Viagra - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Sildenafil

VIAGRA 25 mg film-coated tablets

Viagra package inserts are available for packs:
  • VIAGRA 25 mg film-coated tablets
  • VIAGRA 50 mg film-coated tablets
  • VIAGRA 100 mg film-coated tablets
  • VIAGRA 50 mg orodispersible tablets

Why is Viagra used? What is it for?

VIAGRA contains the active substance sildenafil which belongs to a class of medicines called phosphodiesterase type 5 (PDE5) inhibitors. It helps to relax the blood vessels in the penis, allowing blood to flow to the penis when it is sexually stimulated. VIAGRA will help you get an erection only if it is sexually stimulated.

VIAGRA is a treatment for adult men with erectile dysfunction, sometimes called impotence. This condition occurs when a man is unable to achieve or maintain an "erection suitable for intercourse.

Contraindications When Viagra should not be used

Do not take VIAGRA

  • if you are allergic to sildenafil or any of the other ingredients of this medicine.
  • if you take medicines called nitrates, as this combination can lead to a dangerous lowering of your blood pressure. Tell your doctor if you are taking any of these medicines which are often used to relieve attacks of angina pectoris (or "chest pain"). If you are unsure, consult your doctor or pharmacist.
  • if you are taking any of the medicines known as nitric oxide donors, such as amyl nitrite ('poppers'), as this combination can also cause a dangerous lowering of blood pressure.
  • if you have a severe heart or liver problem.
  • if you have recently had a stroke or heart attack, or if you have low blood pressure.
  • if you have a rare inherited eye disease (such as retinitis pigmentosa).
  • if you have ever had vision loss caused by non-arteritic anterior ischemic optic neuropathy (NAION).

Precautions for use What you need to know before taking Viagra

Talk to your doctor, pharmacist or nurse before taking VIAGRA

  • if you have sickle cell anemia (a red blood cell abnormality), leukemia (cancer of the blood cells), multiple myeloma (cancer of the bone marrow).
  • if you have a deformity of the penis or Peyronie's disease.
  • if you have heart problems. The doctor must carefully check that the condition of the heart allows her to cope with the strain of sexual intercourse.
  • if you currently have a stomach ulcer, or bleeding problems (such as haemophilia).
  • if you experience sudden decrease or loss of vision, stop taking VIAGRA and contact your doctor immediately.
  • You should not use VIAGRA together with other oral or local treatments for erectile dysfunction.

    You should not use VIAGRA with sildenafil-containing pulmonary arterial hypertension (PAH) treatments or any other phosphodiesterase type 5 (PDE5) inhibitor.

    You should not take VIAGRA if you do not have erectile dysfunction. You must not take VIAGRA if you are a woman.

    Special precautions for patients with kidney or liver problems

    If you have kidney or liver problems, you should tell your doctor. Your doctor may decide to give you a lower dose.

    Children and adolescents

    VIAGRA should not be given to people under the age of 18.

    Interactions What drugs or foods can change the effect of Viagra

    Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

    VIAGRA tablets may interfere with some medicines, especially those used to treat chest pain. If a medical emergency occurs, you should tell the doctor, pharmacist or nurse that you have taken VIAGRA and when you used it. Do not take VIAGRA with other medicines unless your doctor tells you to.

    You should not take VIAGRA if you are taking medicines called nitrates because the combination of these medicines can cause a dangerous drop in your blood pressure. Tell your doctor, pharmacist or nurse if you are taking any of these medicines which are often used to relieve attacks of angina pectoris (or "chest pain").

    You should not take VIAGRA if you are using one of the medicines known as nitric oxide donors, such as amyl nitrite ("poppers") because this combination can also cause a dangerous drop in blood pressure.

    If you are taking medicines called protease inhibitors, for example medicines to treat HIV, your doctor may initially prescribe VIAGRA at the lowest dose (25 mg).

    Some patients on alpha-blocker therapy for the treatment of high blood pressure or enlarged prostate may experience dizziness or confusion of mind which may be caused by low blood pressure when sitting or standing up quickly. Some patients have reported these. symptoms when they have taken VIAGRA together with alpha blockers. This is most likely to happen within 4 hours after taking VIAGRA. To reduce the chance of these symptoms occurring, you must be on a regular dose of the alpha blocker before starting treatment with VIAGRA. Your doctor may initiate treatment with a lower strength of VIAGRA (25 mg).

