02 Set LEVITRA 2017 Review (Review,dosage,interactions,effects)
LEVITRA : its dosage
Use in adult men
The recommended dose is 10 mg taken as needed approximately 25 to 60 minutes before any sexual activity.
Based on effectiveness and tolerance, the dose may be increased to 20 mg or decreased to 5 mg.
The maximum recommended dose is 20 mg. It is recommended to use the drug at the most once per day. Levitra can be taken with or without food. The onset of action may be delayed if taken with a high fat meal (see section pharmacokinetic Properties).
Elderly Patients (≥ 65 years)
A dosage adjustment is not necessary in elderly patients. However, an increase up to the maximum dose of 20 mg should be carefully considered taking into account the individual tolerance (see warnings and precautions and adverse reactions).
An initial dose of 5 mg should be considered in patients with hepatic impairment mild to moderate (class A and class B Child-Pugh).
Depending on the tolerance and effectiveness, dose may be increased at a later time. The maximum dose recommended in patients with moderate hepatic impairment (class B Child-Pugh) is 10 mg. (see contraindications and pharmacokinetic Properties).
No dosage adjustment is necessary in patients with renal insufficiency mild to moderate.
In patients with severe renal impairment (creatinine clearance <30 ml/min), a starting dose of 5 mg should be considered.
Based on effectiveness and tolerance, the dose may be increased to 10 mg and 20 mg.
Levitra is not indicated for use in people under the age of 18 years. There is no use justified of Levitra in children and adolescents.
Use in patients taking other medications
Concomitant Administration of CYP3A4 inhibitors
In the case of combination with CYP3A4 inhibitors such as erythromycin or clarithromycin, the dose of vardenafil should not exceed 5 mg (see section Interactions with other medicinal products and other forms of interaction).
Mode of administration
By the oral route.
LEVITRA : its appearance and shape
Film-coated tablets orange round marked with the BAYER-cross on one side and “5” on the other side.
LEVITRA : his presentation
LEVITRA : how it works
Pharmacotherapeutic group: Urology, Drug used in erectile dysfunction. ATC Code : G04BE09.
Vardenafil is an oral treatment for the improvement of the erectile function in men suffering from erectile dysfunction. In natural conditions, ie with sexual stimulation, it restores the erectile function is deficient in increasing the blood flow to the penis.
Penile erection is a haemodynamic process. During sexual stimulation, nitric oxide is released. Nitric oxide then activates the enzyme guanylate cyclase, resulting in increased levels of cyclic guanosine monophosphate (Cgmp) in the corpus cavernosum.
It results in relaxation of the smooth muscles, promoting an increase of blood flow into the penis. The concentration of Cgmp is regulated by both the rate of synthesis via guanylate cyclase and by the rate of degradation via phosphodiesterase (PDE) hydrolyzing the Cgmp.
Vardenafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE5), the main PDE in the corpus cavernosum of the man.
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 levels of Cgmp in the corpus cavernosum.
This is why sexual stimulation is required for vardenafil to produce its beneficial therapeutic effects.
In vitro studies have shown that vardenafil was more selective for PDE5 than for other isozymes of phosphodiesterases are known (15 times more than for PDE6, 130-fold more than for PDE1, 300-fold for PDE11, and 1000-fold higher than for the isoenzymes, PDE2, PDE3, PDE4, PDE7, PDE8, PDE9 and PDE10).
In a study of penile plethysmography (RigiScan), vardenafil 20 mg induces an erection sufficient for penetration (60% rigidity) in some men as early as the fifteenth minute following administration. The overall response of these subjects to vardenafil became statistically significant compared to placebo, 25 minutes after the administration.
Vardenafil causes mild and transient decreases in blood pressure which, in the majority of cases, do not translate into any clinical effect. The mean maximum decreases in systolic blood pressure in the supine position, following administration of 20 mg and 40 mg vardenafil were – 6.9 mmHg and 4.3 mmHg compared to placebo.
