Effex Sildenafil, 100 mg

Medication for the treatment of erectile dysfunction. It starts to work after 30-120 minutes.

Indications

Active ingredient

Composition

Sildenafil citrate,

Associates:

Cellulose microcrystalline,

Calcium hydrophosphate,

Pregelatinized corn starch,

Magnesium stearate,

Sodium croscarmellose,

Silicon dioxide colloidal

Composition of the shell:

Hypromellose (hydroxypropyl methylcellulose), Macrogol 4000 (polyethylene glycol 4000), Titanium dioxide, Polysorbate-80, Talc, Iron oxide red dye, Iron oxide yellow dye

How to take, the dosage

Ingestion.

The recommended dose for most adult patients is 50 mg sildenafil about 1 hour before sexual activity.

The dose may be increased to 100 mg, depending on efficacy and tolerability. The maximum recommended dose is 100 mg. The maximum recommended frequency of use is once daily.

Elderly patients

There is no need to adjust the dose of EFEX® Sildenafil.

Patients with mild to moderate renal impairment (CKR 30-80 ml/min) do not require dose adjustment.

The concomitant use with other drugs

In order to minimize the risk of postural hypotension in patients taking α-adreno-blockers, sildenafil should be started only after hemodynamic stabilization has been achieved in these patients. A reduction in the initial dose of sildenafil should also be considered.

Interaction

The effect of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the action of cytochrome CYP3A4 isoenzymes (main pathway) and CYP2C9, therefore inhibitors of these isoenzymes may decrease sildenafil clearance, and inducers, respectively, increase sildenafil clearance.

Inhibitors of CYP3A4 cytochrome isoenzyme inhibitors (ketoconazole, erythromycin, cimetidine) have been observed to decrease sildenafil clearance.

Cimetidine (800 mg), a non-specific CYP3A4 cytochrome isoenzyme inhibitor, when taken with sildenafil (50 mg) increases sildenafil plasma concentrations by 56%.

Single administration of sildenafil together with erythromycin (500 mg/day 2 times per day) of cytochrome CYP3A4, on the background of achieving constant concentration of erythromycin in blood, leads to increase of AUC of sildenafil by 182 %.

When sildenafil (100 mg once) and saquinavir (1200 mg/day 3 times daily), an HIV protease inhibitor and cytochrome CYP3A4 isoenzyme, were taken together against achieving a constant concentration of saquinavir in the blood, sildenafil Cmax was increased by 140 % and AUC was increased by 210 %. Sildenafil has no effect on the pharmacokinetics of saquinavir.

The stronger CYP3A4 cytochrome isoenzyme inhibitors, such as ketoconazole and itraconazole, may also cause greater changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (100 mg once) and ritonavir (500 mg twice daily), an HIV protease inhibitor and strong cytochrome P450 inhibitor, on reaching a steady blood concentration of ritonavir results in an increase in Cmax of sildenafil by 300% (4 times) and AUC by 1000% (11 times). After 24 hours the plasma concentration of sildenafil is about 200 ng/ml (after a single use of sildenafil – 5 ng/ml).

If sildenafil is used at the recommended doses in patients receiving concomitant strong CYP3A4 cytochrome isoenzyme inhibitors, the Cmax of free sildenafil does not exceed 200 nM and the drug is well tolerated.

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

. In studies involving healthy volunteers, concomitant use of the endothelin receptor antagonist, bosentan (an inducer of the CYP3A4 (moderate), CYP2C9, and possibly CYP2C19 isoenzymes) at equilibrium concentration (125 mg twice daily) and sildenafil at equilibrium concentration (80 mg three times daily) showed a 62.6 % and 52.4 % decrease in AUC and Cmax of sildenafil, respectively. Sildenafil increased the AUC and Cmax of bosentan by 49.8% and 42%, respectively. It has been suggested that concomitant use of sildenafil with potent CYP3A4 isoenzyme inducers, such as rifampicin, may lead to a large decrease in plasma sildenafil concentrations.

. CYP2C9 isoenzyme inhibitors (tolbutamide, warfarin), CYP2D6 (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists do not influence sildenafil pharmacokinetics.

