Sildenafil Citrate

Package leaflet (information for patients)

Tradename
Sildenafil Citrate

Dosage form
Tablets 50 mg.

Description
Round, flat, beveled to the edge white tablets with an imprint in the form of the brand name "V" on one side.

Structure
Active ingredients: Sildenafil Citrate 50 mg.
Excipients: microcrystalline cellulose 102, calcium stearate, aerosil ® 200 (hydrophilic pyrogenic silicon dioxide).

Pharmacotherapeutic group
Treatment of erectile dysfunction, PDE-5 inhibitor

Pharmacological properties
Selective inhibitor of cycloguanosine monophosphate (cGMP) -specific PDE5. PDE5, responsible for the breakdown of cGMP, is contained not only in the cavernous body of the penis, but also in the vessels of the lungs.
Restores impaired erectile function and provides a natural response to sexual arousal. Sildenafil does not have a direct relaxing effect on the corpora cavernosa, but actively enhances the relaxing effect of nitric oxide on this tissue. With sexual arousal, the local release of NO under the influence of sildenafil leads to inhibition of PDE5 and an increase in the level of cGMP in the corpus cavernosum, resulting in relaxation of smooth muscles and increased blood flow in the corpus cavernosum.
As a PDE5 inhibitor, sildenafil increases the content of cGMP in the smooth muscle cells of the pulmonary vessels and causes them to relax. In patients with pulmonary hypertension, taking sildenafil leads to vasodilation of the lungs and, to a lesser extent, others with convulsions.
Sildenafil is selective for PDE5 in vitro. Its activity against PDE5 exceeds the activity against other known PDE isozymes: PDE6, which is involved in the transmission of a light signal in the retina of the eye - 10 times; PDE1 - 80 times; PDE2, PDE4, PDE7-PDE11 - more than 700 times. The activity of sildenafil in relation to PDE5 is more than 4000 times higher than its activity in relation to PDE3, a cAMP-specific PDE, which is involved in the contraction of the heart.
Sildenafil can cause mild and transient color discrimination (blue / green). The supposed mechanism of color vision impairment is the inhibition of PDE6, which is involved in the process of light transmission in the retina. In vitro studies have shown that the effect of sildenafil on PDE6 is 10 times lower than its activity against PDE5.
Pharmacokinetics
After oral administration, sildenafil is rapidly absorbed. The absolute bioavailability averages 40% (25-63%). After a single oral administration in a dose of 100 mg, Cmax is 18 ng / ml and is achieved when taken on an empty stomach for 30-120 minutes. When taking sildenafil in combination with fatty foods, the rate of absorption decreases; Тmax increases by 60 minutes, and Cmax decreases on average by 29%. The Vd of sildenafil in an equilibrium state averages 105 liters. Sildenafil and its main circulating N-desmethyl metabolite are approximately 96% bound to plasma proteins. Protein binding is independent of the total concentration of sildenafil. Less than 0.0002% of the dose (average 188 ng) was found in semen 90 min after taking sildenafil.
Sildenafil is metabolized mainly by the action of hepatic microsomal isoenzymes C YP3A4 (main pathway) and CYP2C9.
The main circulating metabolite, which is formed as a result of the N-desmethylation of sildenafil, undergoes further metabolism. In terms of the selectivity of the action on PDE, the metabolite is comparable to sildenafil, and its activity against PDE5 in vitro is approximately 50% of the activity of sildenafil itself. The concentration of the metabolite in plasma is approximately 40% of that of sildenafil. N-desmethyl metabolite undergoes further metabolism; its terminal T1 / 2 is about 4 hours.
The total clearance of sildenafil from the body is 41 l / h, and T1 / 2 in the terminal phase is 3-5 hours.After oral administration, sildenafil is excreted as metabolites mainly in the feces (approximately 80% of the dose) and to a lesser extent in urine ( approximately 13% of the dose).

Indications for use
Treatment of erectile dysfunction, characterized by an inability to achieve or maintain an erection of the penis sufficient for satisfactory intercourse.
Pulmonary hypertension.