These declines are consistent with the vasodilatory effects of PDE5 inhibitors, probably due to increased Cgmp levels in vascular smooth muscle cells. Vardenafil administered in single doses and repeated up to 40 mg produced no clinically significant changes in ECG in healthy male volunteers.
A randomized, double-blind, crossover, single-dose administration was conducted 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 used as an active internal control.
The effects on the QT interval were measured one hour post dose (average tmax for vardenafil). The primary objective of this study was to exclude an effect above 10 ms (to demonstrate lack of effect), a single dose of vardenafil 80 mg administered by the oral route, on the QTc interval in comparison to placebo and measured, using the correction formula of Fridericia (QTcF= QT/RR1/3), by the change from the basal 1 hour after administration.
The results for vardenafil showed an increase in QTc (Fridericia) of 8 msec (90% CI: 6-9) and 10msec (90% CI : 8-11), respectively, at doses of 10 mg and 80 mg compared to placebo and increase QTci of 4 msec (90% CI : 3-6) and 6 msec (90% CI : 4-7) ), respectively, at doses of 10 mg and 80 mg in comparison to placebo, 1 hour after the administration.
At tmax, only the mean change in QTcF for vardenafil 80 mg was out of the limits established in the study (mean 10 msec, 90% CI : 8-11). Using the formula of individual correction, none of the values found outside the limits.
A study after marketing was conducted in 44 healthy volunteers receiving single doses of 10 mg vardenafil or 50 mg sildenafil were co-administered concomitantly with 400 mg gatifloxacin, a drug with a similar effect on the QT interval.
This study showed for the vardenafil like sildenafil an increase of QTc effect (Frederica) of 4 msec (vardenafil) and 5 msec (sildenafil) when compared to their administration separately. The clinical impact of these variations of QT is currently unknown.
Other information relating to the clinical trials with vardenafil 10 mg, tablet orodispersible
The efficacy and tolerability of vardenafil 10 mg, tablet orodispersible has been demonstrated in a broad population of men, in two clinical trials conducted in 701 patients were randomized, with erectile dysfunction, and processed up to 12 weeks.
The distribution of patients in subgroups pre-defined covering elderly patients (51%), patients with history of diabetes mellitus (29%), dyslipidemia (39%), and hypertension (40%).
By combining the data from two clinical studies conducted with the vardénafil10 mg, tablet orodispersible, the domain score IIEF-EF with vardenafil 10 mg, tablet orodispersible was significantly superior to placebo.
71% of attempts at sexual intercourse have been reported in clinical trials have led to a penetration success, compared to 44% of attempts in the placebo group. These results were also reflected in the sub-groups ;
the attempts of sexual intercourse reported have resulted in a penetration with success in the following proportions :
in elderly patients (65%), in patients with history of diabetes mellitus (63%), in patients with a history of dyslipidemia (66%) and in patients with a history of hypertension (70%).
Approximately 63% of attempts of sexual intercourse reported with vardenafil 10 mg, tablet orodispersible led to a maintenance of erection with success, compared to 26% of attempts at intercourse in the placebo group.
Within sub-groups, 57% (older patients), 56% (patients with a history of diabetes mellitus (dm), 59% (patients with history of dyslipidemia) and 60% (patients with history of hypertension) of all attempts at sexual intercourse reported with vardenafil 10 mg, tablet orodispersible resulted in a maintenance of erection with successful.
Other information on clinical trials
Code of conduct for drivers of vehicles
Effects on ability to drive and use machines have not been studied.
As dizziness and abnormal vision have been reported in clinical trials with vardenafil, patients should know how they react to Levitra, before driving or operating machinery.
LEVITRA : its cons-indications
Hypersensitivity to the active substance or to any of the excipients listed in section Composition.
The concomitant administration of vardenafil with nitrates or nitric oxide donors (such as amyl nitrite) in any form, is contraindicated (see section Interactions with other medicinal products and other forms of interactions pharmacodynamic Properties).
