Tadalafil-SZ tablets 20mg, No. 4

• Erectile disfunction;

• lower urinary tract symptoms in patients with benign prostatic hyperplasia (for a dosage of 5 mg);

• erectile dysfunction in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia (for a dosage of 5 mg).

The drug is taken orally.

erectile disfunction

For patients with frequent sexual activity (more than 2 times a week): the recommended frequency of admission is daily, 1 time / day, 5 mg, at the same time, regardless of food intake. The daily dose can be reduced to 2.5 mg (1/2 tab. 5 mg), depending on individual sensitivity.

For patients with infrequent sexual activity (less than 2 times a week), it is recommended to prescribe the drug Tadalafil-SZ at a dose of 20 mg, immediately before sexual activity, according to the instructions for medical use of the drug.

The maximum daily dose of Tadalafil-SZ is 20 mg.

BPH or Erectile Dysfunction / BPH

The recommended dose of Tadalafil-SZ when administered 1 time / day is 5 mg; the drug should be taken at approximately the same time of the day, regardless of the time of sexual activity. The duration of treatment is determined by the doctor individually.

In patients with mild renal insufficiency (CC from 51 to 80 ml / min) and moderate severity (CC from 31 to 50 ml / min), dose adjustment is not required. In patients with severe renal insufficiency (CC <30 ml / min and on hemodialysis), the use of Tadalafil-SZ is contraindicated.

Pinkish-orange film-coated tablets, round, biconvex; in cross section, the core of the tablet is white or almost white.

1 tab. tadalafil 20 mg

Excipients: lactose monohydrate (milk sugar) - 100.2 mg, lactose monohydrate (lactopress) (milk sugar) - 123 mg, microcrystalline cellulose - 53 mg, croscarmellose sodium (primellose) - 17 mg, crospovidone (Kollidon CL-M) - 5 mg, crospovidone (Kollidon CL) - 2 mg, extra thin hyprolosis (hydroxypropyl cellulose) - 5 mg, hyprolose (hydroxypropyl cellulose) - 2 mg, sodium stearyl fumarate - 2 g, sodium lauryl sulfate - 0.8 mg.

• The use of preparations containing any organic nitrates;

• the presence of contraindications to sexual activity in patients with diseases of the cardiovascular system: myocardial infarction within the last 90 days, unstable angina pectoris, the occurrence of an attack of angina pectoris during intercourse, chronic heart failure class II and higher according to the NYHA classification during the last 6 months, uncontrolled arrhythmias, arterial hypotension (blood pressure less than 90/50 mm Hg), uncontrolled arterial hypertension, ischemic stroke within the last 6 months;

• loss of vision due to non-arterial anterior ischemic neuropathy of the optic nerve (regardless of the connection with the use of PDE5 inhibitors);

• concomitant use with doxazosin, other PDE5 inhibitors, other treatment options for erectile dysfunction, with guanylate cyclase stimulants such as riociguat;

• chronic renal failure (CC less than 30 ml / min);

• age under 18;

• lactase deficiency, lactose intolerance, glucose-galactose malabsorption;

• hypersensitivity to tadalafil or to any substance that is part of the drug.

  Carefully

• Since there is insufficient data in relation to patients with severe hepatic impairment (class C according to the Child-Pugh classification), caution must be exercised when prescribing Tadalafil-SZ to this group of patients. Care must be taken when prescribing the drug Tadalafil-SZ to patients taking alpha1-blockers, since the simultaneous use of these drugs can lead to symptomatic arterial hypotension in some patients. When using a single dose of tadalafil, symptomatic arterial hypotension is not observed when used simultaneously with tamsulosin, a selective alpha1-blocker. The drug Tadalafil-SZ should be used with caution in patients with a predisposition to priapism (with sickle cell anemia,multiple myeloma or leukemia) or in patients with anatomical deformity of the penis (angular curvature, cavernous fibrosis, or Peyronie's disease). You should also be careful while taking it with CYP3A4 isoenzyme inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, clarithromycin, erythromycin, grapefruit juice), antihypertensive drugs, 5-alpha reductase inhibitors.

pharmachologic effect

Tadalafil is a reversible selective inhibitor of specific phosphodiesterase type 5 (PDE5) of cyclic guanosine monophosphate (cGMP). When sexual arousal induces a local release of nitric oxide, inhibition of PDE5 by tadalafil leads to an increase in the concentration of cGMP in the corpus cavernosum of the penis. The consequence of this is relaxation of the smooth muscles of the arteries and blood flow to the tissues of the penis, which causes an erection. Tadalafil has no effect in the absence of sexual arousal.

