Full Prescribing Info
Contents
Sildenafil citrate.
Description
Each tablet contains sildenafil citrate equivalent to sildenafil 50 mg and 100 mg.
Action
Pharmacology: Pharmacodynamics: Sildenafil is an oral therapy for erectile dysfunction. In the natural setting ie, 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 enzyme guanylate 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 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, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects. Sildenafil causes mild and transient decreases in blood pressure which, in the majority of cases, do not translate into clinical effects. The mean maximum decreases 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 increased cGMP levels in vascular smooth muscle. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on EGG.
Mild and transient differences in colour discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in colour discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n=9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (visual acuity, Amsler grid, colour discrimination simulated traffic light, Humphrey perimeter and photostress).
Pharmacokinetics: Absorption: Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral bioavailability is 41% (range 25-63%). After oral dosing of sildenafil AUG and Cmax increase in proportion 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 of 60 minutes and a mean reduction in Cmax of 29%.
Distribution: The mean steady state volume of distribution (Vd) for sildenafil is 105 L, indicating distribution into the tissues. After a single oral dose of 100 mg, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/mL (CV 0%). Since sildenafil (and its major circulating N-desmethyl metabolite) is 96% bound to plasma proteins, this results in the mean maximum free plasma concentration for sildenafil of 18 ng/mL (38 nM). Protein-binding is independent of total drug concentrations.
Metabolism: Sildenafil is cleared 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 has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. The N-desmelhyl metabolite is further metabolised, with a terminal half-life of approximately 4 hr.
Elimination: The total body clearance of sildenafil is 41 L/hr with a resultant terminal phase half-life of 3-5 hr. 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).
Indications/Uses
Iqnyde is indicated for the treatment of erectile dysfunction in adult males, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance.
Dosage/Direction for Use
Adults: For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum recommended daily dose is 100 mg. The maximum recommended dosing frequency is once per day.
Patients with Impaired Renal Function: Dosage adjustments are not required in 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.
Patients with Impaired Hepatic Function: Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis) a 25 mg dose should be considered.
Patients Using other Medications: Given the extent of the interaction with patients receiving concomitant therapy with ritonavir, it is recommended not to exceed a maximum single dose of 25 mg of sildenafil in a 48-hour period. A starting dose of 25 mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors (eg, erythromycin, saquinavir, ketoconazole, itraconazole).
In order to minimize the potential for developing postural hypotension, patients should be stable on alpha-blocker therapy prior to initiating sildenafil treatment. In addition, initiation of sildenafil at lower doses should be considered.
Children: Sildenafil is not indicated for use in children (<18 years old).
Elderly: Dosage adjustments are not required in elderly patients.
Administration: Sildenafil tablets are for oral administration.
Overdosage
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.
Treatment: 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.
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. Agents for the treatment of erectile dysfunction, including sildenafil, should not be used in men for whom sexual activity is inadvisable (eg, patients with severe cardiovascular disorders such as unstable angina or severe cardiac failure). Iqnyde 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. 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).
Special Precautions
A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.
Prior to initiating any treatment for erectile dysfunction, 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 (eg, aortic stenosis, hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as severely impaired autonomic control of blood pressure.
Iqnyde potentiates the hypotensive effect of nitrates. Serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported post-marketing in temporal association with the use of Iqnyde. Most, but not all, of these patients had preexisting 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 Iqnyde without sexual activity. It is not possible to determine whether these events are 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. Visual defects and cases of non-arteritic anterior ischaemic optic neuropathy have been reported in connection with the intake of sildenafil and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, he should stop taking Iqnyde and consult a physician immediately.
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. 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. Initiation of sildenafil at a dose of 25 mg should be considered. In addition, physicians should advise patients what to do in the event of postural hypotensive symptoms.
Studies with human platelets indicate that sildenafil potentiates the antiaggregatory 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 should be administered to these patients only after careful benefit-risk assessment.
Iqnyde is not indicated for use by women.
Caution is required in patient with hepatic or severe renal impairment, and dosage reduction of sildenafil may be necessary. Care is also needed in patients with anatomical deformation of the penis or haematological disorders that may predispose them to priapism. In the events of prolonged erection (for more than 4 hours), patients should seek medical assistance, as penile tissue damage and permanent loss of potency can occur. Patient is also advised to stop taking sildenafil and seek medical advice in cases of sudden visual or hearing loss. Sildenafil should not be given to those with loss of vision in one eye caused by non-arteritic anterior ischaemic optic neuropathy (NAIO), regardless of whether this was in connection with previous phosphodiesterase type 5 inhibitors or not. Patient who experience dizziness or visual disturbances should not drive or operate hazardous machinery.
The safety of sildenafil is uncertain in patients with severe hepatic impairment, bleeding disorders, active peptic ulceration, hypotension, hypertension, a recent history of stroke, myocardial infarction, or life-threatening arrhythmia, unstable angina, heart failure, or retinal disorders such as retinitis pigmentosa a majority of whom have genetic disorders of retinal phosphodiesterases). Licensed product information advises that it should not be used in these groups.
Cardiovascular Disease: For mention of a consensus statement on the use of sildenafil in patients with cardiovascular disease, see previously mentioned text.
Use In Pregnancy & Lactation
Iqnyde is not indicated for use by women.
No relevant adverse effects were found in reproduction studies in rats and rabbits following oral administration of sildenafil.
Adverse Reactions
See table.

Click on icon to see table/diagram/image
Drug Interactions
Sildenafil or other phosphodiesterase type-5 inhibitors may potentiate the hypotensive effects of organic nitrates, and are therefore contraindicated in patients receiving such drugs.
Sildenafil may also enhance the hypotensive effect of nicorandil and use of the two drugs together should be avoided.
Symptomatic hypotension may also occur when phosphodiesterase type-5 inhibitors are given with alpha blockers. Generally, the patient should be stabilised on alpha blocker therapy before the phosphodiesterase type-5 inhibitor is started at a low dose and adjusted according to response.
Drugs that inhibit the cytochrome P-450 isoenzyme CYP3A4, such as cimetidine, delavirdine, erythromycin, itraconazole, and ketoconazole, may reduce the clearance of phosphodiesterase type-5 inhibitors, necessitating a reduction in dosage.
Plasma concentrations of phosphodiesterase type-5 inhibitors are significantly increased by HIV-protease inhibitors, and particularly so by ritonavir-boosted regimens. Such combinations should not be given unless absolutely essential.
Grapefruit juice should be avoided with slldenafil or other phosphodiesterase type-5 inhibitors as it may increase their plasma concentrations.
Inducers of CYP3A4, such as rifampicin, are likely to decrease plasma concentrations of phosphodiesterase type-5 inhibitors.
Plasma concentration of sildenafil reduced by Bosentan.
Plasma concentration of sildenafil possibly increased by clarithromycin, telithromycin and erythromycin.
Sildenafil may enhance hypotensive effect when given with amlodipine. Plasma concentration of sildenafil increased by cimetidine.
Storage
Store below 30°C. Protect from moisture.
MIMS Class
Drugs for Erectile Dysfunction & Ejaculatory Disorders
ATC Classification
G04BE03 - sildenafil ; Belongs to the class of drugs used in erectile dysfunction.
Presentation/Packing
FC tab 50 mg (blue, diamond shaped, biconvex with Pharmaniaga icon on side and '50' on the other) x 4's. 100 mg (blue, diamond shaped, biconvex with Pharmaniaga icon on side and plain on the other) x 4's.
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