Levitra is contraindicated in patients who have loss of vision in one eye due to ischemic optic neuropathy non-arteritic (NAION), that this event has been associated to a previous exposure to an inhibitor of phosphodiesterase type 5 (PDE5) inhibitors (see section warnings and precautions).
The drugs used in the treatment of erectile dysfunction should not be used in men for whom sexual activity is inadvisable (e.g. patients with severe cardiovascular disorders such as unstable angina or severe heart failure [NYHA III or IV]).
The tolerance of vardenafil has not been studied in sub-groups of patients and its use in these patients is therefore contraindicated until further information is available:
– severe hepatic impairment (class C Child-Pugh),
– terminal stage of renal failure requiring dialysis,
– hypotension (blood pressure <90/50 mmHg),
– recent history of stroke or myocardial infarction (within last 6 months),
– unstable angina and hereditary disorders degenerative known of the retina such as retinitis pigmentosa.
The concomitant administration of vardenafil with potent CYP3A4 inhibitors such as ketoconazole and itraconazole (oral form) is contraindicated in men over 75 years of age.
The concomitant use of vardenafil with protease inhibitors anti-HIV such as ritonavir and indinavir is contraindicated, as they are very potent inhibitors of CYP3A4 (see Interactions with other medicinal products and other forms of interaction).
Concomitant administration of inhibitors of PDE5, such as vardenafil, with the stimulators of guanylate cyclase, such as riociguat, is contraindicated because of the risk of symptomatic hypotension (see Interactions with other medicinal products and other forms of interaction).
LEVITRA : its precautions
We will perform a thorough history and a clinical examination to diagnose erectile dysfunction and determine underlying causes of potential before considering drug treatment.
Before initiating treatment of erectile dysfunction, physicians should consider the cardiovascular function of their patients, to the extent that any sexual activity carries a risk of the heart (see section contraindications).
Vardenafil has vasodilating properties, resulting in decreases in mild and transient blood pressure (see section pharmacodynamic Properties). Patients with an obstruction to the ejection of the left ventricle, for example, aortic stenosis, stenosis, sub-aortic hypertrophic, idiopathic, and may be sensitive to the action of vasodilators including inhibitors of the phosphodiesterase type-5.
The drugs used in the treatment of erectile dysfunction should be prescribed with caution in patients with anatomical deformation of the penis (such as angulation, sclerosis of the corpora cavernosa, or Peyronie’s disease), or in patients with conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
The tolerance and efficacy of combinations of Levitra film-coated tablets with Levitra tablet orodispersible or with other treatments for erectile dysfunction have not been studied. Therefore, it is not recommended to resort to such associations. The tolerance to the maximum dose of 20 mg may be reduced in elderly patients (≥ 65 years of age) (see sections Dosage and administration and adverse reactions).
Concomitant use of alpha-blockers
The concomitant use of alpha-blockers and vardenafil may lead, in some patients, symptomatic hypotension because both are vasodilators. Concomitant treatment with vardenafil should only be initiated if the patient has been stabilised on his alpha-blocker therapy.
In patients who are stable on alpha-blocker therapy, treatment with vardenafil should be initiated at the lowest recommended starting dose of 5 mg film-coated tablet. Vardenafil may be administered at any time with tamsulosin or with alfuzosin.
For the other alpha-blockers, a time interval between dosing should be considered in case of concomitant use of vardenafil (see section Interactions with other medicinal products and other forms of interaction). In those patients already taking an optimized dose of vardenafil, alpha-blocker therapy should be initiated at the lowest dose.
In patients treated with vardenafil, the increase in alpha-blocker dose increments may result in a further decrease in blood pressure.
Concomitant Administration of CYP3A4 inhibitors
The concomitant administration of vardenafil with potent cyp 3A4 inhibitors such as itraconazole and ketoconazole (oral form) should be avoided (see section Interaction with other medicinal products and other forms of interaction), as very high plasma concentrations of vardenafil are reached if the medicinal products are combined (see contraindications and Interactions with other medicinal products and other forms of interaction).
