Levitra

Levitra

vardenafil

Manufacturer:

Bayer Indonesia
Full Prescribing Info
Contents
Vardenafil.
Description
LEVITRA 10 mg film coated tablet: each film coated tablet contains 10 mg of vardenafil (11.852 mg of vardenafil monohydrochloride trihydrate).
LEVITRA 20 mg film coated tablet: each film coated tablet contains 20 mg of vardenafil (23.705 mg of vardenafil monohydrochloride trihydrate).
Action
Pharmacotherapeutic group: Medicinal product used in erectile dysfunction. ATC code: G04BE09.
Pharmacology: Pharmacodynamics: Vardenafil is an oral therapy for the improvement of erectile function in men with erectile dysfunction. In the natural setting, i.e. with sexual stimulation it restores impaired erectile function by increasing blood flow to the penis.
Penile erection is a haemodynamic process. During sexual stimulation, nitric oxide is released. It activates the enzyme guanylate cyclase, resulting in an increases level of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. This in turn result in smooth muscle relaxation, allowing increased inflow of blood into the penis. The level of cGMP is regulated by the rate of synthesis via guanylate cyclase and by the rate of degradation via cGMP hydrolyzing phosphodiesterases (PDEs).
Vardenafil is a potent and selective inhibitor of the cGMP specific phosphodiesterase type 5 (PDE5), the most prominent PDE in the human corpus cavernosum. Vardenafil potently enhances the effect of endogenous nitric oxide in the corpus cavernosum by inhibiting PDE5. When nitric oxide is released in response to sexual stimulation, inhibition of PDE5 by vardenafil results in increased corpus cavernosum levels of cGMP. Sexual stimulation is therefore required for vardenafil to produce its beneficial therapeutic effects.
In vitro studies have shown that 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 >1000-fold relative to PDE2, PDE3, PDE4, PDE7, PDE8, PDE9 and PDE10).
In a penile plesthysmography (RigiScan) study, vardenafil 20 mg produced erections considered sufficient for penetration (60% rigidity by RigiScan) in some men as early as 15 minutes after dosing. The overall response of these subjects to vardenafil became statistically significant, compared to placebo, 25 minutes after dosing.
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 under 20 mg and -4.3 mmHg under 40 mg of vardenafil, when compared to placebo. These effects are consistent with the vasodilatory effects of PDE5-inhibitors and are probably due to increased cGMP levels in vascular smooth muscle cells. Single and multiple oral doses of vardenafil up to 40 mg produced no clinically relevant changes in the ECGs of normal male volunteers.
A single dose, double blind, crossover, randomized trial in 59 healthy males compared the effects on the QT interval of vardenafil (10 mg and 80 mg), sildenafil (50 mg and 400 mg) and placebo. Moxifloxacin (400 mg) was included as an active internal control. Effects on the QT interval were measured one hour post dose (average Tmax for vardenafil). The primary objective of this study was to rule out the greater than 10 mesc effect (i.e. to demonstrate lack of effect) of a single 80 mg oral dose of vardenafil QTc interval compared to placebo, as measured by the change in Fridericia's correction formula (QTcF=QT/RR1/3) from baseline at the 1 hour post-dose time point.
The vardenafil result showed an increase in QTc (Fridericia) of 8 msec (90% CI: 6-9) and 10 msec (90% CI: 8-11) at 10 and 80 mg doses compared to placebo and an increase in QTci of 4 msec (90% CI: 3-6) and 6 msec (90% CI: 4-7) at 10 and 80 mg doses compared to placebo, at one hour post-dose. At Tmax, only the mean change in QTcF for vardenafil 80 mg was out of the study established limit (mean 10 msec, 90% CI (8-11). When using the individual correction formula, none of the values were out of the limit.
In a separate post-marketing 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 increase of Fredericia QTc effect of 4 msec (vardenafil) and 5 msec (sildenafil) when compared to either drug alone. The actual impact of these changes is unknown.
