TURBO is indicated in adult men with erectile dysfunction, i.e. with the inability to reach or to maintain an erection suitable for satisfactory sexual activity.

Sexual stimulation is required for TURBO to be effective.

Posology

 

Use in adults

Turbo should be taken as needed about an hour before sexual activity. The recommended dose is 50 mg to be taken on an empty stomach, since concomitant food intake slows down absorption and delays the effect of the orodispersible tablet (see section 5.2).

Based on efficacy and tolerability, the dose can be increased to 100 mg. The maximum dose recommended is 100 mg. For patients who need a dose increase to 100 mg, they must two 50 mg orodispersible tablets should be administered sequentially. The product does not have to be administered more than once a day. If a 25 mg dose is required, use should be recommended of the 25 mg film-coated tablets.

 

Special populations

 

Elderly patients

Dosage adjustments are not required in elderly patients (≥ 65 years).

 

Renal impairment

The dosage recommendations described in the section “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 <30 mL / min), a 25 mg dose should be considered. According to efficacy and tolerability, the dose can be gradually increased to 50 mg and up to 100 mg, as needed.

 

Hepatic impairment

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

 

Pediatric population:

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

 

Use in patients taking other medicines:

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

Before starting sildenafil treatment, to minimize the development of postural hypotension in patients being treated with alpha-blockers, patients should be stabilized with a treatment based on alpha-blockers. In addition, the initiation of treatment must be considered with sildenafil at a dose of 25 mg (see sections 4.4 and 4.5).

 

Method of administration

 

Oral use.

The orodispersible tablet should be placed in the mouth, on the tongue, and allowed to disintegrate before swallow with or without water. The tablet should be taken immediately after removal from the blister. For patients who need a second 50 mg orodispersible tablet to get to a dose of 100 mg, the second tablet should be taken after the first one is completely disintegrated in the mouth.

When the orodispersible tablets are taken with a high-fat meal and not fasting, there is a significant delay in absorption (see section 5.2). It is recommended to take the orodispersible tablets on an empty stomach.

 

Orodispersible tablets can be taken with or without water.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. In accordance with the established effects on the nitric oxide / cyclic guanosine monophosphate metabolic pathway (cGMP) (see section 5.1), sildenafil has been shown 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. Co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulants, such as riociguat, is contraindicated because it could lead to symptomatic hypotension (see paragraph 4.5). Products indicated for the treatment of erectile dysfunction, including sildenafil, should not be used in subjects for whom sexual activity is not recommended (e.g. patients with severe cardiovascular disorders diseases, such as unstable angina or severe heart failure). TURBO is contraindicated in patients who have lost sight in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this event is related or not to previous use of a type 5 phosphodiesterase inhibitor (PDE5) (see section 4.4). The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated until further information is available: severe hepatic impairment, hypotension (blood pressure <90/50 mmHg), recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).

Before considering drug treatment, a medical history must be carried out and an objective examination in order to diagnose erectile dysfunction and determine the causes that may underlie the pathology.

 

Cardiovascular risk factors

Since there is a percentage of cardiac risk associated with sexual activity, before starting any treatment for erectile dysfunction, doctors must examine the cardiovascular condition of patients. Sildenafil possesses vasodilatory properties which result in mild reductions and transient blood pressure (see section 5.1). Before prescribing sildenafil ,Physicians must carefully consider whether these vasodilatory effects may have any negative consequences in patients with certain underlying conditions, especially in combination with sexual activity. Patients most sensitive to vasodilatory effects include patients with obstruction of systolic output (e.g. aortic stenosis, obstructive hypertrophic cardiomyopathy) or those suffering from multiple system atrophy, a rare syndrome that manifests itself in the form of severe impaired autonomic control of blood pressure.

 

TURBO enhances the hypotensive effect of nitrates (see section 4.3).

During the marketing phase of the product, in temporal association with the use of TURBO, Serious cardiovascular events including myocardial infarction, unstable angina, death

sudden cardiac, ventricular arrhythmias, cerebrovascular haemorrhage, transient ischemic attack,

hypertension and hypotension have been reported. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many events have been reported to have occurred during or immediately after sexual intercourse and some immediately after taking TURBO in the absence of sexual activity.

It is not possible to determine whether these events are directly related to these or other factors.