    VIAGRA with food, drink and alcohol

    VIAGRA can be taken with or without food. However, you may find that VIAGRA's onset of effect may be slower if you take it after eating a large meal.

    The consumption of alcoholic beverages may temporarily impair the ability to have an erection. To get the maximum benefit from this medicine, it is advisable to avoid the consumption of large quantities of alcohol before using VIAGRA.

    Warnings It is important to know that:

    Pregnancy, breastfeeding and fertility

    VIAGRA is not indicated for use in women.

    Driving and using machines

    VIAGRA can cause dizziness and can affect vision. Before driving and operating machines you should be aware of how you react to VIAGRA.

    VIAGRA contains lactose

    If you have been told by your doctor that you have an "intolerance to some sugars, such as lactose, contact your doctor before taking VIAGRA.

    Dose, Method and Time of Administration How to use Viagra: Posology

    Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist. The recommended starting dose is 50 mg.

    VIAGRA should not be taken more than once a day.

    Do not take VIAGRA film-coated tablets in combination with VIAGRA orodispersible tablets.

    You should take VIAGRA about one hour before anticipated sexual activity. Swallow the tablet whole with a glass of water.

    If you feel that the effect of VIAGRA is too strong or too weak, talk to your doctor or pharmacist.

    VIAGRA will only help you get an erection if you are sexually stimulated. The time it takes for VIAGRA to take effect varies from person to person, but generally ranges from half an hour to one hour. The effect of VIAGRA may be obtained after a longer period of time if you have just had a substantial meal.

    If VIAGRA does not help you get an erection, or if your erection does not last long enough to complete sexual intercourse, please inform your doctor.

    Overdose What to do if you have taken too much Viagra

    You may notice an increase in side effects and the severity of these effects. Doses greater than 100 mg do not increase efficacy.

    Do not take more tablets than your doctor has prescribed for you.

    If you take more tablets than prescribed, contact your doctor.

    If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

    Side Effects What are the side effects of Viagra

    Like all medicines, this medicine can cause side effects, although not everybody gets them. The side effects reported in association with the use of VIAGRA are usually mild to moderate and of a short duration.

    If you experience any of the following serious side effects, stop taking VIAGRA and contact your doctor immediately:

    • Allergic reaction - this occurs uncommonly (may affect up to 1 in 100 people). Symptoms include sudden wheezing, difficulty breathing or dizziness, swelling of the eyelids, face, lips or throat.
    • Chest pain - occurs uncommonly: If this occurs during or after intercourse:
      • Get into a semi-sitting position and try to relax.
      • Do not use nitrates to treat chest pain.
    • Prolonged and sometimes painful erections - this occurs rarely (may affect up to 1 in 1,000 people). If this type of erection persists continuously for more than 4 hours, contact your doctor immediately.
    • Sudden reduction or loss of vision - rarely occurs.
    • Serious skin reactions - this occurs rarely Symptoms may include severe peeling and swelling of the skin, blisters in the mouth, genitals and around the eyes, fever.

    • Seizures or fits - this occurs rarely.

    Other side effects:

    Very common (may affect more than 1 in 10 people): headache. Common (may affect up to 1 in 10 people): nausea, flushing of the face, flushing (symptoms include a sudden sensation of heat in the upper body), indigestion, increased color intensity of vision, blurred vision, visual disturbances, stuffy nose and dizziness. Uncommon (may affect up to 1 in 100 people): vomiting, skin rash, eye irritation, red eye, eye pain, flashes of light, increased perception of light, sensitivity to light, lacrimation, heart palpitations, racing heart, high blood pressure, low blood pressure, muscle pain, sleepiness, decreased sensitivity to touch, dizziness, ringing in the ears, dry mouth, blocked or congested sinuses, inflammation of the nasal mucosa (symptoms include runny nose, sneezing and congestion nasal), upper abdominal pain, gastroesophageal reflux disease, (symptoms include heartburn), blood in the urine, pain in the arms or legs, nosebleeds, feeling hot and tired. Rare (may affect up to 1 in 1000 people): fainting, stroke, heart attack, irregular heartbeat, temporary reduction in blood supply to certain areas of the brain, sensation ne of constriction in the throat, numb mouth, bleeding from the back of the eye, double vision, reduced visual acuity, abnormal ocular sensitivity, swelling of the eyes or eyelids, appearance of dots or particles in the field of vision, vision of halos around lights , dilation of the pupils, change in the white color of the sclerae (part of the eye), bleeding from the penis, blood in semen, dry nose, swelling of the nasal mucosa, irritability and sudden decrease or loss of hearing. Rare cases of unstable angina (a heart disease) and sudden death have been reported from post-marketing experience. It should be noted that most, but not all, of the men who experienced these side effects had heart problems before using. It is not possible to determine whether these events are directly related to the use of VIAGRA.