Further information on clinical trials: In clinical studies vardenafil was administered to over 3750 men with erectile dysfunction (ED) aged 18-89 years, many of whom had multiple co-morbid conditions. Over 1630 patients have been treated with LEVITRA for six months or longer. Of these, over 730 have been treated for one year or longer. The following patient groups were represented: elderly (22%), patients with hypertension (35%), diabetic mellitus (29%), ischemic heart diseases and other cardiovascular diseases (7%), chronic pulmonary disease (5%), hyperlipidaemia (22%), depression (5%), radical prostatectomy (9%). The following groups were not well represented in clinical trials: elderly (>75 years, 2.4%) and patients with certain cardiovascular conditions (see Contraindications). No clinical trials in CNS disease (except spinal cord injury), patients with severe renal or hepatic impairment, pelvic surgery (except nerve-sparing prostatectomy) or trauma or radiotherapy and hypoactive sexual desire or penile anatomic deformities have been performed.
Across pivotal trials, treatment with vardenafil resulted in an improvement of erectile function compared to placebo. In the small number of patients who attempted intercourse up to four to five hours after dosing the success rate for penetration and maintenance of erection was consistently greater than placebo.
In fixed dose studies in a broad population of men with erectile dysfunction, 68% (5 mg), 76% (10 mg) and 80% (20 mg) of patients experienced successful penetrations (SEP 2) compared to 49% on placebo over a three month study period. The ability to maintain the erection (SEP 3) in this broad ED population was given as 53% (5 mg), 63% (10 mg) and 65% (20 mg) compared to 29% on placebo.
In pooled data from the major efficacy trials, the proportion of patients experiencing successful penetration on vardenafil were as follows: psychogenic erectile dysfunction (77-87%), mixed erectile dysfunction (69-83%), organic erectile dysfunction (64-75%), elderly (52-75%), ischemic heart disease (70-73%), hyperlipidemia (62-73%), chronic pulmonary disease (74-78%), depression (59-69%) and patients concomitantly treated with antihypertensive (62-73%).
In a clinical trial in patient with diabetic mellitus, vardenafil significantly improved the erectile function domain score, the ability to obtain and maintain an erection long enough for successful intercourse and penile rigidity compared to placebo at vardenafil doses of 10 mg and 20 mg. The response rates for the ability to obtain and maintain an erection was 61% and 49% on 10 mg and 64% and 54% on 20 mg vardenafil compared to 36% and 23% on placebo for patients who completed three months treatment.
In a clinical trial in patients post-prostatectomy patients, vardenafil significantly improved the erectile function domain score, the ability to obtain and maintain an erection long enough for successful intercourse and penile rigidity compared to placebo at vardenafil doses of 10 mg and 20 mg. The response rates for the ability to obtain and maintain an erection was 47% and 37% on 10 mg and 48% and 34% on 20 mg vardenafil compared to 22% and 10% on placebo for patients who completed three months treatment.
In a flexible-dose clinical trial in patients with Spinal Cord Injury, vardenafil significantly improved 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 three months treatment which were clinically and statistically significant (p<0.001).
The safety and efficacy of vardenafil was maintained in long term studies.
Pharmacokinetics: Absorption: In LEVITRA film coated tablets, vardenafil is rapidly absorbed with maximum observed plasma concentration reach in some men as early as 15 minutes after oral administration. However 90% of the time, maximum plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral bioavailability is 15%. After oral dosing of vardenafil AUC and Cmax increase almost dose proportionally over the recommended dose range (5-20 mg).
When vardenafil is taken with a high fat meal (containing 57% fat), the rate of absorption is reduced, with an increase in the median tmax of 1 hour and a mean reduction in Cmax of 20%. Vardenafil AUC is not affected. After a meal containing 30% fat, the rate and extent of absorption of vardenafil (tmax, Cmax and AUC) are unchanged compared to administration under fasting conditions.
Distribution: The mean steady state volume of distribution for vardenafil is 208 l, indicating distribution into the tissues. Vardenafil and its major circulating metabolite (M1) are highly bound to plasma proteins (approximately 95% for vardenafil or M1). For vardenafil as well as M1, protein binding is independent of total drug concentration.
Based on measurements of vardenafil in semen of healthy subject 90% minutes after dosing not more than 0.00012% of the administered dose may appear in the semen of patients.
Metabolism: Vardenafil is metabolized predominantly by hepatic metabolism via cytochrome P 450 (CYP) isoform 3 A4 with some contributions from CYP 3 A5 and CYP 2C isoforms.
In human the one major circulating metabolite (M1) results from desethylation of Vardenafil and is subject to further metabolism with a plasma elimination half life of approximately 4 hours. Parts of M1 are in the form of the glucuronide in systemic circulation. Metabolite M1 shows a phosphodiesterase selectivity profile similar to vardenafil and an in vitro potency for phosphodiesterase type 5 of approximately 28% compared to vardenafil, resulting in an efficacy contribution of about 7%.
