Sildocad

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SILDOKAD (SILDOCAD)

Composition:

Active substance: sildenafil;

1 tablet contains sildenafil citrate equivalent to sildenafil 25 mg or 50 mg, or 100 mg;

Excipients: sodium croscarmellose, calcium hydrogen phosphate anhydrous, microcrystalline cellulose, magnesium stearate, purified water, colouring agent Opadry II white 31K58902 (lactose monohydrate; hypromellose, titanium dioxide (E 171); triacetin).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg tablets: film-coated tablets, white in colour, oval-shaped, biconvex, smooth on one side and embossed with ‘B9’ on the other side;

50 mg tablets: film-coated tablets, white in colour, oval-shaped, biconvex, smooth on one side and embossed with ‘C1’ on the other side;

100 mg tablets: film-coated tablets, white in colour, oval-shaped, biconvex, smooth on one side and embossed with ‘436’ on the other side.

Pharmacotherapeutic group.

Agents used in erectile dysfunction. Sildenafil.

ATC code: G04BE03.

Pharmacological Properties

Pharmacodynamics. Sildocad is an oral medication intended for the treatment of erectile dysfunction. During sexual stimulation, the drug restores impaired erectile function by enhancing blood flow to the penis. The physiological mechanism underlying erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual arousal. Released nitric oxide activates the enzyme guanylate cyclase, which stimulates an increase in the level of cyclic guanosine monophosphate (cGMP), leading in turn to relaxation of the smooth muscle of the corpus cavernosum and promoting blood inflow.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for cGMP breakdown. The effect of sildenafil on erection is peripheral. Sildenafil does not exert a direct relaxing effect on isolated human corpus cavernosum tissue, but it strongly potentiates the relaxing effect of NO on this tissue. When the NO/cGMP metabolic pathway is activated during sexual stimulation, inhibition of PDE5 by sildenafil leads to increased cGMP levels in the corpus cavernosum. Thus, for sildenafil to produce the required pharmacological effect, sexual stimulation is necessary. In vitro studies have demonstrated the selectivity of sildenafil’s action on PDE5, which actively participates in the erectile process. The effect of sildenafil on PDE5 is more potent than on other known phosphodiesterases. This effect is 10-fold more potent than its effect on PDE6, which is involved in phototransduction processes in the retina. At the maximum recommended doses, sildenafil’s selectivity for PDE5 is 80 times greater than its selectivity for PDE1, 700 times greater than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11. Specifically, sildenafil’s selectivity for PDE5 is 4000 times greater than for PDE3—a cGMP-specific phosphodiesterase isoenzyme involved in regulating cardiac contractility.

Pharmacokinetics.

Absorption. Sildenafil is rapidly absorbed. Maximum plasma concentration (Cmax) is reached within 30–120 minutes (median 60 minutes) after oral administration on an empty stomach. The mean absolute bioavailability after oral administration is 41% (ranging from 25% to 63%). Within the recommended dose range (25 to 100 mg), AUC (area under the plasma concentration-time curve) and Cmax of sildenafil increase proportionally with dose.

When sildenafil is taken with food, the extent of absorption is reduced, with a mean delay in Tmax by 60 minutes and a mean reduction in Cmax by 29%.

Distribution. The mean steady-state volume of distribution (Vd) is 105 liters, indicating extensive tissue distribution. After a single 100 mg oral dose of sildenafil, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/mL (coefficient of variation 40%). Since the binding of sildenafil and its major N-desmethyl metabolite to plasma proteins is about 96%, the mean maximum free plasma concentration of sildenafil reaches 18 ng/mL (38 nmol). The degree of protein binding is independent of total sildenafil concentrations.

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

Metabolism. Sildenafil is metabolized primarily by hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite results from N-demethylation of sildenafil. The metabolite’s selectivity for PDE5 is comparable to that of sildenafil, while its activity against PDE3 is approximately 50% of the parent compound. Plasma concentrations of this metabolite are about 40% of sildenafil plasma concentrations. The N-desmethyl metabolite undergoes further metabolism, and its elimination half-life is approximately 4 hours.

Elimination. The total clearance of sildenafil is 41 L/h, resulting in an elimination half-life of 3–5 hours. Following both oral and intravenous administration, excretion of sildenafil metabolites occurs predominantly in feces (approximately 80% of the orally administered dose) and to a lesser extent in urine (approximately 13% of the orally administered dose).