Asithromycin (500 mg/day for 3 days) has no effect on the AUC, Cmax, Tmax, elimination rate constant and T½ of sildenafil or its major circulating metabolite. Means

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes – 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IK50 > 150 μmol). When sildenafil is taken at the recommended doses, its Cmax is about

1 μmol, so it is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates both with long-term use of the latter and when prescribed for acute indications. Therefore, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

The concomitant administration of the α-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics resulted in an average additional reduction of systolic/diastolic BP in the supine position of 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 by dizziness (without fainting), have been reported in these patients. In some sensitive patients receiving α-adreno-blockers, concomitant use of sildenafil may lead to symptomatic hypotension.

There are no signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome isoenzyme CYP2C9.

Sildenafil (100 mg) has no effect on the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the cytochrome CYP3A4 isoenzyme, when their blood levels are constant.

The concomitant use of sildenafil at equilibrium (80 mg three times daily) increases the AUC and Cmax of bosentan (125 mg twice daily) by 49.8% and 42%, respectively.

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

Sildenafil (50 mg) does not increase the hypotensive effects of alcohol in healthy volunteers at a maximum blood alcohol concentration of 0.08% (80 mg/dL) on average.

In patients with arterial hypertension, there is no evidence of interaction of sildenafil (100 mg) with amlodipine. The mean additional reduction of BP in the supine position is 8 mm Hg (systolic) and 7 mm Hg (diastolic).

The use of sildenafil in combination with antihypertensive agents does not lead to additional side effects.

Special Instructions

The effect of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the action of cytochrome CYP3A4 isoenzymes (main pathway) and CYP2C9, therefore inhibitors of these isoenzymes may decrease sildenafil clearance, and inducers, respectively, increase sildenafil clearance.

Inhibitors of CYP3A4 cytochrome isoenzyme inhibitors (ketoconazole, erythromycin, cimetidine) have been observed to decrease sildenafil clearance.

Cimetidine (800 mg), a non-specific CYP3A4 cytochrome isoenzyme inhibitor, when taken with sildenafil (50 mg) increases sildenafil plasma concentrations by 56%.

Single administration of sildenafil together with erythromycin (500 mg/day 2 times per day) of cytochrome CYP3A4, on the background of achieving constant concentration of erythromycin in blood, leads to increase of AUC of sildenafil by 182 %.

When taking sildenafil (100 mg once) and saquinavir (1200 mg/day 3 times daily), an inhibitor of HIV protease and cytochrome CYP3A4 isoenzyme, together against achieving a constant concentration of saquinavir in the blood Cmax of sildenafil was increased by 140 % and AUC was increased by 210 %. Sildenafil has no effect on the pharmacokinetics of saquinavir.

The stronger CYP3A4 cytochrome isoenzyme inhibitors, such as ketoconazole and itraconazole, may also cause greater changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (100 mg once) and ritonavir (500 mg twice daily), an HIV protease inhibitor and strong cytochrome P450 inhibitor, on reaching a steady blood concentration of ritonavir results in an increase in Cmax of sildenafil by 300% (4 times) and AUC by 1000% (11 times). After 24 hours the plasma concentration of sildenafil is about 200 ng/ml (after a single use of sildenafil – 5 ng/ml).

If sildenafil is used in recommended doses in patients receiving concomitant strong CYP3A4 cytochrome isoenzyme inhibitors, the Cmax of free sildenafil is less than 200 nM and the drug is well tolerated.

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

. In studies involving healthy volunteers, concomitant use of the endothelin receptor antagonist, bosentan (an inducer of the CYP3A4 (moderate), CYP2C9, and possibly CYP2C19 isoenzymes) at equilibrium concentration (125 mg twice daily) and sildenafil at equilibrium concentration (80 mg three times daily) showed a 62.6 % and 52.4 % decrease in AUC and Cmax of sildenafil, respectively. Sildenafil increased the AUC and Cmax of bosentan by 49.8% and 42%, respectively. It has been suggested that concomitant use of sildenafil with potent CYP3A4 isoenzyme inducers, such as rifampicin, may lead to a large decrease in plasma sildenafil concentrations.

. CYP2C9 isoenzyme inhibitors (tolbutamide, warfarin), CYP2D6 (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists, have no effect on sildenafil pharmacokinetics.

