ךיראתב רשואש ןולעל ההז ןולעה םדבלמ
, ידיחיה םייונישה םנה הזה ןולעב םינמוסמה םייונישה יכ תאזב הריהצמ ינא
ו נכדעה תוכיאה תדועתבו םושירה תדועתב םושרה תא םימאות ןולעב םיעיפומה רישכתה יטרפ לכ
.מ"עב לארשי רייאב םושירה לעב .הנוממ ח
ת קור ,ןמסלדנה רדיינש הליא :םותח
THE FORMAT OF THIS LEAFLET WAS DETERMINED BY THE MINISTRY OF HEALTH AND ITS CONTENT WAS CHECKED AND APPROVED BY IT ON AUGUST 2011. NAME OF THE MEDICINAL PRODUCT
Levitra 5 mg / 10 mg / 20 mg film-coated tablets
QUALITATIVE AND QUANTITATIVE COMPOSITION Levitra 5 mg film-coated tablets: each film-coated tablet contains 5 mg of vardenafil (5.926 mg of vardenafil monohydrochloride trihydrate) Levitra 10 mg film-coated tablets: each film-coated tablet contains 10 mg of vardenafil (11.852 mg of vardenafil monohydrochloride trihydrate) Levitra 20 mg film-coated tablets: each film-coated tablet contains 20 mg of vardenafil (23.705 mg of vardenafil monohydrochloride trihydrate) Levitra 10 mg orodispersibletablets: each orodispersible tablet contains 10 mg of vardenafil (11.852 mg of vardenafil monohydrochloride trihydrate).
Excipient sorbitol and 1.8 mg aspartame per orodispersible tablet
For full list of excipients see section 6.1
PHARMACEUTICAL FORM
Levitra film-coated tablet: orange round, embossed with BAYER-cross on one side and „5“, „10“, or „20“ on the other side).
Levitra 10 mg orodispersible tablets: White uncoated tablet: round biconvex without tablet marking.
CLINICAL PARTICULARS Indication
Treatment of erectile dysfunction (Inability to achieve or maintain 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 and Method of Administration Method of administration
Oral Use. Levitra film-coated tablets can be taken with or without food.
Levitra 10 mg orodispersible tablet should be placed on the tongue until dissolved. It should be
taken by itself without food or liquid in the mouth. It should be taken immediately upon release from the blister. Levitra 10 mg orodispersible tablets can be taken with or without food. Dose regimen
The recommended starting dose is 10 mg Levitra (film-coated tablet or 10 mg Levitra orodispersible tablet) taken as needed approximately 25 - 60 minutes before sexual activity.
Based on efficacy and tolerability, the dose may be increased to 20 mg vardenafil (one 20 mg film-coated tablet) or decreased to 5 mg vardenafil (one 5 mg film-coated tablet).
The maximum recommended dose for Levitra film coated tablets is 20 mg (one 20 mg film-coated tablet) once daily.
The maximum recommended dose for Levitra orodispersible tablets is 10 mg (one 10 mg orodispersible tablet) once daily.
The maximum recommended dose frequency is once per day.
General recommendations
In clinical trials Levitra was shown to be efficacious when taken up to 4 - 5 hours before sexual activity.
Sexual stimulation is required for a natural response to treatment (see section “Pharmacodynamic properties”).
Additional information on special patient populations Geriatric patients (above 65 years): Dose adjustment is not required in elderly patients. Children (from birth to 16 years): Levitra is not indicated for use in children.
Patients with hepatic impairment: No dose adjustment is needed in patients with mild hepatic impairment (Child-Pugh A).
As vardenafil clearance is reduced in patients with moderate hepatic impairment (Child-Pugh B), a starting dose of 5 mg Levitra (one 5 mg film-coated tablet) is recommended, which may subsequently be increased to a maximum dose of 10 mg Levitra film-coated tablet, based on tolerability and efficacy. Patients with moderate hepatic impairment (Child Pugh B) should not use Levitra 10 mg orodispersible tablets.
