Tadalafil

Package leaflet (information for patients)

Tradename
Tadalafil

Dosage form
Tablets 20 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 ingredient: Tadalafil 20 mg.
Excipients: microcrystalline cellulose 102, calcium stearate, aerosil ® 200 (hydrophilic pyrogenic silicon dioxide).

Pharmacotherapeutic group
Treatment of erectile dysfunction, PDE-5 inhibitor

Pharmacological properties
An agent for the treatment of erectile dysfunction, is a reversible selective inhibitor of specific PDE5 cGMP. When sexual arousal induces a local release of nitric oxide, inhibition of PDE5 by tadalafil leads to an increase in cGMP levels in the corpus cavernosum of the penis. The consequence is relaxation of the smooth muscles of the arteries and blood flow to the tissues of the penis, which causes an erection. Tadalafil is ineffective in the absence of sexual stimulation.
Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in the smooth muscles of the corpora cavernosa, in the smooth muscles of the vessels of internal organs, in skeletal muscles, platelets, kidneys, lungs, and cerebellum.
The effect of tadalafil on PDE5 is more active than on other phosphodiesterases. Tadalafil is 10,000 times more active against PDE5 than against PDE1, PDE2, PDE4, which are localized in the heart, brain, blood vessels, liver and other organs. Tadalafil is 10,000 times more active in blocking PDE5 than PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in the contraction of the heart muscle. In addition, tadalafil is approximately 700 times more active against PDE5 than against PDE6, which is found in the retina and is responsible for phototransmission. Tadalafil is also 10,000 times more active against PDE5, compared to its effect on PDE7-PDE10.
Acts within 36 hours. The effect appears within 16 minutes after ingestion in the presence of sexual arousal.
Tadalafil in healthy individuals does not cause significant changes in systolic and diastolic pressure, compared with placebo in the supine position (the average maximum decrease is 1.6 / 0.8 mm Hg, respectively) and standing (the average maximum decrease is 0.2 / 4.6 mm Hg. respectively). Tadalafil does not cause significant changes in heart rate.
Tadalafil does not cause changes in color recognition (blue / green), which is explained by its low affinity for PDE6. In addition, no effect of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size was noted.
There was no clinically significant effect on sperm characteristics in men who took tadalafil in daily doses for 6 months.
Pharmacokinetics
After oral administration, tadalafil is rapidly absorbed. Cmax is reached on average after 2 hours. The rate and degree of absorption do not depend on food intake. The pharmacokinetics of tadalafil in healthy individuals is linear with respect to time and dose. In the dose range from 2.5 to 20 mg, AUC increases in proportion to the dose. Css in plasma is reached within 5 days when taking the drug 1 time / day.
The pharmacokinetics of tadalafil in patients with erectile dysfunction is similar to the pharmacokinetics of the drug in persons without erectile dysfunction.
The Vd is about 63 L, which indicates that tadalafil is distributed in body tissues. At therapeutic concentrations, 94% of tadalafil binds to plasma proteins. In healthy individuals, less than 0.0005% of the administered dose is found in semen.
Metabolized with the participation of the isoenzyme CYP3A4. The main circulating metabolite is methylcatechol glucuronide, which is 13,000 times less active against PDE5 than tadalafil, therefore it is unlikely that this metabolite is clinically significant.
In healthy individuals, the average clearance of tadalafil when taken orally is 2.5 l / h, and the average T1 / 2 is 17.5 hours.Tadalafil is excreted mainly in the form of inactive metabolites, mainly with feces (about 61%) and, to a lesser extent, with urine (about 36%).
In patients with mild renal insufficiency (CC from 51 to 80 ml / min) or moderate (CC from 31 to 50 ml / min) AUC is higher than in healthy individuals.

Indications for use
Erectile dysfunction treatment.