In vitro studies have shown that tadalafil is a selective PDE5 inhibitor. PDE5 is an enzyme found in the smooth muscles of the corpus cavernosum, in the smooth muscles of the vessels of the 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 potent for PDE5 than for PDE1, PDE2, PDE4 and PDE7, which are localized in the heart, brain, blood vessels, liver, leukocytes, skeletal muscles 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 thattaking part in the contraction of the heart muscle. In addition, tadalafil is about 700 times more active against PDE5 than against PDE6, which is found in the retina and is responsible for phototransmission. Tadalafil also has an effect 9000 times more potent against PDE5 compared to its effect on PDE8, PDE9 and PDE10, and 14 times more potent against PDE5 than PDE11. Tissue distribution and physiological effects of PDE8-PDE11 inhibition have not yet been elucidated.Tissue distribution and physiological effects of PDE8-PDE11 inhibition have not yet been elucidated.Tissue distribution and physiological effects of PDE8-PDE11 inhibition have not yet been elucidated.

Tadalafil improves erection and increases the ability to have a full sexual intercourse.

Tadalafil in healthy individuals does not cause significant changes in systolic and diastolic pressure in comparison with placebo in the supine position (the average maximum decrease is 1.6 / 0.8 mm Hg, respectively) and in the standing position (the average maximum decrease is 0.2 / 4.6 mm Hg. . respectively). Tadalafil does not cause a significant change in heart rate.

Tadalafil does not cause changes in color recognition (blue / green), which is explained by its low affinity for PDE6. In addition, there is no observed effect of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size.

Several studies have been conducted to evaluate the effect of daily intake of tadalafil on spermatogenesis. None of the studies observed an undesirable effect on sperm morphology and motility. One study found a decrease in mean sperm concentration compared to placebo. A decrease in sperm concentration was associated with a higher frequency of ejaculation. In addition, there was no undesirable effect on the mean concentration of sex hormones, testosterone, LH and FSH when taking tadalafil compared with placebo.

An improvement in erection was noted in patients with erectile dysfunction of all severity when taking tadalafil 1 time / day.

Mechanism of Action in Patients with Benign Prostatic Hyperplasia (BPH)

Inhibition of PDE5 by tadalafil, leading to an increase in the concentration of cGMP in the cavernous body of the penis, is also observed in the smooth muscles of the prostate gland, bladder and vessels that supply them with blood. Relaxation of vascular smooth muscles leads to an increase in blood perfusion in these organs, and, as a consequence, to a decrease in the severity of BPH symptoms. Relaxation of smooth muscle of the prostate and bladder can further enhance vascular effects.

Pharmacokinetics

Suction

After oral administration, tadalafil is rapidly absorbed. Average Cmax in plasma is achieved on average 2 hours after oral administration. The speed and degree of absorption of tadalafil do not depend on food intake, therefore, the drug Tadalafil-SZ can be used regardless of food intake. The time of intake (morning or evening) does not affect the rate and extent of absorption.

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 patients without erectile dysfunction.

Distribution

The average Vd is about 63 liters, which indicates that tadalafil is distributed in body tissues. At therapeutic concentrations, 94% of plasma tadalafil binds to proteins. Protein binding does not change with impaired renal function.

In healthy volunteers, less than 0.0005% of the administered dose was found in semen.