The pharmacokinetics of vardenafil has not been studied in patients with severe hepatic impairment (Child-Pugh C). (see section “Pharmacokinetic properties”)
No dose adjustment is needed in patients with mild (CrCl > 50-80 mL/min), moderate (CrCl > 30-50 mL/min), or severe (CrCl < 30 mL/min) renal impairment.
The pharmacokinetics of vardenafil have not been studied in patients requiring dialysis. (see section “Pharmacokinetic properties”).
Patients with concomitant use of 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 section “Interaction with other medicinal products and other forms of interaction”). In those patients who are stable on alpha-blocker therapy, Levitra should be initiated at the lowest recommended starting dose of 5 mg Levitra film-coated tablet. Patients treated with alpha blockers should not use Levitra 10 mg orodispersible tablets as a starting dosei. 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 section “Interaction 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. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor
Patients with concomitant use of potent CYP 3A4 inhibitors
The dosage of Levitra film-coated tablets may require adjustment in patients receiving certain CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, indinavir, erythromycin, and clarithromycin). (see section “Warnings and Precautions” and “Interaction with other medicinal products and other forms of interaction”).
A maximum dose of 5 mg Levitra film-coated tablets should not be exceeded when used in combination with the cytochrome P450 (CYP) 3A4 inhibitors erythromycin or clarithromycin. (see section “Warnings and Precautions” and “Interaction with other medicinal products and other forms of interaction”).
A maximum dose of 5 mg Levitra film-coated tablets should not be exceeded when used in combination with the potent cytochrome P450 (CYP) 3A4 inhibitors ketoconazole or itraconazole. Levitra should not be taken with dosages of ketoconazole or itraconazole higher than 200 mg. Concomitant use with HIV protease inhibitors such as indinavir and ritonavir, which are very potent inhibitors of CYP3A4, is contraindicated (see sections “Contraindications, SpecialWarnings and Precautions” and “Interactions with other medicinal products and other forms of interaction”).
Contraindications Levitra film-coated tablets and Levitra orodispersible tablets
Contraindicated in patients with hypersensitivity to the active substance or to any of the excipients.
Consistent with the effects of PDE inhibition on the nitric oxide / cGMP – pathway, PDE5 inhibitors may potentiate the hypotensive effects of nitrates. Levitra is thus contraindicated in patients who are concomitantly treated with nitrates or nitric oxide donors (see section “Interactions with medicinal products and other forms of interaction”).
Concomitant use of Levitra with HIV Protease inhibitors such as indinavir or ritonavir is contraindicated, as they are potent inhibitors of CYP3A4 (see sections “Dosage and method of administration” and “Interaction with other medicinal products and other forms of interaction”).
Special Warnings and Precautions for use
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 for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Levitra 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 type 5 phosphodiesterase inhibitors.
In men for whom sexual activity is not recommendable because of their underlying cardiovascular status, agents for the treatment of erectile dysfunction should generally not be used.
In a study of the effect of Levitra on QT interval in 59 healthy male volunteers, therapeutic (10 mg) and supratherapeutic (80 mg) doses of Levitra produced increases in QTc interval (see
section “Pharmacodynamic properties”).
A postmarketing study evaluating the effect of combining Levitra with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone (see section “Pharmacodynamic properties”). These observations should be considered in clinical decisions when prescribing Levitra 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 Levitra.
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 Levitra with other treatments for erectile dysfunction have not been studied. Therefore the use of such combinations is not recommended.
The safety of Levitra has not been studied in the following sub-groups of patients and its use is therefore not recommended: severe hepatic impairment, endstage renal disease requiring dialysis, hypotension (resting systolic blood pressure of < 90 mm Hg), recent history of stroke or myocardial infarction (within last 6 months), unstable angina, and known hereditary degenerative retinal disorders such as retinitis pigmentosa.
