sprays or patches), isosorbide salts, sodium nitroprusside, amyl nitrite, nicorandil or organic nitrates in any form. Consistent with the effects of PDE inhibition on the nitric oxide / cGMP - pathway, PDE5 inhibitors may potentiate the hypotensive effects of nitrates.
LEVITRA is contraindicated in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors (see PRECAUTIONS). The possibility of undiagnosed cardiovascular disorders in men with erectile dysfunction should be considered before prescribing vardenafil.
The safety of vardenafil has not been studied in patients with the following conditions and its use in such patients is therefore contraindicated until further information is available: unstable angina; resting or orthostatic hypotension (systolic blood pressure <90 mmHg); uncontrolled hypertension; myocardial infarction, stroke, cardiac ischaemia (except stable angina), or life-threatening arrhythmia within the previous 6 months; uncontrolled arrhythmia; severe hepatic impairment; end-stage renal disease requiring dialysis; known hereditary degenerative retinal disorders such as retinitis pigmentosa.
Concomitant use of LEVITRA with HIV Protease inhibitors such as indinavir or ritonavir is contraindicated, as they are highly potent inhibitors of CYP 3A4.
PrecautioNs
Cardiovascular Disease
Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Vardenafil has vasodilator properties which may result in mild and transient decreases in blood pressure. Patients with left ventricular outflow obstruction, e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis, can be sensitive to the action of vasodilators including PDE5 inhibitors.
Patients with congenital QT prolongation (long QT syndrome) and those taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications should avoid using vardenafil. In a study of the effect of vardenafil on QT interval in 59 healthy males, therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced increases in QTc interval.. A postmarketing study evaluating the effect of combining vardenafil with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone (see Clinical Studies). These observations should be considered in clinical decisions when prescribing vardenafil to patients with known history of QT prolongation or patients who are taking medications known to prolong the QT interval. Patients taking Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications or those with congenital QT prolongation, should avoid using vardenafil.
Other Pre-existing Medical Conditions
Agents for the treatment of erectile dysfunction should generally be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease) or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).
The safety and efficacy of combinations of vardenafil with other treatments for erectile dysfunction (including other PDE5 inhibitors) have not been studied. Therefore the use of such combinations is not recommended.
LEVITRA has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore LEVITRA should be given to these patients only after careful benefit-risk assessment. In humans, vardenafil has no effect on bleeding time alone or with aspirin. In vitro studies with human platelets indicate that vardenafil alone did not inhibit platelet aggregation induced by a variety of platelet agonists. With supertherapeutic concentrations of vardenafil a small concentration-dependent enhancement of the antiaggregatory effect of sodium nitroprusside, a nitric oxide donor, was observed. The combination of heparin and Vardenafil had no effect on bleeding time in rats, but this interaction has not been studied in humans.
Use with alpha-blockers
Consistent with vasodilatory effects of alpha-blockers and vardenafil, the concomitant use of LEVITRA with alpha-blockers may lead to symptomatic hypotension in some patients. Concomitant treatment should only be initiated if the patient is stable on his alpha blocker therapy (see Interaction with other Medicines). In those patients who are stable on alpha-blocker therapy, LEVITRA should be initiated at the lowest recommended starting dose of 5 mg. LEVITRA may be administered at any time with tamsulosin.
With other alpha blockers a time separation of dosing should be considered when LEVITRA is prescribed concomitantly (see Interaction with other Medicines). In those patients already taking an optimized dose of LEVITRA, 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 including LEVITRA.
Use with Potent CYP 3A4 Inhibitors
Concomitant use of the potent cytochrome P450 3A4 (CYP 3A4) inhibitors ketoconazole, itraconazole, indinavir, or ritonavir can be expected to produce markedly increased vardenafil plasma levels. A maximum vardenafil dose of 5 mg should not be exceeded if used in combination with ketoconazole, itraconazole, erythromycin or clarithromycin. Vardenafil must not be taken with dosages of ketoconazole and itraconazole higher than 200 mg (see Dosage and Administration) Concomitant use with indinavir or ritonavir is contraindicated, as these drugs are highly potent inhibitors of CYP 3A4. (see CONTRAINDICATIONS and Interactions with other Medicines).
