Sildenafil Zentiva (Tablets) Instructions for Use

Marketing Authorization Holder

Zentiva, a.s. (Slovakia)

Manufactured By

Saneca Pharmaceuticals, a.s. (Slovakia)

ATC Code

G04BE03 (Sildenafil)

Active Substance

Sildenafil (USAN)

Dosage Forms

	Sildenafil Zentiva	Film-coated tablets, 50 mg: 1, 4 or 8 pcs.
		Film-coated tablets, 100 mg: 1, 4 or 8 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, round, biconvex, marked “50” on one side.

Excipients : calcium hydrogen phosphate – 125.76 mg, microcrystalline cellulose – 70 mg, croscarmellose sodium – 8.4 mg, magnesium stearate – 5.6 mg.

Film coating composition sepifilm 3048 yellow (hypromellose 40-45%, microcrystalline cellulose – 30-40%, macrogol 40 stearate – 4-12%, titanium dioxide – 10-15%, quinoline yellow dye – 0.15-0.5%) – 12 mg, macrogol 6000 – 120 mcg.

1 pc. – blisters (1) – carton packs.
1 pc. – blisters (4) – carton packs.
4 pcs. – blisters (2) – carton packs.

Film-coated tablets yellow, round, biconvex, marked “100” on one side.

Excipients : calcium hydrogen phosphate – 251.52 mg, microcrystalline cellulose – 140 mg, croscarmellose sodium – 16.8 mg, magnesium stearate – 11.2 mg.

Film coating composition sepifilm 3048 yellow (hypromellose – 40-45%, microcrystalline cellulose – 30-40%, macrogol 40 stearate – 4-12%, titanium dioxide – 10-15%, quinoline yellow dye – 0.15-0.5%) – 20 mg, macrogol 6000 – 240 mcg.

1 pc. – blisters (1) – carton packs.
1 pc. – blisters (4) – carton packs.
4 pcs. – blisters (2) – carton packs.

Clinical-Pharmacological Group

Erectile dysfunction treatment drug. PDE5 inhibitor

Pharmacotherapeutic Group

Erectile dysfunction treatment agent – PDE5 inhibitor

Pharmacological Action

A drug for the treatment of erectile dysfunction, a PDE5 inhibitor.

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific PDE5. The physiological mechanism of erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. This, in turn, leads to an increase in cGMP levels, subsequent relaxation of the smooth muscle tissue of the corpus cavernosum, and increased blood flow. Sildenafil does not have a direct relaxing effect on the isolated human corpus cavernosum but enhances the effect of NO by inhibiting PDE5, which is responsible for the breakdown of cGMP. The use of sildenafil at recommended doses is ineffective in the absence of sexual stimulation.

Sildenafil is selective for PDE5 in vitro, its activity against PDE5 significantly exceeds its activity against other known PDE isoenzymes.

Pharmacokinetics

The pharmacokinetics of sildenafil in the recommended dose range are linear.

Absorption

After oral administration, Sildenafil is rapidly absorbed. The absolute bioavailability averages 40% (25-63%). In vitro, Sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human PDE5 by 50%. After a single oral dose of sildenafil 100 mg, the mean C_max of free sildenafil in plasma is 18 ng/ml (38 nM) and is achieved when taken on an empty stomach on average within 60 min (30-120 min). When taken with a fatty meal, the rate of absorption decreases: C_max decreases by an average of 29%, and T_max increases by 60 min, but the extent of absorption does not change significantly (AUC decreases by 11%).

Distribution

The V_d of sildenafil at steady state averages 105 L. Sildenafil and its main circulating N-desmethyl metabolite are approximately 96% bound to plasma proteins. Protein binding is independent of total sildenafil concentration. Less than 0.0002% of the dose (average 188 ng) is detected in semen 90 minutes after sildenafil intake.