The safety of Levitra 10 mg orodispersible tablets has not been studied in patients with moderate hepatic impairment, therefore use of Levitra 10 mg orodispersible tablets in these patients is not recommended1.
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 the case of sudden vision loss, he should stop taking Levitra and consult immediately a physician (see section “Undesirable effects”).
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 (see section “Undesirable effects”). Concomitant treatment should only be initiated if the patient is stable on his alpha-blocker therapy (see section “Interaction with other medicinal products and other forms of interaction”). In those patients who are stable on alpha-blocker therapy, the treatment with Levitra should be initiated at the lowest recommended starting dose of 5 mg Levitra film-coated tablets. Patients treated with alpha blockers should not use Levitra 10 mg orodispersible tablets as a starting dose. Levitra may be administered at any time with tamsulosin. With other alpha-blockers
a time separation of dosing should be considered when vardenafil is prescribed concomitantly (see “Interaction 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. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor including vardenafil.
Physicians should advise patients to stop taking LEVITRA, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including LEVITRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see section “Undesirable effects”).
Concomitant use of the potent cytochrome P450 3A4 (CYP3A4) inhibitors ketoconazole, itraconazole, indinavir, or ritonavir can be expected to produce markedly increased vardenafil plasma levels. A maximum dose of 5 mg Levitra film-coated tablets should not be exceeded if used in combination with erythromycin or clarithromycin. A maximum dose of 5 mg Levitra film-coated tablets should not be exceeded if used in combination with ketoconazole and itraconazole. Levitra must not be taken with dosages of ketoconazole and itraconazole higher than 200 mg (see sections “Dosage and method of administration” and “Interaction with other medicinal products and other forms of interaction”). Concomitant use with indinavir or ritonavir, which are highly potent inhibitors of CYP3A4, is contraindicated (see sections “Dosage method of administration”, “Contraindications”, Interactions with Medicinal products and other forms of interaction”).
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, Levitra has no effect on bleeding time alone or with acetylsalicylic acid.
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.
Concomitant intake of grapefruit juice is expected to increase the plasma concentration of vardenafil. The combination should be avoided.
Aspartame: Levitra 10 mg orodispersible tablets contain aspartame, a source of phenylalanine which may be harmful for people with phenylketonuria.
Sorbitol: Levitra 10 mg orodispersible tablets contain sorbitol. Patients with rare hereditary problems of fructose intolerance should not take Levitra 10 mg orodispersible tablets.
Interactions with other medicinal products and other forms of Interaction CYP Inhibitors
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.
Cimetidine (400 mg b.i.d.),a non-specific cytochrome P450 inhibitor, had no effect on vardenafil AUC and Cmax when co-administered with Levitra film-coated tablets 20 mg to healthy volunteers.
Erythromycin (500 mg t.i.d.), a CYP3A4 inhibitor, caused a 4-fold (300%) increase in vardenafil AUC and a 3-fold (200%) increase in Cmax when co-administered with Levitra film-coated tablets 5 mg to healthy volunteers.
Ketoconazole (200 mg), which is a potent CYP3A4 inhibitor, caused a 10-fold (900%) increase in vardenafil AUC and a 4-fold (300%) increase in Cmax when co-administered with Levitra film-coated tablets 5 mg to healthy volunteers.
Co-administration of Levitra film-coated tablets 10 mg with the HIV protease inhibitor indinavir (800 mg t.i.d.) resulted in a 16-fold (1500%) increase in vardenafil AUC and a 7-fold (600%) 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).
Ritonavir (600 mg b.i.d.) resulted in a 13-fold increase in vardenafil Cmax and a 49-fold increase in vardenafil AUC0-24 when co-administered with Levitra film-coated tablets 5 mg. The interaction 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 vardenafil to 25.7 hours.
Concomitant use of potent CYP3A4 inhibitors such as ketoconazole, itraconazole, indinavir or ritonavir can be expected to produce markedly increased vardenafil plasma levels.