NAION
Transient vision loss and cases of non-arteritic ischemic optic neuropathy have been reported in connection with the intake of LEVITRA and other PDE5 inhibitors. The patient should be advised that in case of sudden vision loss, he should stop taking LEVITRA and consult a physician immediately (see Adverse Effects).
Sudden deafness or loss of hearing
Sudden deafness or loss of hearing has been reported in a small number of postmarketing and clinical trial cases with the use of all phosphodiesterase type 5 inhibitors, including LEVITRA. It is not possible to determine whether these reported events are related directly to the use of LEVITRA, to the underlying risk factors for hearing loss, a combination of these factors or to other factors. Physicians should advise patients to stop taking PDE5 inhibitors, including LEVITRA, and seek prompt medical attention in the event of sudden decrease or loss of hearing.
Ability to Drive and Use Machines
Patients should be aware of how they react to vardenafil before driving or operating machinery.
Carcinogenicity
Vardenafil showed no carcinogenic activity when administered orally to rats at doses up to 75 (males) or 25 (females) mg/kg/day or via the drinking water to mice at doses up to 150 (males) or 193 (females) mg/kg/day. The highest doses in these studies were associated with systemic exposure (AUC) to vardenafil >300 (rats) or about 25 (mice) times that expected in men taking 20 mg/day vardenafil.
Genotoxocity
Vardenafil was not genotoxic in assays for gene mutation (reverse mutations in bacterial cells and forward mutations in Chinese hamster V79 cells in vitro) or chromosomal damage (Chinese hamster V79 cells in vitro and mouse micronucleus assay in vivo).
Impairment of Fertility
In a specific clinical trial, single oral doses of 20 mg of vardenafil did not produce any effects on sperm motility or morphology or a variety of parameters indicative for male reproductive function. Based upon measurements of vardenafil in semen of healthy subjects 90 minutes after dosing, not more than 0.00012% of the administered dose appeared in the semen of patients.
Studies in rats showed no effects on fertility, reproductive performance or reproductive organ morphology in males or females given oral doses of vardenafil up to 100 mg/kg/day (systemic exposure >200 times that expected at the maximum recommended dose of 20 mg, based on AUC).
Use in Pregnancy (Category B3)
Vardenafil is not indicated for use by women.
Studies in rats have shown that vardenafil and/or its metabolites cross the placenta and distribute to the fetus. No evidence of embryofetal toxicity or teratogenicity was observed in pregnant rats or rabbits given oral doses of vardenafil up to 18 mg/kg/day. These doses were associated with systemic exposure to vardenafil 125- (rat) or 7- (rabbit) fold greater than that expected at the maximum recommended dose of 20 mg, based on AUC. Higher doses were associated with maternal toxicity, increased embryonic resorptions and delayed fetal development in both species.
Administration of vardenafil 60 mg/kg/day to pregnant rats during late gestation and throughout lactation resulted in increased postnatal pup mortality and delayed physical development. The no-effect-dose of 8 mg/kg/day was associated with systemic exposure approximately 28-fold that expected in humans at the maximum recommended dose of 20 mg vardenafil.
There are no studies of vardenafil in pregnant women.
Use in Lactation
Vardenafil is not indicated for use by women.
Vardenafil and/or its metabolites are excreted in the milk of lactating rats at concentrations up to 19-fold higher that the corresponding maternal plasma concentrations. Increased pre- and post-natal mortality and delayed physical development was observed in offspring from rats treated with oral vardenafil at 60 mg/kg/day during gestation and lactation.
There are no human data on the excretion of vardenafil into breast milk or on the safety of vardenafil exposure in infants.
Interactions with other Medicines
Vardenafil is metabolized predominantly by hepatic enzymes via cytochrome P450 (CYP) isoform 3A4, with some contribution from CYP3A5 and CYP2C isoforms. Therefore, inhibitors of these enzymes may reduce vardenafil clearance.