Elimination: The total body clearance of vardenafil is 56 l/h with a resultant terminal half-life of approximately 4-5 hours. After oral administration, vardenafil is excreted as metabolites predominantly in the faeces (approximately 91-95% of the administered dose) and to a lesser extend in the urine (approximately 2-6% of the administered dose).
Pharmacokinetic in special patients groups: Elderly: No dosage adjustment is required in elderly patients. Vardenafil half life in healthy elderly volunteers (65 years or over) was 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.
Renal insufficiency: In volunteers with mild to moderate renal impairment (creatinine clearance 30-80 ml/min), the pharmacokinetic of vardenafil were similar to that of a normal renal function control group. In volunteers with severe renal impairment (creatinine clearance <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 was observed between creatinine clearance and vardenafil exposure (AUC and Cmax) (see Dosage & Administration). Vardenafil pharmacokinetic have not been studied in patients requiring dialysis (see Contraindications).
Hepatic insufficiency: In patients with mild to moderate hepatic impairment (Child Pugh A and B), the clearance of vardenafil was reduced in proportion to degree of hepatic impairment. In patients with mild hepatic impairment (Child Pugh A) the mean AUC and Cmax increased 17% and 22% respectively, compared to healthy control subjects. In patients with moderate impairment (Child Pugh B) the mean AUC and Cmax increased 160% and 133% respectively, compared to healthy control subject (see Dosage & Administration). The pharmacokinetic of vardenafil in patients with severely impaired hepatic function (Child Pugh C) have not been studied (see Contraindications).
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
Indications/Uses
Treatment of erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance.
In order for LEVITRA to be effective, sexual stimulation is required.
LEVITRA is not indicated for use by women.
Dosage/Direction for Use
Method of Administration: Oral use.
Adult men: The recommended dose is 10 mg taken as needed approximately 25 to 60 minutes before sexual activity. Based on efficacy and tolerability the dose may be increased to 20 mg or decrease to 5 mg. The maximum recommended dose is 20 mg. The maximum recommended dosing frequency is once per day. LEVITRA can be taken with or without food. The onset of activity may be delayed if taken with a high fat meal (see Pharmacology: Pharmacokinetics under Actions).
Additional information special population: Elderly men: Dose adjustment is not warranted based on age alone. It should be considered that co-morbidities increase with age.
Pediatric patients: LEVITRA is not indicated for individuals below 18 years of age.
Use in patients with impaired hepatic function: A starting dose of 5 mg should be considered in patients with mild and moderate hepatic impairment (Child-Pugh A-B). Based on tolerability and efficacy, the dose may be increased. The maximum dose recommended in patients with moderate hepatic impairment (Child Pugh B) is 10 mg (see Pharmacology: Pharmacokinetics under Actions and Contraindications).
Use in patients with impaired renal function: No dosage adjustment is required in patients with mild to moderate renal impairment.
In patients with severe renal impairment (creatinine clearance <30 ml/min), a starting dose of 5 mg should be considered. Based on tolerability and efficacy the dose may be increased to 10 mg and 20 mg.
Use in patients using other medicinal products: When used in combination with CYP 3A4 inhibitor erythromycin, the dose of vardenafil should not exceed 5 mg (see Interactions).
Overdosage
In single dose volunteer studies, vardenafil was tested in doses up to and including 120 mg per day. 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. No muscle or neurological toxicity was identified, however.
In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance, as vardenafil is highly bound to plasma proteins and do not significantly eliminated in the urine.
Contraindications
The co-administration of vardenafil with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated (see Pharmacology: Pharmacodynamics under Actions and Interactions).
LEVITRA is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see Precautions).
Agents for the treatment of erectile dysfunction should generally not be used in men for whom sexual activity is inadvisable (e.g. patients with severe cardiovascular disorders such as unstable angina or severe cardiac failure [New York Heart Association III or IV]).
The safety of vardenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated until further information is available: severe hepatic impairment (Child-Pugh C), end stage renal disease requiring dialysis, hypotension (blood pressure <90/50 mmHg), recent history of stroke or myocardial infarction (within the last 6 months), unstable angina and known hereditary retinal degenerative disorder such as retinitis pigmentosa.
Concomitant use of vardenafil with potent CYP3A4 inhibitors ketoconazole and itraconazole (oral form) is contraindicated in men older than 75 years.