Method of administration and dosage
Inside. The recommended dose for most adult patients is 50 mg of sildenafil approximately 1 hour before sexual activity. Taking into account the effectiveness and tolerability, the dose can be increased to 100 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of use is 1 time per day. Elderly patients No dose adjustment of Sildenafil is required. Renal dysfunction For patients with mild or moderate renal failure (CC 30-80 ml / min), dose adjustment is not required. Concomitant use with other medicinal products To minimize the risk of postural hypotension in patients taking α-adrenergic blockers, sildenafil should be started only after hemodynamic stabilization in these patients is achieved. You should also consider the feasibility of reducing the initial dose of sildenafil (see section Interaction with other medicinal products and Special instructions).

Side effects
From the immune system: infrequently - hypersensitivity reactions.
From the side of the organ of vision: often - blurred vision, blurred vision, cyanopsia; infrequently - eye pain, photophobia, photopsia, chromatopsia, redness of the eyes / sclera injections, changes in the brightness of light perception, mydriasis, conjunctivitis, hemorrhage in the eye tissue, cataract, disruption of the lacrimal apparatus; rarely - swelling of the eyelids and adjacent tissues, a feeling of dryness in the eyes, the presence of rainbow circles in the field of vision around the light source, increased eye fatigue, seeing objects in yellow color (xanthopsia), seeing objects in red (erythropsia), conjunctival hyperemia, mucosal irritation membranes of the eyes, discomfort in the eyes; frequency unknown - non-arteritis anterior ischemic optic neuropathy, retinal vein occlusion, visual field defect, diplopia, temporary loss of vision or decreased visual acuity, increased intraocular pressure, retinal edema, retinal vascular disease, vitreous detachment / vitreous traction.
On the part of the organ of hearing and labyrinth disorders: often - vertigo; infrequently - sudden hearing loss or loss, noise, ringing in the ears, ear pain; frequency unknown - sudden deafness.
From the side of the cardiovascular system: often - "hot flashes"; infrequently - tachycardia, palpitations, decreased blood pressure, increased blood pressure, increased heart rate, unstable angina pectoris, AV block, myocardial infarction, cerebral thrombosis, cardiac arrest, heart failure, abnormalities in ECG readings, cardiomyopathy; rarely - atrial fibrillation, sudden cardiac death, ventricular arrhythmia.
From the hematopoietic system : infrequently - anemia, leukopenia.
From the side of metabolism: infrequently - a feeling of thirst, edema, gout, uncompensated diabetes mellitus, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.
From the respiratory system: often - nasal congestion; infrequently - epistaxis, rhinitis, asthma, dyspnoea, laryngitis, pharyngitis, sinusitis, bronchitis, increased sputum volume, increased cough; rarely - a feeling of tightness in the throat, dryness of the mucous membrane of the nasal cavity, edema from the lysous membrane of the nasal cavity.
From the digestive system: often - nausea, dyspepsia, hemorrhoids, bloating; infrequently - gastroesophageal reflux disease, vomiting, abdominal pain, dryness of the oral mucosa, glossitis, gingivitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function tests, rectal bleeding; rarely - hypesthesia of the oral mucosa.
From the musculoskeletal system: often - back pain; infrequently - myalgia, pain in the extremities, arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia gravis, synovitis.
From the urinary system: infrequently - cystitis, nocturia, urinary incontinence, hematuria.
From the reproductive system: infrequently - an increase in the mammary glands, impaired ejaculation, edema of the genitals, anorgasmia, hematospermia, damage to the tissues of the penis; rarely - prolonged erection and / or priapism, bleeding from the penis.
From the nervous system: very often - headache; often - dizziness, anxiety; infrequently - drowsiness, migraine, ataxia, hypertonicity, neuralgia, neuropathy, paresthesia, hypoesthesia, tremor, vertigo, symptoms of depression, insomnia, unusual dreams, increased reflexes, hypesthesia; rarely - irritability, convulsions, fainting, impaired cerebral circulation, transient ischemic attack ; frequency unknown - migraine.
On the part of the skin and subcutaneous tissues: often - alopecia, erythema, increased sweating at night; infrequently - skin rash, urticaria, herpes simplex, pruritus, increased sweating, skin ulceration, contact dermatitis, exfoliative dermatitis; frequency unknown - Stevens-Johnson syndrome, toxic epidermal necrolysis.
Others: fever, flu-like syndrome, development of infectious diseases are possible; infrequently - a feeling of heat, swelling of the face, photosensitivity reaction, shock, asthenia, increased fatigue, pain of various localization, chills, accidental falls, chest pain, accidental trauma.