    Reporting of side effects

    If you get any side effects, talk to your doctor, pharmacist or nurse. 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. 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. Store at a temperature not exceeding 30 ° C. Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of the month. Store in the original package to protect from moisture. 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.

    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.

    More information about Viagra can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

    01.0 NAME OF THE MEDICINAL PRODUCT

    VIAGRA

    02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

    VIAGRA 25 mg: Each tablet contains 25 mg of sildenafil in the form of citrate.

    VIAGRA 50 mg: Each tablet contains 50 mg of sildenafil in the form of citrate.

    VIAGRA 100 mg: Each tablet contains 100 mg of sildenafil in the form of citrate.

    For excipients, see 6.1.

    03.0 PHARMACEUTICAL FORM

    Film-coated tablets.

    The 25 mg tablets are film-coated and blue in color, have a rounded diamond shape and are marked "PFIZER" on one side and "VGR 25" on the other.

    The 50 mg tablets are film-coated and blue in color, have a rounded diamond shape and are marked "PFIZER" on one side and "VGR 50" on the other.

    The 100 mg tablets are film-coated and blue in color, have a rounded diamond shape and are marked "PFIZER" on one side and "VGR 100" on the other.

    04.0 CLINICAL INFORMATION

    04.1 Therapeutic indications

    Treatment of subjects with erectile dysfunction, or the inability to achieve or maintain an erection suitable for satisfactory sexual activity. Sexual stimulation is required for VIAGRA to be effective.

    04.2 Posology and method of administration

    Oral use.

    Use in adults:

    The recommended dose is 50 mg as needed, taken approximately one hour before sexual activity.

    Based on efficacy and tolerability, the dose can be increased to 100 mg or reduced to 25 mg.

    The maximum recommended dose is 100 mg. The product should not be administered more than once a day. If VIAGRA is taken with meals, the onset of action may be delayed compared to taking it in the fasted state (see Section 5.2).

    Use in the elderly:

    Since sildenafil clearance is reduced in elderly patients (see Section 5.2), a starting dose of 25 mg should be used. Based on efficacy and tolerability, the dose can be increased to 50 mg and 100 mg.

    Use in patients with renal impairment:

    The dosing recommendations described under "Use in adults" also apply to patients with mild to moderate renal impairment (creatinine clearance = 30-80 ml / min).

    Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance

    Use in patients with impaired hepatic function:

    Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis), a 25 mg dose should be considered. Based on efficacy and tolerability, the dose can be increased to 50 mg and 100 mg.

    Use in pediatric patients:

    VIAGRA is not indicated for people under the age of 18.

    Use in patients being treated with other medicinal products:

    With the exception of ritonavir, for which co-administration with sildenafil is not recommended (see Section 4.4) a starting dose of 25 mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors (see Section 4.5).

    04.3 Contraindications

    Hypersensitivity to the active substance or to any of the excipients.

    Consistent with the established effects on the nitric oxide / cyclic guanosine monophosphate (cGMP) pathway (see Section 5.1), sildenafil was found to potentiate the hypotensive effects of nitrates and therefore co-administration with nitric oxide donors ( such as amyl nitrite) or with nitrates in any form is contraindicated.

    Products indicated for the treatment of erectile dysfunction, including sildenafil, 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).

    The safety of use of sildenafil has not been studied in the following patient subgroups and therefore the use of the product is contraindicated in these patients: severe hepatic impairment, hypotension (blood pressure stroke or myocardial infarction and known hereditary degenerative disorders of the retina, such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).

    04.4 Special warnings and appropriate precautions for use

    Before considering drug treatment, a medical history and physical examination should be done in order to diagnose erectile dysfunction and determine the underlying causes of the disease.

