Active ingredients: Vardenafil
Levitra 5 mg film-coated tablets
Levitra package inserts are available for packs:- Levitra 5 mg film-coated tablets
- Levitra 10 mg film-coated tablets
- Levitra 20 mg film-coated tablets
- Levitra 10 mg orodispersible tablets
Why is Levitra used? What is it for?
Levitra contains vardenafil, which belongs to a class of medicines called phosphodiesterase type 5 inhibitors. These medicines are used to treat erectile dysfunction in adult men, a condition that leads to difficulty getting or maintaining an erection.
At least one in ten men occasionally have difficulty getting or maintaining an erection. It can be due to physical or psychological causes or a combination of the two. Whatever the cause, not enough blood is retained in the penis to allow and maintain the erection. "erection, due to changes in the muscles and blood vessels.
Levitra works only in the presence of sexual stimulation. The medicine reduces the action of the chemical in the body, which causes an erection to stop. Levitra allows you to achieve and maintain an erection long enough for intercourse to end satisfactorily.
Contraindications When Levitra is not to be used
Do not take Levitra
- If you are allergic to vardenafil or any of the other ingredients of this medicine (listed in section 6). Signs of an allergic reaction include skin rash, itching, swelling of the face or lips and breathlessness.
- If you are taking medicines containing nitrates, such as glycerol trinitrate for angina, or sources of nitric oxide, such as amyl nitrite. Taking these medicines together with Levitra could dangerously affect your blood pressure.
- If you are taking ritonavir or indinavir, medicines used to treat human immunodeficiency virus (HIV) infections.
- If you are over 75 years of age and are taking ketoconazole or itraconazole, antifungal medicines.
- If you have severe heart or liver problems.
- If you are on kidney dialysis.
- If you have recently had a stroke or heart attack.
- If you have, or have ever had, low blood pressure.
- If your family has a history of degenerative eye diseases (such as retinitis pigmentosa).
- If you have ever had a condition characterized by loss of vision due to damage to the optic nerve from insufficient blood supply, known as non-arteritic anterior ischemic optic neuropathy (NAION).
Precautions for use What you need to know before taking Levitra
Warnings and Precautions
Talk to your doctor or pharmacist before taking Levitra.
Take special care with Levitra
- If you have heart trouble. Sexual activity can be risky for her.
- If you suffer from an irregular heartbeat (cardiac arrhythmia) or inherited heart disease that changes the electrocardiogram.
- If you have a physical condition that causes changes in the shape of the penis. These include conditions called bowing, Peyronie's disease, and fibrosis of the corpora cavernosa.
- If you have a disease that can cause persistent erections (priapism), such as sickle cell anemia, multiple myeloma or leukemia.
- If you have stomach ulcers (also called stomach or peptic ulcers).
- If you have a bleeding disorder (such as haemophilia).
- If you are using other treatments for erection difficulties, including Levitra orodispersible tablets (see section Other medicines and Levitra).
- If you notice sudden decrease or loss of vision stop taking Levitra and contact your doctor immediately.
Children and adolescents
Levitra is not intended for use by children or adolescents under the age of 18.
Interactions What drugs or foods can change the effect of Levitra
Other medicines and Levitra
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines, even those without a prescription.
Some medicines can cause problems, particularly these:
- Nitrates, medicines for angina, or sources of nitric oxide such as amyl nitrite. Taking these medicines together with Levitra could dangerously affect your blood pressure. Do not take Levitra and consult a doctor.
- Medicines to treat arrhythmia, such as quinidine, procainamide, amiodarone or sotalol
- Ritonavir or indinavir, medicines for HIV. Do not take Levitra and consult a doctor.
- Ketoconazole or itraconazole, anti-fungal medicines.
- Erythromycin or clarithromycin, macrolide antibiotics.
- Alpha-blockers, a type of medicine used to treat high blood pressure and enlarged prostate (such as benign prostatic hyperplasia).
Do not use Levitra film-coated tablets in combination with other erectile dysfunction treatments, including Levitra orodispersible tablets.
Levitra with food and drink
- You can take Levitra with or without food - but preferably not after a heavy or high fat meal as this can delay its effect.
- Do not drink grapefruit juice while taking Levitra. It can interfere with the effect of the drug.
- Alcoholic beverages can make erection difficulties worse.
Warnings It is important to know that:
Pregnancy and breastfeeding
Levitra is not intended for use by women.
Driving and using machines In some people
Levitra could make you dizzy or change your vision. If you feel dizzy or have problems with your vision after taking Levitra, do not drive or operate any tools or machines.
Dose, Method and Time of Administration How to use Levitra: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. The recommended dose is 10 mg.
Take a Levitra tablet about 25-60 minutes before sexual activity. If you are sexually stimulated, you will be able to get an erection as early as 25 minutes and up to four to five hours after taking Levitra.
Swallow one tablet with a glass of water
Do not take Levitra film-coated tablets together with any other formulation of Levitra.
Do not take Levitra more than once a day.