Contraindication
Hypersensitivity to sildenafil; joint use with donors of nitric oxide, organic nitrates or nitrites in any form; concomitant use with guanylate cyclase stimulants (such as riociguat); joint use with other drugs for the treatment of erectile dysfunction; liver dysfunction (class C according to the Child-Pugh classification); concomitant use of ritonavir; severe heart failure, unstable angina pectoris, stroke or myocardial infarction in the last 6 months, life-threatening arrhythmias, arterial hypertension (BP> 170/100 mm Hg) or arterial hypotension (BP <90/50 mm Hg) ; veno-occlusive lung disease; loss of vision in one eye due to anterior non-arteritis ischemic neuropathy of the optic nerve, hereditary degenerative diseases of the retina of the eye (retinitis pigmentosa); severe renal failure, when used together with inhibitors of the cytochrome CYP3A4 isoenzyme (erythromycin, saquinavir, ketoconazole, itraconazole); children and adolescents up to 18 years old.
With care: anatomical deformity of the penis (angulation, cavernous fibrosis, or Peyronie's disease); diseases that predispose to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia); bleeding diseases; peptic ulcer of the stomach and duodenum in the acute stage; heart failure, obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), a rare syndrome of multiple systemic atrophy, manifested by severe dysregulation of blood pressure by the autonomic nervous system, hypovolemia; LAS - I or IV functional classes; a history of anterior non-arteritis ischemic neuropathy of the optic nerve; combined use with moderate inhibitors of the isoenzyme CYP3A4 (including erythromycin, saquinavir, clarithromycin, telithromycin and nefazodone) and α-blockers. Combined use with inducers of the isoenzyme CYP3A4.

Overdose
In case of an overdose of Sildenafil, a feeling of dizziness, a strong feeling of heat, nausea and vomiting, a decrease in blood pressure and cloudy eyes may occur.
In the event of one of the symptoms of an overdose, you must consult a doctor so that symptomatic treatment can be prescribed.

Precautions
Since taking sildenafil may develop dizziness, lower blood pressure, development of chromatopsia, blurred vision, etc. side effects, care should be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions. You should also be attentive to the individual action of the drug in these situations, especially at the beginning of treatment and when changing the dosage regimen.

