SILDENAFIL ACTAVIS 100mg tablets medication leaflet

Sildenafil Actavis 25 mg film-coated tablets

Sildenafil Actavis 50 mg film-coated tablets

Sildenafil Actavis 100 mg film-coated tablets

Each tablet contains sildenafil citrate equivalent to 25, 50 or 100 mg of sildenafil.

Sildenafil Actavis 25 mg tablets

Each tablet contains 62.38 mg lactose (as monohydrate).

Sildenafil Actavis 50 mg tablets

Each tablet contains 124.76 mg lactose (as monohydrate).

Sildenafil Actavis 100 mg tablets

Each tablet contains 249.52 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Sildenafil Actavis 25 mg film-coated tablets

Sildenafil Actavis 25 mg film-coated tablets are blue elliptical, biconvex, 10.0 x 5.0 mm and marked“SL25” on one side.

Sildenafil Actavis 50 mg film-coated tablets

Sildenafil Actavis 50 mg film-coated tablets are blue elliptical, biconvex, 13.0 x 6.5 mm and marked“SL50” on one side.

Sildenafil Actavis 100 mg film-coated tablets

Sildenafil Actavis 100 mg film-coated tablets are blue elliptical, biconvex, 17.0 x 8.5 mm and marked“SL100” on one side.

Sildenafil Actavis is indicated in adult men with erectile dysfunction, which is the inability to achieveor maintain a penile erection sufficient for satisfactory sexual performance.

In order for Sildenafil Actavis to be effective, sexual stimulation is required.

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

Based on efficacy and tolerability, the dose may be increased to 100 mg or decreased to 25 mg. Themaximum recommended dose is 100 mg. The maximum recommended dosing frequency is once perday. If Sildenafil Actavis is taken with food, the onset of activity may be delayed compared to thefasted state (see section 5.2).

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

The dosing recommendations described in ‘Use in adults’ apply to patients with mild to moderaterenal 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. Based on efficacy and tolerability, the dose may beincreased step-wise to 50 mg up to 100 mg as necessary.

Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis) a 25 mg doseshould be considered. Based on efficacy and tolerability, the dose may be increased step-wise to50 mg up to100 mg as necessary.

Sildenafil Actavis is not indicated for individuals below 18 years of age.

Use in patients taking other medicinal products

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

In order to minimise the potential of developing postural hypotension in patients receivingalpha-blocker treatment, patients should be stabilised on alpha-blocker therapy prior to initiatingsildenafil treatment. In addition, initiation of sildenafil at a dose of 25 mg should be considered (seesections 4.4 and 4.5).

For oral use.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP)pathway (see section 5.1), sildenafil was shown to potentiate the hypotensive effects of nitrates, and itsco-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is thereforecontraindicated.

The co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators,such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section4.5).

Agents for the treatment of erectile dysfunction, including sildenafil, should not be used in men forwhom sexual activity is inadvisable (e.g. patients with severe cardiovascular disorders such asunstable angina or severe cardiac failure).

Sildenafil Actavis is contraindicated in patients who have loss of vision in one eye because ofnon-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was inconnection or not with previous PDE5 inhibitor exposure (see section 4.4).

The safety of sildenafil has not been studied in the following sub-groups of patients and its use istherefore contraindicated: severe hepatic impairment, hypotension (blood pressure <90/50 mmHg),recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorderssuch as retinitis pigmentosa (a minority of these patients have genetic disorders of retinalphosphodiesterases).

A medical history and physical examination should be undertaken to diagnose erectile dysfunction anddetermine potential underlying causes, before pharmacological treatment is considered.

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascularstatus of their patients, since there is a degree of cardiac risk associated with sexual activity. Sildenafilhas vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 5.1).

Prior to prescribing sildenafil, physicians should carefully consider whether their patients with certainunderlying conditions could be adversely affected by such vasodilatory effects, especially incombination with sexual activity. Patients with increased susceptibility to vasodilators include thosewith left ventricular outflow obstruction (e.g., aortic stenosis, hypertrophic obstructivecardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as severelyimpaired autonomic control of blood pressure.