If you have the impression that the effect of Levitra is too strong or too weak, talk to your doctor. They may advise you to take an alternative formulation of Levitra with a different strength, based on the effect the medicine has on you.
Overdose What to do if you have taken an overdose of Levitra
If you take more Levitra than you should
Patients who take too much Levitra may have more side effects or severe lower back pain. If you take more Levitra than you should, consult your doctor.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Levitra
Like all medicines, this medicine can cause side effects, although not everybody gets them. The effects are mostly mild or moderate.
Some patients have reported partial, sudden, temporary or permanent decrease or loss of vision in one or both eyes. Stop taking Levitra and contact your doctor immediately.
A "sudden decrease or loss of hearing" has been reported.
The likelihood of a side effect occurring is described by the following categories:
Very common
may affect more than 1 in 10 users
- Headache
common
may affect up to 1 in 10 users
- Dizziness
- Flushes
- Runny or stuffy nose
- Bad digestion
Uncommon
may affect up to 1 in 100 users
- Swelling of the skin and mucous membranes including swelling of the face, lips or throat
- Sleep disturbance
- Numbness and decreased tactile perception
- Drowsiness
- Effects on sight; red eyes, effects on color perception, eye pain and discomfort,
- Ringing in the ears; vertigo
- Rapid heartbeat or pounding heart
- Wheezing
- Stuffed nose
- Acid reflux, gastritis, abdominal pain, diarrhea, vomiting; nausea, dry mouth
- Increased levels of liver enzymes in the blood
- Rash, red skin
- Pain in the back or muscles, increased levels of a muscle enzyme (creatine phosphokinase) in the blood, muscle stiffness
- Prolonged erections
- Malaise
Rare
may affect up to 1 in 1,000 users
- Inflammation of the eyes (conjunctivitis)
- Allergic reaction
- Anxiety
- Fainting
- Amnesia
- Convulsion
- Increased pressure in the eye (glaucoma), increased lacrimation
- Effects on the heart (such as heart attack, altered heart beat or angina)
- High or low blood pressure
- Nosebleeds
- Effect on liver function test results
- Sensitivity of the skin to sunlight
- Painful erections
- Chest pain
Very rare or not known:
may affect less than 1 in 10,000 users or frequency cannot be estimated from the available data
- Blood in the urine (hematuria)
- Penile bleeding (penile haemorrhage)
- Presence of blood in the semen (haematospermia)
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after "EXP". The expiry date refers to the last day of that month.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What Levitra contains
- The active ingredient is vardenafil. Each tablet contains 5 mg of vardenafil (as hydrochloride).
- The other ingredients are: Tablet core: crospovidone, magnesium stearate, microcrystalline cellulose, anhydrous colloidal silica. Film-coating: macrogol 400, hypromellose, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172).
What Levitra looks like and contents of the pack
Levitra 5 mg comes in the form of orange film-coated tablets, marked with the BAYER cross on one side and the strength on the other. Packs of 2, 4, 8, 12 or 20 tablets are available in blisters. that not all pack sizes are marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
LEVITRA 5 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg of vardenafil (as hydrochloride).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Round orange tablets, marked with the BAYER cross on one side and "5" on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of erectile dysfunction in adult men. Erectile dysfunction is the inability to achieve or maintain an erection suitable for satisfactory sexual activity.
Sexual stimulation is required for Levitra to be effective.
04.2 Posology and method of administration
Dosage
Use in adult men
The recommended dose is 10 mg as needed, to be taken 25 to 60 minutes before sexual activity. Based on efficacy and tolerability, the dose may be increased to 20 mg or decreased to 5 mg. The maximum recommended dose is 20 mg. The product should not be administered more than once a day. Levitra can be taken with or without meals. If taken with a high fat meal, the effect may be delayed (see section 5.2).
Special categories of patients
Elderly (≥65 years old)
No dosage adjustments are required in elderly patients. However, an increase to the maximum dose of 20 mg should be carefully considered, based on individual tolerability (see sections 4.4 and 4.8).
Impaired liver function
In patients with mild and moderate hepatic impairment (Child-Pugh A-B) a starting dose of 5 mg should be considered. Based on tolerability and efficacy, the dose may subsequently be increased. The maximum recommended dose in patients with moderate hepatic impairment (Child-Pugh B) is 10 mg (see sections 4.3 and 5.2).
Impaired renal function
No dose adjustment is required in patients with mild to moderate renal impairment.
In patients with severe renal impairment (creatinine clearance
Pediatric population
Levitra is not indicated for people under the age of 18. There is no indication for the use of Levitra in children.
Use in patients being treated with other medicinal products
Concomitant use of CYP3A4 inhibitors
When used in combination with CYP3A4 inhibitors such as erythromycin or clarithromycin, the dose of vardenafil should not exceed 5 mg (see section 4.5).
Method of administration
For oral use.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Concomitant administration of vardenafil with nitrates or nitric oxide sources (such as amyl nitrite) in any form is contraindicated (see sections 4.5 and 5.1).