Concomitant use of Levitra with riociguat, a stimulator of soluble guanylate cyclase (sGC) contraindicated (see Riociguat under Interactions).
Concomitant use of vardenafil with HIV protease inhibitor such as ritonavir and indivanir is contraindicated, as they are very potent inhibitors of CYP3A4 (see Interactions).
Hypersensitivity to vardenafil or to any of the excipients.
Contraindicated in patients receiving moderate or potent CYP 3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, erythromycin and clarithromycin.
Special Precautions
A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.
Prior to initiating any treatment of erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. (See Contraindications). Vardenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure (see Pharmacology: Pharmacodynamics under Actions). Patients with left ventricular outflow obstruction, e.g. aortic stenosis and idiopathic hypertrophic subaortic stenosis, can be sensitive to the action of vasodilators including type 5-phosphodiesterase inhibitors.
Agents for the treatment of erectile dysfunction should be used 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 priaprism (such as sickle cell anaemia, multiple myeloma or leukaemia).
The safety and efficacy of combinations of vardenafil with other treatments for erectile dysfunction have not been studied. Therefore the use of such combination is not recommended.
The concomitant use of vardenafil with alpha-blockers may lead to symptomatic hypotension in some patients because both are vasodilator. Concomitant treatment with vardenafil should only be initiated if the patient has been stabilized on this alpha-blocker therapy. In those patients who are stable on alpha-blocker therapy, vardenafil should be initiated at the lowest recommended starting dose of 5 mg. Vardenafil may be administered at any time with tamsulosin or alfuzosin. With other alpha blockers a time separation of dosing should be considered when vardenafil is prescribed concomitantly (see Interactions). In those patients already taking an optimized dose of vardenafil, alpha-blockers 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 vardenafil.
Concomitant use of vardenafil with very potent CYP3A4 inhibitors such as ketoconazole and itraconazole (oral form) should be avoided as very high plasma concentration of vardenafil is reached if the drugs are combined (see Contraindications and Interactions).
Vardenafil dose adjustment might be necessary if the CYP3A4 inhibitors, erythromycin, is given concomitantly (see Contraindications and Interactions).
Concomitant intake of grapefruit juice is expected to increase the plasma concentrations of vardenafil. The combination should be avoided (see Interactions).
Single oral doses of 10 mg and 80 mg of vardenafil have been shown to prolong the QTc interval by a mean of 8 msec and 10 msec, respectively (see Pharmacology: Pharmacodynamics under Actions). The clinical relevance of this finding is unknown and can not be generalized to all patients under all circumstances, as it will depend on the individual risk factor and susceptibilities that may be present at any time in any given patient. Drugs may prolong QTc interval, including vardenafil, are best avoided in patients with relevant risk factors, for example, hypokalaemia, congenital QT prolongation, concomitant administration of antiarrhythmic medication in Class 1a (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol).
Visual defects and cases of non-arteritic ischemic optic neuropathy (NAION) have been reported in connection with the intake of LEVITRA and other PDE5 inhibitors. The patient should be advised that in the case of sudden visual defect, the patient should stop taking LEVITRA and immediately consult a physician (see Contraindications).
In vitro studies with human platelets indicate that vardenafil has no antiaggregatory effect on its own, but a high (super-therapeutic) concentrations vardenafil pontentiates the antiaggregatory effect of the nitric oxide donor sodium nitroprusside. In humans, vardenafil had no effect on bleeding time alone or in combination with acetylsalicylic acid (see Interactions). There is no safety information available on the administration of vardenafil to patients with bleeding disorders or active peptic ulceration. Therefore vardenafil should be administered to these patients only after careful benefit-risk assessment.
Effects on ability to drive and use machines: As dizziness and abnormal vision have been reported in clinical trials with vardenafil, patients should be aware of how they react to LEVITRA, before driving or operating machinery.
Use In Pregnancy & Lactation
LEVITRA is not indicated for use by women.
Adverse Reactions
Over 9500 patients have received LEVITRA in clinical trials. The adverse reactions were generally transient and mild to moderate in nature. The most commonly reported adverse drug reactions occurring in ≥10% of patients are headache and flushing.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following adverse reactions have been reported: See table.


Click on icon to see table/diagram/image


Post marketing reports of another medicinal product of this class: Vascular Disorders: Serious cardiovascular events, including cerebrovascular haemorrhage, sudden cardiac death, transient ischaemic attack, unstable angina and ventricular arrhytmia have been reported post marketing in temporal association with another medicinal product in this class.