    Because there is a percentage of cardiac risk associated with sexual activity, physicians will need to examine the cardiovascular condition of patients before initiating any treatment for erectile dysfunction. Sildenafil possesses vasodilatory properties that result in mild and transient decreases in blood pressure (see Section 5.1) Before prescribing sildenafil, physicians should carefully consider whether these vasodilatory effects may have adverse consequences in patients with certain underlying conditions, especially in association with sexual activity. Patients most sensitive to vasodilatory effects include patients with obstructed systolic output (eg, aortic stenosis, hypertrophic obstructive cardiomyopathy) or those with multiple system atrophy, a rare syndrome manifesting in the form of severely impaired autonomic blood pressure control. .

    VIAGRA potentiates the hypotensive effect of nitrates (see Section 4.3).

    Serious cardiovascular events, including myocardial infarction, angina pectoris intermedia, sudden cardiac death, ventricular arrhythmias, cerebrovascular haemorrhage, transient ischemic attack, hypertension and hypotension have been reported during the marketing phase of the product, in temporal association with the use of VIAGRA. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many events have been reported to occur during or shortly after intercourse and some soon after taking VIAGRA in the absence of sexual activity. It is not possible to determine whether these events are directly related to these or other factors.

    Products indicated for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical deformations of the penis (e.g. angulation, cavernous fibrosis or Peyronie's disease) or in patients with conditions that may predispose to priapism ( e.g. sickle cell anemia, multiple myeloma or leukemia).

    The safety and efficacy of combining sildenafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of these combinations is not recommended.

    Concomitant administration of sildenafil and ritonavir is not recommended (see Section 4.5).

    Sildenafil should be used with caution in patients taking alpha-blockers because concomitant administration may cause symptomatic hypotension in some patients (see Section 4.5). Sildenafil (> 25 mg) should not be used within 4 hours of taking an alpha blocker.

    Studies with human platelets indicate that sildenafil potentiates the antiplatelet effect of sodium nitroprusside in vitro. No information is available regarding the safety of administration of sildenafil in patients with bleeding disorders or with active peptic ulcer. Therefore, sildenafil should be administered to these patients only after a "careful evaluation of the risk-benefit ratio.

    VIAGRA is not indicated for use in women.

    04.5 Interactions with other medicinal products and other forms of interaction

    Effects of other medicinal products on sildenafil

    In vitro studies:

    Sildenafil is metabolised primarily by cytochrome P450 (CYP) isoenzymes 3A4 (major route) and 2C9 (secondary route). Therefore, inhibitors of these isoenzymes may reduce the clearance of sildenafil.

    In vivo studies:

    Pharmacokinetic analysis performed in clinical studies indicates a reduction in sildenafil clearance when co-administered with CYP3A4 inhibitors (eg ketoconazole, erythromycin, cimetidine). Although no increased incidence of adverse events was detected in these patients, when the sildenafil is co-administered with CYP3A4 inhibitors a starting dose of 25 mg should be considered.

    When ritonavir, an HIV protease inhibitor and highly specific cytochrome P450 inhibitor, was co-administered with sildenafil (100 mg single dose), a 300% increase was seen at steady state (500 mg bid) ( 4-fold) in sildenafil Cmax and a 1,000% (11-fold) increase in plasma sildenafil AUC. At 24 hours, sildenafil plasma levels were still approximately 200 ng / mL, compared with approximately 5 ng / ml detected when sildenafil was administered alone. This finding is consistent with the marked effects of ritonavir on a wide range of cytochrome P450 substrates. Sildenafil did not alter the pharmacokinetics of ritonavir. Based on these. pharmacokinetic results, co-administration of sildenafil and ritonavir is not recommended (see Section 4.4.), and in any case the maximum dose of sildenafil should not exceed 25 mg over 48 hours.

    When saquinavir, an HIV protease inhibitor and CYP3A4 inhibitor, was co-administered with sildenafil (100 mg single dose), a 140% increase in sildenafil Cmax was observed at steady state (1200 mg tid). and a 210% increase in sildenafil AUC. Sildenafil did not alter the pharmacokinetics of saquinavir (see Section 4.2). Stronger CYP3A4 inhibitors, such as ketoconazole and itraconazole, are expected to have greater effects.