Levitra is contraindicated in patients who have lost sight in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether or not this event was related to previous use of a phosphodiesterase 5 (PDE5) inhibitor. ) (see section 4.4).
Medicines indicated for the treatment of erectile dysfunction should not be used in individuals for whom sexual activity is not recommended (eg. Patients with severe cardiovascular disorders, such as unstable angina or severe heart failure [class III or IV according to the New York Heart Association]).
The safety of vardenafil has not been studied in patients with the following conditions and its use is therefore contraindicated until further information becomes available:
- severe hepatic impairment (Child-Pugh C),
- end stage renal failure requiring dialysis,
- hypotension (blood pressure
- recent history of stroke or myocardial infarction (within the past 6 months),
- unstable angina and known hereditary degenerative disorders of the retina, such as retinitis pigmentosa.
The concomitant use of vardenafil and the potent CYP3A4 inhibitors ketoconazole and itraconazole (oral forms) is contraindicated in patients over 75 years of age.
The concomitant use of vardenafil and HIV protease inhibitors such as ritonavir and indinavir is contraindicated, as these are very potent inhibitors of CYP3A4 (see section 4.5).
04.4 Special warnings and appropriate precautions for use
Before considering drug treatment, a history and physical examination should be done to diagnose erectile dysfunction and determine its potential causes.
Before initiating any treatment for erectile dysfunction, physicians will need to evaluate the cardiovascular condition of their patients, as there is some cardiac risk associated with sexual activity (see section 4.3). Vardenafil has vasodilatory properties that cause mild and transient decrease in blood pressure. blood pressure (see section 5.1). Patients with left ventricular ejection obstruction, eg aortic stenosis and idiopathic hypertrophic subaortic stenosis, may be sensitive to the action of vasodilators, including phosphodiesterase Type 5 inhibitors.
Medicines indicated for the treatment of erectile dysfunction should be used with caution in patients with anatomical deformations of the penis (e.g. curvature, fibrosis of the corpora cavernosa or Peyronie's disease), or in patients with conditions that may predispose to priapism (e.g. e.g. sickle cell anemia, multiple myeloma or leukemia).
The safety and efficacy of combining Levitra film-coated tablets with Levitra orodispersible tablets or other treatments for erectile dysfunction have not been studied. The use of these associations is therefore not recommended.
Tolerability of the maximum dose of 20 mg may be lower in elderly patients (≥65 years) (see sections 4.2 and 4.8).
Concomitant use of alpha-blockers
Concomitant use of alpha-blockers and vardenafil may lead to symptomatic hypotension in some patients, as both medicinal products are vasodilators. Concomitant treatment with vardenafil should only be initiated when the patient is stabilized on alpha-blocker therapy, starting with lowest recommended starting dose of 5 mg film-coated tablets. Vardenafil can be administered at any time with tamsulosin or alfuzosin, while with other alpha-blockers a time interval between doses should be considered when vardenafil is being administered. prescribed in combination (see section 4.5). In patients already taking vardenafil at an optimal dose, the alpha blocker should be started at the lowest dose. A gradual increase in the alpha blocker dose may be associated with further lowering of blood pressure in patients taking vardenafil.
Concomitant use of CYP3A4 inhibitors
Concomitant use of vardenafil with potent CYP3A4 inhibitors such as itraconazole and ketoconazole (oral forms) should be avoided, as a combination of these medicinal products results in very high plasma concentrations of vardenafil (see sections 4.5 and 4.3).
A dose adjustment of vardenafil may be required when co-administered with moderate CYP3A4 inhibitors such as erythromycin and clarithromycin (see sections 4.5 and 4.2).
Concomitant intake of grapefruit or grapefruit juice is likely to increase the plasma concentrations of vardenafil. This association should be avoided (see section 4.5).
Effect on the QTc interval
Single oral doses of 10 mg and 80 mg of vardenafil have been shown to prolong the QTc interval by an average of 8 msec and 10 msec, respectively. Single doses of 10 mg of vardenafil, given together with 400 mg of gatifloxacin, an active substance with effects similar on the QT interval, showed an additive effect on QTc of 4 msec compared to the effect of each of the two active substances taken individually. The clinical impact of these QT changes is unknown (see section 5.1).
The clinical relevance of these observations is unknown and cannot be generalized to all patients and in all circumstances, since this depends on individual risk factors and the susceptibility that may be present at a given time and in any given patient. It is advisable to avoid the administration of drugs that can prolong the QTc interval, including vardenafil, in patients with relevant risk factors, for example hypokalaemia, congenital QT prolongation, concomitant administration of class 1A antiarrhythmic drugs (ex: quinidine, procainamide) or class III (ex: amiodarone, sotalol).
Effect on sight
Visual disturbances and cases of non-arteritic anterior ischemic optic neuropathy have been reported in association with the use of vardenafil and other PDE5 inhibitors. Levitra and seek medical attention immediately (see section 4.3).