Method of administration and dosage
Tadalafil is taken orally, with or without food, at least 16 minutes before the expected sexual activity, the initial dose is 20 mg. Patients within 36 hours after taking tadalafil can attempt sexual intercourse in order to establish the optimal response time to taking the drug. The recommended maximum frequency of admission is 1 time per day. Elderly men do not need to adjust the dose of tadalafil. With mild and moderate hepatic impairment, the maximum dose of the drug is 10 mg once a day. In severe hepatic impairment, the use of tadalafil is not recommended, since there are no data on the safety of using tadalafil in such patients. In moderate renal failure (with a creatinine clearance of 31-50 ml / min), the initial dose should not exceed 5 mg per day, the maximum dose should not exceed 10 mg every 48 hours. In severe renal failure in patients on hemodialysis, the maximum dose is not more than 5 mg per day. Patients who take CYP3A4 inhibitors, the maximum dose is 10 mg no more often than 1 time in 3 days.
Before using tadalafil, it is necessary to assess the patient's condition and collect anamnesis to identify the causes of erectile dysfunction and select adequate methods of therapy. The combination of tadalafil and other treatments for erectile dysfunction is not recommended. The patient should immediately consult a doctor if an erection occurs that lasts 4 hours or more. Late therapy for priapism leads to irreversible damage to the tissues of the penis. When using tadalafil no reported cases of priapism. You need to know that sexual activity is potentially dangerous for patients who have diseases of the cardiovascular system.

Side effects
Circulatory system: angina pectoris, hypotension, chest pains, hypertension, orthostatic hypotension, myocardial infarction, syncope, palpitations, tachycardia;
nervous system: fatigue, asthenia, dizziness, insomnia, hypesthesia, drowsiness, paresthesia, vertigo, headache; digestive system: dyspepsia, diarrhea, changes in liver function tests, dry mouth, esophagitis, dysphagia, gastroesophageal reflux, increased levels of gamma- glutamyl transpeptidase, nausea, gastritis, vomiting, pain in the upper abdomen;
skin: facial swelling, hot flashes, sweating, rash, itching;
support and movement system: pain in the limbs, neck, back, myalgia, arthralgia;
respiratory system: nasal congestion, epistaxis, dyspnea, pharyngitis;
organ of vision: change in color vision, visual impairment, conjunctivitis, conjunctival hyperemia, increased tearing, eye pain, eyelid edema;
genitourinary system: spontaneous erection, increased erection.

Contraindication
Hypersensitivity, joint intake of organic nitrates, concomitant therapy with alpha- blockers, age up to 18 years; not indicated for use in women.

Overdose
Symptoms: When single doses of up to 500 mg were administered to healthy volunteers and multiple doses of erectile dysfunction up to 1000 mg were administered to patients with erectile dysfunction, the undesirable effects were the same as those of lower doses.
Treatment: standard supportive therapy. Hemodialysis makes little contribution to the elimination of tadalafil.

Precautions
Before starting an appointment for the diagnosis of erectile dysfunction, determining its possible causes and choosing adequate treatment methods, it is necessary to collect anamnesis and assess the patient's condition.
Cerda echno disease
It should be borne in mind that sexual activity has a potential risk for patients with cardiovascular disease. Therefore, the treatment of erectile dysfunction, incl. with the use of tadalafil, should not be carried out in men with cardiovascular disease, in which sexual activity is not recommended.
It should be borne in mind that patients with left ventricular obstruction (eg, aortic stenosis and idiopathic hypertrophic subaortic stenosis) may respond to vasodilators, including PDE5 inhibitors.
Some groups of patients with cardiovascular diseases were not included in clinical trials of the efficacy and safety of tadalafil and therefore its use in these patients is not recommended until further information (see "Restrictions on use").
Prolonged erection
There are rare reports of erection lasting more than 4 hours and priapism (painful erection lasting more than 6 hours) when using compounds of this class. Late treatment of priapism can lead to permanent damage to the tissues of the penis. If an erection lasts more than 4 hours, the patient should immediately consult a doctor.
Before prescribing tadalafil, you should pay attention to the following :
Renal failure (see "Dosage and Administration"). Against the background of tadalafil, patients with moderate renal insufficiency ( Cl creatinine 31-50 ml / min) more often had back pain compared with patients with mild renal insufficiency ( Cl creatinine 51-80 ml / min) or healthy volunteers.
In clinical and pharmacological studies (N = 28) at a dose of 10 mg tadalafil in patients with moderate renal insufficiency ( Cl creatinine 31-50 ml / min), back pain was more often observed compared with patients with mild renal insufficiency ( Cl creatinine 51 –80 ml / min) or with healthy volunteers. At a dose of 5 mg, the frequency and severity of back pain did not differ significantly from those in the general population. No cases of back pain have been reported in hemodialysis patients receiving 10 or 20 mg of tadalafil.
Liver dysfunction and concomitant therapy with strong CYP3A4 inhibitors of cytochrome P450 ( see section "Dosage and Administration").
Are common
Like other PDE5 inhibitors, tadalafil has the properties of a weak systemic vasodilator, which can lead to a short-term decrease in blood pressure (see Pharmacology, Effect on blood pressure).
The safety and efficacy of tadalafil when taken concomitantly with other drugs for the treatment of erectile dysfunction has not been studied, and concomitant use is not recommended.
Tadalafil was not used in patients with increased bleeding tendency or active peptic ulcer. Although tadalafil does not increase bleeding time in healthy volunteers, it is necessary to assess the risk / benefit ratio when using it in patients with increased bleeding tendency or active peptic ulcer.
Use in elderly patients. In clinical studies of tadalafil, approximately 25% of men were over the age of 65. In general, there were no differences in efficacy or safety between elderly and young patients. However, some older men were more sensitive to drugs (see Pharmacology, Elderly age).

