Tedallis - instructions for use, dose, side effects, contraindications

substance: tadalafil adsorbate - 33,333 mg, containing active substance: tadalafil - 5,000 mg, auxiliary substance: silicon dioxide - 28,333 mg;

Excipients: lactose monohydrate 42,327 mg, crospovidone 6,000 mg, low-substituted giprolose 10,000 mg, microcrystalline cellulose, silicified¹ - 26,000 mg, iron oxide yellow (E172) 1.050 mg, iron oxide red (E172) 0.090 mg, sodium stearyl fumarate 1,200 mg.

¹ contains 2% silicon dioxide and 98% microcrystalline cellulose.

Description:Oval, biconvex tablets of light brown color with impregnations of a darker color on the surface of the tablet and with the engraving "T 5" on one side and the risk on the other side and on the ribs of the tablet.

Pharmacotherapeutic group:Erectile dysfunction remedy - PDE5-inhibitor

ATX: & nbsp

G.04.B.E.08 Tadalafil

Pharmacodynamics:

Tadalafil is a reversible selective inhibitor of specific phosphodiesterase type 5 (PDE-5) cyclic guanosine monophosphate (cGMP).When sexual stimulation causes local release of nitric oxide, inhibition of PDE-5 with 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.

Research in vitro showed that tadalafil is a selective inhibitor of PDE-5. PDE-5 is an enzyme present in the smooth muscles of the corpus cavernosum, vessels and internal organs, in skeletal muscles, platelets, kidneys, lungs and the cerebellum. The effect of tadalafil on PDE-5 is more active than on other phosphodiesterases. Tadalafil is 10,000 times more potent for PDE-5 than for other types of phosphodiesterase (PDE-1, PDE-2, PDE-4 and PDE-7) that are localized in the heart, brain, blood vessels, liver, leukocytes and other organs. Tadalafil 10,000 times more actively blocks PDE-5 than PDE-3 - an enzyme that is found in the heart and blood vessels. This selectivity for PDE-5 in comparison with PDE-3 is important, since PDE-3 is an enzyme involved in contraction of the heart muscle. Besides, tadalafil approximately 700 times more active in relation to PDE-5 than PDE-6, found in the retina and is responsible for photo transmission. The effect of tadalafil on PDE-5 is 9000 times more pronounced than its effect on PDE-8, PDE-9 and PDE-10, and 14-fold more pronounced than on PDE-11. The distribution in tissues and the physiological effects of the inhibition of PDE-8-PDE-11 have not yet been elucidated.

Tadalafil in healthy volunteers does not cause a significant change in systolic and diastolic blood pressure in comparison with placebo in the prone position (mean maximum decrease is 1.6 and 0.8 mm Hg, respectively) and in the standing position (the mean maximum decrease is 0, 2 and 4.6 mm Hg, respectively).

Tadalafil does not cause a significant change in the heart rate.

Tadalafil does not cause changes in color recognition (blue / green), which is 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.

To assess the effect of daily administration of tadalafil on spermatogenesis, several studies have been carried out.None of the studies showed an undesirable effect on the morphology of spermatozoa and their mobility. In one study, a decrease in the average concentration of spermatozoa was found compared with placebo. Reducing the concentration of spermatozoa was associated with a higher incidence of ejaculation. In addition, when comparing tadalafil with placebo, there was no adverse 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 possibility of a full sexual intercourse. Tadalafil does not have an 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 with 5 mg of tadalafil once a day for 36 hours after admission, as well as maintaining an erection for 16 min after admission compared with placebo. In studies of primary efficacy, 5 mg of tadalafil 57% and 67% of sexual intercourse attempts were successful compared with 31% and 37% with placebo. In studies of patients with secondary ED on the background of diabetes mellitus, 41% of attempts at intercourse were successful compared with 28% with placebo.

Benign prostatic hyperplasia (BPH)

In patients with BPH tadalafil, inhibiting PDE-5, leads to an increase in the concentration of cGMP not only in the cavernous body of the penis, but also in the smooth muscles of the prostate gland, bladder and blood vessels that supply them. This, in turn, increases the perfusion of blood in these organs and, as a consequence, reduces the severity of BPH symptoms. Relaxing the smooth muscles of the prostate and bladder and inhibiting the afferent innervation of the bladder can further enhance vascular effects.

Clinical studies showed a reduction in BPH symptoms within 1 week after taking 5 mg of tadalafil compared with placebo.

In studies involving patients with ED and symptoms of BPH, with the application of 5 mg of tadalafil, 71.9% of attempts at intercourse were successful compared with 48.3% with placebo,and there was a significant improvement in erectile function and a decrease in symptoms from the prostate gland.

