Tadalafil-SZ

1 tab.:

Active substance: 

tadalafil - 20 mg

excipients (core): 

lactose monohydrate (milk sugar) - 100.2 mg;

lactose monohydrate (lactopress) (milk sugar) - 123.0 mg;

microcrystalline cellulose - 53.0 mg;

croscarmellose sodium (primellose) - 17.0 mg;

crospovidone (Collidone CL-M) - 5.0 mg,

crospovidone (Collidone CL) - 2.0 mg,

extra thin hyperlose (hydroxypropyl cellulose) - 5.0 mg;

hyprolose (hydroxypropyl cellulose) - 2.0 mg;

sodium stearyl fumarate - 2.0 mg;

sodium lauryl sulfate - 0.8 mg;

excipients (shell): 

Opadry II 85F240037 pink -10 mg (polyvinyl alcohol, partially hydrolyzed - 4.0 mg; titanium dioxide E 171 - 2.236 mg; macrogol (polyethylene glycol 3350) - 2.02 mg; talc - 1.48 mg; iron dye oxide (II ) yellow E 172 - 0.143 mg; iron dye oxide (II) red E 172-0.121 mg).

Pharmacodynamics

Tadalafil is a reversible selective inhibitor of specific type 5 phosphodiesterase (PDE-5) cyclic guanosine monophosphate ni (cGMP). When sexual arousal causes local release of nitric oxide, inhibition of PDE-5 by tadalafil leads to an increase in the concentration of cGMP in the cavernous body of the penis. The consequence of this is the relaxation of the smooth muscles of the arteries and the flow of blood 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 PDE-5 inhibitor. PDE-5 is an enzyme found in the smooth muscles of the corpus cavernosum, in the smooth muscles of the vessels of internal organs, in skeletal muscles, platelets, kidneys, lungs and cerebellum. 

The effect of tadalafil on PDE-5 is more active than on other phosphodiesterases. Tadalafil is 10,000 times more potent with respect to PDE-5 than with PDE-1, PDE-2, PDE-4 and PDE-7, which are localized in the heart, brain, blood vessels, liver, white blood cells, skeletal muscles and in other bodies. 

Tadalafil blocks PDE-5 10,000 times more actively than PDE-3, an enzyme found in the heart and blood vessels. This selectivity for PDE-5 compared to PDE-3 is important because PDE-3 is an enzyme involved in the contraction of the heart muscle. In addition, tadalafil is approximately 700 times more active with respect to PDE-5 than with PDE-6, which is found in the retina and is responsible for photo transmission. 

Tadalafil also exhibits an effect of 9000 times more potent for PDE-5 compared to its effect on PDE-8, PDE-9 and PDE-10, and 14 times more potent for PDE-5 compared to PDE-11. Tissue distribution and physiological effects of inhibition of PDE-8 - PDE-11 have not yet been elucidated. Tadalafil improves erection and increases the possibility of a full sexual intercourse.

Tadalafil in healthy individuals does not cause a significant change in systolic and diastolic pressure compared with placebo in the supine position (average maximum decrease is 1.6 / 0.8 mmHg, respectively) and in the standing position (average maximum decrease is 0, 2 / 4.6 mmHg, respectively). 

Tadalafil does not cause a significant change in heart rate. Tadalafil does not cause changes in color recognition (blue / green), due to its low affinity for PDE-6. In addition, there is no effect of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size.

In order to assess the effect of daily intake of tadalafil on spermatogenesis, several studies have been conducted. 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 average concentration of sex hormones, testosterone, luteinizing hormone and follicle-stimulating hormone when taking tadalafil compared with placebo.

There was an improvement in erection in patients with erectile dysfunction of all degrees of severity when taking tadalafil once a day.
The mechanism of action in patients with benign prostatic hyperplasia (BPH)

Inhibition of PDE-5 by tadalafil, which leads 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 blood vessels that supply them with blood. 

The relaxation of vascular smooth muscle leads to an increase in blood perfusion in these organs, and, as a result, to a decrease in the severity of symptoms of BPH. Relaxation of the smooth muscles of the prostate and bladder can further enhance vascular effects.