 

Priapism

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

In post-marketing experience with sildenafil, prolonged erections and priapism have been reported.

If an erection persists for more than 4 hours, the patient should immediately seek medical attention. If priapism is not treated immediately penile tissue damage and permanent loss of potency could result.

 

Concomitant use with other PDE5 inhibitors or with other treatments for erectile dysfunction

The safety and efficacy of combining sildenafil with other PDE5 inhibitors, with others treatments for pulmonary arterial hypertension (IAP) containing sildenafil (REVATIO), or with others treatments for erectile dysfunction have not been studied. Therefore, the use of these associations is not recommended.

 

Effects on sight

Cases of visual disturbances have been reported spontaneously in association with the use of sildenafil and

of other PDE5 inhibitors (see section 4.8). Cases of non-arteritic anterior ischemic optic neuropathy, a rare disease, were reported spontaneously and in an observational study in association with the use of sildenafil and other PDE5 inhibitors (see section 4.8). The patients must be warned that in case of any sudden vision problem, they must stop

taking TURBO and immediately consult a doctor (see section 4.3).

 

Concomitant use with ritonavir

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

 

Concomitant use with alpha-blockers

Caution is advised when sildenafil is administered to patients being treated with alpha-blockers as concomitant administration may cause symptomatic hypotension in some sensitive individuals (see section 4.5). This is most likely to occur within 4 hours subsequent to taking sildenafil. Before starting sildenafil treatment, to reduce to

minimal development of postural hypotension, patients should be stabilized from a point of view

hemodynamic with a treatment based on alpha-blockers. The beginning must be treatment with sildenafil at a dose of 25 mg (see section 4.2). Also, doctors must advise patients what to do in the presence of symptoms of postural hypotension.

 

Effect on bleeding

Studies with human platelets indicate that sildenafil potentiates the antiplatelet effect of sodium nitroprusside in vitro. No information is available regarding the safety of the administration of sildenafil in patients with bleeding disorders or with active peptic ulcer.

Therefore, sildenafil should be administered to these patients only after careful evaluation of the risk-benefit ratio.

 

Women

TURBO is not indicated for use in women.

Effects of other medicinal products on sildenafil

In vitro studies

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

In vivo studies

Population pharmacokinetic analysis in clinical studies indicates a reduction in clearance of sildenafil when given together with CYP3A4 inhibitors (e.g. ketoconazole, erythromycin, cimetidine). Although there was no increased incidence in these patients adverse events, when sildenafil is co-administered with CYP3A4 inhibitors it must

consider a starting dose of 25 mg.

 

When ritonavir, an HIV protease inhibitor and highly specific cytochrome inhibitor P450, was administered together with sildenafil (100 mg single dose), at steady state (500 mg twice daily) there was a 300% (4-fold) increase in sildenafil Cmax  and a 1,000% (11-fold) increase in plasma AUC of sildenafil. At 24 hours later, sildenafil plasma levels were still approximately 200 ng / mL, compared with approximately 5 ng / mL detected when sildenafil was administered alone. This figure is in agreement with the effects that ritonavir exerts on a wide range of cytochrome P450 substrates. Sildenafil has not altered ritonavir pharmacokinetics. 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 within 48 hours.

 

When saquinavir, an HIV protease inhibitor and CYP3A4 inhibitor, was co-administered with sildenafil (100 mg single dose), at steady state (1200 mg three times per day) there was a 140% increase in sildenafil Cmax and a 210% increase in the AUC of sildenafil. 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 administered together with erythromycin, a moderate inhibitor of CYP3A4, at steady state (500 mg twice daily for 5 days) there was a 182% increase detected in sildenafil systemic exposure (AUC). In healthy volunteers no effect of azithromycin (500 mg / day for 3 days) on AUC, Cmax,

tmax, elimination constant or half-life of sildenafil or its major circulating metabolite. The concomitant administration of cimetidine (800 mg), cytochrome P450 inhibitor and a nonspecific CYP3A4, 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 it may lead to modest increases in sildenafil plasma levels.

Administration of single doses of antacid (magnesium hydroxide / aluminum hydroxide) has not modified the bioavailability of sildenafil.