Pharmacokinetics:

Suction

After oral administration tadalafil quickly absorbed. The mean maximum concentration (C_mOh) in the blood plasma is achieved on average 2 hours after ingestion.

The speed and degree of absorption of tadalafil do not depend on the intake of food, so the drug can be used regardless of food intake. The time of administration (in the morning or in the 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 of 2.5 to 20 mg, the area under the concentration-time curve (AUC) increases in proportion to the dose. Equilibrium concentrations in the blood plasma are achieved within 5 days with the drug taken once a day. The pharmacokinetics of tadalafil in patients with an erection disorder 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.

In therapeutic concentrations, 94% of tadalafil binds to blood plasma proteins. Binding to plasma proteins does not change with impaired renal function.

In healthy volunteers, less than 0.0005% of the administered dose is found in the sperm.

Metabolism

Tadalafil is mainly metabolized with the participation of isoenzyme CYP3A4 cytochrome P450. The main circulating metabolite is methylcatechol glucuronide. This metabolite is at least 13,000 times less active against PDE-5 than tadalafil. Consequently, the concentration of this metabolite is not clinically significant.

Excretion

In healthy volunteers, the average clearance of tadalafil with oral intake is 2.5 l / h, and the average half-life (T_1/2) - 17.5 h. Tadalafil is excreted mostly in the form of 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 clearance of tadalafil when ingested, which was expressed in an increase AUC on 25% in comparison with healthy volunteers at the age from 19 till 45 years. This difference is not clinically significant and does not require dose selection.

Patients with renal insufficiency

In clinical studies, it was shown that when taking a single dose of tadalafil (5-20 mg) AUC increases approximately 2-fold in patients with mild (creatinine clearance (CK) 51-80 ml / min), medium (KK 31-50 ml / min) and terminal renal failure (dialysis). Patients on hemodialysis C_mOh Tadalafil is 41% higher than in healthy volunteers. Tadalafil practically not excreted by hemodialysis.

Patients with hepatic insufficiency

The pharmacokinetics of tadalafil in patients with mild and moderate hepatic insufficiency (classes A and B according to the Child-Pugh classification) is comparable to that of healthy volunteers. For patients with severe hepatic impairment (Child-Pugh class C), data are limited, so a benefit / risk ratio should be assessed before using the drug.

Patients with diabetes mellitus

In patients with diabetes on the background of the application of tadalafil AUC less than approximately 19% than in healthy volunteers. This difference does not require a dose adjustment.

Indications:

- Erectile disfunction;

- symptoms of the urinary tract in patients with BPH;

- erectile dysfunction in patients with urinary tract symptoms in patients with BPH.

Contraindications:

- Hypersensitivity to tadalafil or to any substance included in the preparation;

- taking drugs containing any organic nitrates;

- children's age till 18 years;

- the presence of contraindications to sexual activity in patients with diseases of the cardiovascular system: myocardial infarction during the last 90 days, unstable angina, the onset of angina pectoris during intercourse, chronic heart failure II-IV Classes by classification NYHA, uncontrolled arrhythmia, arterial hypotension (BP <90/50 mm Hg), uncontrolled arterial hypertension, ischemic stroke during the last 6 months;

- loss of vision due to non-arterial anterior ischemic neuropathy of the optic nerve (regardless of the connection with the intake of PDE-5 inhibitors);

- simultaneous administration of doxazosin, other drugs for the treatment of erectile dysfunction, stimulants guanylate cyclase (riotsiguat) (cm. section "Interaction with other drugs"");

- daily use in patients with severe renal failure (CC <30 mL / min).

Carefully:

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

- simultaneous application of selective α- adrenoblockers, strong inhibitors of the isoenzyme CYP3A4 (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), inhibitors of 5-alpha-reductase (see section "Interaction with other drugs");

- predisposition to priapism (with sickle-cell anemia, multiple myeloma or leukemia), anatomical deformation of the penis (angular curvature, cavernous fibrosis or Peyronie's disease);

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

Pregnancy and lactation:

The drug is not intended for use in women.

Dosing and Administration:

For oral administration.

Application of the drug with ED

For patients with frequent sexual activity (more than twice a week) the recommended frequency of admission is: daily, 5 mg (1 tablet) once a day, at the same time, regardless of food intake.The dose should be periodically monitored and revised, if necessary. The daily dose can be reduced to 2.5 mg, depending on the individual sensitivity.

The maximum daily dose of the drug is 20 mg.

Use of the drug in BPH or ED + BPH

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

Patients with renal insufficiency severe (QC <30 ml / min or hemodialysis) the use of the drug daily is not recommended.

Patients with renal insufficiency light (KK 51-80 ml / min) and moderate severity (CK 31-50 ml / min) or hepatic impairment light and moderate severity classes (classes A and B according to Child-Pugh classification), as well as elderly patients correction of the dose is not required.