A maximum dose of 5 mg Levitra film-coated tablets should not be exceeded if used in combination with erythromycin or clarithromycin (see sections “Contraindications”, “Special warnings and precautions for use”).
A maximum dose of Levitra film-coated tablets 5 mg should not be exceeded if used in combination with ketoconazole and itraconazole. Levitra must not be taken with dosages of ketoconazole and itraconazole higher than 200 mg (see sections: “Special warnings and precautions for use”, “Dosage and method of administration”).
Concomitant use with indinavir or ritonavir, which are highly potent inhibitors of CYP3A4, is contraindicated (see sections “Dosage and Method of Administration”, “Special Warnings and Precautions for Use”, “Contraindications”).
No potentiation of the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) was observed when Levitra 10 mg film-coated tablets was given at varying time intervals (24 h to down to 1 h) prior to the nitroglycerin dose in a study in 18 healthy male subjects.
The blood pressure lowering effect of sublingual nitrates (0.4 mg) taken 1 and 4 hours after vardenafil administration were potentiated by a 20 mg dose of Levitra film-coated tablets in healthy middle aged subjects. These effects were not observed when vardenafil 20 mg was taken 24 hours before the nitroglycerin.
However, there is no information on the potential hypotensive effects of vardenafil when given in combination with nitrates in patients, and concommitant use is therefore contraindicated (see section: “Contraindications”).
Levitra film-coated tablets 20 mg, when co-administered with glibenclamide (Glyburide, 3.5 mg), did not affect the relative bioavailability of glibenclamide (no effect on AUC and Cmax of glibenclamide). There was no evidence that vardenafil pharmacokinetics were altered by co-administration of glibenclamide.
No pharmacokinetic and pharmacodynamic (prothrombin time and clotting factor II, VII and X) interaction was shown when warfarin (25 mg) was co-administered with 20 mg Levitra film-coated tablets. Vardenafil pharmacokinetics was not affected by co-administration of Warfarin.
No relevant pharmacokinetic interaction was shown when 20 mg Levitra film-coated tablets, was co-administered with nifedipine (30 or 60 mg). The combined treatment of Levitra film-coated
tablets and nifedipine did not lead to pharmacodynamic interaction (as compared to placebo, Levitra film-coated tablets produced mean additional blood pressure reductions of 5.9 mm Hg and 5.2 mm Hg for supine systolic and diastolic blood pressure, respectively).
Since alpha-blocker monotherapy can cause marked lowering of blood pressure, especially postural hypotension and syncope, interaction studies were conducted with Levitra film-coated tablets.
[in patients with benign prostatic hyperplasia (BPH) on stable tamsulosin or terazosin therapy, as well as in normotensive volunteers after short-term alpha blockade].
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 film-coated tablets . Among subjects treated with terazosin, hypotension (standing systolic blood pressure below 85 mm Hg) was observed more frequently when Levitra film-coated tablets 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 film-coated tablets in patients with benign prostatic hyperplasia (BPH) on stable tamsulosin or terazosin therapy. When Levitra film-coated tablets 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 film-coated tablets 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 film-coated tablets 5 mg was given with a 6 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 film-coated tablets 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 film-coated tablets 5 mg was given simultaneously with terazosin 5 or 10 mg, 1 of 21 patients experienced symptomatic postural hypotension. Hypotension was not observed when Levitra film-coated tablets 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 on 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 film-coated tablet. Patients treated with alpha blockers should not use Levitra 10 mg orodospersible tablets as a starting dose. 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 Special Warnings and Precautions for Use).
Lack of pharmacokinetic interaction was shown when digoxin (0.375 mg) in steady-state was co-administered with Levitra 20 mg film-coated tablets over 14 days every other day. There was no evidence that vardenafil pharmacokinetics were altered by co-administration of digoxin.
Single doses of maalox (antacid; magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability (AUC) or the maximum concentration (Cmax) of vardenafil.
