Tadalafil-Teva - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate (spray-dried) 44,125 mg / 88,25 mg / 176,50 mg / 353,00 mg, sodium lauryl sulfate 0.375 mg / 0.75 mg / 1.50 mg / 3.00 mg, povidone-K12 6.25 mg / 12.50 mg / 25.00 mg / 50.00 mg, crospovidone 6.25 mg / 12.50 mg / 25.00 mg / 50.00 mg, sodium stearyl fumarate 0.50 mg / 1.00 mg / 2.00 mg / 4.00 mg;

film sheath: Opadrai II 85F32782 yellow 2.00 mg / 4.00 mg / 7.00 mg / 15.00 mg (polyvinyl alcohol partially hydrolyzed 0,800 mg / 1,600 mg / 2,800 mg / 6,000 mg, macrogol-3350 0,404 mg / 0,808 mg / 1,414 mg / 3,030 mg, titanium dioxide (E 171) 0.344 mg / 0.688 mg / 1.204 mg / 2.580 mg, talc 0.296 mg / 0.592 mg / 1.036 mg / 2.220 mg, ferric iron oxide yellow (E 172) 0.156 mg / 0.312 mg / 0.546 mg / 1.170 mg.

Description:

Dosage 2.5 mg: round biconvex tablets, covered with a film shell from light yellow to yellow with a brownish hue, with an engraving "2.5" on one side.

Dosage of 5 mg: oval biconvex tablets, covered with a film shell from light yellow to yellow with a brownish hue, with an engraving "5" on one side.

Dosage of 10 mg: oval biconvex tablets covered with a film coating from light yellow to yellow with a brownish hue, with a risk and engraving "1" to the left of the risks and "0" to the right of the risks on one side.

Dosage of 20 mg: oval biconvex tablets covered with a film coat from light yellow to yellow with a brownish tinge, with risk and engraving "2" to the left of the risks and "0" to the right of the risks on one side.

Pharmacotherapeutic group:erectile dysfunction remedy - PDE5-inhibitor

ATX: & nbsp

G.04.B.E.08 Tadalafil

Pharmacodynamics:

Mechanism of action

Tadalafil is a reversible selective inhibitor of a specific type 5 phosphodiesterase (PDE-5) cyclic guanosine monophosphate (cGMP). With sexual excitement, local release of nitric oxide occurs (N0) in the cavernous body, oppression of PDE-5 with tadalafil leads to an increase in the concentration of cGMP in the cavernous body. In turn, cGMP causes relaxation of the smooth muscles of the blood vessels and, accordingly, the flow of blood into the cavernous body of the penis, which contributes to the erection. The pharmacological effect is achieved only with the presence of sexual stimulation.

Pharmacodynamic effects

Research in vitro showed that tadalafil is a selective inhibitor of PDE-5, which 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 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 PDE-1, PDE-2 and PDE-4, which are located in the heart, brain, blood vessels, liver, leukocytes, skeletal muscles 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 about 700 times more active in relation to PDE-5 than in relation to PDE-6, found in the retina and responsible for photo-transmission. Tadalafil also exhibits an effect of 10,000 times more potent in relation to PDE-5 in comparison with its effect on PDE-7 - PDE-10.

When using tadalafil in healthy individuals was not observedsignificant changes in systolic and diastolic blood pressure (BP) in the supine position (mean maximum decrease 1.6 / 0.8 mm Hg, respectively) and in the standing position (mean maximum decrease 0.2 / 4.6 mm Hg ., respectively), as well as a significant change in the heart rate (heart rate).

Admission tadalafil did not cause changes in color recognition (blue / green), which is explained by the low affinity for PDE-6. In addition, there was no effect of tadalafil on visual acuity, electroretinogram, intraocular pressure, and pupil size.

With daily administration of tadalafil, there was no undesirable effect on the morphology of the spermatozoa and their mobility. It was reported that the average concentration of spermatozoa decreased, which was associated with a higher frequency of ejaculation. In addition, there was no adverse effect on the average concentration of sex hormones, testosterone, luteinizing and follicle-stimulating hormones with tadalafil.

Pharmacokinetics:

Suction. After oral administration, it is rapidly absorbed. The maximum concentration in the blood plasma (C_mOh) when taken on an empty stomach is achieved within 120 minutes.however, when administered tadalafil absolute bioavailability is not determined.

The speed and degree of absorption of tadalafil do not depend on food intake, therefore tadalafil can be taken regardless of food intake. The time of administration (in the morning or in the evening) had no clinically significant effect on the rate and degree of absorption.

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 in the plasma binds to proteins. Binding to proteins does not change with impaired renal function.

In healthy subjects, less than 0.0005% of the administered dose is found in semen.