Side effects:

According to the World Health Organization (WHO), adverse reactions are classified according to their frequency of development as follows: very often (≥1 / 10), often (≥1 / 100, <1/10),infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, <1/1000) and very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

Immune system disorders

infrequently: hypersensitivity reactions;

rarely: angioedema³.

Disturbances from the nervous system

often: headache;

infrequently: dizziness;

rarely: stroke¹ (including hemorrhagic), transient ischemic attacks¹, fainting, migraine³, epileptic seizure, transient amnesia.

Disturbances on the part of the organ of sight

infrequently: blurred vision, pain in the eyeball;

rarely: violation of visual fields, eyelid swelling, scleral vessels injection, non-arterial anterior ischemic optic neuropathy³, occlusion of retinal vessels³.

Hearing disorders and labyrinthine disorders

infrequently: noise / ringing in the ears;

rarely: sudden hearing loss².

Heart Disease¹

infrequently: palpitation, tachycardia;

rarely: myocardial infarction, ventricular arrhythmias³, unstable angina³.

Vascular disorders

often: "tides" of blood;

infrequently: lowering blood pressure (BP) (in patients taking antihypertensive drugs), increasing blood pressure.

Disturbances from the respiratory system, organs of the chest and fromgladnesses

often: nasal congestion;

infrequently: shortness of breath, nosebleed.

Disorders from the gastrointestinal tract

often: dyspepsia, gastroesophageal reflux;

infrequently: abdominal pain.

Disturbances from the skin and subcutaneous tissue

infrequently: rash, hyperhidrosis (increased sweating);

rarely: hives, Stevens-Johnson syndrome³, exfoliative dermatitis³.

Disturbances from musculoskeletal and connective tissue

often: pain in the back, pain in the extremities, myalgia.

Disorders from the kidneys and urinary tract

often: hematuria.

Violations of the genitals and mammary gland

infrequently: bleeding from the penis, hemospermia;

rarely: prolonged erection, priapism³.

General disorders and disorders at the site of administration

infrequently: chest pain¹;

rarely: swelling of the face³, sudden cardiac death^1,3.

¹They were observed in patients who previously had cardiovascular risk factors.However, it is impossible to determine precisely whether these phenomena are directly related to these risk factors, with tadalafil, with sexual arousal, or with a combination of these or other factors.

²O sudden loss of hearing was reported in a small number of cases during post-marketing and clinical trials with all PDE-5 inhibitors, including tadalafil.

³Adverse reactions observed during post-marketing studies were not observed during clinical placebo-controlled trials.

Overdose:

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

In case of an overdose, symptomatic treatment should be performed. With hemodialysis tadalafil almost not output.

Interaction:

The safety and efficacy of the combination of 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 isoenzyme CYP3A4.

Selective inhibitor of isoenzyme CYP3A4 ketoconazole in a dose of 400 mg / day increases AUC tadalafil (20 mg) 4 times and C_mOh by 22%, and ketoconazole in a dose of 200 mg / day increases AUC tadalafil (10 mg) 2 times and C_mOh by 15% relative to AUC and C_mOh only for tadalafil.

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

Although specific interactions have not been studied, it can be assumed that other HIV protease inhibitors, for example, saquinavir, and inhibitors of the CYP3A4 isoenzyme, such as erythromycin, clarithromycin and itraconazole, and grapefruit juice, increase plasma concentrations of tadalafil and should be used with caution (due to an increased risk of developing unwanted reactions).

Selective inducer of isoenzyme CYP3A4 rifampicin (600 mg / day) reduces the AUC of tadalafil (10 mg) by 88 =% and C_mOh by 46% relative to these values for tadalafil alone. It can be assumed that the simultaneous use of other inducers of the isoenzyme CYP3A4 (such as phenobarbital, phenytoin and carbamazepine) also reduces plasma concentrations of tadalafil.

Simultaneous reception antacid (magnesium hydroxide / aluminum hydroxide) and tadalafil reduces the rate of absorption of tadalafil without changing it AUC.

Effect of tadalafil on other drugs

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

The simultaneous use of tadalafil with doxazosin it is contraindicated. With the simultaneous use of tadalafil (5 mg / day) by healthy volunteers and α-adrenoblocker doxazosin (4-8 mg / day), there was an increase in the hypotensive effect of doxazosin. Some patients experienced symptoms associated with a decrease in blood pressure, including fainting, for 12 hours. In a limited number of studies, there was no significant reduction in blood pressure when using tadalafil by healthy volunteers who took selective α-adrenoblockerstamsulosin, alfuzosin). Despite this, such combinations should be used with caution, starting with a minimal dose of α-blocker with a gradual increase.