    When a single 100 mg dose of sildenafil was co-administered with the CYP3A4 specific inhibitor erythromycin, at steady state (500 mg twice daily for 5 days) there was a 182% increase in systemic exposure to sildenafil. (AUC). In healthy male volunteers, there was no effect of azithromycin (500 mg / day for 3 days) on the AUC, Cmax, tmax, elimination constant or half-life of sildenafil or its major circulating metabolite. Concomitant administration of cimetidine ( 800 mg), cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, and sildenafil (50 mg) in healthy volunteers, caused a 56% increase in plasma concentrations of sildenafil.

    Grapefruit juice is a weak inhibitor of CYP3A4 of intestinal wall metabolism and therefore may result in modest increases in plasma levels of sildenafil.

    Single dose administration of antacid (magnesium hydroxide / aluminum hydroxide) did not change the bioavailability of sildenafil.

    Although no specific interaction studies have been conducted with all medicinal products, the population pharmacokinetic analysis did not show any effects on the pharmacokinetics of sildenafil following concomitant administration with CYP2C9 inhibitors (eg tolbutamide, warfarin, phenytoin). CYP2D6 inhibitors (eg selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and similar diuretics, loop diuretics and potassium-sparing diuretics, angiotensin converting enzyme inhibitors, calcium channel blockers, beta-adrenergic receptor antagonists or inducers of CYP450 metabolism (e.g. rifampicin and barbiturates).

    Effects of sildenafil on other medicinal products

    In vitro studies:

    Sildenafil is a weak inhibitor of the cytochrome P450 isoenzymes: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50> 150 microM). As peak plasma concentrations of approximately 1 microM are achieved at recommended doses, VIAGRA is unlikely to alter the clearance of substrates of these isoenzymes.

    There are no data on interactions between sildenafil and non-specific phosphodiesterase inhibitors, such as theophylline or dipyridamole.

    In vivo studies:

    No significant interactions were observed when sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9. Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid (150 mg).

    Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with maximum blood alcohol levels averaging 80 mg / dl.

    Analysis of data for the following classes of antihypertensive drugs revealed no difference in the tolerability profile between patients who took sildenafil and those treated with placebo: diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists , antihypertensives (vasodilators and centrally acting), neuroadrenergic blockers, calcium channel blockers and alpha-adrenoceptor blockers. In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients, the additional reduction in supine systolic blood pressure was 8 mmHg. The corresponding additional reduction in diastolic blood pressure in the supine position was 7 mmHg These additional blood pressure reductions were comparable to those seen when sildenafil was administered alone to healthy volunteers (see Section 5.1).

    Concomitant administration of sildenafil in patients on alpha-blocker therapy may cause symptomatic hypotension in some patients, particularly with higher sildenafil doses (> 25 mg).

    This is most likely to occur within 4 hours after taking sildenafil (see section 4.4 for precautions).

    Sildenafil (100 mg) did not alter the steady-state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are substrates of CYP3A4.

    Consistent with the established effects on the nitric oxide / cGMP pathway (see Section 5.1), sildenafil has been observed to potentiate the hypotensive effects of nitrates and therefore co-administration with nitric oxide donors or nitrates in any form is contraindicated (see Section 4.3).

    04.6 Pregnancy and breastfeeding

    VIAGRA is not indicated for use in women.

    No relevant adverse events were found in reproduction studies in rats and rabbits following oral administration of sildenafil.

    04.7 Effects on ability to drive and use machines

    As dizziness and disturbed vision have been reported in clinical trials with sildenafil, patients should be aware of how they react to VIAGRA before driving or operating machinery.

    04.8 Undesirable effects

    Adverse reactions have been reported in patients treated at the recommended dose regimen in placebo-controlled clinical trials (incidence = 1%). Adverse reactions were mild to moderate and the incidence and severity increased with dose. In clinical trials with fixed doses, dyspepsia (12%) and visual disturbances (11%) occurred more frequently at dose. 100 mg rather than lower doses The most commonly reported adverse events were headache and hot flashes: see Table 1.

    Very common: > 1/10

    Common: > 1/100 and

    Uncommon: > 1/1000 and

    Rare: > 1 / 10,000 and

    Very rare:

    Table 1


    MedDRA Organ Classification Adverse Reaction Sildenafil (%) N = 3350 Placebo (%) N = 2995 Nervous system disorders Very common Common Headache Dizziness 10,8 2,9 2,8 1,0 Common eye disorders Visual disturbances (increased light brightness, blurred vision) Chromatopsia (mild and transient, mainly increased color intensity to the eye) 2,5 1,1 0,4 0,03 Heart Disorders Common Palpitations 1,0 0,2 Vascular system disorders Very common Hot flashes 10,9 1,4 Respiratory, chest and mediastinal disorders Common Nasal congestion 2,1 0,3 Gastrointestinal disorders Common Dyspepsia 3,0 0,4

    There have been reports of muscle aches when sildenafil was administered more frequently than recommended.