An adaptation of the dosage of vardenafil can be necessary in case of concomitant administration with moderate inhibitors of CYP3A4 such as erythromycin or clarithromycin (see sections Dosage and administration and Interactions with other medicinal products and other forms of interaction).
The concomitant use of grapefruit or grapefruit juice may increase the plasma concentrations of vardenafil. This combination should be avoided (see section Interaction with other medicinal products and other forms of interaction).
Effect on the QTc interval
It has been demonstrated that a single dose of 10 mg and 80 mg vardenafil prolongs, respectively, of 8 msec and 10 msec average of the QTc interval.
Also, the single dose of 10 mg vardenafil administered concomitantly with 400 mg gatifloxacin (an active substance with a similar effect on QT interval), leads to an extension additional of the QTc interval of 4 msec compared to the effect of each active substance taken separately.
The clinical impact of these changes of QT interval is unknown (see section pharmacodynamic Properties).
The clinical relevance of these findings is not known and cannot be generalised to all patients under all circumstances, as it depends on individual risk factors and susceptibilities that may exist at a given time for a given patient.
Drugs that may prolong the QTc interval, including vardenafil, are strongly discouraged in patients with risk factors, for example, hypokalaemia, congenital prolongation of the QT interval, concomitant administration of antiarrhythmic Class Ia (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol).
Effect on vision
Visual defects and cases of ischemic optic neuropathy non-arteritic (NAION) have been reported following the intake of Levitra and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, he should stop taking Levitra and consult immediately a physician (see section contraindications).
Effect on bleeding
In vitro studies with human platelets indicate that vardenafil has no effect on anti-aggregation of platelets alone, but at high doses (supra-therapeutic), vardenafil potently enhances the effect of anti-aggregation of a donor of nitric oxide, sodium nitroprusside.
In humans, vardenafil alone, or in combination with acetylsalicylic acid has no effect on bleeding time (see section Interactions with other medicinal products and other forms of interaction). There is no information available on the safety of vardenafil in patients with bleeding disorders or active peptic ulceration.
Also, in these patients, vardenafil should be administered only after a careful assessment of the benefit-risk ratio.
LEVITRA : Its interactions
Effects of other medicinal products on vardenafil
In vitro studies
Vardenafil is metabolised predominantly by hepatic enzymes via the isoform 3A4 of cytochrome P450 (CYP), with some contribution from CYP3A5 and CYP2C isoforms. The inhibitors of these isoenzymes may reduce vardenafil clearance.
In vivo studies
It has not been observed to potentiate the hypotensive effect of sublingual nitroglycerin (0.4 mg) in combination with vardenafil (10 mg) was given at varying time intervals (from 1 hour to 24 hours) prior to the dose of nitroglycerin in a study in 18 healthy male volunteers.
The vardenafil 20 mg (film-coated tablet) potentiated the hypotensive effect of sublingual nitroglycerin (0.4 mg) taken 1 and 4 hours after vardenafil administration to healthy subjects of average age. No effect on blood pressure was observed when nitroglycerin was taken 24 hours after administration of a single dose of vardenafil 20 mg (film-coated tablet).
However, we do not have any information on the possible potentiation by vardenafil the hypotensive effect of nitrates. Therefore, their concomitant use is contraindicated (see section contraindications).
The nicorandil is a hybrid molecule, activator of potassium channels and derived nitrate. Because of the component-derived nitrate, it can result in a serious interaction with vardenafil.
Given that the administration of alpha-blocker monotherapy can cause marked hypotension, especially orthostatic hypotension and syncope, drug-drug interaction studies were conducted with vardenafil.
Cases of arterial hypotension (sometimes symptomatic) was reported in two studies of interaction in a significant number of healthy volunteer normotensive, after titration forced by alpha-blockers tamsulosin or terazosin to high doses, in association with vardenafil.
Among subjects treated with terazosin, hypotension was observed more frequently when vardenafil and terazosin were given simultaneously than when the dosing was separated by a time interval of 6 hours.
