Fremitus pills 20mg, 1pc

Composition

Active ingredient: tadalafil-20,000 mg.

Auxiliary substances:  lactose monohydrate (milk sugar) – 273,300 mg; microcrystalline cellulose-57,000 mg; croscarmellose sodium-24,000 mg; hyprolose-2,660 mg; sodium lauryl sulfate-1,140 mg; magnesium stearate-1,900 mg. Shell composition:  hypromellose – 5,800 mg; macrogol-4,000-1,700 mg; titanium dioxide-2,300 mg; iron oxide yellow dye-0.200 mg

Pharmacological action

Tadalafil is a reversible selective inhibitor of specific phosphodiesterase type 5 (PDE-5) cyclic guanosine monophosphate (cGMP). When sexual arousal causes a local release of nitric oxide, inhibition of PDE5 by tadalafil leads to an increase in the concentration of cGMP in the penile cavernosa. The result is a relaxation of the smooth muscles of the arteries 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 PDE-5. PDE-5 is an enzyme present in smooth muscle of the cavernous body, blood vessels and 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 against PDE-5 than against other types of phosphodiesterase (PDE-1, PDE-2, PDE-4, and PDE-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 PDE-5 than PDE-3, an enzyme found in the heart and blood vessels. This selectivity for PDE-5 over PDE-3 is important because PDE-3 is an enzyme involved in heart muscle contraction. In addition, tadalafil is approximately 700 times more active against PDE-5 than PDE-6, which is found in the retina and is responsible for photo transmission. The effect of tadalafil on PDE-5 is 9,000 times more pronounced than its effect on PDE-8, PDE-9 and PDE-10, and 14 times more pronounced than on PDE-11. The distribution in tissues and physiological effects of PDE-8 – PDE-11 inhibition have not yet been elucidated. Tadalafil in healthy volunteers did not cause significant changes in systolic and diastolic blood pressure compared to placebo in the supine position (the average maximum decrease is 1.6 and 0.8 mm Hg, respectively) and in the standing position (the average maximum decrease is 0.2 and 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 due to its low affinity for PDE-6. In addition, tadalafil does not affect visual acuity, electroretinogram, intraocular pressure and pupil size. Several studies have been conducted to evaluate the effect of daily tadalafil on spermatogenesis. No adverse effects on sperm morphology and motility were observed in any of the studies. One study found a decrease in the average sperm count compared to placebo. A decrease in sperm concentration was associated with a higher ejaculation rate. In addition, when comparing tadalafil with placebo, there was no undesirable effect on the average concentration of sex hormones (testosterone, luteinizing hormone and follicle-stimulating hormone). Erectile Dysfunction (ED)In the conducted studies, tadalafil showed a statistically significant improvement in erectile function and the ability to conduct a full-fledged sexual intercourse. Tadalafil has no effect in the absence of sexual arousal. The efficacy and safety of tadalafil has been studied in clinical trials. There was an improvement in erection in patients with ED of all degrees of severity when taking 5 mg of tadalafil once a day for 36 hours after use, as well as maintaining an erection for 16 minutes after use compared to placebo. In studies of the primary efficacy of 5 mg tadalafil,57% and 67% of sexual intercourse attempts were successful, compared to 31% and 37% with placebo. In studies of patients with secondary ED with diabetes mellitus,41% of attempts at sexual intercourse were successful, compared with 28% with placebo. Benign prostatic hyperplasia (BPH)In patients with BPH, tadalafil, by inhibiting PDE-5, leads to an increase in the concentration of cGMP not only in the corpus cavernosum of the penis, but also in the smooth muscles of the prostate, bladder and blood vessels that supply them. This, in turn, increases blood perfusion in these organs and, as a result, reduces the severity of BPH symptoms. Relaxation of prostate and bladder smooth muscle and inhibition of afferent innervation of the bladder may further enhance vascular effects. Clinical studies have shown a reduction in BPH symptoms within 1 week after taking 5 mg of tadalafil compared to placebo. In studies involving patients with ED and BPH symptoms,71.9% of sexual intercourse attempts were successful with 5 mg of tadalafil compared to 48.3% with placebo, and there was a significant improvement in erectile function and a decrease in prostate symptoms.