Sildenafil Actavis potentiates the hypotensive effect of nitrates (see section 4.3).

Serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death,ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension andhypotension have been reported post-marketing in temporal association with the use of sildenafil.

Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many events werereported to occur during or shortly after sexual intercourse and a few were reported to occur shortlyafter the use of sildenafil without sexual activity. It is not possible to determine whether these eventsare related directly to these factors or to other factors.

Agents for the treatment of erectile dysfunction, including sildenafil, should be used with caution inpatients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or

Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (suchas sickle cell anaemia, multiple myeloma or leukaemia).

Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. Inthe event of an erection that persists longer than 4 hours, the patient should seek immediate medicalassistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potencycould result.

The safety and efficacy of combinations of sildenafil with other PDE5 inhibitors, or other pulmonaryarterial hypertension (PAH) treatments containing sildenafil (REVATIO), or other treatments forerectile dysfunction have not been studied. Therefore the use of such combinations is notrecommended.

Cases of visual defects have been reported spontaneously in connection with the intake of sildenafiland other PDE5 inhibitors (see section 4.8). Cases of non-arteritic anterior ischaemic optic neuropathy,a rare condition have been reported spontaneously and in an observational study in connection withthe intake of sildenafil and other PDE5 inhibitors (see section 4.8). Patients should be advised that inthe event of any sudden visual defect, they should stop taking Sildenafil Actavis and consult aphysician immediately (see section 4.3).

Co-administration of sildenafil with ritonavir is not advised (see section 4.5).

Caution is advised when sildenafil is administered to patients taking an alpha-blocker, as theco-administration may lead to symptomatic hypotension in a few susceptible individuals (seesection 4.5). This is most likely to occur within 4 hours post sildenafil dosing. In order to minimise thepotential for developing postural hypotension, patients should be hemodynamically stable onalpha-blocker therapy prior to initiating sildenafil treatment. Initiation of sildenafil at a dose of 25 mgshould be considered (see section 4.2). In addition, physicians should advise patients what to do in theevent of postural hypotensive symptoms.

Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodiumnitroprusside in vitro. There is no safety information on the administration of sildenafil to patients withbleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to thesepatients only after careful benefit-risk assessment.

Sildenafil Actavis is not indicated for use by women.

Excipents

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to sayessentially ‘sodium-free’.

Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (majorroute) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafilclearance and inducers of these isoenzymes may increase sildenafil clearance.

Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearancewhen co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine).

Although no increased incidence of adverse events was observed in these patients, when sildenafil isadministered concomitantly with CYP3A4 inhibitors, a starting dose of 25 mg should be considered.

Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, atsteady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in a 300% (4-fold)increase in sildenafil Cmax and a 1,000% (11-fold) increase in sildenafil plasma AUC. At 24 hours, theplasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mLwhen sildenafil was administered alone. This is consistent with ritonavir’s marked effects on a broadrange of P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics. Based on thesepharmacokinetic results co-administration of sildenafil with ritonavir is not advised (see section 4.4)and in any event the maximum dose of sildenafil should under no circumstances exceed 25 mg within48 hours.

Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state(1200 mg three times a day) with sildenafil (100 mg single dose) resulted in a 140% increase insildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavirpharmacokinetics (see section 4.2). Stronger CYP3A4 inhibitors such as ketoconazole anditraconazole would be expected to have greater effects.

When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182% increase in sildenafilsystemic exposure (AUC). In normal healthy male volunteers, there was no evidence of an effect ofazithromycin (500 mg daily for 3 days) on the AUC, Cmax, tmax, elimination rate constant, orsubsequent half-life of sildenafil or its principal circulating metabolite. Cimetidine (800 mg), acytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, caused a 56% increase in plasmasildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers.

Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modestincreases in plasma levels of sildenafil.

Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailabilityof sildenafil.