In pre-clinical and clinical studies, a significant increase in the hypotensive effect was demonstrated with simultaneous use of PDE-5 inhibitors and riotsiguata (stimulator guanylattsiklazy), so the reception of such a combination of drugs is contraindicated.

Tadalafil has systemic vasodilator properties and can enhance the effect of antihypertensive drugs aimed at reducing blood pressure. The following groups of antihypertensive drugs were studied: blockers of "slow" calcium channels (amlodipine), angiotensin-converting enzyme inhibitors (enalapril), beta-blockers (metoprolol), thiazide diuretics (bendofluazid), angiotensin II receptor blockers. In addition, in patients with poorly controlled hypertension, taking several antihypertensive drugs, there was a somewhat greater decrease in blood pressure. In the vast majority of patients, this reduction was not associated with the development of hypotensive symptoms. Patients receiving treatment with antihypertensive drugs and taking tadalafil, appropriate clinical recommendations should be given.

With the simultaneous use of tadalafil and finasteride (5α-reductase inhibitor), there was no change in the profile of the adverse reactions compared to the placebo + finasteride, however, when taking these medications, care should be taken because of insufficient clinical data.

The studies confirmed that tadalafil Does not inhibit or induce isoenzymes of the cytochrome P450 system CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, CYP2E1. Tadalafil does not have a clinically significant effect on pharmacokinetics or pharmacodynamics theophylline (substrate CYP1A2), does not affect AUC S-varmarin or R-varmarin (substrates CYP2C9) and does not change the prothrombin time when taken concomitantly with warfarin.

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

Bioavailability ethinyl estradiol and terbutaline when administered together with tadalafilom increases, but the clinical significance of this interaction is not determined.

Tadalafil does not affect the concentration alcohol, as well as alcohol does not affect the concentration of tadalafil. At high doses of alcohol (0.7 g / kg), taking tadalafil at a dose of 20 mg did not cause a statistically significant decrease in the average blood pressure.In some patients, postural dizziness and orthostatic hypotension were observed. 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 that when taking alcohol separately. The effect of alcohol on cognitive function when taking tadalafil (10 mg) does not increase.

The study of interactions between tadalafil and drugs for the treatment of diabetes mellitus not carried out.

Special instructions:

Diagnosis of ED and BPH should include the identification of the underlying cause of the disease, the appropriate medical examination, the definition of treatment tactics and an individual assessment of the benefit / risk ratio.

Sexual activity has a potential risk for patients with cardiovascular diseases, therefore treatment of ED should not be performed in men with heart diseases in which sexual activity is not recommended.

Like other PDE-5 inhibitors, tadalafil can have a systemic vasodilator effect, which can lead to a transient decrease in blood pressure and enhance the hypotensive effect of nitrates, αadrenoblockers (see Fig.section "Interaction with other drugs"). Before prescribing the drug, it is necessary to carefully evaluate the likelihood of such unwanted reactions in patients with cardiovascular diseases.

Patients with a presumptive diagnosis of BPH should be screened to exclude prostate cancer.

Non-arterial anterior ischemic optic neuropathy (NAPION) is the cause of visual impairment, including complete loss of vision. There are rare post-marketing reports on cases of development of NAPION, in time associated with the intake of PDE-5 inhibitors. It is currently impossible to determine whether there is a direct link between the development of NAPION and the intake of PDE5 inhibitors or other factors. It is necessary to warn patients that in case of sudden loss of vision, stop taking tadalafil and seek medical help. Patients should also be informed that people who have undergone NAPION have a higher risk of re-developing NAPION.

There are reports of the occurrence of priapism in the use of PDE-5 inhibitors, including tadalafil. Patients should be informed of 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, resulting in irreversible impotence.

The effectiveness of the drug in patients who underwent a surgical operation on the pelvic organs or a radical non-neuroserving prostatectomy is unknown.

Effect on the ability to drive transp. cf. and fur:

Despite the fact that the incidence of dizziness against the background of placebo and tadalafil is the same, during the treatment period it is necessary to be cautious when driving vehicles and engaging in other potentially dangerous activities that require an 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 the intake of alcohol.

Form release / dosage:Tablets, 5 mg.

Packaging:

For 2, 4 or 7 tablets in Al / Al blister.

1, 2, 3, 4, 5, 6 or 7 blisters with 2 tablets; or 1, 2, 3, 4 or 7 blisters with 4 tablets; or 1, 2 or 4 blisters with 7 tablets in a pack of cardboard along with instructions for use.

Storage conditions:

In the original packaging in a dry place, at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004014

Date of registration:08.12.2016

Expiration Date:08.12.2021

The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia

Manufacturer: & nbsp

SANDOZ ILAC SANAYI VE TICARET, A.S. Turkey

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp19.01.2017

Illustrated instructions

Instructions

Tedallis® (Tedallis)