Elderly Patients. In healthy elderly volunteers (aged 65 years and older), reduced clearance of sildenafil was observed, resulting in approximately 90% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite compared to younger healthy volunteers (aged 18–45 years). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%.

Renal Impairment. In volunteers with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil remained unchanged after a single 50 mg oral dose. Mean AUC and Cmax of the N-desmethyl metabolite increased by 126% and 73%, respectively, compared to age-matched volunteers with normal renal function. However, due to high inter-individual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance <30 mL/min), sildenafil clearance was reduced, leading to mean increases in AUC and Cmax by 100% and 88%, respectively, compared to volunteers of similar age with normal renal function. Additionally, AUC and Cmax of the N-desmethyl metabolite increased significantly by 79% and 200%, respectively.

Hepatic Impairment. In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh classes A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with normal liver function. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Clinical characteristics.

Indications.

Sildocad is recommended for use in men with erectile dysfunction, defined as the inability to achieve or maintain a penile erection sufficient for successful sexual performance.

For effective action of Sildocad, sexual stimulation is required.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form (since sildenafil affects the nitric oxide/cyclic guanosine monophosphate (cGMP) metabolic pathway and potentiates the hypotensive effect of nitrates).
  • Concomitant use of PDE5 inhibitors (including sildenafil) with guanylate cyclase stimulators such as riociguat is contraindicated, as it may lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").
• Conditions in which sexual activity is not recommended (e.g., severe cardiovascular disorders such as unstable angina or severe heart failure).
• Sudden vision loss in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this condition was associated with prior use of PDE5 inhibitors.
• Conditions such as severe hepatic impairment, arterial hypotension (blood pressure below 90/50 mm Hg), recent stroke or myocardial infarction, and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal phosphodiesterases), since the safety of sildenafil has not been studied in these patient subgroups.

Interaction with other medicinal products and other types of interactions.

Effects of other medicinal products on sildenafil.

In vitro studies. Sildenafil metabolism is primarily mediated by cytochrome P450 (CYP) isoform 3A4 (major pathway) and isoform 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance, while inducers of these isoenzymes may increase sildenafil clearance.

In vivo studies. Population pharmacokinetic analysis of clinical trial data demonstrated reduced sildenafil clearance when co-administered with CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, cimetidine). Although increased incidence of adverse events was not observed during concomitant use of sildenafil and CYP3A4 inhibitors, consideration should be given to initiating sildenafil at a dose of 25 mg.

Concomitant administration of the HIV protease inhibitor ritonavir, a very potent inhibitor of P450, at steady-state concentration (500 mg once daily) and sildenafil (single dose of 100 mg) resulted in a 300% increase in sildenafil Cmax (4-fold) and a 1000% increase in plasma AUC (11-fold). After 24 hours, plasma sildenafil levels were still approximately 200 ng/mL compared to approximately 5 ng/mL when sildenafil was administered alone, indicating a significant effect of ritonavir on a broad range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Due to these pharmacokinetic data, concomitant use of sildenafil and ritonavir is not recommended (see section "Special precautions for use"); in any case, the maximum sildenafil dose should not exceed 25 mg within 48 hours.

Concomitant administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady-state dose (1200 mg three times daily) and sildenafil (single 100 mg dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in AUC. No effect of sildenafil on saquinavir pharmacokinetics was observed (see section "Dosage and administration"). More potent CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to have a more pronounced effect.

Administration of sildenafil (single 100 mg dose) with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days) resulted in an 182% increase in sildenafil AUC. In healthy male volunteers, azithromycin (500 mg daily for 3 days) did not affect AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor), at a dose of 800 mg, when co-administered with sildenafil 50 mg in healthy volunteers, increased plasma concentrations of sildenafil by 56%.

Grapefruit juice is a weak inhibitor of intestinal CYP3A4 and may cause a moderate increase in plasma levels of sildenafil.

Single administration of antacids (magnesium hydroxide/aluminum hydroxide) did not affect sildenafil bioavailability.

Although specific interaction studies with all medicinal products have not been conducted, population pharmacokinetic analysis data indicate that sildenafil pharmacokinetics were not altered when co-administered with medicinal products belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers, β-adrenergic blockers, or CYP450 metabolism inducers (e.g., rifampicin, barbiturates).

In a study involving healthy male volunteers, concomitant administration of the endothelin antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19) at steady state (125 mg twice daily) and sildenafil at steady state (80 mg three times daily) resulted in a 62.6% and 55.4% reduction in AUC and Cmax of sildenafil, respectively. Therefore, concomitant use of potent CYP3A4 inducers such as rifampicin may lead to a more pronounced decrease in plasma sildenafil concentrations.