    The following uncommon or rare adverse events have been reported during post-marketing surveillance:

    Table 2 shows the frequencies and not the real incidence rates as these cannot be calculated with the accuracy of clinical studies in which the real numbers of treated patients are known.

    Table 2


    Immune system disorders Very rare hypersensitivity reactions (including skin rash) Ocular disorders Uncommon eye pain eye redness / inflammation Cardiac disorders Uncommon tachycardia Very rare myocardial infarction, angina pectoris intermedia, sudden cardiac death, ventricular arrhythmias Vascular system disorders Rare epistaxis, hypotensive episodes after use of sildenafil in combination with alpha-blockers (see Sections 4.4 and 4.5) Very rare syncope, cerebrovascular haemorrhage, hypertension, hypotension (see Section 4.4), transient ischemic attack (see Section 4.4.) Gastrointestinal disorders Uncommon He retched Disorders of the reproductive system and breast Very rare prolonged erections, priapism

    04.9 Overdose

    In volunteer studies with single doses up to 800 mg, adverse reactions were similar to those seen with lower doses, but the incidence rate and severity of events were increased. Administration of 200 mg doses did not result in increased efficacy, but the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances) was increased.

    In the event of an overdose, necessary standard supportive measures should be taken.

    Hemodialysis does not accelerate renal clearance because sildenafil is highly bound to plasma proteins and is not eliminated in the urine.

    05.0 PHARMACOLOGICAL PROPERTIES

    05.1 Pharmacodynamic properties

    Pharmacotherapeutic group: Drugs used in erectile dysfunction. ATC code G04B E03

    Sildenafil represents an oral therapy for erectile dysfunction. Under normal conditions, i.e. in the presence of sexual stimulation, sildenafil restores impaired erectile function by increasing blood flow to the penis.

    The physiological mechanism responsible for penile erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide in turn activates the enzyme guanyl cyclase which causes an increase in guanosine levels. cyclic monophosphate (cGMP), causing smooth muscle relaxation in the corpus cavernosum and thus allowing blood to flow.

    Sildenafil is a potent selective inhibitor of cGMP-specific type 5 phosphodiesterase (PDE5) in the corpus cavernosum, where PDE5 is responsible for the breakdown of cGMP. Sildenafil acts peripherally on erections. Sildenafil does not have a direct relaxing effect on the corpus cavernosum isolated from humans, but it effectively increases the relaxing effect of nitric oxide (NO) on this tissue. When the NO / cGMP pathway is activated, as it does with the sexual stimulation, the inhibition of PDE5 by sildenafil causes an increase in the levels of cGMP in the corpus cavernosum. Therefore, sexual stimulation is required for sildenafil to produce its expected beneficial pharmacological effects.

    In vitro studies have shown that sildenafil has a selectivity for PDE5, which is involved in the erection process. Its effect is higher for PDE5 than for other phosphodiesterases. It has a 10 times higher selectivity for PDE6, which is involved in phototransduction of the retina. At maximum recommended doses, it has 80 times the selectivity for PDE1 and over 700 times for PDE2, 3, 4, 7, 8, 9, 10 and 11. In particular, the selectivity of sildenafil for PDE5 is 4,000 times greater to that for PDE3, the specific cAMP phosphodiesterase isoenzyme involved in the control of cardiac contractility.

    Two clinical studies were conducted to specifically evaluate the time interval after taking the drug within which sildenafil can produce an erection in response to sexual stimulation. In a study conducted with penile plethysmography (RigiScan) in patients with stomach empty, the mean time to onset in sildenafil-treated subjects who had erections with 60% stiffness (sufficient for intercourse) was 25 minutes (range 12-37 minutes). In another study with RigiScan, still 4-5 hours after administration, sildenafil produced an erection in response to sexual stimulation.

