INSTRUCTION

for medical use of the medicinal product

SILDENAFIL 50 ANANTA

SILDENAFIL 100 ANANTA

Composition:

Active substance: sildenafil;

1 film-coated tablet contains sildenafil citrate equivalent to sildenafil 50 mg or 100 mg;

Excipients: microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium, cagnesium stearate, Opadry II blue 31K80956 (lactose monohydrate, hypromellose, titanium dioxide (Е 171), triacetin, indigo carmine (Е 132)), Opadry transparent 02K19253 (hypromellose, triacetin), purified water.

Pharmaceutical form. Film-coated tablets.

Basic physical and chemical properties:

tablets 50 mg: blue, round, biconvex, film-coated tablets with mark «125» on one side and mark «J»  and scoring line on the other side;

tablets 100 mg: blue, round, biconvex, film-coated tablets with mark «126» on one side and mark «J»  and scoring line on the other side.

Pharmaceutical group. Drugs used for erectile dysfunction. Sildenafil. ATC Code: G04B E03.

Pharmacological properties.

Pharmacodynamics. Sildenafil is an oral drug intended to treat 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 penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the guanylate cyclase enzyme, which results in increased levels of cyclic guanosine monophosphate (cGMP), therefore, producing smooth muscle relaxation in the corpus cavernosum and allowing the inflow of blood.

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

Studies in vitro have shown that sildenafil has a selective effect on PDE5, which is involved in the erection process. Its effect is more potent on PDE5 than on any other known phosphodiesterases. The effect is 10-fold more potent than the effect on PDE6, which is involved in the phototransduction pathway in the retina. At maximal recommended doses, sildenafil selectivity for PDE5 is 80-fold more than to PDE1, and 700-fold more than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. In particular, sildenafil has greater than 4000-fold selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility.

There have been some clinical studies specifically designed to assess the time window after dosing during which sildenafil could produce an erection in response to sexual stimulation. In a penile plethysmography study involving 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. Another RigiScan study showed that sildenafil was still able to produce an erection in response to sexual stimulation 4-5 hours post-dose.

Sildenafil causes mild and transient decreases in blood pressure, which, in the majority of cases, do not have clinical manifestations. The average maximum decrease in supine systolic blood pressure following 100 mg oral dosing of sildenafil was 8.4 mmHg. The corresponding change in supine diastolic blood pressure was 5.5 mmHg. These decreases in blood pressure are consistent with the vasodilatory effects of sildenafil, probably due to the increased cGMP levels in vascular smooth muscles. Single oral doses of sildenafil up to 100 mg in healthy volunteers had no clinically relevant effects on ECG.

In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (>70% stenosis of at least one coronary artery), the average resting systolic and diastolic blood pressures decreased by 7% and 6% respectively compared to the baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output, and did not impair blood flow through the stenosed coronary arteries.

No clinically significant differences were demonstrated for the time before the occurrence of limiting stenocardia when using sildenafil, compared with using placebo in studies that used the exercise stress test involving patients with erectile dysfunction and chronic stable stenocardia who constantly applied antianginal medications (except nitrates).

Mild and transient differences in colour blindness (blue/green) were detected in some patients 1 hour after the administration of 100 mg dose of sildenafil. These effects completely disappeared in 2 hours after the intake. The possible mechanism of this change in colour blindness is related to the inhibition of PDE6, which is involved in the phototransduction reaction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In the study involving patients with documented macular degeneration, the use of sildenafil (single dose, 100 mg) demonstrated no significant changes in the conducted visual tests (visual acuity, Amsler grid, simulation of traffic light colors detection, Humphrey perimeter and photostress).

There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers.

There are data on clinical studies on sildenafil administration by patients aged 19 to 87 years. The following groups of patients were presented: elderly patients, patients with hypertension, patients with diabetes, ischemic heart disease, hyperlipidemia, spinal cord injuries, depression, transurethral resection of prostate and radical prostatectomy. Groups of patients, which were not adequately represented or included in the clinical studies: patients after pelvic surgery, patients after radiotherapy, patients with severe renal or hepatic failure and patients with some cardiovascular diseases.