Interaction with other medicinal products
The effect of other drugs on the pharmacokinetics of sildenafil The metabolism of sildenafil occurs mainly under the influence of cytochrome isoenzymes CYP3A4 (main pathway) and CYP2C9, therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inducers, respectively, increase the clearance of sildenafil. A decrease in the clearance of sildenafil was noted with the simultaneous use of inhibitors of the isoenzyme of cytochrome CYP3A4 (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a nonspecific inhibitor of the cytochrome CYP3A4 isoenzyme, when taken together with sildenafil (50 mg), causes an increase in plasma concentration of sildenafil by 56%. A single dose of 100 mg of sildenafil in conjunction with erythromycin (500 mg / day 2 times in the denment of cytochrome CYP3A4, against the background of reaching a constant concentration of erythromycin in the blood, leads to an increase in the AUC of sildenafil by 182%. When sildenafil is taken together (100 mg once) and saquinavir (1200 mg / day 3 times a day), an inhibitor of HIV protease and cytochrome CYP3A4 isoenzyme, against the background of reaching a constant concentration of saquinavir in the blood, the Cmax of sildenafil increased by 140%, and the AUC increased by 210%. Sildenafil does not affect the pharmacokinetics of saquinavir. Stronger inhibitors of the cytochrome CYP3A4 isoenzyme, such as ketoconazole and itraconazole, may also cause stronger changes in the pharmacokinetics of sildenafil.Concomitant use of sildenafil (100 mg once) and ritonavir (500 mg twice a day), an inhibitor of HIV protease and a strong inhibitor of cytochrome P450, against the background of reaching a constant concentration of ritonavir in the blood, leads to an increase in Cmax of sildenafil by 300% (4 times), and AUC by 1000% (11 times). After 24 hours, the concentration of sildenafil in the blood plasma is about 200 ng / ml (after a single use of one sildenafil - 5 ng / ml). If sildenafil is used in the recommended doses by patients receiving simultaneously strong inhibitors of the cytochrome CYP3A4 isoenzyme, then the Cmax of free sildenafil does not exceed 200 nM, and the drug is well tolerated. A single dose of an antacid (magnesium hydroxide / aluminum hydroxide) does not affect the bioavailability of sildenafil. In studies involving healthy volunteers with the simultaneous use of an endothelin receptor antagonist, bosentan (inducer of the isoenzyme CYP3A4 (moderate), CYP2C9 and possibly CYP2C19) at an equilibrium concentration (125 mg twice a day) and sildenafil at an equilibrium concentration (80 mg three times per day), there was a decrease in AUC and Cmax of sildenafil by 62.6% and 52.4%, respectively. Sildenafil increased the AUC and Cmax of bosentan by 49.8% and 42%, respectively. It is assumed that the simultaneous use of sildenafil with powerful inducers of the isoenzyme CYP3A4, such as rifampicin, can lead to a large decrease in the concentration of sildenafil in blood plasma. Inhibitors of the cytochrome CYP2C9 isoenzyme (tolbutamide, warfarin), cytochrome CYP2D6 isoenzyme (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors, do not exert calcium antagonists on calcium pharmacokinetics. Azithromycin (500 mg / day for 3 days) has no effect on AUC, Cmax, Tmax, excretion rate constant and T½ of sildenafil or its main circulating metabolite. Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes - 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50> 150 μmol). When taking sildenafil in recommended doses, its Cmax is about 1 μmol, therefore it is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes. Sildenafil enhances the hypotensive effect of nitrates both with prolonged use of the latter and with their appointment for acute indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated. With the simultaneous administration of the α-blocker doxazosin (4 mg and 8 mg) and sildenafil (50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional decrease in systolic / diastolic blood pressure in the supine position was 9/5 mm rt. Art. and 8/4 mm Hg. Art., respectively, and in the standing position - 11/4 mm Hg. Art. and 4/5 mm Hg. Art., respectively. Reported rare cases of the development of symptomatic postural hypotension in such patients, manifested in the form of dizziness (without fainting). In some sensitive patients receiving α-adrenergic blockers, concomitant use of sildenafil can lead to symptomatic hypotension. Signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome CYP2C9 isoenzyme, have not been identified. Sildenafil (100 mg) has no effect on the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the cytochrome CYP3A4 isoenzyme, at a constant level in the blood. The simultaneous use of sildenafil in an equilibrium state (80 mg three times a day) leads to an increase in the AUC and Cmax of bosentan (125 mg twice a day) by 49.8% and 42%, respectively. Sildenafil (50 mg) does not cause an additional increase in bleeding time when acetylsalicylic acid (150 mg) is taken. Sildenafil (50 mg) does not enhance the hypotensive effect of alcohol in healthy volunteers with a maximum blood alcohol concentration of an average of 0.08% (80 mg / dL). In patients with arterial hypertension, there were no signs of interaction between sildenafil (100 mg) and amlodipine. The average additional decrease in blood pressure in the supine position is 8 mm Hg. Art. (systolic) and 7 mm Hg. Art. (diastolic). The use of sildenafil in combination with antihypertensive drugs does not lead to additional side effects.

Special instructions
Before starting to take sildenafil for the treatment of erectile dysfunction, a cardiovascular system should be examined.
Sexual stimulation is a prerequisite for the effectiveness of sildenafil.
Should not be used in patients for whom sexual activity is undesirable.
If an erection lasts more than 4 hours, you should immediately seek medical help. If immediate medical intervention was not carried out, damage to the tissues of the penis and a complete loss of potency is possible.
Influence on the ability to drive vehicles and mechanisms
During the period of sildenafil use, especially at the beginning of treatment and when changing the dosage regimen, patients should be careful when driving vehicles and mechanisms, as well as when engaging in other potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.

Pregnancy and elbowing
During pregnancy, it is possible to use it for the treatment of pulmonary hypertension in cases where the intended benefit to the mother outweighs the potential risk to the fetus or infant. If necessary, use during lactation should decide on the termination of breastfeeding.

Influence on the ability to drive vehicles and work with mechanisms
Does not affect.

Storage conditions
Store in a dry, dark place at a temperature not exceeding 25 ° C, out of the reach of children.

Shelf life
3 years. Do not use after the expiration date printed on the package.

Vacation conditions
Without recipe.

Packaging
Sildenafil Citrate 50 mg Tablets. There are 25 tablets in a blister. 2 blisters are packed in a cardboard box together with an enclosed leaflet.