Effect on bleeding
Studies in vitro with human platelets indicate that vardenafil does not, in itself, have an antiplatelet effect, but at high (super-therapeutic) concentrations potentiates the antiplatelet effect of the source of nitrous oxide sodium nitroprusside. In man, vardenafil, from alone or in combination with acetylsalicylic acid, had no effect on bleeding time (see section 4.5). No information is available regarding the safety of vardenafil administration in patients with bleeding disorders or with active peptic ulcer. Vardenafil should therefore only be administered to these patients after a careful risk-benefit assessment.
04.5 Interactions with other medicinal products and other forms of interaction
Effects of other medicinal products on vardenafil
Education in vitro
Vardenafil is metabolised primarily by hepatic enzymes via the cytochrome P450 (CYP) isoform 3A4, with some contribution from the CYP3A5 and CYP2C isoforms. Therefore, inhibitors of these isoenzymes may reduce the clearance of vardenafil.
Education in vivo
Administration of indinavir (800 mg 3 times daily), an HIV protease inhibitor and potent CYP3A4 inhibitor, together with vardenafil (10 mg film-coated tablets), resulted in a 16-fold increase in AUC and 7 times the vardenafil Cmax After 24 hours, the plasma levels of vardenafil had dropped to approximately 4% of the maximum plasma level (Cmax).
Co-administration of vardenafil with ritonavir (600 mg twice daily) resulted in a 13-fold increase in vardenafil Cmax and a 49-fold increase in AUC 0-24 of vardenafil when co-administered with vardenafil 5 mg . The interaction is a consequence of the blockade of the hepatic metabolism of vardenafil by ritonavir, a very strong inhibitor of CYP3A4 which also inhibits CYP2C9. Ritonavir significantly prolongs the half-life of vardenafil up to 25.7 hours (see section 4.3).
Administration of the potent CYP3A4 inhibitor ketoconazole (200 mg) together with vardenafil (5 mg) resulted in a 10-fold increase in vardenafil AUC and 4-fold Cmax (see section 4.4).
Although no specific interaction studies have been conducted, the use of other potent CYP3A4 inhibitors (such as itraconazole) should be considered to result in plasma levels of vardenafil comparable to those produced by ketoconazole. Concomitant use of vardenafil with potent CYP3A4 inhibitors such as itraconazole and ketoconazole (oral use) should be avoided (see sections 4.3 and 4.4). Concomitant use of vardenafil with itraconazole or ketoconazole is contraindicated in patients over 75 years of age. (see section 4.3).
Administration of erythromycin (500 mg 3 times daily), a CYP3A4 inhibitor, together with vardenafil (5 mg), resulted in a 4-fold increase in vardenafil AUC and 3-fold Cmax. Although a specific interaction study has not been conducted, concomitant administration of clarithromycin should be expected to result in similar effects on vardenafil AUC and Cmax. When vardenafil is used in combination with a moderate CYP3A4 inhibitor such as erythromycin or clarithromycin, a dose adjustment may be required (see sections 4.2 and 4.4). Cimetidine (400 mg twice daily), a non-specific inhibitor of cytochrome P450, co-administered with vardenafil (20 mg) to healthy volunteers, had no effect on vardenafil AUC and Cmax.
Grapefruit juice, being a weak inhibitor of intestinal CYP3A4 metabolism, may lead to a modest increase in plasma levels of vardenafil (see section 4.4).
The pharmacokinetics of vardenafil (20 mg) were unaffected by concomitant administration with the H2 antagonist ranitidine (150 mg twice daily), digoxin, warfarin, glibenclamide, alcohol (mean maximum blood levels alcohol of 73 mg / dl) or single doses of antacid (magnesium hydroxide / aluminum hydroxide).
Although no specific interaction studies have been conducted with all medicinal products, the population pharmacokinetic analysis revealed no effects on the pharmacokinetics of vardenafil following concomitant administration with the following medicinal products: acetylsalicylic acid, ACE inhibitors, beta-blockers, weak inhibitors of CYP3A4, diuretics and medicines for the treatment of diabetes (sulphonylureas and metformin).
Effects of vardenafil on other medicinal products
There are no data on the interaction between vardenafil and nonspecific phosphodiesterase inhibitors, such as theophylline or dipyridamole.
Education in vivo
In a study in 18 healthy male volunteers, no potentiation of the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) was observed following administration of vardenafil (10 mg) at different time intervals (from 1 to 24 hours) prior to the nitroglycerin dose. 20 mg of vardenafil film-coated tablets potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg), taken 1 and 4 hours after the administration of vardenafil a healthy middle-aged patients. No effect on blood pressure was observed when nitroglycerin was taken 24 hours after administration of a single 20 mg film-coated tablet. However, as no information is available regarding a possible potentiation by vardenafil of the hypotensive effects of nitrates in patients, concomitant use with this class of drugs is contraindicated (see section 4.3).
Nicorandil is a hybrid that works as a nitrate and as a drug that activates potassium channels. As a nitrate it can cause serious interactions when given together with vardenafil.