Although specific interaction studies were not conducted for all medicinal products, populationpharmacokinetic analysis showed no effect of concomitant treatment on sildenafil pharmacokineticswhen grouped as CYP2C9 inhibitors (such as tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors(such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and relateddiuretics, loop and potassium sparing diuretics, angiotensin converting enzyme inhibitors, calciumchannel blockers, beta-adrenoreceptor antagonists or inducers of CYP450 metabolism (such asrifampicin, barbiturates). In a study of healthy male volunteers, co-administration of the endothelinantagonist, bosentan, (an inducer of CYP3A4 [moderate], CYP2C9 and possibly of CYP2C19) atsteady state (125 mg twice a day) with sildenafil at steady state (80 mg three times a day) resulted in62.6% and 55.4% decrease in sildenafil AUC and Cmax, respectively. Therefore, concomitantadministration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases inplasma concentrations of sildenafil.

Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it hasthe potential to result in a serious interaction with sildenafil.

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4(IC50>150 µM). Given sildenafil peak plasma concentrations of approximately 1 µM afterrecommended doses, it is unlikely that Sildenafil Actavis will alter the clearance of substrates of theseisoenzymes.

There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such astheophylline or dipyridamole.

Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil wasshown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxidedonors or nitrates in any form is therefore contraindicated (see section 4.3).

Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment thehypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of thecombination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, includingsildenafil, is contraindicated (see section 4.3).

Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead tosymptomatic hypotension in a few susceptible individuals. This is most likely to occur within 4 hourspost sildenafil dosing (see sections 4.2 and 4.4). In three specific drug-drug interaction studies, thealpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administeredsimultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy.

In these study populations, mean additional reductions of supine blood pressure of 7/7 mmHg,9/5 mmHg, and 8/4 mmHg, and mean additional reductions of standing blood pressure of 6/6 mmHg,11/4 mmHg, and 4/5 mmHg, respectively, were observed. When sildenafil and doxazosin wereadministered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reportsof patients who experienced symptomatic postural hypotension. These reports included dizziness andlight-headedness, but not syncope.

No significant interactions were shown 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 acetyl salicylic acid(150 mg).

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

Pooling of the following classes of antihypertensive medication: diuretics, beta-blockers,

ACE inhibitors, angiotensin II antagonists, antihypertensive medicinal products (vasodilator andcentrally-acting), adrenergic neurone blockers, calcium channel blockers and alpha-adrenoceptorblockers, showed no difference in the side effect profile in patients taking sildenafil compared toplacebo treatment. In a specific interaction study, where sildenafil (100 mg) was co-administered withamlodipine in hypertensive patients, there was an additional reduction on supine systolic bloodpressure of 8 mmHg. The corresponding additional reduction in supine diastolic blood pressure was7 mmHg. These additional blood pressure reductions were of a similar magnitude to those seen whensildenafil was administered alone to healthy volunteers (see section 5.1).

Addition of a single dose of sildenafil to sacubitril/valsartan at steady state in patients withhypertension was associated with a significantly greater blood pressure reduction compared toadministration of sacubitril/valsartan alone. Therefore, caution should be exercised when sildenafil isinitiated in patients treated with sacubitril/valsartan.

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

In healthy male volunteers, sildenafil at steady state (80 mg t.i.d.) resulted in a 49.8% increase inbosentan AUC and a 42% increase in bosentan Cmax (125 mg b.i.d.).

Sildenafil Actavis is not indicated for use by women.

There are no adequate and well-controlled studies in pregnant or breast-feeding women.

No relevant adverse effects were found in reproduction studies in rats and rabbits following oraladministration of sildenafil.

There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil inhealthy volunteers (see section 5.1).

No studies on the effects on the ability to drive and use machines have been performed.

As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be awareof how they react to Sildenafil Actavis, before driving or operating machinery.

The safety profile of sildenafil is based on 9,570 patients in 74 double-blind placebo-controlledclinical studies. The most commonly reported adverse reactions in clinical studies among sildenafiltreated patients were headache, flushing, dyspepsia, nasal congestion, dizziness, nausea, hot flush,visual disturbance, cyanopsia and vision blurred.

Adverse reactions from post-marketing surveillance has been gathered covering an estimated period>10 years. Because not all adverse reactions are reported the frequencies of these reactions cannot bereliably determined.

In the table below all medically important adverse reactions, which occurred in clinical trials at anincidence greater than placebo are listed 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)).