Nicorandil is a hybrid agent combining calcium channel activator and nitrate properties. The nitrate component implies a potential for serious interaction with sildenafil.

Effects of sildenafil on other medicinal products.

In vitro studies. Sildenafil is a weak inhibitor of cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC50 > 150 µmol). Since peak plasma concentrations of sildenafil are approximately 1 µmol, the effect of Sildocad on the clearance of substrates of these isoenzymes is unlikely.

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

In vivo studies. Since sildenafil affects nitric oxide/cyclic guanosine monophosphate (cGMP) metabolism, it has been established that sildenafil potentiates the hypotensive effect of nitrates; therefore, concomitant use with nitric oxide donors or nitrates in any form is contraindicated (see section "Contraindications").

Riociguat. Preclinical studies demonstrated additive systemic blood pressure-lowering effects when PDE5 inhibitors were used concomitantly with riociguat. Clinical studies have shown that riociguat enhances the hypotensive effect of PDE5 inhibitors. In patients participating in the study, no positive clinical effect was observed with concomitant use of PDE5 inhibitors and riociguat. Concomitant use of riociguat with PDE5 inhibitors (including sildenafil) is contraindicated (see section "Contraindications").

Concomitant use of sildenafil and α-adrenergic blockers may lead to symptomatic hypotension in some susceptible patients. This reaction most commonly occurred within 4 hours after sildenafil administration (see section "Special precautions for use" and "Dosage and administration"). In three drug interaction studies, the α-adrenergic blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were co-administered to patients with benign prostatic hyperplasia whose condition was stabilized on doxazosin. In these populations, mean additional reductions in supine blood pressure were 7/7 mm Hg, 9/5 mm Hg, and 8/4 mm Hg, and mean reductions in standing blood pressure were 6/6 mm Hg, 11/4 mm Hg, and 4/5 mm Hg, respectively. Symptomatic orthostatic hypotension has occasionally been reported with concomitant use of sildenafil and doxazosin in patients whose condition was stabilized on doxazosin. These reports included episodes of dizziness and presyncope, but no syncope.

No significant interactions were observed with concomitant administration of sildenafil (50 mg) and tolbutamide (250 mg) or warfarin (40 mg), both metabolized by CYP2C9.

Sildenafil (50 mg) did not prolong bleeding time induced by acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers at a mean maximum blood ethanol level of 80 mg/dL.

In patients taking sildenafil, no differences in adverse effect profile compared to placebo were observed with concomitant use of antihypertensive drug classes such as diuretics, β-blockers, ACE inhibitors, angiotensin II antagonists, vasodilators, centrally acting antihypertensives, adrenergic neuron blockers, calcium channel blockers, and α-adrenergic blockers. In a specific interaction study with concomitant administration of sildenafil (100 mg) and amlodipine in patients with arterial hypertension, an additional 8 mm Hg reduction in supine systolic blood pressure was observed. The corresponding diastolic blood pressure reduction was 7 mm Hg. These additional blood pressure reductions were comparable in magnitude to those observed with sildenafil alone in healthy volunteers (see section "Pharmacological properties").

Sildenafil 100 mg did not affect the pharmacokinetic parameters of the HIV protease inhibitors saquinavir and ritonavir, which are CYP3A4 substrates.

In healthy male volunteers, administration of sildenafil at steady state (80 mg three times daily) increased AUC and Cmax of bosentan (125 mg twice daily) by 49.8% and 42%, respectively.

Special precautions for use.

Before initiating therapy, a medical history should be obtained and a physical examination performed to diagnose erectile dysfunction and determine its possible causes.

Cardiovascular risk factors. Since sexual activity carries a certain cardiovascular risk, physicians should evaluate the cardiovascular status of patients before any treatment for erectile dysfunction is initiated. Sildenafil has vasodilatory effects that may manifest as mild and transient reduction in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, physicians must carefully consider whether this effect could adversely affect patients with underlying cardiovascular conditions, particularly when combined with sexual activity. Patients who may be more sensitive to vasodilators include those with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with the rare multisystem atrophy syndrome, one of the manifestations of which is severe autonomic nervous system dysfunction in blood pressure regulation.

Sildokad potentiates the hypotensive effect of nitrates (see section "Contraindications").