On the basis of results of interaction studies conducted with vardenafil in patients with benign prostatic hyperplasia (BPH) under treatment stable tamsulosin, terazosin or alfuzosin :
● No decrease in symptomatic blood pressure was not observed in any patients
receiving treatment with stable tamsulosin, when vardenafil (film-coated tablet) was
administered at doses of 5, 10, or 20 mg, while 3 of the 21 patients treated with tamsulosin
have presented of arterial pressures systolic transient of less than 85 mmHg.
● A case of symptomatic orthostatic hypotension was observed in one of 21 patients treated with 5 mg of vardenafil (film-coated tablet) in combination with 5 or 10 mg of terazosin. This hypotension was not observed when the administrations of 5 mg of vardenafil and terazosin were administered every 6 hours.
● When vardenafil (film-coated tablet) was administered at doses of 5 or 10 mg in patients receiving treatment with stable from alfuzosin, no reduction in symptomatic blood pressure has not been observed in these patients, in comparison to placebo.
Therefore, concomitant treatment with vardenafil should be initiated only if the patient is stable on his alpha-blocker therapy. In these patients, vardenafil should be initiated at the lowest recommended starting dose of 5 mg.
Levitra may be administered at any time with tamsulosin or with alfuzosin. As for the other alpha-blockers, a time interval between dosing should be considered in case of concomitant use of vardenafil (see section warnings and precautions).
No specific interaction was observed in case of concomitant administration of vardenafil (film-coated tablet 20 mg) with warfarin (25 mg), which is metabolised by CYP2C9, or digoxin (0.375 mg). The relative bioavailability of glibenclamide (3.5 mg) was not altered by the coadministration of vardenafil (20 mg). In a specific study during which vardenafil (20 mg) was administered with nifedipine extended-release tablets (30 mg and 60 mg) in hypertensive patients, it was observed a further decrease of the systolic blood pressure of 6 mmHg in the supine position, and a further reduction of 5 mmHg of the diastolic pressure in the supine position, accompanied by an increase in heart rate of 4 bpm.
When making simultaneous, vardenafil (film-coated tablet 20 mg) did not potentiate the effects of alcohol (mean blood concentration alcohol limit of 73 mg/dl) on the blood pressure or the heart rate and the pharmacokinetics of vardenafil is not changed.
Vardenafil (10 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid (2 x 81 mg).
Preclinical studies have shown an increase of the hypotensive effect of systemic when the inhibitors of PDE5 were associated with riociguat. In clinical studies, it has been demonstrated that riociguat increased the hypotensive effects of inhibitors of PDE5.
It has not been demonstrated to benefit the association in the study population. The concomitant use of riociguat with inhibitors of PDE5, such as vardenafil, is contraindicated (see section contraindications).
LEVITRA : Its incompatibilities
In case of overdose
In studies carried out in healthy volunteers, single doses of vardenafil (film-coated tablet) up to 80 mg per day were tolerated without exhibiting serious adverse reactions.
Vardenafil administered in higher doses and more frequently than the recommended dosing regimen (film-coated tablet 40 mg twice a day) resulted in the onset of back pain severe. This was not associated with any form of muscle toxicity or neurological.
In case of overdose the usual measures of symptomatic treatment should be implemented according to the needs. Renal dialysis is not expected to accelerate clearance, as vardenafil is highly bound to plasma proteins and not eliminated significantly in the urine.
Pregnancy – Breast-Feeding
Levitra is not indicated for use by women. No studies with vardenafil have not been conducted in pregnant women.
No data on fertility is available.
LEVITRA : side effects
Adverse effects reported in clinical trials conducted with Levitra film-coated tablets or Levitra 10 mg tablet orodispersible, were generally transient and mild to moderate in intensity. Adverse effects the most commonly reported, occurring in at least 10% of patients, are headache.
The adverse reactions are presented according to the convention MedDRA in terms of frequency : very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10000 to <1/1000), and frequency not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.