Interaction with other medicinal products
Cytochrome P450 inhibitors
Tadalafil is metabolized primarily with the participation of CYP3A4. Drugs that inhibit CYP3A4 can increase the effect of tadalafil (see "Dosage and Administration").
Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4, increased the AUC of tadalafil (20 mg once) by 312% and Cmax by 22% compared to taking only tadalafil at the same dose. Ketoconazole (200 mg daily) increased the AUC of tadalafil (10 mg once) by 107% and Cmax by 15% compared to taking only tadalafil at the same dose.
The HIV protease inhibitor ritonavir (200 mg twice daily), which inhibits CYP3A4, CYP2C9, CYP2C19 and CYP2D6, increased the AUC of tadalafil (20 mg once) by 124% without affecting Cmax. Although specific interactions have not been studied, it can be assumed that other inhibitors of HIV protease may increase the activity of tadalafil ( see "Dosage and Administration").
Based on these results, in patients treated simultaneously with tadalafil CYP3A4 potent inhibitors should not exceed a dose of tadalafil 10 mg and receive tadalafil more than 1 time for 72 hours.
Other inhibitors of cytochrome P450. Although specific interactions have not been studied, it is assumed that CYP3A4 inhibitors such as erythromycin, itraconazole, and grapefruit juice may increase the exposure of tadalafil.
Cytochrome P450 inducers
CYP3A4 inducing drugs could reduce the effect of tadalafil.
Rifampicin (600 mg daily), which is an inducer of CYP3A4, reduced the AUC of tadalafil (10 mg once) by 88% and Cmax by 46% compared to taking only tadalafil at the same dose. Although specific interactions have not been studied, it is assumed that other inducers of CYP3A4, such as carbamazepine, phenytoin, phenobarbital, may reduce the exposure of tadalafil. By orrektirovki dose is not required.
Gastrointestinal remedies
H2 antihistamines. An increase in gastric pH while taking nizatidine did not have a significant effect on the pharmacokinetics of tadalafil.
Antacids. The simultaneous use of an antacid (magnesium hydroxide / aluminum hydroxide) and tadalafil reduces the rate of absorption without changing the AUC of tadalafil.
Drugs metabolized schiesya with the participation of cytochrome P450
It is not expected that tadalafil will cause clinically significant inhibition or induction of the clearance of drugs metabolized with the participation of various cytochrome P450 isoforms. Studies have shown that tadalafil does not inhibit or induce cytochrome P450 isoforms : CYP1A2, CYP3A4, CY P2C9, CYP2C19, CYP2D6 and CYP2E1.
CYP1A2 substrate. Tadalafil had no clinically significant effect on theophylline pharmacokinetics. When taking tadalafil in patients receiving theophylline, there was a small increase (3 beats / min) in the increase in heart rate due to theophylline.
CYP3A4 substrates. Tadalafil had no clinically significant effect on the AUC of midazolam and lovastatin.
CYP2C9 substrates. Tadalafil clinically did not significantly affect the AUC of S- warfarin / R- warfarin, did not affect the effect of warfarin on PT.
Alcohol
Alcohol and PDE5 inhibitors, including tadalafil, are weak systemic vasodilators; when combined, the hypotensive effect of each individual compound may increase. Significant alcohol consumption in combination with tadalafil may increase the likelihood of orthostatic signs and symptoms, including increased heart rate, decreased blood pressure, dizziness, and headache.
Antihypertensive nye means
PDE5 inhibitors, including tadalafil, are weak systemic vasodilators.
Alpha blockers
Doxazosin. When healthy volunteers took 20 mg of tadalafil together with the alpha1-blocker doxazosin (8 mg daily), a significant increase in the hypotensive effect of doxazosin was revealed.
Tamsulosin. In a clinical and pharmacological study in healthy volunteers with a single dose of 20 mg of tadalafil and a daily intake of 0.4 mg of tamsulosin, a selective alpha1A adrenergic blocker, no significant decrease in blood pressure was found. Based on data on a significant increase in the hypotensive effect of doxazosin (alpha1-blocker) and the absence of a significant effect with daily intake of 0.4 mg of tamsulosin (alpha1A-blocker), the use of tadalafil in patients receiving any alpha- blocker (with the exception of 0.4 mg of tamsulosin 1 time per day), azano is contraindicated (see "Contraindications").
Dru Gia antihypertensive agents
Amlodipine. A study was conducted to evaluate the interaction of amlodipine (5 mg daily) and 10 mg tadalafil. Tadalafil did not affect the level of amlodipine in the blood, the effect of amlodipine on the plasma level of tadalafil was also not observed. The average decrease in SBP / DBP in the "lying" position after taking 10 mg of tadalafil in patients taking amlodipine was 3/2 mm Hg. Art. versus placebo. In a similar study using tadalafil 20 mg, a clinically significant effect was also not observed.
Metoprolol. A study to assess the interaction of sustained-release metoprolol (25 to 200 mg daily) and 10 mg of tadalafil showed that the average decrease in systolic blood pressure / blood pressure in the supine position after taking 10 mg of tadalafil in patients taking metoprolol was 5/3 mm Hg. Art. versus placebo.
Bendrofluazide. A study was conducted to evaluate the interaction of bendrofluazide (2.5 mg daily) and 10 mg tadalafil. The average decrease in SBP / DBP in the "lying" position after taking 10 mg of tadalafil in patients taking bendrofluazide was 6/4 mm Hg. Art. versus placebo.
Enalapril. A study of the interaction of enalapril (10 to 20 mg daily) and 10 mg of tadalafil showed that the average decrease in SBP / DBP in the supine position after taking 10 mg of tadalafil in patients taking enalapril was 4/1 mm Hg. Art. versus placebo.
Angiotensin II receptor blockers (and other antihypertensive drugs). A study was conducted to evaluate the interaction of angiotensin II receptor blockers and 20 mg tadalafil. In this study, patients took any drug from the group of angiotensin II receptor blockers in the form of a monocomponent or combined drug, or in the regimen of complex antihypertensive therapy. Outpatient BP measurement revealed a difference in SBP / DBP of 8/4 mm Hg. Art., between tadalafil and placebo.
Acetylsalicylic acid. Tadalafil does not potentiate the increase in bleeding time caused by acetylsalicylic acid.