Pharmacokinetics of absorption After oral use, tadalafil is rapidly absorbed. The average maximum concentration (Cmax) in blood plasma is reached on average 2 hours after oral use. The rate and degree of absorption of tadalafil does not depend on food intake, so the drug can be used regardless of food intake. The time of use (morning or evening) has no clinically significant effect on the rate and degree of absorption. The pharmacokinetics of tadalafil in healthy volunteers are linear with respect to 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. Steady-state plasma concentrations are reached within 5 days when the drug is taken once a day. The pharmacokinetics of tadalafil in patients with erectile dysfunction are 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 body’s tissues. At therapeutic concentrations,94% of tadalafil binds to plasma proteins. Binding to plasma proteins 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 PDE5 than tadalafil. Therefore, the concentration of this metabolite is not clinically significant. Elimination In healthy volunteers, the average oral clearance of tadalafil is 2.5 l / h, and the average half-life (T 1/2) is 17.5 h. Tadalafil is mainly excreted as inactive metabolites, mainly by the intestine (about 61% of the dose) and, to a lesser extent, by the kidneys (about 36% of the dose). Elderly patients Healthy elderly volunteers (65 years and older) had a lower oral clearance of tadalafil, which resulted in a 25% increase in AUC compared to healthy volunteers aged 19 to 45 years. This difference is not clinically significant and does not require dose adjustment. Patients with renal insufficiency Clinical studies have shown that when taking a single dose of tadalafil (5-20 mg), AUC increases approximately 2-fold in patients with mild (creatinine clearance (creatinine clearance) 51-80 ml / min), moderate (creatinine clearance 31-50 ml/min) and end-stage renal insufficiency (dialysis). In hemodialysis patients, the Cmax of tadalafil was 41% higher than in healthy volunteers. Tadalafil is practically not excreted during hemodialysis. Patients with hepatic insufficiency The pharmacokinetics of tadalafil in patients with mild and moderate hepatic insufficiency (Child-Pugh class A and B) are comparable to those in healthy volunteers. For patients with severe hepatic insufficiency (Child-Pugh class C), data are limited, so the benefit / risk ratio should be evaluated before using the drug. Patients with diabetes mellitus In patients with diabetes mellitus, the AUC of tadalafil is approximately 19% lower than in healthy volunteers. This difference does not require dose adjustment.

Indications

• erectile dysfunction;
• lower urinary tract symptoms in patients with BPH (for a dosage of 5 mg);
• erectile dysfunction in patients with urinary tract symptoms in patients with BPH (for a dosage of 5 mg).

Contraindications

• hypersensitivity to tadalafil or any substance included in the composition of the drug;
• taking medications containing any organic nitrates;
• children up to age 18 years;
• presence of contraindications to sexual activity in patients with diseases of the cardiovascular system: myocardial infarction within the last 90 days, unstable angina, occurrence of angina during sexual intercourse, chronic heart failure II-IV class NYHA classification, uncontrolled arrhythmias, hypotension (BP <90/50 mm Hg. century), uncontrolled hypertension, ischemic stroke within the last 6 months;
• loss of vision due to partiranno of the anterior ischemic optic neuropathies (regardless of the context of inhibitors PDE-5);
• concomitant use of doxazosin, other drugs for the treatment of erectile dysfunction, guanylate cyclase stimulants (riociguat) (see section “Interaction with other drugs”);
• use in patients with severe renal insufficiency (CC
• lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution

• , severe hepatic insufficiency (Child-Pugh class C) due to insufficient data on the effectiveness/safety of the drug;
• simultaneous use of selective alpha-blockers. strong inhibitors of CYP3A4 (ritonavir, saquinavir, ketoconazole, Itraconazole, erythromycin), inhibitors of 5-alpha-reductase inhibitor (see section “Interaction with other medicines”);
• a predisposition to priapism (sickle cell anemia, multiple myeloma, or leukemia), anatomical deformation 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 (Immune system disorders: infrequently-hypersensitivity reactions; rarely-angioedema 3. Nervous system disorders: often-headache; infrequently dizziness; rarely-stroke 1 (including hemorrhagic), transient ischemic attacks 1, syncope, migraine 3, epileptic seizure, transient amnesia. Visual disorders: infrequently – blurred vision, pain in the eyeball; rarely – visual field disorders, eyelid swelling, scleral vascular injection, non – arterial anterior ischemic optic neuropathy 3, retinal vascular occlusion 3. Hearing disorders and labyrinth disorders: infrequently – tinnitus/ringing; rarely – sudden hearing loss 2. Cardiac disorders 1: infrequently – palpitation, tachycardia; rarely – myocardial infarction, ventricular arrhythmias 3, unstable angina 3. Vascular disorders: often – “hot flashes” of blood; infrequently-a decrease in blood pressure (in patients taking antihypertensive drugs), an increase in blood pressure. Respiratory, thoracic and mediastinal disorders: often-nasal congestion; infrequently-shortness of breath, nosebleeds. Disorders of the gastrointestinal tract: often-dyspepsia, gastroesophageal reflux; infrequently-abdominal pain. Skin and subcutaneous tissue disorders: infrequently-rash, hyperhidrosis (excessive sweating); rarely-urticaria, Stevens-Johnson syndrome 3, exfoliative dermatitis 3. Musculoskeletal and connective tissue disorders: often-back pain, pain in the extremities, myalgia. Disorders of the kidneys and urinary tract: often-hematuria. Genital and breast disorders: infrequently-penile bleeding, hemospermia; rarely-prolonged erection, priapism 3. General disorders and disorders at the injection site: infrequently-chest pain 1; rarely-facial edema 3, sudden cardiac death 1,3.1 Have been observed in patients with previous cardiovascular risk factors. However, it is not possible to determine whether these events are directly related to these risk factors, tadalafil, sexual arousal, or a combination of these or other factors. 2 Sudden hearing loss has been reported in a small number of cases in post-marketing and clinical trials involving all PDE-5 inhibitors, including tadalafil. 3 Adverse reactions detected in post-marketing studies that were not observed in clinical placebo-controlled studies.

Interaction

The safety and efficacy 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 the participation of the CYP3A4 isoenzyme. A selective inhibitor of the CYP3A4 isoenzyme ketoconazole at a dose of 400 mg / day increases the AUC of tadalafil (20 mg) by 4 times and Cmax by 22%, and ketoconazole at a dose of 200 mg/day increases the AUC of tadalafil (10 mg) by 2 times and Cmax by 15% relative to the AUC and Cmax for tadalafil only. Ritonavir (200 mg twice daily), an inhibitor of the isoenzymes CYP3A4, CYP2C9, CYP2C19 and CYP2D6, increases the AUC of tadalafil (20 mg) by 2 times without changing the Cmax. Although specific interactions have not been studied, it can be assumed that other HIV protease inhibitors, such as saquinavir, and inhibitors of the CYP3A4 isoenzyme, such as erythromycin, clarithromycin, and itraconazole, as well as grapefruit juice, increase plasma concentrations of tadalafil and should be used with caution (due to the increased risk of adverse reactions). The selective inducer of the CYP3A4 isoenzyme rifampicin (600 mg/day) reduces the AUC of tadalafil (10 mg) by 88% and Cmax by 46% relative to these values for tadalafil alone. It can be assumed that the simultaneous use of other inducers of the CYP3A4 isoenzyme (such as phenobarbital, phenytoin and carbamazepine) It also reduces plasma concentrations of tadalafil. Concomitant use of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduces the rate of absorption of tadalafil without changing its AUC. Effect of tadalafil on other drugs tadalafil is known to enhance the hypotensive effect of nitrates. This occurs as a result of the additive action of nitrates and tadalafil on the metabolism of nitric oxide II (N0) and cGMP. Therefore, the use of tadalafil against the background of taking nitrates is contraindicated. Concomitant use of tadalafil with doxazosin is contraindicated. When tadalafil (5 mg/day) was administered concomitantly in healthy volunteers and the alpha-blocker doxazosin (4-8 mg/day), the hypotensive effect of doxazosin was increased. Some patients experienced symptoms associated with a decrease in blood pressure, including fainting, for 12 hours. In a limited number of studies, no significant reduction in blood pressure was observed with the use of tadalafil in healthy volunteers taking selective alpha-blockers (tamsulosin. alfuzosin). Despite this, such combinations should be used with caution, starting with a minimum dose of alpha-blockers with a gradual increase. In preclinical and clinical studies, a significant increase in the antihypertensive effect was shown with the simultaneous use of PDE-5 inhibitors and riociguate (a guanylate cyclase stimulator), so taking such a combination of drugs is contraindicated. Tadalafil has systemic vasodilating properties and may enhance the effect of antihypertensive agents aimed at reducing blood pressure. The following groups of antihypertensive drugs were studied: slow calcium channel blockers (amlodipine), angiotensin-converting enzyme inhibitors (enalapril), beta-blockers (metoprolol), thiazide diuretics (bendofluazide), angiotensin II receptor blockers. Additionally, patients with poorly controlled arterial hypertension who took several antihypertensive agents showed a slightly greater decrease in blood pressure. In the vast majority of patients, this decrease was not associated with the development of hypotensive symptoms. Patients receiving antihypertensive medications and taking tadalafil should be given appropriate clinical recommendations. Concomitant use of tadalafil and finasteride (5-alpha reductase inhibitor) there was no change in the adverse reaction profile compared to the placebo + finasteride combination, but caution should be exercised when taking these drugs due to insufficient clinical data. Studies have confirmed that tadalafil does not inhibit or induce cytochrome P 450 isoenzymes CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, or 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 co-administered with warfarin. Tadalafil (10 mg,20 mg) does not increase the duration of bleeding caused by acetylsalicylic acid (ASA). The bioavailability of ethinyl estradiol and terbutaline when taken orally together with tadalafil increases, but the clinical significance of this interaction has not been determined. Tadalafil does not affect the concentration of alcohol, nor does alcohol 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 average blood pressure. Some patients experienced postural vertigo 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. Interactions between tadalafil and drugs for the treatment of diabetes mellitus have not been studied.