Bioavailability of Levitra 20 mg film-coated tablet was not affected by co-administration of the H2-antagonist ranitidine (150 mg b.i.d.).
Levitra 10 mg and 20 mg film-coated tablets did not influence the bleeding time when taken alone or in combination with low dose acetylsalicylic acid (2 x 82 mg tablets).
Levitra 20 mgfilm-coated tablets did not potentiate the hypotensive effects of alcohol (0.5 g/kg bw). The pharmacokinetics of vardenafil were not altered.
Population pharmacokinetic investigations of phase III data revealed no significant effect of acetylsalicylic acid, ACE-inhibitors, beta-blockers, weak CYP3A4-inhibitors, diuretics and medications for the treatment of diabetes (sulfonylureas and metformin) on the pharmacokinetics of vardenafil.
Grapefruit juice being a weak inhibitor of CYP3A4 gut wall metabolism, may give rise to modest increases in plasma levels of vardenafil. There are no data on the interaction of vardenafil and non- specific phosphodiesterase inhibitors such as theophylline or dipyridamole.
Pregnancy and Lactation
Levitra is not indicated for use by women.
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.
Undesirable Effects Placebo controlled clinical trials (ADRs):
When Levitra film-coated tablets or Levitra orodispersible tablets were taken as recommended, the
following adverse drug reactions were reported in placebo controlled clinical trials:
Table 1: Adverse Drug Reactions reported by ≥ 1% of the patients treated with Levitra film-coated tablets or Levitra 10 mg orodispersible tablets and more frequent on drug than placebo in placebo controlled trials on 5 mg, 10 mg, and 20 mg vardenafil. System organ class Adverse drug reaction Vardenfil Medical Entity (ME) (N=9155) (N=5500) Nervous system disorders Vascular Disorders Respiratory, Thoracic and Mediastinal Disorders Gastrointestinal Disorders Musculoskeletal and Connective Tissue Disorders All Clinical trials (ADRs):
The following adverse drug reactions were reported in patients given Levitra film-coated tablets or
Levitra orodispersible tablets in all clinical trials. Table 2: Adverse drug reactions reported in patients in all clinical trials world-wide which are either reported as drug-related in ≥ 0.1% of the patients or rare and considered serious in their nature System Organ Uncommon
≥ 1% to < 10%
≥ 0.1% to < 1%
≥ 0.01% to < 0.1% Infection and Infestations Immune System Disorders Psychiatric Disorders Nervous System Disorders Eye Disorders incl. related Investigations Ear and Labyrinth Disorders Cardiac Disorders incl. related Investigations Vascular Disorders incl. related Investigations Respiratory, Thoracic and Meditational Disorders Gastrointestinal Disorders incl. Investigations System Organ Uncommon
≥ 1% to < 10%
≥ 0.1% to < 1%
≥ 0.01% to < 0.1% Hepatobiliary System Disoder Subcutaneous Tissue Disorders AUDITORY: sudden decrease or loss of hearing, tinnitus
Post Marketing
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
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. 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.
Overdose
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 tolerated without producing serious adverse side effects. This was confirmed in a study with 40 mg Levitra once daily doses over 4 weeks.
When 40 mg 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 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.
PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties
Penile erection is a hemodynamic 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 cylase 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. The actual cGMP level is regulated by the rate of synthesis via the guanylate cylase 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 phospho-diesterase 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.
Trials on purified enzyme preparations have shown that vardenafil is a very potent and highly selective inhibitor of PDE5, with an IC50 for human PDE5 of 0.7 nM.
The inhibitory effect of vardenafil is more potent on PDE5 than on other known phospho-diesterases (> 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 erectile response:
In a placebo controlled Rigiscan study, 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.
Clinical Studies:
Unless otherwise stated, the below studies are conducted with Levitra film-coated tablets. The results are considered valid for Levitra 10 mg orodispersible tablets as well.