Pharmacokinetics

Suction

After ingestion, tadalafil is rapidly absorbed. The average maximum concentration (Stax) in plasma is achieved on average 2 hours after ingestion.

The rate and degree of absorption of tadalafil is independent of food intake, therefore, the drug Tadalafil-SZ can be used regardless of food intake. The time of admission (morning or evening) does not affect the rate and extent of absorption. 

The pharmacokinetics of tadalafil in healthy individuals is linear in terms of time and dose. In the dose range from 2.5 to 20 mg, the area under the concentration-time curve (AUC) increases in proportion to the dose. Equilibrium plasma concentrations are reached within 5 days when taking the drug once a 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 volume of distribution is about 63 liters, which indicates that tadalafil is distributed in the tissues of the body. 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 cytochrome P450 isoenzyme CYP3A4. The main circulating metabolite is methylcatecholglucuronide. This metabolite is at least 13,000 times less active against PDE-5 than tadalafil. Therefore, the concentration of this metabolite is not clinically significant.

Breeding

In healthy volunteers, the average clearance of tadalafil when taken orally is 2.5 l / h, and the average half-life 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).

Special groups of patients
Age over 65

Healthy volunteers aged 65 years and older had a lower clearance of tadalafil when taken orally, which was expressed in an increase in the area under the concentration-time curve by 25% compared with healthy volunteers aged 19 to 45 years. This difference is not clinically significant and does not require dose selection.

Renal failure

In patients with mild renal failure (creatinine clearance from 51 to 80 ml / min) and moderate severity (creatinine clearance from 31 to 50 ml / min), as well as in patients with end-stage renal failure undergoing hemodialysis, tadalafil exposure (AUC) approximately doubled. 

In patients on hemodialysis, Stax was 41% higher compared with healthy volunteers. Excretion of tadalafil by hemodialysis is negligible.

Liver failure

The pharmacokinetics of tadalafil in patients with mild to moderate hepatic impairment (Child-Pugh classification A and B) is comparable to that in healthy volunteers. For patients with severe hepatic impairment (Child-Pugh class C), insufficient data. When prescribing the drug Tadalafil-SZ, patients with severe hepatic insufficiency must first conduct a risk assessment and the benefits of using the drug.

Patients with diabetes

In patients with diabetes mellitus with tadalafil, the area under the concentration-time curve was less than about 19%, compared with healthy volunteers. This difference does not require dose selection.

• Erectile dysfunction;
• symptoms of the lower urinary tract in patients with benign prostatic hyperplasia (for a dosage of 5 mg);
• erectile dysfunction in patients with symptoms of lower urinary tract on the background of benign prostatic hyperplasia (for a dosage of 5 mg).

• Hypersensitivity to tadalafil or any substance that is part of the drug;
• taking preparations containing any organic nitrates;
• contraindications to sexual activity in patients with diseases of the cardiovascular system: myocardial infarction in the last 90 days, unstable angina pectoris, occurrence of angina pectoris during intercourse, chronic heart failure class II and above according to NYHA classification over the past 6 months, uncontrolled arrhythmias, arterial hypotension (blood pressure <90/50 mm Hg), uncontrolled arterial hypertension, ischemic stroke over the past 6 months;
• loss of vision due to non-arterial anterior ischemic optic neuropathy (NAPION) (regardless of association with the administration of PDE-5 inhibitors);
• simultaneous use with doxazosin, other PDE-5 inhibitors, other therapies for erectile dysfunction, with guanylate cyclase stimulants such as riotsiguat;
• chronic renal failure (Cl creatinine <30 ml / min);
• lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• age to 18 years.

The most common adverse events in patients with erectile dysfunction and BPH are headache and dyspepsia, as well as back pain, myalgia.
In accordance with the WHO classification, all reactions are distributed according to the system of organs and the frequency of development: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1U0000, <1 \ 1000); very rarely (<1/10000), the frequency is unknown (it is impossible to determine the frequency of occurrence of reactions from the available data).

Immune system disorders:

Infrequently: hypersensitivity reactions. Rarely: angioedema. Violations of the nervous system:

Often: headache.
Infrequently: dizziness.
Rarely: stroke '(including acute cerebrovascular accident (ONMK) hemorrhagic type), fainting, transient ischemic attack, migraine, epileptic seizures, transient amnesia. 

Disorders from the organ of vision:
Infrequently: blurred visual perception, pain in the eyeball.
Rarely: visual field disturbances, eyelid swelling, conjunctival hyperemia, non-arterial anterior ischemic optic neuropathy, retinal vascular occlusion.

Hearing disorders and labyrinth disorders:

Infrequently: ringing in the ears.
Rarely: sudden hearing loss.

Heart disorders:
Infrequently: palpitations, tachycardia.
Rarely: myocardial infarction, ventricular arrhythmias, unstable angina pectoris.

Violations of the vessels: Often: "flushes" of blood to the face.

Infrequently: a decrease in blood pressure, an increase in blood pressure.
Disorders from the respiratory system, chest and mediastinal organs:

Often: nasal congestion.
Infrequently: shortness of breath, nosebleeds.
Gastrointestinal disorders:

Often: dyspepsia.
Infrequently: abdominal pain, gastroesophageal reflux, diarrhea in patients over 65 years old, vomiting, nausea.

Disorders of the skin and subcutaneous tissue:
Infrequently: rash.
Rarely: urticaria, Stevens-Johnson syndrome, exfoliative dermatitis, hyperhidrosis (excessive sweating).

Violations of the musculoskeletal and connective tissue:

Often: back pain, myalgia, pain in the limbs. Disorders from the kidneys and urinary tract: Infrequently: hematuria.

Violations of the genitals and mammary gland: Infrequently: prolonged erection.
Rarely: priapism, hematospermia, bleeding from the penis.

General disorders:
Infrequently: chest pain, peripheral edema, fatigue. Rarely: facial swelling, sudden cardiac death.

'Observed in patients previously having cardiovascular risk factors. However, it is impossible to accurately determine whether these phenomena are directly related to these risk factors, to tadalafil, to sexual arousal, or to a combination of these or other factors.

Adverse reactions identified during post-marketing use, not observed during clinical placebo-controlled studies.

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

The effect of other drugs on tadalafil

Tadalafil is mainly metabolized by the CYP3A4 isoenzyme. A selective inhibitor of the isoenzyme CYP3A4 ketoconazole (400 mg per day) increases the exposure of a single dose of tadalafil (AUC) by 312% and Stax by 22%, and ketoconazole (200 mg per day) increases the exposure of a single dose of tadalafil (AUC) by 107% and Stax by 15% relative to AUC and Stax values ​​for only one tadalafil.

Ritonavir (200 mg twice daily), an inhibitor of CYP3A4, 2C9, 2C19 and 2D6 isoenzymes, increases the exposure to a single dose of tadalafil (AUC) by 124% without changing Stax. 

Although specific interactions have not been studied, it can be assumed that other HIV protease inhibitors, such as saquinavir, as well as CYP3A4 isoenzyme inhibitors such as erythromycin, clarithromycin, and itraconazole and grapefruit juice, can increase plasma tadalafil concentrations blood. The role of carriers (e.g., P-glycoprotein) in the distribution of tadalafil is unknown. 

There is the possibility of drug interactions mediated by inhibition of carriers. The selective inducer of CYP3A4 isoenzyme, rifampicin (at a dose of 600 mg per day), reduces the exposure of a single dose of tadalafil (AUC) by 88% and Stax by 46%, relative to AUC and Stax values ​​for only one tadalafil. 

It can be assumed that the simultaneous use of other inducers of the CYP3A4 isoenzyme (such as phenobarbital, phenytoin, or carbamazepine) should also reduce tadalafil plasma concentrations.

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

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

The safety and effectiveness of the combination of tadalafil with other treatments for erectile dysfunction or other PDE-5 inhibitors have not been studied, therefore, the use of such combinations is not recommended.

The effect of tadalafil on other drugs

Tadalafil is known to enhance the hypotensive effect of nitrates. This occurs as a result of the additive effect of nitrates and tadalafil on the metabolism of nitric oxide II (N0) and cGMP. Therefore, the use of tadalafil while taking nitrates is contraindicated.

Tadalafil does not have a clinically significant effect on the clearance of drugs whose metabolism occurs with the participation of cytochrome P450. Studies have confirmed that tadalafil does not inhibit or induce the isoenzymes CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, CYP2E1. Tadalafil does not have a clinically significant effect on the AUC of S-warfarin or R-warfarin. Tadalafil does not affect the action of warfarin in relation to prothrombin time.

Tadalafil does not potentiate an increase in the duration of bleeding caused by the intake of acetylsalicylic acid.

Tadalafil has systemic vasodilating properties and can enhance the effect of antihypertensive drugs aimed at lowering blood pressure. Additionally, in patients taking several antihypertensive drugs, in which arterial hypertension was poorly controlled, a slightly larger decrease in blood pressure was observed. 

In the vast majority of patients, this decrease was not associated with hypotensive symptoms. Patients receiving treatment with antihypertensive drugs and taking tadalafil should be given appropriate clinical recommendations. No significant decrease in blood pressure was observed with the simultaneous use of tadalafil and selective alpha-1A-blocker tamsulosin by healthy volunteers.

The simultaneous use of tadalafil with doxazosin is contraindicated. When tadalafil was used by healthy volunteers who took doxazosin (4-8 mg per day), alpha] blocker, an increase in the hypotensive effect of doxazosin was observed. Some patients experienced symptoms associated with a decrease in blood pressure, including fainting.

The simultaneous administration of riotsiguat with PDE-5 inhibitors, including tadalafil, is contraindicated, because riotsiguat enhances the hypotensive effect of PDE-5 inhibitors.
Studies of the drug interaction of tadalafil and 5-alpha-reductase inhibitors have not been conducted, with their simultaneous administration caution should be exercised.

Tadalafil causes an increase in the bioavailability of ethinyl estradiol when administered orally.
A similar increase in bioavailability can be expected with terbutaline, but the clinical consequences have not been established.

Tadalafil did not affect the concentration of alcohol, nor did alcohol affect the concentration of tadalafil. At high doses of alcohol (0.7 g / kg), tadalafil did not cause a statistically significant decrease in mean arterial 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 does not have a clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline.

For oral administration.

The use of the drug Tadalafil-SZ according to the indications of erectile dysfunction (ED)
For patients with frequent sexual activity (more than twice a week): the recommended frequency of administration is 5 mg daily, once a day, at the same time, regardless of the dose food. The daily dose can be reduced to 2.5 mg (1/2 tablet of 5 mg), depending on individual sensitivity.

For patients with infrequent sexual activity (less than twice a week): it is recommended to prescribe the drug Tadalafil-SZ in 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.

The use of the drug Tadalafil-SZ according to the indication of BPH or ED / BPH.

The recommended dose of Tadalafil-SZ when used once a 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 set by the doctor individually.

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

Symptoms: when administered once to healthy volunteers, tadalafil in 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 applying lower doses.

Treatment: symptomatic. With hemodialysis, tadalafil is practically not excreted.

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

Priapism has been reported with PDE-5 inhibitors, including tadalafil. Patients should be informed about the need to immediately seek medical help in case of an erection lasting 4 hours or more. Untimely treatment of priapism leads to damage to the tissues of the penis, resulting in irreversible impotence.

The safety and efficacy of a combination of Tadalafil-SZ with other PDE-5 inhibitors and treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended. Like other PDE-5 inhibitors, tadalafil has systemic vasodilating properties, which can lead to a transient decrease in blood pressure. 

Before prescribing the drug Tadalafil-SZ, doctors should carefully consider whether patients with cardiovascular disease will not be undesirable 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 associated with the administration of PDE-5 inhibitors. IN

it is currently impossible to determine whether there is a direct relationship between the development of NAPION and the intake of PDE-5 inhibitors or other factors. Doctors should recommend that patients in case of sudden loss of vision stop taking tadalafil and seek medical help. 

Doctors should also inform patients that people who have undergone NAPION have an increased risk of re-developing NAPION. Patients with a presumptive diagnosis of BPH should be screened to rule out prostate cancer.

The effectiveness of the drug Tadalafil-SZ in patients who underwent surgery on the pelvic organs or radical neurosaving prostatectomy is unknown.

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

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.