Metabolism

Tadalafil is mainly metabolized with the participation of the isoenzyme CYP3A4 of cytochrome P450. The main circulating metabolite is methylcatechol glucuronide. This metabolite is at least 13,000 times less active against PDE5 than tadalafil. Therefore, the concentration of this metabolite is not clinically relevant.

Withdrawal

In healthy volunteers, 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 through the intestines (about 61% of the dose) and, to a lesser extent, by the kidneys (about 36% of the dose).

Pharmacokinetics in special patient groups

Healthy volunteers aged 65 and over had a lower oral clearance of tadalafil, which was reflected in an increase in AUC by 25% compared with healthy volunteers aged 19 to 45 years. This difference is not clinically significant and does not require dose adjustment.

In patients with mild renal insufficiency (CC from 51 to 80 ml / min) and moderate severity (CC from 31 to 50 ml / min), as well as in patients with end-stage renal failure on hemodialysis, exposure to tadalafil (AUC) approximately doubled. In patients on hemodialysis, Cmax was 41% higher than in healthy volunteers. The elimination of tadalafil by hemodialysis is negligible.

The pharmacokinetics of tadalafil in patients with mild to moderate hepatic impairment (class A and B according to Child-Pugh classification) is comparable to that in healthy volunteers. Insufficient data are available for patients with severe hepatic impairment (Child-Pugh class C). When prescribing the drug Tadalafil-SZ to patients with severe hepatic impairment, it is necessary to first assess the risks and benefits of using the drug.

In patients with diabetes mellitus while using tadalafil, the AUC was approximately 19% less than in healthy volunteers. This difference does not require dose adjustment.

Side effect

From the immune system: infrequently - hypersensitivity reactions; rarely - angioedema 2.

From the nervous system: often - headache; infrequently - dizziness; rarely - stroke1 (including acute cerebrovascular accident of the hemorrhagic type), fainting, transient ischemic attacks1, migraine2, epileptic seizures2, transient amnesia.

From the side of the organ of vision: infrequently - blurred vision, pain in the eyeball; rarely - visual field disturbance, eyelid swelling, conjunctival hyperemia, non-arterial anterior ischemic optic neuropathy2, retinal vascular occlusion2.

On the part of the organ of hearing and labyrinth disorders: infrequently - ringing in the ears; rarely - sudden hearing loss.

From the side of the heart1: infrequently - palpitations, tachycardia; rarely - myocardial infarction, ventricular arrhythmias2, unstable angina2.

From the side of the vessels: often - 'hot flushes' of blood to the face; infrequently - a decrease in blood pressure, an increase in blood pressure.

From the respiratory system: often - nasal congestion; infrequently - shortness of breath, nosebleeds.

From the digestive system: often - dyspepsia; infrequently - abdominal pain, gastroesophageal reflux, diarrhea in patients over 65, vomiting, nausea.

On the part of the skin and subcutaneous tissues: infrequently - rash; rarely - urticaria, Stevens-Johnson syndrome2, exfoliative dermatitis2, hyperhidrosis.

From the musculoskeletal system: often - back pain, myalgia, pain in the limbs.

From the urinary system: infrequently - hematuria.

On the part of the genitals and mammary gland: infrequently - prolonged erection; rarely - priapism2, hematospermia, bleeding from the penis.

Others: infrequently - chest pain1, peripheral edema, fatigue; rarely - facial edema2, sudden cardiac death1,2.

1 Observed in patients with previous cardiovascular risk factors. However, it is impossible to determine with certainty whether these events are directly related to these risk factors, tadalafil, sexual arousal, or a combination of these or other factors.

2 Adverse reactions identified in post-marketing use that were not observed in clinical placebo-controlled studies.

3 More often observed when tadalafil was used in patients already taking antihypertensive drugs.

Application during pregnancy and lactation

Tadalafil-SZ is not intended for use in women.

Application for violations of liver function

Since there is insufficient data in relation to patients with severe hepatic impairment (class C according to the Child-Pugh classification), caution should be exercised when prescribing Tadalafil-SZ to this group of patients.

Application for impaired renal function

The use of the drug is contraindicated in chronic renal failure (CC less than 30 ml / min).