Although no specific interaction studies have been conducted with all medicines, the analysis Population pharmacokinetics showed no effect on the pharmacokinetics of sildenafil following concomitant treatment with CYP2C9 inhibitors (e.g. tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (e.g. selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide diuretics and the like, loop diuretics and potassium, angiotensin converting enzyme inhibitors, calcium channel blockers, antagonists beta-adrenergic receptors or inducers of CYP450 metabolism (e.g. rifampicin and barbiturates). In a study conducted on healthy male volunteers, the co-administration of the antagonist endothelin bosentan (an inducer of CYP3A4 [moderate], CYP2C9 and possibly CYP2C19) at steady state (125 mg twice daily) and sildenafil at steady state (80 mg three times daily

day) produced a decrease of 62.6% and 55.4% in the AUC and Cmax of sildenafil respectively. Therefore, concomitant administration of strong CYP3A4 inducers, such as rifampicin, may cause larger decreases in sildenafil plasma concentrations.

 

Nicorandil is a hybrid that works as a nitrate and as a drug that activates potassium channels. In nitrate quality can lead to serious interactions when given together with sildenafil.

 

Effects of sildenafil on other medicinal products

In vitro studies

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50> 150 μM). Since peak plasma concentrations of approximately 1 μM, TURBO 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

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 with nitrates in any form is contraindicated

(see section 4.3).

 

Riociguat: Preclinical studies have shown an additive systemic blood pressure reducing effect when PDE5 inhibitors have been combined with riociguat. Clinical studies have shown that riociguat increases the hypotensive effect of PDE5 inhibitors. There was no evidence of a clinical effect favorable association in the population studied. The concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section 4.3).

Concomitant administration of sildenafil in patients on alpha-blocker therapy may cause symptomatic hypotension in some sensitive individuals. This is most likely to occur by 4 hours after taking sildenafil (see sections 4.2 and 4.4). In three direct interaction studies the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg or 100 mg) were co-administered in patients with benign prostatic hypertrophy (BPH) stabilized with doxazosin-based therapy. Mean reductions were observed in these population studies

additional supine pressure of 7/7 mmHg, 9/5 mmHg and 8/4 mmHg respectively and mean additional reductions in standing blood pressure of 6/6 mmHg respectively, 11/4 mmHg and 4/5 mmHg. When sildenafil and doxazosin were administered together in patients stabilized with doxazosin therapy have rarely been reported

reported symptomatic postural hypotension. These cases included dizziness and confusion of the mind, but not syncope.

No significant interactions were observed when sildenafil (50 mg) was administered together with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9.

Sildenafil (50 mg) did not enhance the increase in bleeding time caused by the acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with levels

maximum blood alcohol levels corresponding on average to 80 mg / dl.

The analysis of data relating to the following classes of antihypertensive drugs did not reveal any difference in tolerability profile between patients who took sildenafil and those treated with placebo: diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensives (vasodilator and centrally acting), neuroadrenergic blockers, calcium channel blockers and alpha adrenoceptors. During a specific interaction study, in which sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients, the additional reduction in blood pressure

supine systolic was 8 mmHg. The corresponding additional reduction on the Supine diastolic blood pressure was 7 mmHg.

These additional blood pressure reductions were comparable to those seen when sildenafil was administered as monotherapy to healthy volunteers (see section 5.1).

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

In healthy male volunteers, steady state sildenafil (80 mg three times daily) caused an increase by 49.8% of the AUC of bosentan and a 42% increase in the Cmax of bosentan (125 mg twice daily day).

The use of TURBO in women is not indicated.

There are no adequate and well-controlled studies on the use of the medicine during pregnancy or during breastfeeding.

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

No effect on sperm motility or morphology was observed following the administration of single oral doses of 100 mg sildenafil to healthy volunteers (see section 5.1)

TURBO may have a slight influence on the ability to drive and use machines.

Since dizziness and visual disturbances have been reported in clinical trials with sildenafil,

patients should be aware of how react to TURBO before driving and operating machines.

Summary of the safety profile

The safety profile of TURBO is based on 9570 patients treated with the dosing regimen recommended in 74 double-blind placebo-controlled clinical trials. The most adverse reactions commonly reported in patients treated with sildenafil in clinical trials are headache, flushing, dyspepsia, nasal congestion, dizziness, nausea, flushing, visual discomfort, cyanopsia and blurred vision.

Adverse reactions from post-marketing surveillance have been collected from a period

estimated> 10 years. As not all adverse reactions are reported to the holder of the marketing authorization and included in the pharmacovigilance database, the frequencies of these reactions cannot be reliably established.