In the post-marketing period, serious cardiovascular adverse reactions have been reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, arterial hypertension, and arterial hypotension, which temporally coincided with the use of Sildokad. Most, but not all, of these patients had underlying cardiovascular risk factors. Many of these adverse reactions occurred during or immediately after sexual intercourse, while only a few occurred shortly after taking Sildokad without sexual activity. Therefore, it is not possible to determine whether the development of such adverse reactions is directly related to risk factors or whether other contributing factors are involved.

Priapism. Medications for the treatment of erectile dysfunction, including sildenafil, should be administered with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients with conditions that may predispose to priapism (e.g., sickle cell anaemia, multiple myeloma, or leukaemia).

Post-marketing reports have included cases of prolonged erection and priapism. If an erection lasts longer than 4 hours, patients should seek immediate medical assistance. Without prompt treatment, priapism may lead to penile tissue damage and permanent loss of erectile function.

Concomitant use with other PDE5 inhibitors or other erectile dysfunction therapies. The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other medications for the treatment of pulmonary arterial hypertension containing sildenafil (e.g., Revatio), or with other erectile dysfunction treatments, have not been studied. Therefore, such combinations are not recommended.

Effect on vision. Spontaneous reports of visual disturbances have been associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Spontaneous reports and observations in a surveillance study have also reported cases of non-arteritic anterior ischaemic optic neuropathy (NAION), a rare condition, associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be advised that in the event of sudden visual impairment, Sildokad should be discontinued immediately and medical advice sought (see section "Contraindications").

Concomitant use with ritonavir. Concomitant use of sildenafil and ritonavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with α-adrenoreceptor blockers. Sildenafil should be used with caution in patients taking α-adrenoreceptor blockers, as this combination may lead to symptomatic hypotension in some susceptible individuals. Symptomatic hypotension usually occurs within 4 hours after sildenafil administration. To minimize the potential for postural hypotension in patients taking α-adrenoreceptor blockers, their condition should first be stabilized on these agents before initiating sildenafil therapy. Consideration should also be given to starting with a dose of 25 mg (see section "Dosage and administration"). Patients should also be informed about appropriate actions to take if symptoms of orthostatic hypotension occur.

Effect on bleeding. In vitro studies on human platelets have shown that sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside. There is no information available on the safety of sildenafil use in patients with bleeding disorders or acute peptic ulcer. Therefore, sildenafil may be used in these patient groups only after careful assessment of the benefit-risk ratio.

The tablet film coating contains lactose. Sildokad should not be administered to men with the following rare hereditary conditions: galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

After administration of a 100 mg dose to healthy volunteers, no effect on sperm morphology or motility was observed (see section "Pharmacodynamics").

Hearing loss. Physicians should advise patients to discontinue PDE5 inhibitors, including Sildokad, and seek immediate medical help if they experience sudden decrease or loss of hearing. Such events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with PDE5 inhibitor use, including Sildokad. It is not possible to determine whether these events are directly related to PDE5 inhibitor use or to other factors.

Concomitant use with antihypertensive agents. Sildokad has systemic vasodilatory effects and may further reduce blood pressure in patients taking antihypertensive medications. In a specific drug interaction study, concomitant oral administration of amlodipine (5 mg or 10 mg) and Sildokad (100 mg) resulted in an average additional reduction in systolic blood pressure of 8 mm Hg and diastolic blood pressure of 7 mm Hg.

Sexually transmitted diseases. Sildokad does not protect against sexually transmitted infections. Consideration should be given to advising patients on appropriate preventive measures to protect against sexually transmitted diseases, including human immunodeficiency virus (HIV).

Use during pregnancy or breastfeeding.

Sildokad is not intended for use in women.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect on the ability to drive or operate machinery have been conducted.

Since dizziness and visual disturbances have been reported during clinical studies with sildenafil, patients should take these potential adverse reactions into account before engaging in potentially hazardous activities.

Method of Administration and Dosage

The medication is taken orally.

Adults. The recommended dose of Sildokad is 50 mg, taken as needed approximately one hour before sexual activity. Depending on 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 frequency of administration is once daily. When Sildokad is taken with food, the onset of action may be delayed compared to administration on an empty stomach.

Elderly patients. Dose adjustment is not required for elderly patients (≥ 65 years of age).

Patients with renal impairment. For patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the recommended dose is the same as stated above under "Adults."

In patients with severe renal impairment (creatinine clearance < 30 mL/min), clearance of sildenafil is reduced; therefore, a starting dose of 25 mg should be considered. Depending on efficacy and tolerability, the dose may be gradually increased to 50 mg and then to 100 mg, if necessary.