Metabolism

Sildenafil is metabolized primarily in the liver by the action of isoenzymes CYP3A4 (main pathway) and CYP2C9 (minor pathway). The main circulating metabolite, which is formed as a result of N-demethylation of sildenafil, undergoes further metabolism. In terms of selectivity of action on PDE, the metabolite is comparable to sildenafil, and its activity against PDE5 in vitro is approximately 50% of the activity of sildenafil. The plasma concentration of the metabolite is approximately 40% of the sildenafil concentration. The N-desmethyl metabolite undergoes further metabolism. T_1/2 is about 4 h.

Excretion

The total clearance of sildenafil is 41 L/h, and the terminal T_1/2 is 3-5 h. After oral administration, as well as after IV administration, Sildenafil is excreted as metabolites, mainly in the feces (about 80% of the oral dose) and, to a lesser extent, in the urine (about 13% of the oral dose).

Pharmacokinetics in special patient groups

In healthy elderly patients (over 65 years of age), the clearance of sildenafil is reduced, and the plasma concentration of free sildenafil is approximately 40% higher than in young patients (18-45 years). Age does not have a clinically significant effect on the incidence of adverse effects.

In mild (CrCl 50-80 ml/min) and moderate (CrCl 30-49 ml/min) renal impairment, the pharmacokinetics of sildenafil after a single oral dose of 50 mg do not change. In severe renal impairment (CrCl ≤30 ml/min), the clearance of sildenafil is reduced, leading to approximately a twofold increase in AUC (100%) and C_max(88%) compared to the corresponding values in patients with normal renal function of the same age group.

In patients with liver cirrhosis (Child-Pugh class A and B), the clearance of sildenafil is reduced, leading to an increase in AUC (84%) and C_max(47%) compared to those in patients with normal liver function of the same age group. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Indications

• Treatment of erectile dysfunction characterized by the inability to achieve or maintain a penile erection sufficient for satisfactory sexual intercourse.

The drug is effective only with sexual stimulation.

ICD codes

Dosage Regimen

The drug is taken orally 1 hour before sexual activity. When taking the drug with food, the onset of action of the drug may be delayed compared to taking on an empty stomach.

The recommended dose is 50 mg. Depending on efficacy and tolerability, this dose may be increased to 100 mg. The maximum recommended dose and frequency of use is 100 mg once/day.

In elderly patients, dose adjustment is not required.

In patients with mild to moderate renal impairment (CrCl 30-80 ml/min), dose adjustment is not required.

In patients with impaired liver function (Child-Pugh classes A and B), the use of the drug must be agreed with the attending physician.

Patients receiving concomitant treatment with other inhibitors of the CYP3A4 isoenzyme (erythromycin, saquinavir, ketoconazole, itraconazole) should consult a doctor before starting the drug.

To reduce the risk of orthostatic hypotension in patients taking alpha-blockers, sildenafil should be initiated only after the condition has stabilized on alpha-blocker therapy.

Adverse Reactions

Classification of the frequency of adverse effects (WHO): very common (>1/10), common (from >1/100 to <1/10), uncommon (from >1/1000 to <1/100), rare (from >1/10,000 to <1/1000), very rare (<1/10,000, including isolated reports).

Nervous system disorders: very common – headache; common – dizziness; uncommon – drowsiness, hypoesthesia; rare – stroke, syncope; frequency unknown – transient ischemic attack, seizures, incl. recurrent.

Cardiovascular system disorders: common – flushing; uncommon – palpitations, tachycardia; rare – increased or decreased BP, myocardial infarction, atrial fibrillation; frequency unknown – ventricular arrhythmia, unstable angina, sudden death.

Eye disorders: common – visual impairment, color vision disturbance; uncommon – conjunctival lesion, lacrimation disorder; frequency unknown – anterior ischemic optic neuropathy, retinal vascular occlusion, visual field defects.

Ear and labyrinth disorders: uncommon – vertigo, tinnitus; rare – deafness.

Respiratory system disorders: common – nasal congestion; rare – epistaxis.

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

Allergic reactions: uncommon – skin rash; frequency unknown – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

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

Other: rare – chest pain, fatigue.