In addition, the frequency of medically important adverse reactions reported from post-marketingexperience is included as not known.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Medically important adverse reactions reported at an incidence greater than placebo incontrolled clinical studies and medically important adverse reactions reported throughpost-marketing surveillance

System Organ Very Common Uncommon Rare

Class common (≥ 1/100 and (≥ 1/1000 and (≥ 1/10000 and(≥ 1/10) <1/10) <1/100) <1/1000

Infections and Rhinitisinfestations

Immune system Hypersensitivitydisorders

System Organ Very Common Uncommon Rare

Class common (≥ 1/100 and (≥ 1/1000 and (≥ 1/10000 and(≥ 1/10) <1/10) <1/100) <1/1000

Nervous system Headache Dizziness Somnolence, Cerebrovasculardisorders Hypoaesthesia accident,

Transientischaemic attack,

Seizure,*

Seizurerecurrence,*

Eye disorders Visual colour Lacrimation Non-arteriticdistortions**, disorders***, anterior ischaemic

Visual Eye pain, optic neuropathydisturbance, Photophobia, (NAION), *

Vision Photopsia, Retinal vascularblurred Ocular occlusion,*hyperaemia, Retinal

Visual haemorrhage,brightness, Arteriosclerotic

Conjunctivitis retinopathy,

Retinal disorder,

Glaucoma,

Visual fielddefect,

Diplopia,

Visual acuityreduced,

Myopia,

Asthenopia,

Vitreous floaters,

Iris disorder,

Mydriasis,

Halo vision,

Eye oedema,

Eye swelling,

Eye disorder,

Conjunctivalhyperaemia,

Eye irritation,

Abnormalsensation in eye,

Eyelid oedema,

Scleraldiscoloration

Ear and Vertigo, Deafnesslabyrinth Tinnitusdisorders

System Organ Very Common Uncommon Rare

Class common (≥ 1/100 and (≥ 1/1000 and (≥ 1/10000 and(≥ 1/10) <1/10) <1/100) <1/1000

Cardiac Tachycardia, Sudden cardiacdisorders Palpitations death,*

Myocardialinfarction,

Ventriculararrhythmia,*

Atrial fibrillation,

Unstable angina

Vascular Flushing, Hypertension,disorders Hot flush Hypotension

Respiratory, Nasal Epistaxis, Throat tightness,thoracic and congestion Sinus congestion Nasal oedema,mediastinal Nasal drynessdisorders

Gastrointestinal Nausea, Gastro Hypoaesthesiadisorders Dyspepsia oesophagael oralreflux disease,

Vomiting,

Abdominal painupper,

Dry mouth

Skin and Rash Stevens-Johnsonsubcutaneous Syndrome (SJS),*tissue disorders Toxic Epidermal

Necrolysis(TEN)*

Musculoskeletal Myalgia,and connective Pain in extremitytissue disorders

Renal and Haematuriaurinarydisorders

Reproductive Penilesystem and haemorrhage,breast disorders Priapism,*

Haematospermia,

Erectionincreased

General Chest pain, Irritabilitydisorders and Fatigue,administration Feeling hotsite conditions

System Organ Very Common Uncommon Rare

Class common (≥ 1/100 and (≥ 1/1000 and (≥ 1/10000 and(≥ 1/10) <1/10) <1/100) <1/1000

Investigations Heart rateincreased

*Reported during post-marketing surveillance only

**Visual colour distortions: Chloropsia, Chromatopsia, Cyanopsia, Erythropsia and Xanthopsia

***Lacrimation disorders: Dry eye, Lacrimal disorder and Lacrimation increased

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In single dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen atlower doses, but the incidence rates and severities were increased. Doses of 200 mg did not result inincreased efficacy but the incidence of adverse reactions (headache, flushing, dizziness, dyspepsia,nasal congestion, altered vision) was increased.

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis isnot expected to accelerate clearance as sildenafil is highly bound to plasma proteins and not eliminatedin the urine.

Pharmacotherapeutic group: Urologicals; Drugs used in erectile dysfunction, ATC Code: G04BE03.

Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i.e. with sexual stimulation,it restores impaired erectile function by increasing blood flow to the penis.