Demonstrated Interactions
Erythromycin
Erythromycin (500 mg t.i.d.), a CYP3A4 inhibitor, caused a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax when co-administered with vardenafil (5 mg) to healthy volunteers. When used in combination with erythromycin, a maximum vardenafil dose of 5 mg should not be exceeded.
Ketoconazole
Ketoconazole (200 mg), which is a potent CYP3A4 inhibitor, caused a 10-fold increase in vardenafil AUC and a 4-fold increase in Cmax when co-administered with Vardenafil (5 mg) to healthy volunteers. When used in combination with ketoconazole, a maximum vardenafil dose of 5 mg should not be exceeded. Vardenafil must not be taken with dosages of ketoconazole higher than 200 mg (see Dosage and Administration).
Indinavir
Co-administration of vardenafil (10 mg) with the HIV protease inhibitor indinavir (800 mg t.i.d.) resulted in a 16-fold increase in vardenafil AUC and a 7-fold increase in vardenafil Cmax. At 24 hours after co-administration, the plasma levels of vardenafil were approximately 4% of the maximum Vardenafil plasma level (Cmax). Concomitant use of indinavir and vardenafil is contraindicated.
Ritonavir
Ritonavir (600 mg b.i.d.) resulted in a 13-fold increase of vardenafil Cmax and a 49-fold increase in vardenafil AUC0-24 when coadministered with vardenafil 5 mg. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a highly potent CYP 3A4 inhibitor, which also inhibits CYP 2C9. Ritonavir significantly prolonged the half-life of vardenafil to 25.7 hours. Concomitant use with ritonavir is contraindicated.
Potential Interactions
CYP 3A4 Inhibitors
Concomitant use of other potent CYP 3A4 inhibitors (such as ketoconazole, itraconazole, indinavir, or ritonavir) can be expected to produce markedly increased vardenafil plasma levels (See Demonstrated Interactions). A maximum vardenafil dose of 5 mg should not be exceeded if used in combination with ketoconazole, itraconazole, erythromycin or clarithromycin. Vardenafil must not be taken with dosages of ketoconazole higher than 200 mg (see Dosage and Administration). Concomitant use with the HIV protease inhibitors indinavir or ritonavir is contraindicated, as these drugs are highly potent inhibitors of CYP3A4.
Nitrates, Nitric Oxide Donors
There is limited information on the potential hypotensive effects of vardenafil when given in combination with nitrates. Based on experience with other PDE5 inhibitors, some patients may experience clinically significant hypotension if vardenafil and nitrates are coadministered and concomitant use is therefore contraindicated (see CONTRAINDICATIONS).
Nitrates should not be administered for at least 24 hours (approximately 5 half-lives) after the last dose of vardenafil. A longer washout period should observed if the patient has been taking concomitant drugs, such as CYP3A4 inhibitors, which impair vardenafil metabolism.
Nicorandil is a hybrid of potassium channel opener and nitrate. Due to the nitrate component it has the potential to have serious interaction with vardenafil.
Antihypertensive agents
Limited information is available on concomitant use of vardenafil and antihypertensive agents. Population pharmacokinetic investigations of phase III data revealed no significant effect of ACE-inhibitors, beta-blockers or diuretics on the pharmacokinetics of vardenafil. However, a potential for additive hypotensive effect exists, and until further information is available, caution should be exercised when prescribing vardenafil in combination with antihypertensive agents.
Alpha blockers
Since alpha blocker monotherapy can cause marked lowering of blood pressure, especially postural hypotension and syncope, interaction studies were conducted with vardenafil.
In two interaction studies with healthy normotensive volunteers after forced titration of the alpha-blockers tamsulosin or terazosin to high doses over 14 days or fewer, hypotension (in some cases symptomatic) was reported in a significant number of subjects after co-administration of LEVITRA. Among subjects treated with terazosin, hypotension (standing systolic blood pressure below 85 mm Hg) was observed more frequently when LEVITRA and terazosin were given to achieve simultaneous Cmax than when the dosing was administered to separate Cmax by 6 hours. Because these studies were conducted using healthy volunteers after forced titration of the alpha blocker to high doses (subjects were not stable on alpha-blocker therapy), these studies may have limited clinical relevance.