Since alpha-blocker monotherapy can cause marked reduction in blood pressure, especially postural hypotension and syncope, interaction studies between alpha-blockers and vardenafil have been conducted. In two interaction studies in normotensive healthy volunteers, after forced titration to high doses of the alpha-blockers tamsulosin or terazosin, hypotension (in some cases symptomatic) was reported in a significant number of subjects after concomitant administration of vardenafil. treated with terazosin, the finding of hypotension was more frequent when vardenafil and terazosin were administered concurrently than when the administration was separated by a 6 hour interval.
Based on the results of interaction studies conducted with vardenafil in patients with benign prostatic hypertrophy (BPH), on stable therapy with tamsulosin, terazosin or alfuzosin, it was observed that:
• When vardenafil (film-coated tablets) was administered in doses of 5, 10 or 20 mg in addition to stable therapy with tamsulosin, there was no symptomatic reduction in blood pressure, although in 3/21 subjects treated with tamsulosin. systolic blood pressure values in standing position were transiently lower than 85 mmHg.
• When vardenafil 5 mg (film-coated tablets) was co-administered with terazosin 5 or 10 mg, one in 21 patients experienced symptomatic postural hypotension. Hypotension was not observed when the administration of vardenafil 5 mg and terazosin was separated by a 6 hour interval.
• When vardenafil (film-coated tablets) was administered in doses of 5 or 10 mg in addition to stable therapy with alfuzosin, there was no symptomatic reduction in blood pressure compared to placebo.
Therefore, concomitant treatment with vardenafil should only be initiated when the patient is on stable alpha-blocker therapy, starting with the lowest recommended starting dose of 5 mg. Levitra can be administered at any time with tamsulosin or alfuzosin, while with other alpha blockers a time interval between doses should be considered when prescribing vardenafil in combination (see section 4.4).
No significant interactions were found when warfarin (25 mg), which is metabolised by CYP2C9, or digoxin (0.375 mg) were co-administered with vardenafil (20 mg film-coated tablets). The relative bioavailability of glibenclamide (3.5 mg) was not affected by concomitant administration of vardenafil (20 mg). In a specific study, where vardenafil (20 mg) was administered together with slow-release nifedipine (30 mg or 60 mg) in hypertensive patients, a further reduction in supine systolic blood pressure of 6 mmHg and supine diastolic blood pressure of 5 mmHg, accompanied by an increase in heart rate of 4 bpm.
Following taking vardenafil (20 mg film-coated tablets) together with alcohol (mean maximum blood alcohol levels of 73 mg / dl), vardenafil did not potentiate the effects of alcohol on blood pressure and heart rate. and the pharmacokinetics of vardenafil were not changed.
Vardenafil (10 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid (2 x 81 mg).
04.6 Pregnancy and lactation
Levitra is not indicated for use in women. There are no studies with vardenafil in pregnant women.
No fertility data are available.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
As dizziness and altered vision have been reported in clinical trials with vardenafil, patients should be aware of how they react to Levitra before driving or operating machinery.
04.8 Undesirable effects
Adverse reactions reported in clinical trials with Levitra film-coated tablets or Levitra 10 mg orodispersible tablets were generally transient and of mild or moderate intensity. The most commonly reported adverse reaction is headache, which occurred in 10% or more of patients.
Adverse reactions are classified according to the MedDRA convention on frequency: very common (≥1 / 10), common (≥1 / 100,
Within each frequency class, undesirable effects are reported in descending order of severity.
The following adverse reactions have been reported:
* Sudden decrease or loss of hearing has been reported in a small number of cases in postmarketing and clinical trials with the use of PDE5 inhibitors, including vardenafil.
At a dose of Levitra 20 mg film-coated tablets, elderly patients (≥ 65 years old) experienced headache (16.2% vs 11.8%) and dizziness (3.7% vs 0.7%) more frequently. , compared to younger patients (
In general, the incidence of adverse events (especially "dizziness") has been observed to be slightly higher in patients with a history of hypertension.
During-to-market reports of another "other medicinal product of the same class."
Vascular pathologies
In temporal association with the use of another drug of this class, severe cardiovascular reactions, including cerebrovascular haemorrhage, sudden cardiac death, transient ischemic attack, unstable angina and ventricular arrhythmia, have been reported during the marketing phase of the product.
04.9 Overdose
In volunteer studies with single doses up to 80 mg per day of vardenafil (film-coated tablets), the drug was tolerated without major adverse reactions.
When vardenafil was administered at higher doses and more frequently than the recommended dosing regimen (40 mg film-coated tablets twice daily), cases of severe lower back pain, however not associated with muscle or neurological toxicity, have been reported.
In the event of an overdose, necessary supportive measures should be taken. Renal dialysis does not accelerate clearance as vardenafil is highly bound to plasma proteins and is not significantly eliminated in the urine.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: urologicals, drugs used in erectile dysfunction, ATC code: G04B E09.