Patients with hepatic impairment. In patients with hepatic impairment (e.g., cirrhosis), clearance of sildenafil is reduced; therefore, a starting dose of 25 mg should be considered. Depending on efficacy and tolerability, the dose may be gradually increased to 50 mg and then to 100 mg, if necessary.

Patients taking other medicinal products. If patients are concurrently taking CYP3A4 inhibitors (see section "Interaction with other medicinal products and other forms of interaction"), a starting dose of 25 mg should be considered (except for ritonavir, which is not recommended to be co-administered with sildenafil; see section "Special warnings and precautions for use").

To minimize the potential risk of postural hypotension in patients taking α-adrenoreceptor blockers, their condition should be stabilized on α-adrenoreceptor blockers before initiating sildenafil therapy. Additionally, a starting dose of 25 mg should be considered (see sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

Children

Sildenafil is not indicated for use in individuals under 18 years of age.

Overdose

During clinical studies in volunteers, administration of single doses of sildenafil up to 800 mg resulted in adverse reactions similar to those observed with lower doses, but occurring more frequently and with greater severity. Administration of sildenafil at a dose of 200 mg did not increase efficacy but led to an increased incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

In the event of overdose, standard supportive measures should be implemented as necessary. Hemodialysis is unlikely to accelerate sildenafil clearance due to the high degree of plasma protein binding and the absence of urinary elimination of sildenafil.

Adverse Reactions

The safety profile of the medicinal product Sildocad is based on data from 9,570 patients in 74 double-blind, placebo-controlled clinical studies. The most commonly reported adverse reactions were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, hot flushes, visual disturbances, cyanopsia, and blurred vision. Information on adverse reactions from post-marketing surveillance was collected over a period of more than 10 years. Since not all adverse reactions were reported to the marketing authorization holder and not all were included in the safety database, the frequency of such reactions cannot be reliably determined.

All clinically significant adverse reactions observed during clinical trials more frequently than with placebo are listed below according to System Organ Class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000). Additionally, the frequency of clinically significant adverse reactions reported during post-marketing experience is defined as unknown. Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and infestations

Uncommon: rhinitis.

Immune system disorders

Uncommon: hypersensitivity.

Nervous system disorders

Very common: headache.

Common: dizziness.

Uncommon: somnolence, hypoesthesia.

Rare: stroke, transient ischaemic attack, seizures*, seizure recurrence*, syncope.

Eye disorders

Common: colour vision disorders**, visual disturbances, blurred vision.

Uncommon: lacrimation disorders***, eye pain, photophobia, photopsia, eye hyperaemia, visual brightness, conjunctivitis.

Rare: non-arteritic anterior ischaemic optic neuropathy*, retinal vessel occlusion*, retinal haemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floaters, iris disorders, mydriasis, halos around lights, eye oedema, eyelid swelling, eye disorders, conjunctival hyperaemia, eye irritation, abnormal sensations in the eye, eyelid oedema, scleral discolouration.

Ear and labyrinth disorders

Uncommon: dizziness, tinnitus.

Rare: deafness.

Cardiac disorders

Uncommon: tachycardia, palpitations.

Rare: sudden cardiac death*, myocardial infarction, ventricular arrhythmia*, atrial fibrillation, unstable angina.

Vascular disorders

Common: facial flushing, hot flushes.

Uncommon: hypertension, hypotension.

Respiratory, thoracic and mediastinal disorders

Common: nasal congestion.

Uncommon: epistaxis, nasal sinus congestion.

Rare: throat tightness, nasal mucosal oedema, nasal dryness.

Gastrointestinal disorders

Common: nausea, dyspepsia.

Uncommon: gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth.

Rare: oral hypoesthesia.

Skin and subcutaneous tissue disorders

Uncommon: rash.

Rare: Stevens-Johnson syndrome*, toxic epidermal necrolysis*.

Musculoskeletal and connective tissue disorders

Uncommon: myalgia, limb pain.

Renal and urinary disorders

Uncommon: haematuria.

Reproductive system and breast disorders

Rare: penile haemorrhage, priapism*, haemospermia, prolonged erection.

General disorders and administration site conditions

Uncommon: chest pain, increased fatigue, feeling of warmth.

Rare: irritation.

Investigations

Uncommon: increased heart rate.

* Reported only during post-marketing experience.