For Levitra orodispersible tablets:
Efficacy and safety of Levitra 10 mg orodispersible tablets were separately demonstrated in a broad population in two studies including 701 ED patients who were treated up to 12 weeks. The distribution of patients in the predefined subgroups was covering elderly patients (51.3%) included, patients with history of diabetes mellitus (28.7%) included, dyslipidemia (39.2%) and hypertension (39.7%).
In pooled data from the two Levitra 10 mg orodispersible tablets trials, 71.3% of all sexual attempts reported had successful penetration compared to 43.9 % of all attempts in the placebo group. These results were also reflected in subgroups, in elderly patients (66,9 %), in patients with history of diabetes mellitus (63.4%), patients with history of dyslipidemia (66.4%) and hypertension (69.7%) of all sexual attempts reported had successful penetration.
About 62.7% of all reported sexual attempts with Levitra 10 mg orodispersible tablets were successful in terms of erection maintenance compared to about 26.0% of all placebo-controlled sexual attempts. In the predefined subgroups 56,7% (elderly patients), 56% (patients with history of diabetes mellitus), 59% (patients with history of dyslipidemia) and 60% (patients with history of hypertension) of all reported attempts with Levitra 10 mg orodispersible tablets were successful in terms of maintenance of erection.
The efficacy of Levitra 10 mg orodispersible tablets was demonstrated regardless of baseline erectile dysfunction severity, etiology (organic, psychogenic, and mixed), duration of ED, ethnicity and age.
Vardenafil demonstrated clinically meaningful and statistically significant improvement of erectile function compared to placebo in all major efficacy trials including special populations.
Across clinical trials worldwide, vardenafil was administered to over 17.000 men with erectile dysfunction (ED), many of whom had multiple other medical conditions. Over 2500 patients were treated with vardenafil for 6 months or longer. Of these, 900 patients have been treated for one year or longer.
In a randomized, double blind, placebo controlled, fixed dose trial, based on a global assessment question (GAQ), vardenafil improved erections in 65%, 80% and 85% of the patients on 5 mg, 10 mg and 20 mg, respectively, at 6 months compared to 28% 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 vardenafil. 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 months study period. Vardenafil was efficacious in patients regardless of baseline severity, etiology (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, Levitra demonstrated clinically meaningful and statistically significant improvement in erectile function in a 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 Levitra film-coated tablets at all time points. Improved erectile function response rates as based on GAQ were 59% on 10 mg and 65% on 20 mg Levitra film-coated tablets compared to 13% 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 3 months were 60% for 10 mg and 71% for 20 mg Levitra film-coated tablets, compared to 12% for placebo. Patients with ED and Diabetes Mellitus: In patients with diabetes mellitus, Levitra demonstrated clinically meaningful and statistically significant improvement in erectile function in a 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 compared to placebo for the tested doses of 10 mg and 20 mg Levitra film-coated tablets at all time points during 3 months of treatment. In this population, which is typically more resistant to therapy, response rates for improvement of erection as based on GAQ were 57% on 10 mg, and 72% on 20 mg Levitra film-coated tablets compared to 13% on placebo for patients who completed 3 months of the trial.
Patients in the active treatment group were continued on blinded active therapy of Levitra film-coated tabletsfor a total of 6 months. These patients demonstrated response rates of 66% and 74% for 10 mg and 20 mg Levitra film-coated tablets, respectively.
Patients with Spinal Cord Injury: In patients with ED secondary to traumatic spinal cord injury, Levitra film-coated tablets 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 Levitra film-coated tablets compared to 9% on placebo. The response rates for the ability to obtain and maintain an erection were 76% and 59% on Levitra film-coated tablets 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 Levitra 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 Levitra film- coated tablet or 50 mg sildenafil were co-administered concomitantly with 400 mg gatifloxacin, a drug with comparable QT effect. Both Levitra film-coated tablets 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 Special Warnings and Precautions for use). Effects on vision:
In a specific clinical trial, evaluation of visual function at a Levitra film-coated tablet dose of 40 mg (twice the maximum recommended daily dose) revealed no effects of Levitra film-coated tablets 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 20mg Levitra film-coated tablets were administered over 8 weeks versus placebo. Retinal function was measured by ERG and FM-100 test 2, 6 and 24 hours after dosing. Levitra did not produce clinically significant retinal effects in healthy men compared to placebo.