Vardenafil is an oral therapy to improve erectile function in patients with erectile dysfunction. Under normal conditions, i.e. in the presence of sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis.
Penile erection is a hemodynamic process. During sexual stimulation, nitric oxide is released. The latter activates the enzyme guanyl cyclase, which causes increased levels of cyclic guanosine monophosphate (cGMP) in the corpora cavernosa. , in turn, produces the relaxation of smooth muscle, allowing a greater flow of blood to the penis. The levels of cGMP are regulated by the rate of synthesis, through guanyl cyclase, and by the rate of degradation, through phosphodiesterases (PDE) which hydrolyze the cGMP.
Vardenafil is a potent and selective inhibitor of cGMP-specific type 5 phosphodiesterase (PDE5), the predominant PDE in the corpora cavernosa in humans. Vardenafil, by inhibiting PDE5, greatly enhances the effect of nitric oxide. endogenous in the corpora cavernosa. When nitric oxide is released in response to sexual stimulation, inhibition of PDE5 by vardenafil causes increased cGMP levels in the corpora cavernosa. Therefore, sexual stimulation is required for vardenafil to produce its beneficial therapeutic effects.
Studies in vitro demonstrated that vardenafil is more potent on PDE5 than it is on other known phosphodiesterases (> 15 times compared to PDE6,> 130 times compared to PDE1,> 300 times compared to PDE11 and> 1,000 times compared to PDE2, PDE3, PDE4 , PDE7, PDE8, PDE9 and PDE10).
In a study conducted with penile plethysmography (RigiScan), erections sufficient for penetration (60% stiffness) were recorded in some subjects as early as 15 minutes after administration of a 20 mg dose of vardenafil. The overall response of these subjects to vardenafil became statistically significant compared to placebo 25 minutes after dosing.
Vardenafil causes a mild and transient decrease in blood pressure which, in the majority of cases, does not translate into clinical symptoms. The mean maximum decrease in supine systolic blood pressure following doses of 20 and 40 mg of vardenafil was - 6.9 mmHg for 20 mg and - 4.3 mmHg for 40 mg of vardenafil, in comparison with placebo. These effects are consistent with the vasodilatory effect of PDE5 inhibitors and are likely due to increased levels of cGMP in smooth muscle cells. Single and multiple oral doses of vardenafil up to 40 mg produced no clinically relevant effects on ECGs from healthy volunteers.
A randomized, crossover, double-blind, single-dose study with 59 healthy volunteers compared the QT effects of vardenafil (10 mg - 80 mg), sildenafil (50 mg and 400 mg) and placebo. Moxifloxacin (400 mg) was included as an internal active control. Effects on the QT segment were measured one "hour after dosing (mean tmax for vardenafil). The primary objective of this study was to exclude an effect greater than 10 msec (to demonstrate, therefore, lack of effect) of a single oral dose of vardenafil 80 mg on the QT segment compared to placebo, as measured by the change in Fridericia's correction formula (QTcF = QT / RR1 / 3) from baseline compared to one hour after dosing. Vardenafil demonstrated an increase in QTc (Fridericia) of 8 msec (90% CI: 6-9) and 10 msec (90% CI: 8-11) at doses of 10 and 80 mg compared to placebo and an increase in QTc of 4 msec (90% CI: 3-6) and 6 msec (90% CI: 4-7) at the dose of 10 mg and 80 mg compared to placebo, one "hour after dosing. At tmax only the mean in QTcF of vardenafil 80 mg was outside the study limits (mean 10 msec, 90% CI: 8-11) .No values outside the limits were found using the individual correction formula.
In another post-marketing study in 44 healthy volunteers, single doses of 10 mg of vardenafil or 50 mg of sildenafil were administered together with 400 mg of gatifloxacin, a drug with similar effects on the QT interval. Both vardenafil and sildenafil resulted in an increase in the effect on QTc Friedericia of 4 msec (vardenafil) and 5 msec (sildenafil), compared to the effect of each drug taken alone. The actual clinical impact of these changes is unknown.
Learn more about clinical trials with Levitra 10 mg orodispersible tablets
The efficacy and safety of Levitra 10 mg orodispersible tablets were demonstrated separately in a large population in two randomized studies involving 701 patients with erectile dysfunction treated for up to 12 weeks. The distribution of patients in the predefined subgroups included elderly patients (51%), patients with a history of diabetes mellitus (29%), dyslipidemia (39%) and hypertension (40%).
In the overall evaluation of the data from the two clinical trials with Levitra 10 mg orodispersible tablets, IIEF-EF scores obtained with Levitra 10 mg orodispersible tablets were significantly higher than placebo.
Satisfactory penetration was achieved in 71% of all reported intercourse attempts in clinical trials compared with 44% of all attempts in the placebo group. Similar results were also observed in the subgroups, in elderly patients (65%), in patients with a history of diabetes mellitus (63%), dyslipidemia (66%) and hypertension (70%). attempts at sexual intercourse.