Myocardial infarction (MI) have been reported in temporal association with the use of vardenafil and sexual activity, but it is not possible to determine whether myocardial infarction is related directly to vardenafil or to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these factors.
In a study evaluating visual function which twice the maximum recommended dose of vardenafil, some patients were found to have mild and transient impairment of colour discrimination in the blue/green range and in the purple range one hour after dosing. These changes had improved by six hours and no changes were present at 24 hours. The majority of these patients had no subjective visual symptoms.
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 postmarketing 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.
Sudden deafness or loss of hearing has been reported in a small number of postmarketing and clinical trial cases with the use of all PDE5 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.
Drug Interactions
Effects of other medicinal products on vardenafil: In vitro studies: 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 isoenzymes may reduce vardenafil clearance.
In vivo studies: Co-administration of the HIV protease inhibitor indinavir (800 mg t.i.d) a potent CYP3A4 inhibitor, with vardenafil (10 mg) resulted in a 16-fold increase in vardenafil AUC and a 7-fold increases in vardenafil Cmax. At 24 hours, the plasma levels of vardenafil had fallen to approximately 4% of the maximum vardenafil plasma level (Cmax).
Co-administration of vardenafil with ritonavir (600 b.i.d.) resulted in a 13-fold increase in vardenafil Cmax and a 49-fold increase in Vardenafil AUCO-24 whhen co-administered with vardenafil 5 mg. The indication is a consequence of blocking hepatic metabolism of LEVITRA by ritonavir, a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half life of LEVITRA to 25.7 hours. (See Contraindications).
Co-administration of Ketoconazole (200 mg), a potent CYP3A4 inhibitor, with vardenafil (5 mg) resulted in a 10-fold increase in vardenafil AUC and a 4-fold increase in vardenafil Cmax (see Precautions).
Although specific interaction studies have not been conducted, the concomitant use of other potent CYP3A4 inhibitors (such itraconazole) can be expected to produce vardenafil plasma levels comparable to those produced by ketoconazole. Concomitant use of vardenafil with potent CYP3A4 inhibitors such as itraconazole and ketoconazole (oral form) should be avoided (see Contraindications and Precautions). In men older than 75 years the concomitant use of vardenafil with itrakonazole or ketoconazole is contraindicated (see Contraindications).
Co-administration of Erythromycin (500 mg t.i.d), a CYP3A4 inhibitor, with vardenafil (5 mg) resulted in a 4-fold increase in vardenafil AUC and a-3 fold increase in Cmax. When used in combination with erythromycin, vardenafil dose adjustment might be necessary (see Dosage & Administration and Precautions). Cimetidine (400 mg b.i.d), a non-specific cytochrome P450 inhibitor, had no effect on vardenafil AUC and Cmax when co-administered with vardenafil (20 mg) to healthy volunteers.
Grapefruit juice being a weak inhibitor of CYP3A4 gut wall metabolism may give rise to modest increases in plasma levels of vardenafil (see Precautions).
The pharmacokinetics of vardenafil (20 mg) was not affected by co-administration with the H2-antagonist ranitidine (150 mg b.i.d), digoxin, warfarin, glibenclamide, alcohol (mean maximum blood alcohol level of 73 mg/dL) or single doses of antacid (magnesium hydroxide/aluminum hydroxide).
Although specific interaction studies were not conducted for all medicinal products, population pharmacokinetics analysis showed no effect on vardenafil pharmacokinetics of the following concomitant medicinal products: acetylsalicylic acid, ACE inhibitors, beta-blockers, weak CYP3A4 inhibitors, diuretics and medications for the treatment of diabetes (sulfonylureas and metformin).
Effects of vardenafil on other medicinal products: There are no data on the interaction of vardenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.
In vivo studies: No potentiation of the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) was observed when vardenafil (10 mg) was given at varying time intervals (1 h to 24 h) prior to the dose of nitroglycerin in a study in 18 healthy male subjects.
Vardenafil 20 mg potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) taken 1 and 4 hours after vardenafil administration to healthy middle aged subjects. No effect on blood pressure was observed when nitroglycerin was taken 24 hours after administration of a single dose of vardenafil 20 mg. However, there is no information on the possible potentiation of the hypotensive effects of nitrates by vardenafil in patients, and concomitant use is therefore contraindicated. (See Contraindications).