    Sildenafil causes mild and transient decreases in blood pressure which, in most cases, do not translate into clinical effects. The mean of the maximum reductions in supine systolic blood pressure following oral administration of 100 mg of sildenafil was 8.4 mmHg. The corresponding change in supine diastolic blood pressure was 5.5 mmHg. These decreases in blood pressure are part of the vasodilatory effects of sildenafil, possibly due to the increased levels of cGMP in smooth vascular muscle.

    Administration of single oral doses of sildenafil up to 100 mg to healthy volunteers produced no clinically relevant effects on ECG. In a study on the haemodynamic effects of a single oral dose of 100 mg sildenafil in 14 patients with severe coronary artery disease (CAD) (stenosis of at least one "coronary artery> 70%), mean resting systolic and diastolic blood pressure values ​​decreased by 7% and 6% respectively from baseline. Mean systolic pulmonary pressure decreased by 9%. Sildenafil did not alter cardiac output and did not impair blood circulation through stenotic coronary arteries.

    No clinically significant differences in angina onset times were observed between sildenafil and placebo in a double-blind, placebo-controlled study of 144 patients with erectile dysfunction and chronic stable angina undergoing stress testing taking usually antianginal drugs (with the exception of nitrates).

    In some subjects, with the aid of the Farnsworth-Munsell 100 HUE test, one hour after the administration of a 100 mg dose, slight and transient alterations in color perception (blue / green) were detected, without evident effects. 2 hours after administration. It is assumed that the mechanism underlying this alteration in color perception is related to the inhibition of PDE6, which is involved in the cascade phototransduction in the retina. Sildenafil does not affect visual acuity or color sense. In a placebo-controlled study in a small number of patients (n = 9) with documented early age-related macular degeneration, the use of sildenafil (single 100 mg dose) showed no clinically significant changes in vision tests (visual acuity, Amsler reticle, ability to perceive colors with simulation of traffic lights, Humprey perimetry and photostress).

    No effect on sperm motility or morphology was observed following administration of single oral doses of 100 mg sildenafil to healthy volunteers.

    Learn more about clinical trials

    In clinical trials, sildenafil was administered to over 3,000 patients aged 19 to 87 years. The following patient groups were included: elderly (21%), patients with hypertension (24%), diabetes mellitus (16%), ischemic heart disease and other cardiovascular diseases (14%), hyperlipidemia (14%), spinal cord injury spinal (6%), depression (5%), transurethral resection of the prostate (5%), radical prostatectomy (4%). The following patient groups were not significantly represented or were excluded from clinical trials: patients undergoing pelvic surgery, patients undergoing radiotherapy, patients with severe renal or hepatic impairment, and patients with specific cardiovascular conditions (see Section 4.3).

    In the fixed dose clinical trials, the percentage of patients who reported improvement was 62% (25 mg), 74% (50 mg) and 82% (100 mg), compared with 25% reported with placebo. In controlled clinical trials, the discontinuation rate due to sildenafil was low and similar to that reported with placebo.

    In all clinical studies, the percentage of patients who reported improvement during sildenafil treatment was as follows: psychogenic erectile dysfunction (84%), mixed erectile dysfunction (77%), organic erectile dysfunction (68%), elderly (67%), diabetes mellitus (59%), ischemic heart disease (69%), hypertension (68%), TURP (61%), radical prostatectomy (43%), spinal cord injury (83%), depression (75 %).The safety and efficacy of sildenafil was maintained in long-term studies.

    05.2 Pharmacokinetic properties

    Absorption:

    Sildenafil is rapidly absorbed. Maximum plasma concentrations are reached within 30 to 120 minutes (mean 60 minutes) of oral administration in the fasted state. The mean absolute bioavailability after oral administration is 41% (range 25-63%). After oral administration of sildenafil, when the drug is used at the recommended dose range (25-100 mg), the AUC and Cmax increase in proportion to the dose.

    When sildenafil is taken with meals, the rate of absorption is reduced with a mean delay in T of 60 minutes and a mean reduction in C of 29%.

    Distribution:

    The mean steady-state volume of distribution of sildenafil (Vd), i.e. distribution into tissues, is 105 l. Following the use of a single 100 mg oral dose, the mean maximum plasma concentration of sildenafil is approximately 440 ng / ml (CV 40%). Since sildenafil (and its major circulating metabolite N-desmethyl) is 96% bound to plasma proteins, resulting in a mean maximum plasma concentration of free sildenafil of 18 ng / ml (38 nM) Protein binding is independent of total drug concentrations.