With Levitra orodispersible tablets, approximately 63% of reported intercourse attempts were successful in terms of maintaining an erection compared to approximately 26% of all attempts in the placebo group. erection maintenance in 57% (elderly patients), 56% (patients with a history of diabetes mellitus), 59% (patients with a history of dyslipidemia) and 60% (patients with a history of hypertension) of all reported attempts using Levitra 10 mg orodispersible tablets.
Learn more about clinical trials
In clinical trials, vardenafil was administered to over 17,000 patients with erectile dysfunction (ED), aged 18 to 89 years, many of whom had multiple associated conditions. Over 2,500 patients have been treated with vardenafil for a period of at least six months. Of these, over 900 have been treated for a year or more.
The following groups of patients were represented: elderly (22%), hypertensive (35%), diabetes mellitus (29%), ischemic heart disease and other cardiovascular diseases (7%), chronic pulmonary disease (5%), hyperlipidemia (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 section 4.3). No clinical studies have been performed in patients with CNS disorders (except spinal cord injury), patients with severe renal or hepatic impairment, pelvic surgery (except bilateral nerve sparing prostatectomy), trauma, radiation therapy, decreased sexual desire or anatomical abnormalities of the penis.
In the pilot studies, treatment with vardenafil (film-coated tablets) resulted in an improvement in erectile function compared to placebo. In the small number of patients who had intercourse up to four to five hours after administration, the success rate for penetration and maintenance of erection was consistently higher than for placebo.
In the fixed-dose studies (film-coated tablets), in an enlarged patient population with ED, 68% (5 mg), 76% (10 mg) and 80% (20 mg) of patients achieved satisfactory penetration ( SEP2) compared to 49% of placebo during the 3 months of the study. The ability to maintain an erection (SEP 3) in this enlarged population was achieved in 53% (5 mg), 63% (10 mg) and 65% (20 mg) compared to 29% in placebo.
From the assembled data from the main efficacy studies, the proportion of patients who had satisfactory penetration following the administration of vardenafil was as follows: psychogenic erectile dysfunction (77-87%), mixed erectile dysfunction (69-83%) dysfunction organic erectile (64-75%), elderly (52-75%), ischemic heart disease (70-73%), hyperlipidemia (62-73%), chronic lung disease (74-78%), depression (59-69%) ), and patients treated concomitantly with antihypertensives (62-73%).
In a clinical study in patients with diabetes mellitus, vardenafil significantly improved the degree of erectile function, the ability to obtain and maintain an erection of sufficient duration to complete satisfactory intercourse, and penile rigidity compared to placebo. in patients who completed three months of treatment, the response rate to the ability to obtain and maintain an erection was 61% and 49% with 10 mg and 64% and 54% with vardenafil 20 mg, compared with 36% and 23% reported with placebo.
In a clinical study in prostatectomised patients, vardenafil, at doses of 10 mg and 20 mg, significantly improved the degree of erectile function, the ability to obtain and maintain an erection of sufficient duration to complete sexual intercourse, compared to placebo. satisfactory and penile rigidity. For patients who completed three months of treatment, the response rate to the ability to obtain and maintain an erection was 47% and 37% with 10 mg and 48% and 34% with 20 mg of vardenafil, compared with 22% and 10% reported with placebo.
In a flexible-dose clinical study in patients with spinal cord injury, vardenafil significantly improved the degree of erectile function, the ability to obtain and maintain an erection of sufficient duration to complete satisfactory intercourse, and penile rigidity compared to placebo. . The number of patients returning to a normal IIEF score (≥26) was 53% for vardenafil versus 9% for placebo. achieving and maintaining an erection was 76% and 59% with vardenafil compared to 41% and 22% with placebo, which is significant from both a clinical and statistical point of view (p
The efficacy and tolerability of vardenafil were maintained in long-term studies.
05.2 Pharmacokinetic properties
Bioequivalence studies have shown that Levitra 10 mg orodispersible tablet is not bioequivalent to the 10 mg film-coated tablet; therefore the orodispersible formulation should not be used as equivalent to Levitra 10 mg film-coated tablets.
Absorption
In the case of Levitra film-coated tablets, vardenafil is rapidly absorbed, with maximum plasma concentrations already found, in some subjects, 15 minutes after oral administration. In 90% of cases, however, maximum plasma concentrations are reached within 30-120 minutes (median 60 minutes) of oral administration in the fasted state. The mean absolute bioavailability is 15%. After oral administration of vardenafil, AUC and C increase almost dose proportionally over the recommended dose range (5 - 20 mg).
When Levitra film-coated tablets are taken with a high-fat meal (57% fat content) the rate of absorption is reduced, with an increase in median tmax of 1 hour and an average reduction in Cmax of 20%, without modifications of the AUC. After a meal containing 30% fat, the rate and extent of vardenafil absorption (tmax, Cmax and AUC) are unchanged from dosing in the fasted state.