In fixed dose studies, the proportion of patients reporting that treatment improved their erections was higher than in the placebo group. In controlled clinical trials, the rate of sildenafil discontinuation was low and similar to the placebo group.

In all these studies, the patients using sildenafil reported improvements in psychogenic erectile dysfunction, mixed erectile dysfunction, organic erectile dysfunction; the elderly – in diabetes mellitus, ischemic heart disease, hypertension, transurethral resection of prostate, radical prostatectomy, spinal cord injury and depression. The safety and efficacy of sildenafil was confirmed by long-term studies.

Pharmacokinetics.

Absorption. Sildenafil is rapidly absorbed. Maximum observed drug plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) after its oral administration in the fasted state. The average absolute oral bioavailability is 41% (range 25-63%). In the recommended dose range (from 25 to 100 mg) AUC and C_max  values increase proportionally to the dose). When sildenafil is taken with food, the rate of absorption is reduced with an average delay in T_max up to 60 minutes and an average reduction in C_max of 29%.

Distribution. The average steady volume of distribution (V_d) of sildenafil is 105 l, which demonstrates drug distribution into the tissues. After a single oral dose of 100 mg, the average maximum total plasma concentration of sildenafil is approximately 440 ng/mL (CV 40%). Since sildenafil (and its major circulating N-desmethyl metabolite) is 96% bound to plasma proteins, this results in the average maximum free plasma concentration of sildenafil of 18 ng/mL (38 nM). Protein binding does not depend on total drug concentrations.

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

Metabolism.

Sildenafil is metabolised predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil. This metabolite’s selectivity to PDE5 is similar to sildenafil and metabolite’s activity for PDE5 is approximately 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those of sildenafil. The N-desmethyl metabolite is further metabolized with a terminal half-life of approximately 4 h.

Elimination

The total body clearance of sildenafil is 41 l/h resulting in its half-life of 3-5 h. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose).

The elderly

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years). Due to age differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%.

Renal failure. In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 mL/min), the pharmacokinetics of sildenafil remained unchanged after receiving a 50 mg single oral dose. The average AUC and C_max of the N-desmethyl metabolite increased up to 126% and up to 73% respectively, compared to volunteers of the same age 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 average increases in AUC and C_max of 100% and 88% respectively compared to volunteers of the same age with no renal impairment. In addition, N-desmethyl metabolite AUC and C_max values were significantly increased by 200% and 79% respectively.

Hepatic failure. In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh A and B) sildenafil clearance was reduced, resulting in increases in AUC (84%) and C_max (47%) compared to volunteers of the same age with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function has not been studied.

Clinical particulars.

Indications.

Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance.

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

Contraindications.

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

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

– 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 section «Interaction with other medicinal agents and other forms of interaction»).

– Conditions, in which sexual activity is inadvisable (e.g. patients with severe cardiovascular disorders such as unstable stenocardia or severe cardiac failure).

– Sildenafil is contraindicated in patients who have loss of vision in one eye because of non-arterial ischaemic optic neuropathy, regardless of whether this episode was in connection or not with previous PDE5 inhibitors exposure.

– The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated: 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).

Interaction with other medicinal products and other forms of interaction.

Effects of other medicinal products on sildenafil.

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

Analysis of clinical trial data indicated a reduction in sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, and cimetidine). Although no increased incidence of adverse events was observed in these patients, when sildenafil is administered concomitantly with CYP3A4 inhibitors, a starting dose of 25 mg is recommended.

Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg once a day) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C_max and a 1,000% (11-fold) increase in sildenafil plasma AUC. In 24 hours, the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was administered alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. Sildenafil has no effect on ritonavir pharmacokinetics. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is not advised, and the maximum dose of sildenafil should under no circumstances exceed 25 mg within 48 hours.

Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady concentration (1200 mg three times a day) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil C_max and a 210% increase in sildenafil AUC. Sildenafil has no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have greater effects.

When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, C_max, t_max, elimination rate constant, or subsequent half-life of sildenafil or its main circulating metabolite. Cimetidine (800 mg), a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, caused a 56% increase in plasma sildenafil 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 modest increases in plasma levels of sildenafil.

Single doses of antacids (magnesium hydroxide/aluminium hydroxide) do not affect the bioavailability of sildenafil.