Interaction studies were conducted with LEVITRA in patients with benign prostatic hyperplasia (BPH) on stable tamsulosin or terazosin therapy. When LEVITRA was given at doses of 5, 10 or 20 mg on a background of stable therapy with tamsulosin, there was no clinically relevant mean maximal additional reduction in blood pressure. When LEVITRA 5 mg was dosed simultaneously with tamsulosin 0.4 mg, 2 of 21 patients experienced a standing systolic blood pressure below 85 mm Hg. When LEVITRA 5 mg was given with a six hour dose separation from tamsulosin, 2 of 21 patients experienced a standing systolic blood pressure below 85 mm Hg.
In a subsequent study in patients with BPH, when LEVITRA 10 mg and 20 mg was dosed simultaneously with tamsulosin 0.4 or 0.8 mg there were no cases of standing systolic blood pressure below 85 mm Hg. When LEVITRA 5 mg was given simultaneously with terazosin 5 or 10 mg, one of 21 patients experienced symptomatic postural hypotension. Hypotension was not observed when LEVITRA 5 mg and terazosin administration was separated by 6 hours. This should be considered when deciding about a time separation of dosing.
Concomitant treatment should be initiated only if the patient is stable of his alpha blocker therapy. In those patients who are stable on alpha-blocker therapy, LEVITRA should be initiated at the lowest recommended starting dose of 5 mg. LEVITRA may be administered at any time with tamsulosin. With other alpha blockers a time separation of dosing should be considered when LEVITRA is prescribed concomitantly (see Precautions).
Interactions shown not to exist
Glibenclamide
Vardenafil (20 mg), when co-administered with glibenclamide (3.5 mg), did not affect the relative bioavailability of glibenclamide (no effect on AUC and Cmax of glibenclamide).
Warfarin
No pharmacokinetic or pharmacodynamic (prothrombin time and clotting factor II, VII and X) interactions were shown when warfarin (25 mg) was co-administered with vardenafil (20 mg). Vardenafil pharmacokinetics were not affected by co-administration of warfarin.
Nifedipine
Co-administration of vardenafil (20 mg) did not alter the bioavailability (AUC and Cmax) of nifedipine (30 mg or 60 mg). The combined treatment of vardenafil and nifedipine did not lead to pharmacodynamic interaction (as compared to placebo, vardenafil produced mean additional blood pressure reductions of 5.9 mmHg and 5.2 mmHg for supine systolic and diastolic blood pressure, respectively).
Digoxin
Lack of pharmacokinetic interaction was shown when digoxin (0.375 mg daily) in steady state was co-administered with vardenafil (20 mg) over 14 days every other day.
Antacids
Single doses of Mylanta (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability (AUC) or the maximum concentration (Cmax) of vardenafil.
Ranitidine, Cimetidine
Bioavailability of vardenafil (20 mg) was not affected by co-administration of the H2-antagonists ranitidine (150 mg b.i.d.) and cimetidine, a non-specific cytochrome P450 inhibitor (400 mg b.i.d.).
Aspirin
Vardenafil (10 mg) did not influence bleeding time when taken alone or in combination with low dose aspirin (2 x 81 mg tablets).
Ethanol
Vardenafil (20 mg) did not potentiate the hypotensive effects of ethanol (0.5 g/kg bodyweight). The pharmacokinetics of ethanol and vardenafil were not significantly altered by coadministration.
Other Drugs
Population pharmacokinetic investigations of phase III data revealed no significant effect of aspirin, weak CYP 3A4-inhibitors, and medications for the treatment of diabetes (sulfonylureas and metformin) on the pharmacokinetics of vardenafil.
Adverse EFFECTS
Vardenafil was administered to over 9500 patients during clinical trials worldwide (Status March 2004). Vardenafil was generally very well tolerated. Adverse events were generally transient and mild to moderate in nature.