Contraindications

• Concomitant use of nitric oxide donors or organic nitrates or nitrites in any dosage forms;
• Concomitant use of other drugs that stimulate erection, ritonavir;
• Patients for whom sexual activity is undesirable (including those with severe cardiovascular diseases such as unstable angina, severe heart failure);
• Arterial hypotension (BP less than 90/50 mm Hg);
• Recent cerebrovascular accident;
• Recent myocardial infarction;
• Hereditary degenerative retinal diseases, incl. retinitis pigmentosa (a minority of such patients have a genetic disorder of retinal PDE);
• Severe hepatic failure;
• Children and adolescents under 18 years of age;
• Female gender;
• Hypersensitivity to sildenafil or to any component of the drug.

With caution the drug should be used in case of anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie’s disease); diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocytopenia); diseases accompanied by bleeding; exacerbation of gastric and duodenal ulcers; in patients taking alpha-blockers (risk of orthostatic hypotension).

Use in Pregnancy and Lactation

According to the registered indication, the drug is not intended for use in women.

Use in Hepatic Impairment

Contraindication: severe hepatic failure.

In patients with impaired liver function (Child-Pugh classes A and B), the use of the drug must be agreed with the attending physician.

Use in Renal Impairment

In patients with mild to moderate renal impairment (CrCl 30-80 ml/min), dose adjustment is not required.

In severe renal impairment (CrCl ≤30 ml/min), the clearance of sildenafil is reduced, leading to approximately a twofold increase in AUC (100%) and C_max(88%) compared to the corresponding values in patients with normal renal function of the same age group.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

In elderly patients, dose adjustment is not required.

Special Precautions

Before prescribing the drug for the diagnosis of erectile dysfunction, a complete medical history must be taken and a physical examination performed.

Before starting any treatment for erectile dysfunction, the patient’s cardiovascular status should be determined, as there is a certain degree of risk associated with sexual activity. Drugs intended for the treatment of erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable.

It has vasodilating properties leading to minor transient decreases in BP. However, increased susceptibility to vasodilators is observed in patients with left ventricular outflow tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy), or in patients with the rare syndrome of multiple system atrophy, manifested by severe autonomic nervous system dysregulation of BP.

In the post-registration period, serious cardiovascular disorders have been reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmias, cerebrovascular hemorrhage, transient ischemic attack, increased or decreased BP, which were temporally associated with the use of sildenafil. Most of these patients had pre-existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse, and only a small number occurred shortly after taking sildenafil without sexual activity, so it is impossible to determine whether these events are directly related to these or to other factors.

Since the concomitant use of sildenafil and alpha-blockers may lead to symptomatic hypotension in some sensitive patients, Sildenafil should be prescribed with caution to patients taking alpha-blockers. To minimize the risk of orthostatic hypotension in patients taking alpha-blockers, sildenafil should be initiated only after hemodynamic stabilization has been achieved in these patients. Consideration should be given to reducing the initial dose of sildenafil. In addition, patients should be informed about what actions to take in case of symptoms of orthostatic hypotension.

Sildenafil enhances the antiplatelet effect of sodium nitroprusside (a nitric oxide donor) on human platelets in vitro. There is no information on the safety of the drug in patients with internal bleeding or active peptic ulcer, so in such cases the drug should be used only after careful assessment of the benefit-risk ratio of therapy.

Effect on ability to drive vehicles and operate machinery

No negative effect on the ability to drive a car or other technical means was observed during the use of the drug. However, since a decrease in BP, the development of chromatopsia, and blurred vision are possible, one should be attentive to the individual effect of the drug, especially at the beginning of treatment and when changing the dosage regimen, and exercise caution when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms with a single use of the drug at a dose of up to 800 mg, adverse reactions were the same as when using the drug at lower doses, but occurred more frequently. When using the drug at a dose of 200 mg, there was no increase in efficacy, but the frequency of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual impairment) increased.

Treatment standard measures to maintain vital body functions; symptomatic therapy. Dialysis does not accelerate clearance, since Sildenafil is largely bound to plasma proteins and is not excreted in the urine.