Although specific interaction studies were not conducted for all medicinal products, population pharmacokinetic analysis showed no effect on sildenafil pharmacokinetics when used concurrently with CYP2C9 inhibitors (such as tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, loop and potassium sparing diuretics, angiotensin converting enzyme inhibitors, calcium channel blockers, beta-adrenoreceptor antagonists or inducers of CYP450 metabolism (such as rifampicin, barbiturates).

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

Effects of sildenafil on other medicinal products.

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 after recommended doses, it is unlikely that Sildenafil will alter the clearance of substrates of these isoenzymes.

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

Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors or nitrates in any form is therefore contraindicated.

Concomitant administration of sildenafil by patients receiving alpha-blocker therapy may lead to symptomatic hypotension in a some susceptible individuals. This is most likely to occur within 4 hours post sildenafil dosing. In specific drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously 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 were administered simultaneously by patients stabilized on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-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 with mean 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 and centrally-acting), adrenergic neurone blockers, calcium channel blockers and alpha-adrenoceptor blockers, showed no difference in the side effect profile in patients taking sildenafil compared to placebo treatment. In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8 mmHg. The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg. These additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was administered alone to healthy volunteers.

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

Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section «Contraindications»).

Precautions for use.

Prior to initiating any treatment for erectile dysfunction, medical history of the patient should be studied and the patient’s state should be examined to diagnose the erectile dysfunction and determine its possible causes. Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Sildenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure. Prior to prescribing sildenafil, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, especially in combination with sexual activity. Patients with increased susceptibility to vasodilators include those with left ventricular outflow obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as severely impaired autonomic control of blood pressure.

Sildenafil potentiates the hypotensive effect of nitrates.

Serious cardiovascular adverse events, including myocardial infarction, unstable stenocardia, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported in temporal association with the use of Sildenafil. Most but not all of these patients had pre-existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse and a few were reported to occur shortly after the use of Sildenafil without sexual activity. It is not possible to determine whether these events were related directly to these factors or to other factors.

Agents for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).

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

Cases of visual defects and non-arteritic anterior ischaemic optic neuropathy in connection with the intake of sildenafil and other PDE5 inhibitors have been reported.  Patients should be advised that in the event of any sudden visual defect, they should stop taking Sildenafil and consult a physician immediately.

Co-administration of sildenafil with ritonavir is not recommended.

Caution is advised when sildenafil is administered by patients taking alpha-blockers, as the co-administration may lead to symptomatic hypotension in some susceptible individuals (see section 4.5). This is most likely to occur within 4 hours post sildenafil dosing. In order to minimise the potential for developing postural hypotension, patients should be hemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. The starting dose of sildenafil 25 mg is advised. In addition, physicians should advise patients what to do in the event of postural hypotensive symptoms.

Studies with human platelets indicate that sildenafil in vitro potentiates the antiaggregatory effect of sodium nitroprusside . There is no safety information on the administration of sildenafil by patients with bleeding disorders or active peptic ulceration. Therefore, sildenafil should be administered by these patients only after a careful benefit-risk assessment.

The film coating of the tablet contains lactose. Sildenafil should not be administered to men with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Hearing loss. Physicians should advise patients to stop use PDE5 inhibitors, including sildenafil, and immediately address for medical aid in case of sudden hearing impairment or hearing loss. These phenomena, which can be also accompanied by tinnitus and dizziness, might occur due to use of PDE5 inhibitors, including sildenafil. It is impossible to determine whether these phenomena are associated with the use of PDE5 inhibitors or other factors.

Co-administration with hypotensive agents. Sildenafil has systemic vasodilating effect and may reduce blood pressure in patients who use antihypertensive agents. In a separate study of drug interaction with concomitant oral intake of amlodipine (5 mg or 10 mg) and sildenafil (100 mg), the average additional reductions in systolic pressure by 8 mm Hg and diastolic - by 7 mmHg were observed.

Sexually transmitted infections. The use of sildenafil does not protect against sexually transmitted diseases. Consideration should be given to instruct patients about necessary precautions to protect themselves against sexually transmitted diseases, including human immunodeficiency virus.

Fertility. There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers.

Pregnancy and lactation.