Placebo controlled clinical trials (adverse events)
When vardenafil was taken as recommended, the following adverse events were reported more commonly with vardenafil than placebo in placebo-controlled clinical trials (Table 3):
Table 3: Adverse events reported by ≥ 2% of patients treated with vardenafil and more frequent on drug than placebo in all placebo-controlled trials of 5 mg, 10 mg, and 20 mg vardenafil.
| Adverse event | Vardenafil n=3293 | Placebo n= 1861 |
|---|---|---|
| HEADACHE | 12.9% | 3.5% |
| FLUSHING (incl. hot flush, feeling hot, erythema) | 11.8% | 0.9% |
| NASAL CONGESTION (incl oedema mucosal, rhinitis, rhinorrhoea) | 4.9% | 0.7% |
| DYSPEPSIA | 3.0% | 0.3% |
| INFLUENZA (incl influenza like illness) | 2.0% | 1.6% |
All clinical trials (Adverse Drug Reactions)
The following adverse drug reactions were reported in patients given vardenafil in all clinical trials (Status: March 2004):
The listing of treatment-emergent ADRs was decided according to a predefined algorithm. In the frequency categories, ADRs were included when they occurred on the day of the last intake or the next day according to the following criteria:
Rare: 1-2 serious resp. WHO Critical Terms, and unusual in the absence of drug therapy.
Uncommon: ≥ 3-9 important for advice, monitoring and treatment decision; ≥ 10 all.
Common and Very Common: all.
The following table contains all Adverse Drug Reactions reported in patients in all clinical trials world-wide which are WHO Critical Term (special attention warranted because of possible association with serious disease states) or of otherwise clinical relevance.
| System Organ Class |
Very Common ≥ 10% |
Common ≥1% to <10% |
Uncommon ≥ 0.1% to <1% |
Rare ≥ 0.01% to <0.1% |
|---|---|---|---|---|
| Immune System Disorders | Hypersensitivity | |||
| Psychiatric Disorders | Anxiety | |||
| Nervous System Disorders | Headache | Dizziness | Somnolence | Syncope Seizure Transient global amnesia |
| Eye Disorders incl. related Investigations | Lacrimation increased Visual disturbance [incl. Visual brightness] |
Intraocular pressure increased | ||
| Cardiac Disorders incl. related Investigations | Angina pectoris Myocardial ischaemia |
|||
| Vascular Disorders incl. related Investigations | Flushing [incl. Hot flush, feeling hot, erythema] |
Hypertension [incl. Blood pressure increased] Hypotension [incl. Blood pressure decreased] Orthostatic hypotension |
||
| Respiratory, Thoracic and Mediastinal Disorders | Nasal congestion [incl. Oedema mucosal, rhinitis rhinorrhoea] | Dyspnoea Epistaxis |
Laryngeal oedema | |
| Gastrointestinal Disorders incl. related Investigations | Dyspepsia Nausea |
Abnormal liver function tests [incl. Hepatic enzyme
increased, alanine aminotransferase increased, aspartate aminotransferase
increased] GGTP increased |
||
| Skin and Subcutaneous Tissue Disorders | Face oedema [incl. Swelling face] Photosensitivity reaction |
|||
| Musculoskeletal and Connective Tissue Disorders incl. related Investigations | Back pain Myalgia Blood creatine phosphokinase increased |
Muscle rigidity | ||
| Reproductive System and Breast Disorders | Erection increased (prolonged or painful erections) Priapism |
Post-Marketing Experience
From post-marketing experience with another drug of this class, the following serious adverse events have been reported:
| Body system: | Adverse Events: |
|---|---|
| Cardiovascular: | cerebrovascular haemorrhage, pulmonary haemorrhage, subarachnoid and intracerebral haemorrhages, sudden cardiac death, transient ischaemic attack, ventricular arrhythmia |
| Nervous system: | seizure |
| Special senses: | decreased vision / temporary vision loss |
| Urogenital: | haematuria |
Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 inhibitors, including LEVITRA. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.
Visual disturbances including vision loss (temporary or permanent) have been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 inhibitors, including LEVITRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or to other factors.