 

Tabular list of adverse reactions

The table below lists all clinically important adverse reactions, which occurred and verified in clinical trials with an incidence higher than that of placebo and are divided by system organ class and frequency (very common (≥1 / 10), common (≥1 / 100 to <1/10), uncommon (≥1 / 1,000 to <1/100), rare (≥1 / 10,000 to <1 / 1,000).

Within each frequency class, the undesirable effects are reported in order of severity decreasing.

 

Table 1: Clinically important adverse reactions reported with an incidence greater than that of placebo in controlled clinical trials and clinically adverse reactions important ones reported during post-marketing surveillance.

 

System Organ class	Very common (³ 1/10)	Common (³ 1/100 and <1/10)	Uncommon (³ 1/1000 and <1/100)	Rare (³ 1/10,000 and <1/1000)
Infections and infestations			Rhinitis
Immune system disorders			Hypersensitivity
Nervous system disorders	Headache	Dizziness	Somnolence, hypoesthesia	Cerebrovascular accidents, transient ischemic attack, convulsions *, recurrent convulsions *, syncope
Eye disorders		Altered perception of colors **, visual disturbances, blurred vision	Lacrimation disorders ***, eye pain, photophobia, photopsia, ocular hyperaemia, increased perception of light, conjunctivitis	Non-arteritic anterior ischemic optic neuropathy (NAION) *, retinal vascular occlusion *, retinal haemorrhage, arteriosclerotic retinopathy, retinal pathology, glaucoma, visual field defects, diplopia, reduced visual acuity, myopia, asthenopia, fly flies, pathology of the iris, mydriasis, halo vision, eye edema, eye swelling, eye disorders, conjunctival hyperaemia, eye irritation, abnormal eye sensitivity, eyelid edema, discoloration of the sclera
Ear and labyrinth disorders			Vertigo, tinnitus	Deafness
Cardiac disorders			Tachycardia; Palpitations	Sudden cardiac death *, heart attack myocardial, ventricular arrhythmia *, atrial fibrillation, unstable angina
Vascular disorders		Hot flush; Flushing	Hypotension
Respiratory, thoracic and mediastinal disorders		Nasal congestion	Epistaxis; Sinus congestion	Throat tightness; Nasal dryness; Nasal oedema
Gastrointestinal disorders		Nausea; Dyspepsia	Gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth	Hypoaesthesia oral
Skin and subcutaneous tissue disorders			Rash	Stevens-Johnson Syndrome (SJS) *, necrotic epidermolysis toxic (TEN) *
Musculoskeletal and connective tissue disorders			Myalgia; Pain in extremity
Renal and urinary disorders			Hematuria
Reproductive system and breast disorders				Penile haemorrhage, priapism *, haematospermia, prolonged erections
General disorders and administration site conditions			Chest pain, fatigue, feeling of heat	Irritability
Investigations			Heart rate increased

 

* Reported only during post-marketing surveillance.

** Distortions of color vision: Chloropsia, achromatopsia, Cyanopsia, Erythropsia and Xantopsia

*** Lacrimation Disorders: Dry eye, lacrimation disorders and increased tearing

Reporting of suspected adverse reactions

 

The National Pharmacovigilance Center (NPC):

Fax: +966-11-205-7662

Call NPC at +966-11-2038222, Ext 2317-2356-2340

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

In single dose studies in volunteers up to 800 mg, adverse reactions were similar to those seen with lower doses, but the incidence rate and severity of events were increased.

The administration of 200 mg doses did not result in an increase in efficacy, but the incidence of adverse reactions (headache, hot flashes, dizziness, dyspepsia, nasal congestion, visual disturbances) increased.

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

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

Pharmacotherapeutic group: urologicals; drugs used for erectile dysfunction. ATC code G04B E03.

 

Mechanism of action

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 the levels of cyclic guanosine monophosphate (cGMP), producing relaxation of smooth muscle in the corpus cavernosum and thus allowing the blood supply.

 

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 occurs with sexual stimulation, the inhibition of PDE5 by sildenafil causes an increase in cGMP levels in the corpus cavernosum. Therefore, sexual stimulation is required for sildenafil to produce its expected beneficial pharmacological effects.