Drug Interactions

The metabolism of sildenafil occurs mainly in the liver under the action of isoenzymes CYP3A4 (main pathway) and CYP2C9, so inhibitors of these isoenzymes may reduce the clearance of sildenafil, and inducers, respectively, increase the clearance of sildenafil. With simultaneous use of inhibitors of the CYP3A4 isoenzyme (such as ketoconazole, erythromycin, cimetidine), a decrease in the clearance of sildenafil was noted. Cimetidine (800 mg), a non-specific inhibitor of the CYP3A4 isoenzyme, when used concomitantly with sildenafil (50 mg), causes an increase in sildenafil plasma concentration by 56%. A single dose of sildenafil 100 mg simultaneously with erythromycin, a specific inhibitor of the CYP3A4 isoenzyme (when using erythromycin 500 mg twice/day for 5 days), against the background of achieving a steady-state concentration of erythromycin in the blood, leads to an increase in the AUC of sildenafil by 182%.

With simultaneous use of sildenafil (in a single dose of 100 mg) and saquinavir, which is both an HIV protease inhibitor and an inhibitor of the CYP3A4 isoenzyme (when using saquinavir at a dose of 1200 mg three times/day), against the background of achieving C_ss of saquinavir in the blood, C_max of sildenafil in the blood increased by 140%, and AUC increased by 210%. Sildenafil did not affect the pharmacokinetic parameters of saquinavir. Stronger inhibitors of the CYP3A4 isoenzyme, such as ketoconazole or itraconazole, may cause more pronounced changes in the pharmacokinetics of sildenafil.

With the simultaneous use of sildenafil (a single dose of 100 mg) and ritonavir, which is an HIV protease inhibitor and a strong inhibitor of cytochrome P450 system isoenzymes (when using ritonavir at 500 mg twice a day), against the background of achieving a constant ritonavir blood level, the C_max of sildenafil increased by 300% (4 times), and the AUC by 1000% (11 times). After 24 hours, the plasma concentration of sildenafil was approximately 200 ng/ml (with a single use of sildenafil alone – 5 ng/ml).

If Sildenafil is taken at recommended doses by patients who are simultaneously receiving strong inhibitors of the CYP3A4 isoenzyme, the C_max of free sildenafil does not exceed 200 nM, and the drug is well tolerated.

A single use of an antacid (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.

Inhibitors of the CYP2C9 isoenzyme (such as tolbutamide, warfarin), the CYP2D6 isoenzyme (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide-like diuretics, ACE inhibitors, and calcium antagonists do not affect the pharmacokinetic parameters of sildenafil.

Simultaneous use of azithromycin (500 mg/day for 3 days) does not affect the AUC, C_max, T_max, elimination rate constant, and T_1/2 of sildenafil or its main circulating metabolite.

Sildenafil is a weak inhibitor of the CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 isoenzymes (IC₅₀ >150 µmol). It is unlikely that Sildenafil can affect the clearance of substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates, both during long-term use and during acute use. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

With the simultaneous use of the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the mean additional reduction in supine systolic/diastolic blood pressure was 9/5 mmHg and 8/4 mmHg, respectively, and in the standing position – 11/4 mmHg and 4/5 mmHg, respectively. Rare cases of symptomatic postural hypotension manifested as dizziness (without fainting) have been reported in such patients. In certain sensitive patients receiving alpha-blockers, the simultaneous use of sildenafil may lead to symptomatic hypotension.

No signs of significant interaction of sildenafil with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the CYP2C9 isoenzyme, were found.

Sildenafil at a dose of 100 mg does not affect the pharmacokinetic parameters of HIV protease inhibitors at their C_ss in the blood, such as saquinavir and ritonavir, which are also substrates of the CYP3A4 isoenzyme.

Sildenafil (50 mg) does not cause an additional increase in bleeding time when used with acetylsalicylic acid (150 mg).

Sildenafil (50 mg) does not enhance the hypotensive effect of ethanol in healthy volunteers with a mean blood ethanol C_max of 80 mg/dL.

In patients with arterial hypertension, no signs of interaction between sildenafil (100 mg) and amlodipine were found. The use of sildenafil in combination with antihypertensive agents does not lead to the occurrence of additional side effects.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.