The physiological mechanism responsible for erection of the penis involves the release of nitric oxide(NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzymeguanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP),producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in thecorpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheralsite of action on erections. Sildenafil has no direct relaxant effect on isolated human corpuscavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMPpathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results inincreased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order forsildenafil to produce its intended beneficial pharmacological effects.

Studies in vitro have shown that sildenafil is selective for PDE5, which is involved in the erectionprocess. Its effect is more potent on PDE5 than on other known phosphodiesterases. There is a 10-foldselectivity over PDE6 which is involved in the phototransduction pathway in the retina. At maximumrecommended doses, there is an 80-fold selectivity over PDE1, and over 700-fold over PDE2, 3, 4, 7,8, 9, 10 and 11. In particular, sildenafil has greater than 4,000-fold selectivity for PDE5 over PDE3,the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility.

Two clinical studies were specifically designed to assess the time window after dosing during whichsildenafil could produce an erection in response to sexual stimulation. In a penile plethysmography(RigiScan) study of fasted patients, the median time to onset for those who obtained erections of 60%rigidity (sufficient for sexual intercourse) was 25 minutes (range 12-37 minutes) on sildenafil. In aseparate RigiScan study, sildenafil was still able to produce an erection in response to sexualstimulation 4-5 hours post-dose.

Sildenafil causes mild and transient decreases in blood pressure which, in the majority of cases, do nottranslate into clinical effects. The mean maximum decreases in supine systolic blood pressurefollowing 100 mg oral dosing of sildenafil was 8.4 mmHg. The corresponding change in supinediastolic blood pressure was 5.5 mmHg. These decreases in blood pressure are consistent with thevasodilatory effects of sildenafil, probably due to increased cGMP levels in vascular smooth muscle.

Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevanteffects on ECG.

In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients withsevere coronary artery disease (CAD) (>70% stenosis of at least one coronary artery), the mean restingsystolic and diastolic blood pressures decreased by 7% and 6% respectively compared to baseline.

Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiacoutput, and did not impair blood flow through the stenosed coronary arteries.

A double-blind, placebo-controlled exercise stress trial evaluated 144 patients with erectiledysfunction and chronic stable angina who regularly received anti-anginal medicinal products (exceptnitrates). The results demonstrated no clinically relevant differences between sildenafil and placebo intime to limiting angina.

Mild and transient differences in colour discrimination (blue/green) were detected in some subjectsusing the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evidentafter 2 hours post-dose. The postulated mechanism for this change in colour discrimination is relatedto inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil hasno effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patientswith documented early age-related macular degeneration (n=9), sildenafil (single dose, 100 mg)demonstrated no significant changes in the visual tests conducted (visual acuity, Amsler grid, colourdiscrimination simulated traffic light, Humphrey perimeter and photostress).

There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil inhealthy volunteers (see section 4.6).

In clinical trials sildenafil was administered to more than 8000 patients aged 19-87. The followingpatient groups were represented: elderly (19.9%), patients with hypertension (30.9%), diabetesmellitus (20.3%), ischaemic heart disease (5.8%), hyperlipidaemia (19.8%), spinal cord injury (0.6%),depression (5.2%), transurethral resection of the prostate (3.7%), radical prostatectomy (3.3%). Thefollowing groups were not well represented or excluded from clinical trials: patients with pelvicsurgery, patients post-radiotherapy, patients with severe renal or hepatic impairment and patients withcertain cardiovascular conditions (see section 4.3).

In fixed dose studies, the proportions of patients reporting that treatment improved their erections were62% (25 mg), 74% (50 mg) and 82% (100 mg) compared to 25% on placebo. In controlled clinicaltrials, the discontinuation rate due to sildenafil was low and similar to placebo.

Across all trials, the proportion of patients reporting improvement on sildenafil were as follows:psychogenic erectile dysfunction (84%), mixed erectile dysfunction (77%), organic erectiledysfunction (68%), elderly (67%), diabetes mellitus (59%), ischaemic 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.

The European Medicines Agency has waived the obligation to submit the results of studies with thereference medicinal product containing sildenafil in all subsets of the paediatric population for thetreatment of erectile dysfunction. See 4.2 for information on paediatric use.

Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oralbioavailability is 41% (range 25-63%). After oral dosing of sildenafil AUC and Cmax increase inproportion with dose over the recommended dose range (25-100 mg).

When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in tmax of60 minutes and a mean reduction in Cmax of 29%.

The mean steady state volume of distribution (Vd) for sildenafil is 105 l, indicating distribution into thetissues. After a single oral dose of 100 mg, the mean maximum total plasma concentration of sildenafilis approximately 440 ng/mL (CV 40%). Since sildenafil (and its major circulating N-desmethylmetabolite) is 96% bound to plasma proteins, this results in the mean maximum free plasmaconcentration for sildenafil of 18 ng/mL (38 nM). Protein binding is independent of total drugconcentrations.

In healthy volunteers receiving sildenafil (100 mg single dose), less than 0.0002% (average 188 ng) ofthe administered dose was present in ejaculate 90 minutes after dosing.

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepaticmicrosomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil.

This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potencyfor PDE5 approximately 50% that of the parent drug. Plasma concentrations of this metabolite areapproximately 40% of those seen for sildenafil. The N-desmethyl metabolite is further metabolised,with a terminal half-life of approximately 4 h.

The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half-life of 3-5 h. Aftereither oral or intravenous administration, sildenafil is excreted as metabolites predominantly in thefaeces (approximately 80% of administered oral dose) and to a lesser extent in the urine(approximately 13% of administered oral dose).

Healthy, elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting inapproximately 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolitecompared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasmaprotein binding, the corresponding increase in free sildenafil plasma concentration was approximately40%.

In volunteers with mild to moderate renal impairment (creatinine clearance=30-80 mL/min), thepharmacokinetics of sildenafil were not altered after receiving a 50 mg single oral dose. The mean

AUC and Cmax of the N-desmethyl metabolite increased 126% and 73% respectively, compared toage-matched volunteers with no renal impairment. However, due to high inter-subject variability,these differences were not statistically significant. In volunteers with severe renal impairment(creatinine clearance <30 mL/min), sildenafil clearance was reduced, resulting in mean increases in

AUC and Cmax of 100% and 88% respectively compared to age-matched volunteers with no renalimpairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased79% and 200% respectively.

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh A and B) sildenafil clearance wasreduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteerswith no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impairedhepatic function have not been studied.

Non-clinical data revealed no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity toreproduction and development.

Lactose monohydrate

Microcrystalline cellulose

Povidone K29-32

Croscarmellose sodium

Magnesium stearate

Film-coat:

Hypromellose

Titanium dioxide (E171)

Macrogol 6000

Indigo carmine aluminium lake (E132)

Not applicable.

3 years.

Store below 30°C.

Sildenafil Actavis 25 mg film-coated tablets

PVC-PVDC/Aluminium blisters in cartons of 1, 2, 4, 8, 12 or 24 tablets.

Sildenafil Actavis 50 mg film-coated tablets

PVC-PVDC/Aluminium blisters in cartons of 1, 2, 4, 8, 12 or 24 tablets.

Sildenafil Actavis 100 mg film-coated tablets

PVC-PVDC/Aluminium blisters in cartons of 1, 2, 4, 8, 12 or 24 tablets.

Not all pack sizes may be marketed.

No special requirements.

Actavis Group PTC ehf.

Dalshraun 1220 Hafnarfjörður

Iceland

Sildenafil Actavis 25 mg film-coated tablets

EU/1/09/595/001

EU/1/09/595/002

EU/1/09/595/003

EU/1/09/595/004

EU/1/09/595/005

EU/1/09/595/016

Sildenafil Actavis 50 mg film-coated tablets

EU/1/09/595/006

EU/1/09/595/007

EU/1/09/595/008

EU/1/09/595/009

EU/1/09/595/010

EU/1/09/595/017

Sildenafil Actavis 100 mg film-coated tablets

EU/1/09/595/011

EU/1/09/595/012

EU/1/09/595/013

EU/1/09/595/014

EU/1/09/595/015

EU/1/09/595/018

Date of first authorisation: 10 December 2009

Date of latest renewal: 4 September 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/.