Asithromycin (500 mg/day for 3 days) has no effect on the AUC, Cmax, Tmax, elimination rate constant and T½ of sildenafil or its major circulating metabolite. Means

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes – 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IK50 > 150 μmol). When sildenafil is taken at the recommended doses, its Cmax is about

1 μmol, so it is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates both with long-term use of the latter and when prescribed for acute indications. Therefore, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

The concomitant administration of the α-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics resulted in a mean additional reduction of systolic/diastolic BP in the supine position of 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 by dizziness (without fainting), have been reported in these patients. In some sensitive patients receiving α-adreno-blockers, concomitant use of sildenafil may lead to symptomatic hypotension.

There are no signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome isoenzyme CYP2C9.

Sildenafil (100 mg) has no effect on the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the cytochrome CYP3A4 isoenzyme, when their blood levels are constant.

The concomitant use of sildenafil at equilibrium (80 mg three times daily) increases the AUC and Cmax of bosentan (125 mg twice daily) by 49.8% and 42%, respectively.

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

Sildenafil (50 mg) does not increase the hypotensive effects of alcohol in healthy volunteers at a maximum blood alcohol concentration of 0.08% (80 mg/dL) on average.

In patients with arterial hypertension, there is no evidence of interaction of sildenafil (100 mg) with amlodipine. The mean additional reduction of BP in the supine position is 8 mm Hg (systolic) and 7 mm Hg (diastolic).

The use of sildenafil in combination with antihypertensive agents does not lead to additional side effects.

Contraindications

Hypersensitivity to sildenafil or any other component of the drug.

The use in patients receiving nitric oxide donors, organic nitrates or nitrites in any form, either continuously or intermittently, because EFEX® Sildenafil increases the hypotensive effects of nitrates.

The safety and effectiveness of EFEX® Sildenafil when used together with other erectile dysfunction treatments have not been studied, therefore such combinations are not recommended. Co-administration with ritonavir.

Liver function abnormalities.

Chronic renal failure of severe severity. Severe heart failure, unstable angina pectoris, stroke or myocardial infarction within the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mm Hg) or hypotension (BP < 90/50 mm Hg). EFEX® Sildenafil is not indicated for use in children under 18 years of age. EFEX® Sildenafil is not indicated for use in women.

With caution

Anatomic deformity of the penis (angulation, cavernous fibrosis, or Peyronie’s disease) (see section “Special Precautions”). Diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia). Diseases accompanied by bleeding. Exacerbation of gastric and 12 duodenal ulcer. Hereditary retinitis pigmentosa.

Side effects

The most common side effects were headache and “hot flashes. Generally, the side effects of EFEX® Sildenafil are mild to moderate and transient. In fixed-dose studies, the incidence of some adverse events has been shown to increase with increasing dose.

The frequency of side effects is classified according to World Health Organization guidelines: Very common (≥1/10), common (≥1/10 to < 1/10), infrequent (≥1/1000 to < 1/100), rare (≥1/10000 to < 1/1000), very rare (< 1/10000), including individual reports; frequency unknown (the incidence cannot be determined from available data).

Immune system disorders: infrequent hypersensitivity reactions (including skin rash), allergic reactions.

Visual organ disorders: frequent – blurred vision, visual disturbances, cyanopsia; infrequent – eye pain, photophobia, photopsia, chromatopsia, eye redness/sclera injections, changes in brightness of light perception, mydriasis, conjunctivitis, bleeding in eye tissue, cataracts, disorders of the lacrimal system; rare – swelling of the eyelids and adjacent tissues, dry eye sensation, iridescent circles in the field of vision around the light source, increased eye fatigue, seeing objects in yellow (xanthopsia), seeing objects in red (erythropsia), conjunctival hyperemia, irritation of the mucous membrane in the eyes, unpleasant sensations in the eyes; frequency unknown – non-arteritic anterior ischemic optic neuropathy (NAINZN), retinal vein occlusion, visual field defects, diplopia*, temporary vision loss or decreased visual acuity, increased intraocular pressure, retinal edema, retinal vascular disease, vitreous detachment/vitreal traction.

Hearing organ: infrequent – sudden decrease or loss of hearing, tinnitus, tinnitus pain, tinnitus ringing.