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 alphablockers tamsulosin or terazosin to high doses, hypotension (in some cases symptomatic) was reported in a significant number of subjects after co-administration of vardenafil. Among subjects treated with terazosin, hypotension was observed more frequently when vardenafil and terazosin were given simultaneous than when the dosing was separate by a time interval of 6 hours.
Based on the result of interaction studies conducted with vardenafil in patients with benign prostatic hyperplasia (BPH) on stable tamsulosin or terazosin therapy: *When vardenafil was given at doses of 5, 10 or 20 mg on a background of stable therapy with tamsulosin, there was no symptomatic reduction in blood pressure, although 3/21 tamsulosin treated subjects exhibited transient standing systolic blood pressures of less than 85 mmHg. *When vardenafil 5 mg was given simultaneously with terazosin 5 or 10 mg, one of 21 patients experienced symptomatic postural hypotension. Hypotension was not observed when vardenafil 5 mg and terazosin administration was separated by 6 hours.
When 5 mg vardenafil or 10 mg vardenafil was dosed 4 hours after alfuzosin, with blood pressure and pulse evaluated over the 10-hour interval after vardenafil dosing, compared to placebo, there was no clinically relevant mean maximal additional reduction in blood pressure. One patient experienced a decrease from baseline in standing systolic blood pressure greater than 30 mm Hg following vardenafil 5 mg; and one patient experienced a decrease from baseline in standing systolic blood pressure greater than 30 mm Hg following vardenafil 10 mg. There were no instances of standing systolic blood pressure below 85 mm Hg in this study. Two patients reported dizziness following vardenafil 5 mg; and one patient reported dizziness following vardenafil 10 mg, and one patient reported dizziness following placebo. Since interaction, a time separation is not required when dosing LEVITRA with alfuzosin. There were no cases of syncope in this study or in the earlier tamsulosin or terazosin studies.
Combination dosing with LEVITRA and alpha-blockers should always occur after the patient is stable on the same dose of the alpha-blocker. LEVITRA treatment should begin at the lowest recommended dose. Additionally, a 6-hr time separation of the doses should be considered when dosing terazosin and LEVITRA; with tamsulosin or alfuzosin, no time separation for dosing is necessary.
Therefore concomitant treatment should be initiated only if the patient is stable on his alpha blocker therapy. In those patients who are stable on alpha-blocker therapy, vardenafil should be initiated at the lowest recommended starting dose of 5 mg. LEVITRA may be administered at any time with tamsulosin or alfuzosin. With other alpha blockers a time separation of dosing should be considered when vardenafil is prescribed concomitantly (see Precautions).
Animal models showed an additive systemic blood pressure lowering effect when sildenafil or vardenafil was combined with riociguat. Increasing the dose of sildenafil or vardenafil resulted in a greater than proportional decrease in systemic blood pressure in some cases.
In an exploratory study, single doses of riociguat administered to patients with pulmonary arterial hypertension (PAH) treated with sildenafil showed additive hemodynamic effects. A higher rate of discontinuation, predominately due to hypotension, was observed in PAH patients treated with a combination of sildenafil and riociguat compared to those treated with sildenafil alone.
Concomitant use of Levitra with riociguat, a stimulator of sGC, is contraindicated (see Contraindications).
No significant interactions were shown when warfarin (25 mg), which is metabolized by CYP2C9, or digoxin (0.375 mg) was co-administered with vardenafil (20 mg). The relative bioavailability of glibenclamide (3.5 mg) was not affected when co-administered with vardenafil (20 mg). In a specific study, where vardenafil (20 mg) was co-administered with slow release nifedipine (30 mg or 60 mg) in hypertensive patients, there was an additional reduction on supine systolic blood pressure of 6 mmHg and supine diastolic blood pressure of 5 mmHg accompanied with an increase in heart rate of 4 bpm.
When Vardenafil (20 mg) and alcohol (mean maximum blood alcohol level of 73 mg/dL) were taken together, vardenafil did not potentiate the effects of alcohol on blood pressure and heart rate and the pharmacokinetics of vardenafil were not altered.
Vardenafil (10 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid (2 x 81 mg).
Storage
Store below 30°C.
Shelf life: 36 months.
ATC Classification
G04BE09 - vardenafil ; Belongs to the class of drugs used in erectile dysfunction.
Presentation/Packing
FC tab 10 mg x 4's. 20 mg x 4's.
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