How to take it, course of use and dosage

For oral use.Use of the drug in EDD For patients with frequent sexual activity (more than twice a week) the recommended frequency of use: daily,5 mg (1 tablet) 1 time a day, at the same time, regardless of food intake. The dose should be monitored periodically and reviewed if necessary. The daily dose can 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 use is 20 mg (1 tablet or 4 tablets at 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. Use of the drug for BPH or ED + BPH The recommended dose of the drug is 5 mg (1 tablet) once a day. The drug should be taken at approximately the same time of day, regardless of food intake and time of sexual activity. The duration of treatment is determined by the doctor individually. In patients with severe renal insufficiency (CCIn patients with mild renal insufficiency (creatinine clearance 51-80 ml/min) and moderate renal insufficiency (creatinine clearance 31-50 ml/min) or mild to moderate hepatic insufficiency (Child-Pugh class A and B), as well as in elderly patients, no dose adjustment is required.

Overdose

When tadalafil was administered once at a dose of up to 500 mg to healthy individuals and repeatedly at a dose of up to 100 mg/day to patients with ED, adverse reactions were comparable, as with lower doses. In case of overdose, it is necessary to carry out symptomatic treatment. During hemodialysis, tadalafil is practically not excreted.

Special instructions

Diagnosis of ED and BPH should include identification of the underlying cause of the disease, appropriate medical examination, determination of treatment tactics and individual assessment of the benefit / risk ratio. Sexual activity has a potential risk for patients with cardiovascular diseases, so ED treatment should not be performed in men with such heart diseases, in which sexual activity is not recommended. Like other PDE5 inhibitors, tadalafil may have a systemic vasodilating effect, which may lead to a transient decrease in blood pressure and an increase in the hypotensive effect of nitrates, alpha-blockers (see the section “Interaction with other drugs”). Before prescribing the drug, it is necessary to carefully assess the likelihood of such adverse reactions in patients with cardiovascular diseases. Patients with a suspected BPH diagnosis should be screened to rule out prostate cancer. 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 NAPION development that are associated with the use of PDE5 inhibitors. Currently, it is not possible to determine whether there is a direct relationship between the development of NAPION and the use of PDE5 inhibitors or other factors. Patients should be warned to stop taking tadalafil and seek medical attention in case of sudden vision loss. Patients should also be informed that people who have had NAPION have an increased risk of developing NAPION again. Priapism has been reported with PDE5 inhibitors, including tadalafil. Patients should be informed about the need to seek immediate medical attention in the event of an erection lasting 4 hours or more. Untimely treatment of priapism leads to damage to the tissues of the penis, which can lead to irreversible impotence. The efficacy of the drug in patients undergoing pelvic surgery or radical nerve-sparing prostatectomy is unknown.

Influence on the ability to drive vehicles and mechanisms

Despite the fact that the frequency of dizziness with placebo and tadalafil is the same, during treatment, caution should be exercised when driving vehicles and engaging in other potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions. Patients should be aware of the possible development of drowsiness when taking the drug, especially at the beginning of therapy or in combination with alcohol intake.

Storage conditions

At a temperature not exceeding 25 °C. Keep out of reach of children.

Shelf

life is 3 years. Do not use after the expiration date.

Active ingredient

Tadalafil

Conditions of release from pharmacies

By prescription

Dosage form

Tablets