In other trials, daily use of Levitra film-coated tablets 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: For Levitra 10 mg orodispersible tablets:
No notable changes in the mean values from baseline to Week 12 (LOCF) in heart rate, systolic, or diastolic blood pressure were observed in the two clinical studies.
There were no notable treatment or age group differences with respect to change from baseline in heart rate, PR interval, QRS interval. There was no sign of a prolongation of the QT/QT-c interval irrespective of age of patients. There were no consistent treatment group differences with respect to ECG findings pointing to safety issues.
In placebo-controlled clinical pharmacology studies with Levitra 10 mg and 20 mg, the mean maximum decreases in supine systolic and diastolic blood pressure were neglegible in comparison to placebo. There was only a small compensatory increase in heart beat per minute.
Single oral doses of Levitra to 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 Levitra film-coated tablet on QT interval was evaluated in a single-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg) crossover 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 film-coated tablet (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 film-coated tablet (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 summarizes 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.
Heart Rate QT Uncorrected Fridericia QT Individual QT Drug/Dose Correction Correction
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 Levitra film-coated tablets 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 Levitra 20 mg for 6 months. In addition, vardenafil had no effect on serum levels of testosterone, luteinizing hormone, or follicle stimulating hormone.
Pharmacokinetic properties 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.
Due to a considerable first-pass effect, the mean absolute oral bioavailability is about 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 60 minutes and a mean reduction in Cmax of 20%. Vardenafil AUC was not affected. After a normal meal (containing 30% fat) vardenafil pharmacokinetic parameter (Cmax, Tmax, and AUC) were not affected at all.
Based on these results vardenafil can be taken with or without food.
The median time to reach Cmax in patients receiving Levitra 10 mg orodispersible tablets in the fasted state varied between 45 to 90 minutes. After administration of 10 mg Levitra orodispersible tablets to patients, mean vardenafil AUC was increased by 21 to 29 % while mean Cmax was 8 to 19 % lower in comparison to 10 mg Levitra film coated tablets. A high fat meal had no effect on vardenafil AUC and tmax while it resulted in a mean reduction in vardenafil Cmax by 35%. Based on these results Levitra 10 mg orodispersible tablets can be taken before or after food. If Levitra orodispersible tablet is taken with water, the AUC is reduced by 29 % and median tmax is shortened by 60 minutes while Cmax is not affected. Levitra orodispersible tablets should be taken without water.
Bioequivalence studies have shown that Levitra 10 mg orodispersible tablets is not bioequivalent to Levitra 10 mg film-coated tablets; therefore, the orodispersible formulation should not be used as an equivalent to Levitra 10 mg film-coated tablets.
Distribution:
The mean steady state volume of distribution (Vss) for vardenafil is 208 L, 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 metabolized predominantly by hepatic enzymes via CYP3A4, with some contribution from CYP3A5 and CYP2C9 isoforms.
Mean elimination half life (t1/2) is about 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 plasma elimination half life of the metabolite M1 is approximately 4 hours, comparable to the parent drug.
Parts of M1 are in form of its glucuronide-conjugate (glucuronic acid) 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%.
The mean terminal half life of vardenafil in patients receiving Levitra 10 mg orodispersible tablets varied between about 4 – 6 hours. The elimination half life of the metabolite M1 is between 3 to 5 hours, similar to parent drug.