Sildenafil is not indicated for use by women.

Effects on reaction rates while driving vehicles and operating other machinery.

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

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

Routes of administration and dosage.

Sildenafil is designed for oral intake.

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

Adults.

The recommended dose is 50 mg taken as needed approximately one hour before sexual activity. Based on the efficacy and tolerability, the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg.

The maximum recommended dosing frequency is once a day. If Sildenafil is taken with food, its effect may be delayed compared to the fasted state.

Elderly.

Dosage adjustments are not required in elderly patients.

Renal failure.

The dosing recommendations described in «Adults» apply to patients with mild to moderate renal impairment (creatinine clearance is 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 the efficacy and tolerability, the dose may be increased up to 50 mg and to 100 mg as necessary.

Hepatic failure.

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

Use in patients taking other medicinal products (e.g. ketoconazole, erythromycin, cimetidine, ritonavir). For detailed information, see section «Interaction with other medicinal products and other forms of interaction».

For patients who use CYP3A4 inhibitors, except for ritonavir, the use of which concomitantly with sildenafil is not recommended, the recommended initial dose is 25 mg.

In order to minimise the potential risk of developing postural hypotension in patients receiving alpha-blocker treatment, patients should be stabilized on alpha-blocker therapy prior to initiating sildenafil treatment. The recommended starting dose of sildenafil is 25 mg.

Children.

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

Overdose.

In single dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence and severity rates were increased. Doses of 200 mg did not result in increased 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. Haemodialysis is not expected to accelerate sildenafil clearance, as sildenafil is highly bound to plasma proteins and not eliminated in the urine.

Adverse reactions.

The most commonly reported adverse reactions were headache, flushing, dyspepsia, nasal congestion, dizziness and colour vision deficiency.

All clinically significant adverse reactions that occurred in clinical trials at an incidence higher than when taking placebo are listed below according to the classification “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 clinically significant adverse reactions reported in post-marketing experience is specified as Unknown.

Immune system disorders: rare – hypersensitivity.

Nervous system disorders: very common – headache; common – dizziness; uncommon – somnolence, hypoaesthesia; rare – stroke, syncope; unknown – transient ischaemic attack, seizure, seizure recurrence.

Eye disorders: common – visual disturbances, colour vision deficiency; uncommon – conjunctivitis, lacrimation disorders, other visual disturbances; unknown – non-arteritic anterior ischaemic optic neuropathy, retinal vascular occlusion, visual field defects.

Ear and labyrinth disorders: uncommon – vertigo, tinnitus; rare – deafness (several cases of sudden hearing impairment or sudden hearing loss during the administration of PDE5, including sildenafil, have been reported).

Vascular disorders: common – hot flushes; rare – hypertension, hypotension.

Cardiac disorders: uncommon – palpitations, tachycardia; rare – myocardial infarction, atrial fibrillation; unknown – ventricular arrhythmia, unstable stenocardia, sudden cardiac death.

Respiratory, thoracic and mediastinal disorders: common – nasal congestion; rare – epistaxis.

Gastrointestinal disorders: common – dyspepsia; uncommon – nausea, vomiting, dry mouth.

Skin and subcutaneous tissue disorders: uncommon – rash; unknown – Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: uncommon – myalgia.

Reproductive system and breast disorders: unknown – priapism, prolonged erection.

General disorders: uncommon – chest pain, fatigue.

Examinations: uncommon – heart rate increased.

Storage life. 2 years.

Storage conditions.

Store in the original package at the temperature not exceeding 25°C. Keep out of reach of children.

Package. 4 tablets in a blister, 1 blister in a pack.

Terms of dispensing. On prescription.

Manufacturer. Hetero Labs Limited.

Manufacturer’s registered address.

Unit V, Block V and V-A, TCIIC – Formulation SEZ, S. №№ 439, 440, 441 і 458, Polepally Village, Jadcherla Mandal, Mahabubnagar, Telangana 509301, India.

Or

Manufacturer.

Artura Pharmaceutical’s Pvt. Ltd.

Manufacturer’s registered address.

1505 Portia Rd, Sri City SEZ, Satayavedu Mandal, Chittoor District – 517 588, Andhra Pradesh, India.

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

Date of last review. 07.11.18