Myocardial infarction (MI) has been reported in temporal association with the use of vardenafil and sexual activity, but it is not possible to determine whether MI is related directly to vardenafil, or to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these factors.
Dosage and Administration
The recommended starting dose of LEVITRA is 10 mg, taken orally 25 to 60 minutes before sexual activity. Sexual activity can be initiated as soon as 15 minutes and as long as 4-5 hours after taking LEVITRA.
The maximum recommended dose frequency is once per day.
LEVITRA can be taken with or without food.
Sexual stimulation is required for a natural response to treatment.
Dose Range
Based on efficacy and tolerability, the LEVITRA dose may be increased to 20 mg or decreased to 5 mg. The maximum recommended dose is 20 mg once daily.
Elderly (above 65 years)
A starting dose of 5 mg should be considered for patients ≥ 65 years old.
Children (from birth to 16 years)
LEVITRA is not indicated for use in children.
Hepatic impairment
No dose adjustment is needed in patients with mild hepatic impairment (Child-Pugh A).
Vardenafil clearance is reduced in patients with moderate hepatic impairment (Child-Pugh B), supporting a starting dose of 5 mg, which may subsequently be increased to 10 mg, based on tolerability and efficacy.
The pharmacokinetics of vardenafil have not been studied in patients with severe hepatic impairment (Child-Pugh C), therefore vardenafil should not be used in these patients.
Renal impairment
No dose adjustment is needed in patients with mild (CLcr > 50-80 mL/min), moderate (CLcr > 30-50 mL/min), or severe (CLcr < 30 mL/min) renal impairment.
The pharmacokinetics of vardenafil have not been studied in patients requiring dialysis, therefore vardenafil should not be used in these patients.
Concomitant medication
Consistent with vasodilatory effects of alpha-blockers and vardenafil, the concomitant use of LEVITRA with alpha-blockers may lead to symptomatic hypotension in some patients. Concomitant treatment should only be initiated if the patient is stable on his alpha blocker therapy (see Interaction with other Medicines). In those patients who are stable on alpha-blocker therapy, LEVITRA should be initiated at the lowest recommended starting dose of 5mg LEVITRA may be administered at any time with tamsulosin. With other alpha blockers a time separation of dosing should be considered when LEVITRA is prescribed concomitantly (see Interaction with other Medicines).
In those patients already taking an optimised dose of vardenafil, 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 including vardenafil.
A maximum dose of 5 mg should not be exceeded when LEVITRA is used in combination with the cytochrome P450 (CYP) 3A4 inhibitors erythromycin or clarithromycin. A maximum dose of 5 mg should not be exceeded when used in combination with the potent cytochrome P450 (CYP) 3A4 inhibitors ketoconazole and itraconazole. LEVITRA must not be taken with dosages of ketoconazole and itraconazole higher than 200 mg. Concomitant use with indinavir and ritonavir is contraindicated, as these drugs are highly potent inhibitors of CYP 3A4.
Overdosage
In single dose volunteer studies, vardenafil was tested in doses up to and including 80 mg per day. Even the highest dosage tested (80 mg per day) was generally tolerated without producing serious adverse side effects. This was confirmed in a study with 40 mg once daily doses over 4 weeks.
When 40 mg was administered twice daily, cases of severe back pain were observed. However, no muscle or neurological toxicity was identified.
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.
Presentation
LEVITRA is sold in blister packs of 4 and 8 tablets.
LEVITRA 5 mg, LEVITRA 10 mg and LEVITRA 20 mg tablets contain vardenafil hydrochloride trihydrate equivalent to 5 mg, 10 mg and 20 mg of vardenafil, respectively. All LEVITRA tablets are orange film-coated round tablets with an embossed BAYER cross on one side and the dose strength ("5", "10", or "20") on the other side.
Shelf life: 30 months, Store below 30 °C.
Medicine Classification
Prescription Medicine
Name and Address of the Sponsor
Bayer New Zealand Limited
Argus Place,
Hillcrest,
North Shore,
Auckland
New Zealand
Date of Preparation:
14th October 2008
® Registered trademark of Bayer AG