Sildenafil Cipla 50 mg, 100 mg FC tablets.

u2022 SILDENAFIL CIPLA is indicated only for the treatment of erectile dysfunction.

u2022 THIS PRODUCT IS NOT AN APHRODISIAC.

Posology

Use in adults

The recommended dose is 50 mg, taken as needed approximately one hour before sexual activity. Based on efficacy and toleration, 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 per day.

The following factors are associated with increased plasma levels of SILDENAFIL CIPLA: Age > 65 (40 % increase in AUC), hepatic impairment (e.g. cirrhosis, 80 %), severe renal impairment (creatinine clearance < 30 mL/min, 100 %), and concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin 182 %, saquinavir 210 %, ketoconazole, itraconazole 200 %, ritonavir 1 000 %).

Special populations

Use in patients with mild to moderately impaired renal function

A starting dose of 25 mg should not be exceeded.

Use in patients with mild to moderately impaired hepatic function

Since SILDENAFIL CIPLA clearance is reduced in patients with hepatic impairment (e.g. cirrhosis), a starting dose of 25 mg should not be exceeded.

Use in elderly patients

Healthy elderly volunteers (65 years or over) had a reduced clearance of SILDENAFIL CIPLA. A starting dose of 25 mg should be considered in patients older than 65 years of age.

Use in patients using potent CYP 3A4 inhibitors

Given the extent of the interaction with patients receiving concomitant therapy with cytochrome P450 3A4 inhibitors (e.g. ritonavir, erythromycin, saquinavir, ketoconazole, itraconazole), SILDENAFIL CIPLA should not be used concomitantly with these medicines (see section 4.3). SILDENAFIL CIPLA was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors or nitrates in any form is therefore contraindicated.

Use in children

SILDENAFIL CIPLA is not indicated for use in children.

Method of administration

SILDENAFIL CIPLA tablets are for oral administration.

u2022 Hypersensitivity to sildenafil or to any of the excipients (see section 6.1).

u2022 Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), SILDENAFIL CIPLA was shown to potentiate the hypotensive effects of acute and chronic nitrates, and its administration to patients who are concurrently using nitric oxide donors, organic nitrates or organic nitrites in any form either regularly or intermittently is therefore contraindicated.

u2022 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 4.5).

u2022 Concomitant use of SILDENAFIL CIPLA with potent cytochrome P450 3A4 inhibitors e.g. ritonavir, erythromycin, saquinavir, ketoconazole and itraconazole is contraindicated.

u2022 Medicines for the treatment of erectile dysfunction, including SILDENAFIL CIPLA, should not be used in men for whom sexual activity is inadvisable (e.g. patients with severe cardiovascular disorders such as unstable angina or severe cardiac failure).

u2022 SILDENAFIL CIPLA is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see section 4.4).

u2022 The use of SILDENAFIL CIPLA is contraindicated in patients with severe hepatic impairment and patients with severe impairment of renal function (creatinine clearance < 30 mL/min) not on haemodialysis or continuous ambulatory peritoneal dialysis.

u2022 The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated: 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).

A thorough medical history and physical examination should be undertaken to diagnose erectile dysfunction, determine potential underlying causes, and identify appropriate treatment.

Cardiovascular risk factors

There is a potential for cardiac risk of sexual activity in patients with pre-existing cardiovascular disease. Therefore, treatment for erectile dysfunction, including SILDENAFIL CIPLA should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. SILDENAFIL CIPLA has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers. Medical practitioners should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely 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 CIPLA potentiates the hypotensive effect of nitrates (see section 4.3).

Serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular dysrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported post-marketing in temporal association with the use of SILDENAFIL CIPLA. 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 CIPLA without sexual activity. It is not possible to determine whether these events are related directly to these factors or to other factors.

Priapism

Medicines for the treatment of erectile dysfunction, including SILDENAFIL CIPLA, should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronieu2019s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia). Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

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

The safety and efficacy of combinations of sildenafil with other PDE5 inhibitors, or other pulmonary arterial hypertension (PAH) treatments containing sildenafil or other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Effects on vision

Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil and other PDE5 inhibitors (see section 4.8). Cases of non-arteritic anterior ischaemic optic neuropathy (NAION) have been reported spontaneously and in an observational study in connection with the intake of sildenafil and other PDE5 inhibitors (see section 4.8). Patients should be advised that in the event of any sudden visual defect, they should stop taking SILDENAFIL CIPLA and consult a medical practitioner immediately (see section 4.3).

Retinal detachment

There have been reports indicating that regular use of phosphodiesterase 5 inhibitors (PDE5Is), such as sildenafil, may increase the risk of reversible serous retinal detachment (SRD). Although no clinical trials have established a causal relationship, it is imperative that regular users of PDE5Is remain vigilant for ocular adverse events associated with these medicines and report any visual deficits to their doctors. It is also essential for prescribing doctors to be aware of this association and consider the potential risks before prescribing PDE5Is to their patients.

Concomitant use with ritonavir

Co-administration of SILDENAFIL CIPLA with ritonavir is contraindicated (see section 4.5).