** Colour vision disorders: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.

*** Lacrimation disorders: dry eyes, lacrimation disorders, increased lacrimation.

The following events were observed in < 2% of patients in controlled clinical trials; causal relationship has not been established. Reports included events with a probable relationship to the use of the medicinal product. Events not listed were mild and reports were too imprecise to be meaningful.

General: facial oedema, photosensitivity reactions, shock, asthenia, pain, sudden fall, abdominal pain, sudden injury.

Cardiovascular system: angina pectoris, AV block, migraine, postural hypotension, myocardial ischaemia, cerebral vessel thrombosis, sudden cardiac arrest, ECG abnormalities, cardiomyopathy.

Gastrointestinal system: glossitis, colitis, dysphagia, gastritis, gastroenteritis, oesophagitis, stomatitis, abnormal liver function tests, rectal bleeding, gingivitis.

Blood and lymphatic system disorders: anaemia, leucopenia.

Metabolism and nutrition disorders: thirst, oedema, gout, unstable diabetes, hyperglycaemia, peripheral oedema, hyperuricaemia, hypoglycaemia, hypernatraemia.

Musculoskeletal system: arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

Nervous system: ataxia, neuralgia, neuropathy, paraesthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes.

Respiratory system: asthma, dyspnoea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.

Skin: urticaria, herpes, pruritus, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

Specific sensations: sudden decrease or loss of hearing, ear pain, eye haemorrhage, cataract, dry eyes.

Genitourinary system: cystitis, nocturia, increased frequency of urination, galactorrhoea, urinary incontinence, ejaculation disorders, genital swelling, anorgasmia.

Post-marketing experience. The following adverse reactions have been identified after marketing authorization. Because these reactions are reported voluntarily from an undefined population size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events were included due to their seriousness, frequency of reporting, lack of clear alternative explanation, or a combination of these factors.

Cardiovascular and cerebrovascular events. Serious cardiovascular, cerebrovascular, and vascular events have been reported, including cerebral haemorrhage, subarachnoid haemorrhage, intracerebral haemorrhage, and pulmonary haemorrhage, which occurred in temporal association with Sildocad administration. Most, but not all, patients had pre-existing cardiovascular risk factors. Many of these events occurred during or immediately after sexual activity, and several occurred immediately after Sildocad use without sexual activity. Other events occurred within hours or days after Sildocad use and sexual activity. It is not possible to determine whether these events are directly related to the use of the drug, to sexual activity, to pre-existing risk factors, to a combination of these factors, or to other factors.

Blood and lymphatic system disorders: vaso-occlusive crisis. In a small, prematurely terminated study of Revatio (sildenafil) in patients with pulmonary arterial hypertension secondary to sickle cell anaemia, vaso-occlusive crises requiring hospitalization were reported more frequently with sildenafil than with placebo. The clinical relevance of this information for patients taking Sildocad for the treatment of erectile dysfunction is unknown.

Nervous system disorders: anxiety, transient global amnesia.

Specific sensations.

Hearing. After marketing authorization, cases of sudden decrease or loss of hearing, occurring in temporal association with Sildocad use, have been reported. In some cases, medical conditions and other factors that could have contributed to hearing-related adverse reactions were reported. In many cases, follow-up medical information is lacking. It is not possible to determine whether these events are directly related to Sildocad use, to pre-existing risk factors for hearing loss, to a combination of these factors, or to other factors.

Vision: transient vision loss, eye redness, eye burning, increased intraocular pressure, retinal oedema, retinal vascular disorders or haemorrhage, vitreous detachment.

Rarely, after marketing authorization, cases of non-arteritic anterior ischaemic optic neuropathy (NAION), a cause of vision loss including permanent vision loss, have been reported in temporal association with PDE5 inhibitors, including Sildocad. Many, but not all, patients had pre-existing anatomical or vascular risk factors for NAION, including (but not limited to): small cup-to-disc ratio (crowded optic disc), age over 50 years, hypertension, coronary artery disease, hyperlipidaemia, and smoking. It is not possible to determine whether these events are directly related to PDE5 inhibitor use, to pre-existing anatomical or vascular risk factors, to a combination of these factors, or to other factors.

Reporting suspected adverse reactions. Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the product. Healthcare professionals should report any suspected adverse reactions in accordance with national regulatory requirements.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging.

4 or 10 tablets in a blister. 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Jubilant Generics Limited.

Manufacturer's address and place of business.

Village Sikandarpur, Bhainswal, Roorkee-Dehradun Highway, Bhagwanpur, District Roorkee Haridwar, Uttarakhand, IN-247661, India.