In patients with mild renal insufficiency (CC from 51 to 80 ml / min) and moderate severity (CC from 31 to 50 ml / min), dose adjustment is not required.

Application in children

The use of the drug under the age of 18 is contraindicated.

Use in elderly patients

Healthy volunteers aged 65 and over had a lower oral clearance of tadalafil, which was reflected in an increase in AUC by 25% compared with healthy volunteers aged 19 to 45 years. This difference is not clinically significant and does not require dose adjustment.

special instructions

Diagnosis of erectile dysfunction should include identification of the potential underlying cause, appropriate medical evaluation, and treatment.

Sexual activity has a potential risk for patients with cardiovascular disease. Therefore, the treatment of erectile dysfunction, incl. the drug Tadalafil-SZ, should not be carried out in men with heart diseases in which sexual activity is not recommended.

There have been reports of the occurrence of priapism with the use of PDE5 inhibitors, including tadalafil. Patients should be informed about the need for immediate medical attention in case of an erection lasting 4 hours or more. Late treatment of priapism leads to damage to the tissues of the penis, resulting in irreversible impotence.

The safety and efficacy of the combination of Tadalafil-SZ with other PDE5 inhibitors and treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Like other PDE5 inhibitors, tadalafil has systemic vasodilating properties, which can lead to a transient decrease in blood pressure. Before prescribing the drug Tadalafil-SZ, you should carefully consider whether patients with cardiovascular disease will be exposed to unwanted effects due to such vasodilating effects.

Non-arterial anterior ischemic optic neuropathy (NAPION) is a cause of visual impairment, including complete loss of vision. There are rare post-marketing reports of cases of the development of NAPION, in time associated with the intake of PDE5 inhibitors. It is currently impossible to determine whether there is a direct link between the development of NAPION and the use of PDE5 inhibitors or other factors. Patients should be advised to stop taking tadalafil in case of sudden loss of vision and seek medical attention. It is necessary to inform patients that people who have undergone NAPION have an increased risk of re-developing NAPION.

Patients suspected of having BPH should be screened to rule out prostate cancer.

The efficacy of Tadalafil-SZ in patients undergoing surgery on the pelvic organs or radical neurosaving prostatectomy is unknown.

Influence on the ability to drive vehicles and mechanisms

During the period of treatment with Tadalafil-SZ, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.

Overdose

With a single appointment to healthy volunteers of tadalafil at a dose of up to 500 mg and patients with erectile dysfunction - repeatedly up to 100 mg / day, the undesirable effects were the same as when using lower doses.

Treatment: in case of overdose, it is necessary to carry out standard symptomatic treatment. With hemodialysis, tadalafil is practically not excreted.

Drug interactions

Effect of other drugs on tadalafil

Tadalafil is mainly metabolized with the participation of the CYP3A4 isoenzyme. Selective inhibitor of the isoenzyme CYP3A4 ketoconazole (400 mg / day) increases the exposure of a single dose of tadalafil (AUC) by 312% and Cmax by 22%, and ketoconazole (200 mg / day) increases the exposure of a single dose of tadalafil (AUC) by 107% and Cmax by 15% relative to AUC and Cmax values ??for tadalafil alone.

Ritonavir (200 mg 2 times / day), an inhibitor of isoenzymes CYP3A4, 2C9, 2C19 and 2D6, increases the exposure of a single dose of tadalafil (AUC) by 124% without changing Cmax. Despite the fact that the specific interaction has not been studied, it can be assumed that other inhibitors of HIV protease, for example, saquinavir, as well as inhibitors of the isoenzyme CYP3A4, such as erythromycin, clarithromycin, itraconazole and grapefruit juice, may increase the concentration of tadalafil in blood plasma.

The role of transporters (eg, P-glycoprotein) in the distribution of tadalafil is unknown. There is the possibility of drug interactions mediated by inhibition of vectors.