Concomitant use with alpha-blockers

Caution is advised when sildenafil is administered to patients taking an alpha-blocker, as the co-administration may lead to symptomatic hypotension in a few susceptible individuals (see section 4.5). To minimize the potential for developing postural hypotension, patients should be haemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Initiation of sildenafil at a dose of 25 mg should be considered (see section 4.2). In addition, medical practitioners should advise patients what to do in the event of postural hypotensive symptoms.

Effect on bleeding

Studies with human platelets indicate that sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside in vitro. There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore, SILDENAFIL CIPLA should be administered with caution to these patients.

Hearing loss

A sudden unilateral or bilateral decrease or loss of hearing (sensorineural deafness) with or without associated vestibular symptoms has been reported with the use of PDE5 inhibitors, including SILDENAFIL CIPLA. There is insufficient information regarding the reversibility of hearing loss and the role of underlying risk factors for hearing loss in individual subjects.

Women

SILDENAFIL CIPLA is not indicated for use by women. SILDENAFIL CIPLA contains lactose, which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effects of other medicines on sildenafil

In vitro studies

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

In vivo studies

Population pharmacokinetic 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 should be considered.

Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg twice daily) 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. At 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 had no effect on ritonavir pharmacokinetics. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is contraindicated (see section 4.3).

Co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1 200 mg three times daily) with sildenafil (100 mg single dose) resulted in a 140 % increase in sildenafil C max and a 210 % increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics (see section 4.2). 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 principal 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 antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of sildenafil.

Although specific interaction studies were not conducted for all medicines, population pharmacokinetic analysis showed no effect of concomitant treatment on sildenafil pharmacokinetics when grouped as 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).

In a study of healthy male volunteers, co-administration of the endothelin antagonist, bosentan, (an inducer of CYP3A4 [moderate], CYP2C9 and possibly of CYP2C19) at steady state (125 mg twice a day) with sildenafil at steady state (80 mg three times a day) resulted in 62,6 % and 55,4 % decrease in sildenafil AUC and C max, respectively. Therefore, concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma concentrations of sildenafil.

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 medicines

In vitro studies

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 > 150 u03bcM). Given sildenafil peak plasma concentrations of approximately 1 u03bcM after recommended doses, it is unlikely that SILDENAFIL CIPLA will alter the clearance of substrates of these isoenzymes.

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

In vivo studies

Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), 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 (see section 4.3).

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 4.3).

Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in a few susceptible individuals. This is most likely to occur within 4 hours post sildenafil dosing (see sections 4.2 and 4.4). In three specific 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 to 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 medicines (vasodilator and centrally acting), adrenergic neuron 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 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 three times a day) resulted in a 49,8 % increase in bosentan AUC and a 42 % increase in bosentan C max (125 mg twice a day).

SILDENAFIL CIPLA is not indicated for use in 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 oral administration of sildenafil. There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers.

SILDENAFIL CIPLA may have a minor influence on the ability to drive and use machines. As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware how they react to SILDENAFIL CIPLA before driving or operating machinery.

MedDRA system organ class Frequency Adverse reactions Infections and infestations Less frequent Rhinitis Immune system disorders Less frequent Hypersensitivity Nervous system disorders Frequent Headache, dizziness Less frequent Somnolence, hypoaesthesia, cerebrovascular accident, transient ischaemic attack, syncope Frequency unknown Seizure, seizure recurrence Eye disorders Frequent Visual colour distortions, visual disturbance, blurred vision Less frequent Lacrimation disorders, eye pain, photophobia, photopsia, ocular hyperaemia, visual brightness, conjunctivitis, retinal haemorrhage, arteriosclerotic retinopathy, retinal disorder, glaucoma, visual field defect, diplopia, visual acuity reduced, myopia, asthenopia, vitreous floaters, iris disorder, mydriasis, halo vision, eye oedema, eye swelling, eye disorder, conjunctival hyperaemia, eye irritation, abnormal sensation in eye, eyelid oedema, scleral discoloration Frequency unknown Non-arteritic anterior ischaemic optic neuropathy (NAION), retinal vascular occlusion, serious retinal detachment (SRD) Ear and labyrinth disorders Less frequent Vertigo, tinnitus, deafness Cardiac disorders Less frequent Tachycardia, palpitations, myocardial infarction, atrial fibrillation, unstable angina Frequency unknown Sudden cardiac death, ventricular dysrhythmia Vascular disorders Frequent Flushing, hot flush Less frequent Hypertension, hypotension Respiratory, thoracic and mediastinal disorders Frequent Nasal congestion Less frequent Epistaxis, sinus congestion, throat tightness, nasal oedema, nasal dryness Gastrointestinal disorders Frequent Nausea, dyspepsia Less frequent Gastro oesophageal reflux disease, vomiting, abdominal pain upper, dry mouth, oral hypoaesthesia Skin and subcutaneous tissue disorders Less frequent Rash Frequency unknown Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) Musculoskeletal and connective tissue disorders Less frequent Myalgia, pain in extremity Renal and urinary disorders Less frequent Haematuria Reproductive system and breast disorders Less frequent Penile haemorrhage, haematospermia, increased erection Frequency unknown Priapism General disorders and administration site conditions Less frequent Chest pain, fatigue, feeling hot, irritability Investigations Less frequent Increased heart rate Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on the SAHPRA website or to Cipla Medpro (Pty) Ltd. by e-mail to [email protected] or telephone to 080 222 6662 (toll free).

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