 

Pharmacodynamic 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-fold selectivity for PDE6, which is involved in phototransduction of the retina. At maximum recommended doses, it has 80-fold selectivity for PDE1 and over 700-fold for PDE2, 3, 4, 7, 8, 9, 10 and 11. Specifically, sildenafil's selectivity for PDE5 is 4,000-fold higher to that for PDE3, the specific cAMP phosphodiesterase isoenzyme involved in the control of cardiac contractility.

 

Clinical efficacy and safety

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 the sexual stimulus. In a study conducted with penile plethysmography (RigiScan) in patients on an empty stomach, 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 blood pressure reductions 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 conducted on 14 patients with severe coronary artery disease (CAD) (stenosis of at least one coronary artery> 70%), the mean resting systolic and diastolic blood pressure 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.

 

A double-blind, placebo-controlled study evaluated 144 patients with erectile dysfunction and chronic stable angina undergoing exercise testing who regularly took antianginal medicines (with the exception of nitrates). The results showed no clinically relevant differences between sildenafil and placebo with regard to the time taken to limit angina.

 

In some subjects, with the aid of the Farnsworth-Munsell 100 HUE test, slight and transient changes in color perception (blue / green) were detected one hour after the administration of a dose of 100 mg, 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) did not show clinically significant changes in the 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 (see section 4.6).

 

Learn more about clinical trials

In clinical trials, sildenafil has been administered to over 8000 patients aged 19 to 87 years. The following patient groups were included: elderly (19.9%), patients with hypertension (30.9%), diabetes mellitus (20.3%), ischemic heart disease (5.8%), hyperlipidemia (19.8 %), spinal cord injury (0.6%), depression (5.2%), transurethral resection of the prostate (3.7%), radical prostatectomy (3.3%). The following patient groups were not significantly

represented or 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.

 

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies for the treatment of erectile dysfunction with TURBO in all subsets of the pediatric population. See section 4.2 for information on pediatric use.

Absorption

Sildenafil is rapidly absorbed. Maximum plasma concentrations are reached within 30-120 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), AUC and C increase in proportion to the dose.

When the film-coated tablets are taken with meals, the absorption rate of sildenafil is reduced with a mean delay in tmax of 60 minutes and a mean reduction in Cmax of 29%.

 

In a clinical study conducted on 36 healthy males aged 45 or older, the 50 mg orodispersible tablets taken without water were shown to be bioequivalent to the 50 mg film-coated tablets. In the same study, the AUC was unchanged, but the mean Cmax was 14% lower when the 50 mg orodispersible tablets were administered with water compared to the 50 mg film-coated tablets.

 

When the orodispersible tablets are taken with a high-fat meal, the absorption rate of sildenafil is reduced, with a median delay in T of approximately 3.4 hours and a reduction in mean C and AUC of respectively. approximately 59% and 12%, compared with the administration of orodispersible tablets in the fasted state (see section 4.2).

 

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, this results in a mean maximum free sildenafil plasma concentration of 18 ng / mL (38 nM).

Protein binding is independent of total drug concentrations.

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

 

Biotransformation

Sildenafil is primarily 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 metabolized, with a terminal half-life of approximately 4 hours.

 

Elimination

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

 

Pharmacokinetics in special patient groups :

 

Elderly

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% above 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%.

 

Renal Insufficiency

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 metabolite N-desmethyl increased by up to 126% and up to 73%, respectively, compared to comparable age 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 <30 mL / min) a reduction in sildenafil clearance was observed, resulting in mean increases in AUC (100%) and Cmax (88%) compared to comparable age volunteers who they did not have renal impairment. Furthermore, the AUC and Cmax of the N-desmethyl metabolite increased significantly, by 200% and 79%, respectively.

 

Hepatic insufficiency

In volunteers with mild-to-moderate liver 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 which did not show hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Non-clinical data reveal no special risks for humans based on conventional studies of pharmacological safety, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive and developmental toxicity.

Mannitol

Microcrystalline cellulose

Crospovidone

Croscarmellose sodium

Sucralose

Povidone K-30

Lemon Flavour

Peppermint flavour (C-7531)

Peppermint flavour P96511-71

Magnesium stearate

Not applicable.

2 years

Store below 30° C

Store in the original carton.

Alu/Alu Blister pack 4’s count and 4 tablets per box.

Keep all medicine out of reach and sight of children.