Special instructions
With extreme caution and only if absolutely necessary, it is possible to use tadalafil in patients with severe renal insufficiency (CC≤30 ml / min) and severe hepatic insufficiency.
During treatment with tadalafil, patients with moderate renal insufficiency (CC from 31 to 50 ml / min) were more likely to have back pain compared with patients with mild renal insufficiency (CC from 51 to 80 ml / min) or healthy volunteers... Patients with KK≤50 ml / min tadalafil follows blows applied with caution.
Therefore, the treatment of erectile dysfunction, incl. with the use of tadalafil should not be carried out in men with heart diseases in which sexual activity is not recommended.
Consideration should be given to the potential risk of complications during sexual activity in patients with diseases of the cardiovascular system: myocardial infarction within the last 90 days; unstable angina or angina that occurs during intercourse; chronic heart failure (II functional class and higher according to the NYHA classification), which has developed within the last 6 months; uncontrolled heart rhythm disturbances; arterial hypotension (blood pressure less than 90/50 mm Hg ) or uncontrolled arterial hypertension; a stroke in the past 6 months.
Precautions should be used tadalafil in patients with predisposition to priapism (e.g., sickle cell anemia, multiple myeloma or leukemia) or in patients with anatomical deformation of the penis (e.g., angulation, cavernous fibrosis or illness Peyronie ).
The patient should be informed about the need to immediately consult a doctor in case of an erection lasting 4 hours or more. Untimely treatment of priapism leads to damage to the tissues of the penis, as a result of which a long-term loss of potency may occur.
No cases of priapism have been reported with tadalafil.
It is not recommended to use tadalafil in combination with other treatments for erectile dysfunction.

Pregnancy and elbowing
The drug is not used in women.

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
Tadalafil 20 mg Tablets. There are 25 tablets in a blister. 2 blisters are packed in a cardboard box together with an enclosed leaflet.