A selective inducer of the CYP3A4 isoenzyme, rifampicin (at a dose of 600 mg / day), reduces the exposure of a single dose of tadalafil (AUC) by 88% and Cmax by 46%, relative to AUC and Cmax values ??for tadalafil alone. It can be assumed that the simultaneous use of other inducers of the CYP3A4 isoenzyme (such as phenobarbital, phenytoin or carbamazepine) should also reduce the concentration of tadalafil in blood plasma.

The simultaneous administration of an antacid (magnesium hydroxide / aluminum hydroxide) and tadalafil reduces the rate of absorption of tadalafil without changing the AUC for tadalafil.

An increase in gastric pH as a result of taking the histamine H2 receptor blocker nizatidine did not affect the pharmacokinetics of tadalafil.

Ѕезопасность и эффективность комбинации тадалафила с другими видами лечени¤ нарушений эрекции или другими ингибиторами ‘?Ё5 не изучались, поэтому применение подобных комбинаций не рекомендуетс¤.

¬ли¤ние тадалафила на другие препараты

»звестно, что тадалафил усиливает гипотензивное действие нитратов. Ёто происходит в результате аддитивного действи¤ нитратов и тадалафила на метаболизм оксида азота II (Nќ) и цvћ‘. ѕоэтому применение тадалафила на фоне приема нитратов противопоказано.

“адалафил не оказывает клинически значимого действи¤ на клиренс препаратов, метаболизм которых протекает с участием цитохрома –450. »сследовани¤ подтвердили, что тадалафил не ингибирует и не индуцирует изоферменты CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, CYP2E1.

“адалафил не оказывает клинически значимого вли¤ни¤ на AUC S-варфарина или R-варфарина. “адалафил не вли¤ет на действие варфарина в отношении протромбинового времени.

“адалафил не потенцирует увеличение длительности кровотечени¤, вызывного приемом ацетилсалициловой кислотой.

“адалафил обладает системными сосудорасшир¤ющими свойствами и может усиливать действие гипотензивных препаратов, направленное на снижение ј?. ?ополнительно у пациентов, принимавших несколько гипотензивных средств, у которых артериальна¤ гипертензи¤ плохо контролировалась, наблюдалось несколько большее снижение ј?. ” подавл¤ющего большинства пациентов это снижение не было св¤зано с гипотензивными симптомами. ѕациентам, получающим лечение гипотензивными препаратами и принимающим тадалафил, должны быть даны соответствующие клинические рекомендации. Ќе наблюдалось значимого снижени¤ ј? при одновременном применении здоровыми добровольцами тадалафила и селективного альфа1ј-адреноблокатора тамсулозина.

ќдновременное применение тадалафила с доксазозином противопоказано. ѕри применении тадалафила здоровыми добровольцами, принимавшими доксазозин (4-8 мг/сут), альфа1-адреноблокатор, наблюдалось усиление гипотензивного действи¤ доксазозина. Ќекоторые пациенты испытывали симптомы, св¤занные со снижением ј?, включа¤ обморок.

ќдновременный прием риоцигуата с ингибиторами ‘?Ё5, включа¤ тадалафил, противопоказан, т.к. риоцигуат усиливает гипотензивное действие ингибиторов ‘?Ё5.

»сследований лекарственного взаимодействи¤ тадалафила и ингибиторов 5-альфа-редуктазы не проводилось, при их одновременном приеме следует соблюдать осторожность.

“адалафил вызывает увеличение биодоступности этинилэстрадиола при приеме внутрь.

—ходное повышение биодоступности можно ожидать при приеме тербуталина, однако клинические последстви¤ не установлены.

Tadalafil did not affect the concentration of ethanol, as well as ethanol did not affect the concentration of tadalafil. At high doses of alcohol (0.7 g / kg), taking tadalafil did not cause a statistically significant decrease in the mean blood pressure. Some patients experienced postural dizziness and orthostatic hypotension. When taking tadalafil in combination with lower doses of alcohol (0.6 g / kg), a decrease in blood pressure was not observed, and dizziness occurred with the same frequency as when taking alcohol alone.

Tadalafil has no clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline.