Freimitus, 5 mg 28 pcs.

Tadalafil is a reversible selective inhibitor of specific phosphodiesterase type 5 (FDE-5) cyclic guanosine monophosphate (cGMP). When sexual arousal causes local release of nitric oxide, inhibition of FDE-5 by tadalafil leads to increased concentration of cGMP in the cavernous body of the penis. The consequence of this is relaxation of arterial smooth muscles and blood flow to the tissues of the penis, which causes an erection.

In vitro studies have shown that tadalafil is a selective inhibitor of FDE-5. FDE-5 is an enzyme present in the smooth muscles of the cavernous body, vessels and internal organs, in skeletal muscles, platelets, kidneys, lungs and cerebellum. The action of tadalafil on FDE-5 is more active than on other phosphodiesterases.

Tadalafil is 10,000 times more potent against FDE-5 than other types of phosphodiesterases (FDE-1, FDE-2, FDE-4 and FDE-7), which are localized in the heart, brain, blood vessels, liver, white blood cells and other organs. Tadalafil is 10,000 times more active in blocking FDE-5 than FDE-3, an enzyme found in the heart and blood vessels. This selectivity for FDE-5 over FDE-3 is important because FDE-3 is an enzyme involved in heart muscle contraction.

In addition, tadalafil is approximately 700 times more active against FDE-5 than FDE-6 found in the retina, which is responsible for phototransmission. Tadalafil is 9,000 times more potent against FDE-5 than it is against FDE-8, FDE-9, and FDE-10, and 14 times more potent than it is against FDE-11. The tissue distribution and physiological effects of FDE-8 to FDE-11 inhibition have not yet been elucidated.

Tadalafil in healthy volunteers causes no significant change in systolic and diastolic blood pressure compared to placebo in the supine position (mean maximum decrease is 1.6 and 0.8 mmHg, respectively) and in the standing position (mean maximum decrease is 0.2 and 4.6 mmHg, respectively).

Tadalafil causes no significant change in heart rate.

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

To evaluate the effect of daily tadalafil administration on spermatogenesis, several studies have been conducted. No adverse effect on sperm morphology and motility was observed in any of the studies. One study found a decrease in average sperm concentration compared to placebo.

The decrease in sperm concentration was associated with a higher frequency of ejaculation. In addition, when comparing tadalafil to placebo there was no undesirable effect on the average concentration of sex hormones (testosterone, luteinizing hormone and follicle stimulating hormone).

Erectile Dysfunction (ED)

Tadalafil has shown statistically significant improvement in erectile function and the ability to have a full sexual intercourse in studies. Tadalafil has no effect in the absence of sexual arousal.

The efficacy and safety of tadalafil have been studied in clinical trials. There was an improvement in erection in patients with ED of all degrees of severity when tadalafil 5 mg was taken once daily for 36 h after intake, and maintenance of erection within 16 min after intake compared to placebo.

In studies of primary efficacy with 5 mg tadalafil, 57% and 67% of sexual attempts were successful compared to 31% and 37% with placebo. In studies of patients with ED secondary to diabetes, 41% of intercourse attempts were successful compared to 28% with placebo.

Benign prostatic hyperplasia (BPH)

In patients with BPH, tadalafil, by inhibiting FDE-5, increases cGMP concentration not only in the penile cavernous body but also in the smooth muscles of the prostate, bladder, and blood vessels that supply them. It increases blood perfusion in these organs and as a result reduces symptoms of BPH.

Relaxation of smooth muscles of the prostate and bladder and inhibition of afferent innervation of the bladder may further enhance vascular effects.

In clinical studies, a reduction in symptoms of BPH within 1 week of taking 5 mg of tadalafil compared to placebo has been shown.

In studies including patients with ED and symptoms of BPH, 71.9% of sexual attempts were successful with tadalafil 5 mg compared to 48.3% with placebo, and there was a significant improvement in erectile function and reduction in prostate symptoms.

Indications

– Lower urinary tract symptoms in patients with BPH (for 5 mg dosage);

Erectile dysfunction in patients with urinary tract symptoms in patients with BPH (for 5 mg dosage).

Active ingredient

How to take, the dosage

For oral administration.

The use of the drug in ED

For patients with frequent sexual activity (more than twice a week), the recommended frequency of administration is daily, 5 mg (1 tablet) once daily, at the same time, regardless of meals.

The dose should be periodically monitored and reviewed, if necessary. The daily dose may be reduced to 2.5 mg depending on individual sensitivity.

For patients with infrequent sexual activity (less than twice a week), the recommended frequency of administration is 20 mg (1 tablet or 4 tablets in a dose of 5 mg) immediately before sexual activity according to the instructions for medical use.

The maximum daily dose of the drug is 20 mg.

The use of the drug in BPH or ED + BPH

The recommended dose of the drug is 5 mg (1 tablet) once daily. The drug should be taken at approximately the same time of the day, regardless of meals and time of sexual activity. The duration of treatment is determined by the doctor individually.

In patients with severe renal insufficiency (CK < 30 ml/min or hemodialysis) the use of the drug is contraindicated.

In patients with mild renal failure (CKR 51-80 ml/min) and moderate renal failure (CKR 31-50 ml/min) or mild to moderate hepatic failure (Child-Pugh grades A and B) and in elderly patients, no dose adjustment is required.

Interaction

The safety and effectiveness of combining tadalafil with other treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended.

The effect of other drugs on tadalafil

Tadalafil is mainly metabolized with participation of CYP3A4 isoenzyme. Selective CYP3A4 isoenzyme inhibitor ketoconazole in dose 400 mg/day increases AUC of tadalafil (20 mg) 4 times and Cmax by 22%, and ketoconazole in dose 200 mg/day increases AUC of tadalafil (10 mg) 2 times and Cmax by 15% compared to AUC and Cmax for tadalafil alone.

Ritonavir (200 mg 2 times/day), an inhibitor of the CYP3A4, CYP2C9, CYP2C19, and CYP2D6 isoenzymes, increases the AUC of tadalafil (20 mg) 2-fold without changing Cmax.

The selective CYP3A4 isoenzyme inducer rifampicin (600 mg/day) reduces the AUC of tadalafil (10 mg) by 88% and Cmax by 46% relative to these values for tadalafil alone. Concomitant use of other CYP3A4 isoenzyme inducers (such as phenobarbital, phenytoids and carbamazepine) may also be expected to reduce plasma concentrations of tadalafil.

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

The effect of tadalafil on other drugs

Tadalafil is known to increase the hypotensive effect of nitrates. This is due to the additive effect of nitrates and tadalafil on nitric oxide II (NO) and cGMP metabolism. Therefore, the use of tadalafil against nitrates is contraindicated.

Simultaneous use of tadalafil with doxazosin is contraindicated. When tadalafil (5 mg/day) is used concomitantly in healthy dobrbbyvoybmen and the alpha-adrenoblocker doxazosin (4-8 mg/day), an increase in the hypotensive effect of doxazosin has been observed. Some patients experienced symptoms associated with a decrease in BP, including fainting, within 12 h.

In a limited number of studies, no significant BP reduction was observed with tadalafil in healthy volunteers taking selective alpha-adrenoblockers (tamsulosin. alfuzosin). Despite this, such combinations should be used with caution, starting with the lowest dose of an alpha-adrenoblocker and gradually increasing it.

Preclinical and clinical studies have shown a significant increase in the hypotensive effect with concomitant use of FDE-5 inhibitors and riociguat (guanylate cyclase stimulator), so this combination of drugs is contraindicated.

Tadalafil has systemic vasodilator properties and may increase the effect of hypotensive drugs aimed at reducing BP. The following groups of hypotensive drugs were studied: slow calcium channel blockers (amlodipine), angiotensin-converting enzyme inhibitors (enalapril), beta-adrenoblockers (metoprolol), thiazide diuretics (bendofluazide), angiotensin II receptor blockers.

Additionally, in patients with poorly controlled arterial hypertension who were taking several hypotensive agents, a slightly greater decrease in BP was observed. In the vast majority of patients, this decrease was not associated with the development of hypotensive symptoms. Patients treated with hypotensive medications and taking tadalafil should be given appropriate clinical advice.

No change in adverse reaction profile was observed with concomitant use of tadalafil and finasteride (5-alpha reductase inhibitor) compared to use of placebo + finasteride combination, but caution should be exercised when taking these drugs due to insufficient clinical data.

Studies have confirmed that tadalafil neither inhibits nor induces the cytochrome P450 system isoenzymes CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, CYP2E1. Tadalafil has no clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline (CYP1A2 substrate), does not affect the AUC of S-warfarin or R-warfarin (CYP2C9 substrates) and does not alter prothrombin time when taken simultaneously with warfarin.

Tadalafil (10 mg, 20 mg) does not increase the duration of bleeding caused by acetylsalicylic acid (ASA).

The bioavailability of ethinylestradiol and terbutaline is increased when taken orally with tadalafil, but the clinical significance of this interaction has not been determined.

Tadalafil has no effect on alcohol concentration, and alcohol also has no effect on tadalafil concentration. At high doses of alcohol (0.7 g/kg), tadalafil administration did not cause a statistically significant decrease in mean BP. Postural dizziness and orthostatic hypotension were observed in some patients. When tadalafil was taken in combination with lower doses of alcohol (0.6 g/kg), no BP decrease was observed, and dizziness occurred with the same frequency as when alcohol was taken alone.

There have been no studies of interactions between tadalafil and diabetes medications.

Special Instructions

Diagnosis of ED and BPH should include identification of the underlying cause, appropriate physical examination, determination of treatment strategy, and individualized benefit-risk assessment.

Sexual activity has potential risks for patients with cardiovascular disease, so treatment for ED should not be given in men with heart conditions for which sexual activity is not recommended.

Patients with a suspected diagnosis of BPH should be examined to rule out prostate cancer.

Non-arterial anterior ischemic optical neuropathy (NAPION) causes visual impairment, including total vision loss. There have been rare post-marketing reports of cases of NAPION, time-consistently associated with the administration of FDE-5 inhibitors. At this time, it is not possible to determine whether there is a direct link between the development of NAPION and the intake of FDE-5 inhibitors or other factors.

Patients should be cautioned that if there is a sudden loss of vision, tadalafil should be stopped and medical attention should be sought. Patients should also be informed that people who have had NAPION have an increased risk of developing NAPION again.

The efficacy of the drug in patients who have undergone pelvic surgery or radical nerve-sparing prostatectomy is unknown.

While the incidence of dizziness on placebo and tadalafil is similar, caution should be exercised during treatment when driving motor vehicles and engaging in other potentially hazardous activities that require increased concentration and rapid psychomotor reactions.

Patients should be aware of the possible development of somnolence when taking the drug, especially at the beginning of therapy or in combination with alcohol intake.

Contraindications

– taking drugs containing any organic nitrates;

– childhood age under 18 years;

– presence of contraindications to sexual activity in patients with cardiovascular diseases: myocardial infarction within the last 90 days, unstable angina, occurrence of an angina attack during sexual intercourse, chronic heart failure NYHA classes II-IV, uncontrolled arrhythmia, arterial hypotension (BP < 90/50 mm Hg. std.), uncontrolled arterial hypertension, ischemic stroke within the last 6 months;

– loss of vision due to nonarterial anterior ischemic optic neuropathy (regardless of the relationship to the intake of FDE-5 inhibitors);

– use in patients with severe renal impairment (CK < 30 ml/min).

– lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

– Severe hepatic impairment (Child-Pugh class C) due to insufficient data on the efficacy/safety of the drug;

– predisposition to priapism (in sickle cell anemia, multiple myeloma or leukemia), anatomical deformity of the penis (angular curvature, cavernous fibrosis or Peyronie’s disease).

Side effects

According to the World Health Organization (WHO), adverse reactions are classified according to their frequency of development as follows: Very common (≥1/10), common (≥1/100, < 1/10), infrequent (≥1/1000, < 1/100), rare (≥1/10000, < 1/1000) and very rare (< 1 /10000); frequency unknown – the incidence could not be determined from available data.

Immune system disorders: infrequent hypersensitivity reactions; rare – angioedema3.

Nervous system disorders: common – headache; infrequent – dizziness; rare – stroke1 (including hemorrhagic), transient ischemic attacks1, syncope, migraine3, epileptic seizure, transient amnesia.

Visual disorders: infrequent – blurred vision, pain in the eyeball; rarely – visual field disturbance, swollen eyelids, sclera vascular injection, nonarterial anterior ischemic optical neuropathy3, retinal vascular occlusion3.

Hearing and labyrinth disorders: infrequent – tinnitus/tinnitus; rarely – sudden hearing loss2.

Heart disorders1: infrequent – palpitations, tachycardia; rare – myocardial infarction, ventricular rhythm disturbances3, unstable angina3.

Vascular disorders: often – “flushes” of blood; infrequent – decreased blood pressure (BP) (in patients taking hypotensive agents), increased BP.

Respiratory system, thoracic and mediastinal disorders: frequently – nasal congestion; infrequently – dyspnea, nasal bleeding.

Gastrointestinal disorders: frequently – dyspepsia, gastroesophageal reflux; infrequently – abdominal pain.

Skin and subcutaneous tissue disorders: infrequent – rash, hyperhidrosis (increased sweating); rarely – urticaria, Stevens-Johnson syndrome3, exfoliative dermatitis3.

Muscular and connective tissue disorders: often – back pain, pain in the extremities, myalgia.

Renal and urinary tract disorders: often – hematuria.

Gender and mammary gland disorders: infrequent – bleeding from the penis, hemospermia; rarely – prolonged erection, priapism3.

General disorders and disorders at the site of administration: infrequent – chest pain1; rare – facial edema3, sudden cardiac death1,3.

1 Observed in patients with previous cardiovascular risk factors. However, it cannot be determined for certain whether these phenomena are directly related to these risk factors, to tadalafil, to sexual arousal, or to a combination of these or other factors.

3 Adverse reactions found in post-marketing studies not observed in clinical placebo-controlled studies.

Overdose

When tadalafil is administered once in a dose of up to 500 mg in healthy individuals and repeatedly in a dose of up to 100 mg/day in patients with ED, adverse reactions were comparable, as were the use of lower doses.

Similarities