    In healthy volunteers who received sildenafil (100 mg single dose), less than 0.0002% (mean 188 ng) of the administered dose was detected in the ejaculate obtained 90 minutes after administration.

    Metabolism:

    Sildenafil is mainly metabolised by hepatic microsomal isoenzymes CYP3A4 (major route) and CYP2C9 (secondary route). The main metabolite is derived from the N-demethylation of sildenafil. This metabolite has a selectivity profile for phosphodiesterase similar to that of sildenafil and an in vitro potency for PDE5 equal to approximately 50% of that of the parent drug.

    Plasma concentrations of this metabolite are approximately 40% of those observed for sildenafil. The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 hours.

    Elimination:

    Total body clearance of sildenafil is 41 l / h and terminal half-life is 3-5 hours. After oral or intravenous administration, sildenafil is eliminated as metabolites, mainly in faeces (approximately 80% of the administered oral dose). and to a lesser extent in the urine (approximately 13% of the administered oral dose).

    Pharmacokinetics in particular groups of patients

    Senior citizens:

    In elderly healthy volunteers (= 65 years) a reduction in sildenafil clearance was observed, with plasma concentrations of sildenafil and the active metabolite N-desmethyl approximately 90% higher than those found in younger healthy volunteers (18-45 years). ). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentrations was approximately 40%.

    Kidney failure:

    In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 ml / min), no alterations in the pharmacokinetics of sildenafil were observed following administration of a single 50 mg oral dose. The mean AUC and Cmax of the Ndesmethyl metabolite increased by 126% and 73%, respectively, compared to age-matched volunteers who did not have renal impairment. However, due to the high inter-subject variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance

    Liver failure:

    In volunteers with mild-to-moderate hepatic cirrhosis (Child-Pugh A and B), a reduction in sildenafil clearance was observed, resulting in an increase in AUC (84%) and Cmax (47%), compared to volunteers of comparable age. who did not have hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

    05.3 Preclinical safety data

    Non-clinical data reveal no risk for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive toxicity.

    06.0 PHARMACEUTICAL INFORMATION

    06.1 Excipients

    Internal part: microcrystalline cellulose, calcium hydrogen phosphate (anhydrous), croscarmellose sodium, magnesium stearate.

    Coating: hypromellose, titanium dioxide (E171), lactose, triacetin, indigo carmine aluminum lake (E132).

    06.2 Incompatibility

    Not relevant.

    06.3 Period of validity

    5 years.

    06.4 Special precautions for storage

    Store at a temperature not exceeding 30 ° C.

    Store in the original package to keep away from moisture.

    06.5 Nature of the immediate packaging and contents of the package

    Aclar / Aluminum blisters in packs of 1, 4, 8 or 12 tablets.

    06.6 Instructions for use and handling

    No special instructions.

    07.0 MARKETING AUTHORIZATION HOLDER

    Pfizer Limited, Sandwich, Kent CT13 9NJ, United Kingdom.

    08.0 MARKETING AUTHORIZATION NUMBER

    1 tablet 25 mg - EU / 1/98/077/001 - AIC n ° 034076012 / E

    4 tablets 25 mg - EU / 1/98/077/002 - AIC n ° 034076024 / E

    8 tablets 25 mg - EU / 1/98/077/003 - AIC n ° 034076036 / E

    12 tablets 25 mg - EU / 1/98/077/004 - AIC n ° 034076048 / E

    1 tablet 50 mg - EU / 1/98/077/005 - AIC n ° 034076051 / E

    4 tablets 50 mg - EU / 1/98/077/006 - AIC n ° 034076063 / E

    8 tablets 50 mg - EU / 1/98/077/007 - AIC n ° 034076075 / E

    12 tablets 50 mg - EU / 1/98/077/008 - AIC n ° 034076087 / E

    1 tablet 100 mg - EU / 1/98/077/009 - AIC n ° 034076099 / E

    4 tablets 100 mg - EU / 1/98/077/010 - AIC n ° 034076101 / E

    8 tablets 100 mg - EU / 1/98/077/011 - AIC n ° 034076113 / E

    12 tablets 100 mg - EU / 1/98/077/012 - AIC n ° 034076125 / E

    09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

    14 September 1998/11 November 2003

    10.0 DATE OF REVISION OF THE TEXT

    November 11, 2003

    11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

    12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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