Cardiovascular system disorders: frequent – “flushes”; infrequent – tachycardia, palpitations, decreased blood pressure, increased blood pressure, increased heart rate, unstable angina, atrioventricular block, myocardial ischemia, cerebral vascular thrombosis, cardiac arrest, heart failure, deviations in electrocardiogram readings, cardiomyopathy; rare – atrial fibrillation.

Blood and lymphatic system disorders: infrequent – anemia, leukopenia.

Mechanisms and nutrition: infrequent – sensation of thirst, edema, gout, uncompensated diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatriemia.

Respiratory system: frequently – nasal congestion; infrequently – nasal bleeding, rhinitis, asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased volume of sputum, increased coughing; rarely – feeling of tightness in the throat, dry nasal mucosa, swelling of the nasal mucosa.

Gastrointestinal disorders: Nausea, dyspepsia; infrequent – gastroesophageal reflux disease, vomiting, abdominal pain, dry oral mucosa, glossitis, gingivitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal “liver” functional tests, rectal bleeding; rarely – oral mucosa hypoesthesia.

Musculoskeletal system:

often – back pain; infrequent – myalgia, pain in the extremities, arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia gravis, synovitis.

Urogenital system disorders: infrequent – cystitis, nycturia, breast enlargement, urinary incontinence, hematuria, ejaculation disorders, genital edema, anorgasmia, hematospermia, penile tissue damage; rarely – prolonged erection and/or priapism.

In the central and peripheral nervous system: very common – headache; common – dizziness; infrequent – somnolence, migraine, ataxia, hypertonicity, neuralgia, neuropathy, paresthesia, tremor, vertigo, symptoms of depression, insomnia, unusual dreams, increased reflexes, hypoesthesia; rare – convulsions*, recurrent convulsions*, syncope, cerebrovascular disorders, transient ischemic attack.

Skin and subcutaneous tissue disorders: infrequent – skin rash, urticaria, herpes simplex, pruritus, increased sweating, skin ulceration, contact dermatitis, exfoliative dermatitis; frequency unknown – Stevens-Johnson syndrome, toxic epidermal necrolysis.

Reproductive system disorders: rarely – bleeding from the penis.

Others: infrequent – sensation of fever, facial edema, photosensitivity reaction, shock, asthenia, increased fatigue, pain of various localizations, chills, accidental falls, pain in the chest area, accidental injury; rarely – irritability.

* Side effects identified in post-marketing studies.

Cardiovascular Complications

In the postmarketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as severe cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension, and hypotension) that were temporarily associated with sildenafil use. Most, but not all, of these patients had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity, and some were noted after sildenafil administration without subsequent sexual activity. It is not possible to establish a direct relationship between the reported adverse events and these or other factors.

Visual impairment

In rare cases during post-registration use of all FDE5 inhibitors, including sildenafil, nonarteritic anterior ischemic optic neuropathy (NPINZN) was reported, a rare condition and cause of visual impairment or loss. Most of these patients had risk factors, such as a decreased ratio of excavation and optic disc diameters (“stagnant disc”), age over 50 years, diabetes mellitus, hypertension, coronary heart disease, hyperlipidemia, and smoking. The observational study evaluated whether recent use of a class of FDE5 inhibitor drugs was associated with the acute onset of NSAIDs. The results indicated an approximately 2-fold increased risk of NSAIDs within 5 half-lives of FDE5 inhibitor use. According to a 5-day opioid), moderate isoenzyme inhibitor literature, the annual incidence of NSAIDs is 2.5-11.8 cases per 100,000 men aged ≥50 years in the general population. Patients should be advised to discontinue sildenafil therapy in the event of sudden vision loss and immediately consult a physician. Individuals who have already had a history of NSAIDs have an increased risk of a recurrence of NSAIDs. Therefore, the physician should discuss this risk with such patients and also discuss with them the potential chance of adverse effects of FDE5 inhibitors. PDE5 inhibitors, including sildenafil, should be used with caution in these patients and only in situations where the expected benefits outweigh the risks.

Overdose

When using EFEX® Sildenafil in doses higher than recommended, adverse events were similar to those noted above, but were generally more frequent.

The treatment is symptomatic. Hemodialysis does not accelerate excretion of the drug because sildenafil is firmly bound to plasma proteins and is not excreted by the kidneys.

Similarities