Excretion:
The total body clearance of vardenafil is 56 L/h 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: Geriatric patients (above 65 years): Vardenafil hepatic clearance in healthy elderly volunteers (65 years or over) was reduced as compared to volunteers of younger age (45 years and below). On average, geriatric males takingvardenafil had a 52% higher AUC than younger males which is within the variability observed in clincial trials. Vardenafil AUC and Cmax in elderly patients (65 years or over) taking Levitra 10 mg orodispersible tablets were increased by 31 to 39 % and 16 to 21 %, respectively, in comparison to patients aged 45 years and below. Vardenafil was not found to accumulate in the plasma in patients aged 45 years and below or 65 years or over following once-daily dosing of 10 mg orodispersible tablet over ten days.
No overall differences in safety or effectiveness were observed between elderly and younger subjects in placebo controlled clinical trials.
Patients with renal insufficiency In patients with mild (CrCl > 50–80 mL/min) to moderate (CrCl > 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 (CrCl < 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.
The pharmacokinetics of vardenafil has not been studied in patients requiring dialysis.
Patients with 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%), compared to healthy control subjects.
In patients with moderate hepatic impairment (Child-Pugh B), vardenafil AUC was increased 2.6-fold (160%) and Cmax was increased 2.3-fold (130%), compared to healthy control subjects.
The pharmacokinetics of vardenafil has not been studied in patients with severe hepatic impairment (Child-Pugh C).
Preclinical safety data
Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and toxicity to reproduction.
In acute toxicity studies the LD50 was 190 mg/kg in the rat. Light microscopic, electron-microscopic, and ophtalmologic investigations revealed no oculotoxic effects. In chronic toxicity studies NOEL is 3 mg/kg bw day in male rats and NOEL is 3 mg/kg bw day in the dog. The toxicities observed in experimental animals revealed cardiovascular effects as the prominent toxicological findings as known for PDE5 inhibitors. Other toxicological findings on the pancreas, exocrine glands and the thyroid in rats could be expected by the pharmacologic properties of a phosphodiesterase inhibitor, and were not observed in mice or dogs.
Carcinogenicity:
Vardenafil is not carcinogenic in rats and mice when administered daily for 24 months at 225 (rats) and 450 (mice) times the maximum recommended human dose of 20 mg, respectively (calculation based on 60 kg body weight in men). The exposure in terms of AUC achieved in rats and mice was more than 360 (male rats) and more than 25 (male mice) times the exposure in men given the maximum recommended human dose of 20 mg.
Reproduction toxicology:
No relevant adverse effects with regard to fertility and embryonic development were found in reproduction studies in rats and rabbits following oral administration of vardenafil.
Mutagenicity:
No indication for genotoxic/mutagenic activity of vardenafil could be found in vitro (Ames, HPRT, Cyt. in vitro) and in vivo (MNT).
PHARMACEUTICAL PARTICULARS List of excipients:
crospovidone, magnesium stearate, microcrystalline cellulose, colloidal silicon dioxide (silica colloidal anhydrous).
polyethylene glycol (macrogol 400), hypromellose (hydroxy-propyl-methylcellulose), titanium dioxide (E171), ferric oxide yellow (E172), ferric oxide red (E172).
Aspartame, flavor peppermint, magnesium stearate, crospovidone, mannitol, silica colloidal hydrated, sorbitol, Pharmaburst®
Incompatibilities: Shelf life:
All strengths: 36 months in PP/Alu-blister
Levitra 10 mg orodispersible tablet:Special precautions for storage: Levitra 10 mg orodispersible tablet:
Store in the original package, below 30ºC
Nature and contents of container:
PP/Aluminium foil blisters in cartons of 2, 4, 8 and 12 tablets. Not all pack sizes may be marketed. Levitra 10 mg orodispersible tablet:
Alu/Alu blisters in cartons of 1, 2, or 4 tablets. Not all pack sizes may be marketed. Instructions for use / handling:
Not applicable. MANUFACTURER: Bayer Schering Pharma, Leverkusen, Germany REGISTRATION HOLDER: Bayer Israel Ltd. 36 Hacharash St., Hod Hasharon 45240