Vardenafil is rapidly absorbed following administration without water of Levitra 10 mg orodispersible tablets. The median time to reach Cmax ranges from 45 to 90 minutes and is similar or slightly longer (8-45 min) than that of the film-coated tablets. With 10 mg orodispersible tablets the mean AUC of vardenafil increased by 21-29% (in middle-aged and elderly patients with erectile dysfunction) or 44% (in young healthy subjects) compared to the film-coated tablets, such as result of the local absorption of a small amount of drug in the oral cavity.There is no constant difference in mean Cmax between orodispersible tablets and film-coated tablets.
In subjects who took Levitra 10 mg orodispersible tablets with a high-fat meal, no effect on vardenafil AUC and tmax was observed, while Cmax was reduced by 35% when taken on a fed basis. Based on these results Levitra 10 mg orodispersible tablets can be taken with or without food.
If Levitra 10 mg orodispersible tablets are taken with water, the AUC is reduced by 29%, the Cmax remains unchanged, and the median tmax decreases by 60 minutes compared to taking without water. Levitra 10 mg orodispersible tablets should be taken without liquids.
Distribution
The mean steady-state volume of distribution of vardenafil is 208 l, indicating that the drug is distributing into tissues.
Vardenafil and its major circulating metabolite (M1) are both highly bound to plasma proteins (approximately 95% for vardenafil or M1). For both vardenafil and M1, protein binding is independent of total drug concentrations.
Based on measurements in healthy volunteers 90 minutes after vardenafil administration, a maximum of 0.00012% of the administered dose may appear in the semen of patients.
Biotransformation
Vardenafil, in Levitra film-coated tablets, is mainly metabolised by hepatic enzymes via the cytochrome P450 (CYP) isoform 3A4, with some contribution from the CYP3A5 and CYP2C isoforms.
The major circulating metabolite in humans (M1) is derived from the de-ethylation of vardenafil and is further metabolised, with an elimination half-life of approximately 4 hours. In the systemic circulation, M1 is partly present in the form of glucuronide. The metabolite M1 has a selectivity profile for phosphodiesterases similar to that of vardenafil and a potency in vitro for type 5 phosphodiesterase equal to about 28% of that of the unchanged drug, contributing to the efficacy for about 7%.
After taking Levitra 10 mg orodispersible tablets, the mean terminal half-life of vardenafil ranges from 4 to 6 hours. The elimination half-life of the metabolite M1 is similar to that of the parent drug, ranging from 3 to 5 hours.
Elimination
Total body clearance of vardenafil is 56 l / h with a terminal half-life of approximately 4-5 hours. After oral administration, vardenafil is eliminated as metabolites mainly in the faeces (approximately 91-95% of the administered dose). and to a lesser extent in the urine (approximately 2-6% of the administered dose).
Pharmacokinetics in particular groups of patients
Senior citizens
Hepatic clearance of vardenafil in healthy elderly volunteers (65 years and older) was reduced compared to that of younger healthy volunteers (18 - 45 years). On average, in elderly males who took Levitra film-coated tablets, the AUC of vardenafil was 52% and the Cmax 34% higher than that seen in younger males (see section 4.2).
In elderly patients (65 years or older) who took Levitra orodispersible tablets the AUC and Cmax of vardenafil were increased, respectively, by 31-39% and 16-21%, compared to patients aged equal or younger. to 45 years. There was no accumulation of vardenafil in the plasma of patients 45 years of age or older or 65 years of age or older following a once daily dose of Levitra 10 mg orodispersible tablets for 10 days.
Impaired renal function
In volunteers with mild to moderate renal impairment (creatinine clearance 30 - 80 mL / min), the pharmacokinetics of vardenafil were similar to that of a normal renal function control group. In patients with severe renal impairment (creatinine clearance
Impaired liver function
In patients with mild to moderate hepatic impairment (Child-Pugh A and B), there was a reduction in vardenafil clearance proportional to the degree of hepatic impairment. In patients with mild hepatic impairment (Child-Pugh A), an increase in vardenafil AUC and Cmax of 17% and 22% was observed compared to healthy control volunteers. In patients with moderate hepatic impairment (Child-Pugh B), an increase in vardenafil AUC and Cmax of 160% and 133%, respectively, was observed compared to the corresponding values in healthy control volunteers (see section 4.2). The pharmacokinetics of vardenafil in patients with severe hepatic impairment (Child-Pugh C) have not been studied (see section 4.3).
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive toxicity.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablet:
Crospovidone
Magnesium stearate
Microcrystalline cellulose
Anhydrous colloidal silica
Coating film:
Macrogol 400
Hypromellose
Titanium dioxide (E171)
Yellow iron oxide (E172)
Red iron oxide (E172)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
PP / Aluminum blisters in cartons of 2, 4, 8, 12 and 20 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions for disposal.
07.0 MARKETING AUTHORIZATION HOLDER
Bayer Pharma AG
13342 Berlin
Germany
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/03/248 / 001-004, 021
035734019
035734021
035734033
035734045
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 6 March 2003
Date of most recent renewal: 6 March 2008
10.0 DATE OF REVISION OF THE TEXT
March 2012