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

Excretion. In healthy individuals, the average clearance of tadalafil with oral intake is 2.5 liters / hour, and the average half-life is 17.5 hours. Tadalafil is excreted mainly in the form of inactive metabolites, mainly with feces (about 61% dose) and to a lesser extent by the kidneys (about 36% of the dose).

The linear dependence of time and clinical effect of tadalafil is in the dose range from 2.5 mg to 20 mg. The equilibrium state of the concentration of tadalafil in blood plasma is 5 days when taken once a day.

Pharmacokinetics the special patient groups

Elderly patients

Healthy volunteers of the elderly (65 years and over) had a lower clearance of tadalafil for oral administration, which was expressed in an increase in the area under the concentration-time curve (AUC) by 25% 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

With a single admission of tadalafil in a dose of 5 to 20 mg AUC increased by 2 times in patients with renal insufficiency mild (creatinine clearance 51-80 ml / min) or moderate (CK 31-50 ml / min) severity and in patients with terminal stage on dialysis. Have patients on hemodialysis, FROM_mOh was 41% higher than in healthy volunteers. Hemodialysis contributes to the insignificant elimination of tadalafil.

Patients with hepatic insufficiency

The pharmacokinetics of tadalafil in patients with mild and moderate hepatic insufficiency is comparable with pharmacokinetics in healthy volunteers with a dose of 10 mg. Pharmacokinetics when taking tadalafil more than 10 mg in patients with impaired liver function was not evaluated. There is insufficient data on the pharmacokinetics of tadalafil in severe hepatic insufficiency (on the Child-Pugh class C).

Patients with diabetes mellitus

In patients with diabetes on the background of the application of tadalafil AUC was less by about 19% than in healthy volunteers. This difference does not require an individual dose adjustment.

Indications:

Erectile disfunction.

Contraindications:

Hypersensitivity to tadalafil or any other component of the drug.

Simultaneous use of tadalafil, nitrates and nitrate-like drugs, because tadalafil enhances the hypotensive effect of nitrates due to NO/ cGMP interaction.

Presence of contraindications to sexual activity in patients with cardiovascular diseases:

- myocardial infarction within the last 90 days;

- unstable angina or the onset of an attack withangina pectoris during sexual intercourse;

- chronic heart failure of II-IV classes by classification NYHA: 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 intake of PDE-5 inhibitors).

Simultaneous reception of doxazosin, as well as drugs for the treatment of erectile dysfunction.

Daily (more than 2 times a week) application in patients with severe renal failure (CC less than 30 ml / min).

Insufficiency of lactase, lactose intolerance and glucose-galactose malabsorption.

Children under 18 years.

Carefully:

In severe renal failure (QC less than 30 ml / min), severe liver failure (Child-Pugh class C), simultaneous use with alpha-blockers, in patients with a predisposition to priapism (in sickle cell anemia, multiple myeloma or leukemia) or with anatomical deformation of the penis (angular curvature, cavernous fibrosis or Peyronie's disease); when used simultaneously with potent inhibitors of isoenzyme CYP3A4 (ritonavir. saquinavir, ketoconazole, itraconazole, erythromycin), hypotensive drugs.

Pregnancy and lactation:

Tadalafil-Teva is not used in women.

Pregnancy

Single cases of tadalafil in pregnancy have been described. The use of tadalafil during pregnancy is not recommended.

Breastfeeding period

Available pharmacodynamic / toxicological data in animals indicate the penetration of tadalafil into breast milk, so the drug Tadalafil-Teva should not be used during breastfeeding.

Dosing and Administration:

Inside, regardless of food intake.

erectile disfunction

The recommended dose is 10 mg before the alleged sexual intercourse.

In patients in whom the drug Tadalafil-Teva at a dose of 10 mg is not effective, a dose of 20 mg is used. Tadalafil-Teva should be taken at least 30 minutes before sexual activity.

The maximum frequency of Tadalafil-Teva is 1 time per day.

Doses of 10 mg and 20 mg are used immediately before sexual activity and are not recommended for daily use. For patients with frequent sexual activity (more than twice a week), the use of the drug Tadalafil-Teva at a dose of 5 mg daily, once a day at the same time, is recommended.The daily dose can be reduced to 2.5 mg, depending on the individual sensitivity.

For patients with infrequent sexual Activity (less than 2 times a week) recommended the use of the drug Tadalafil-Teva in a dose of 20 mg immediately before sexual activity. The maximum daily dose of 20 mg.

Special group of patients

In elderly patients correction of the dose is not required.

In patients with mild or moderate renal insufficiency correction of the dose is not required. The maximum dose in patients with severe renal insufficiency is 10 mg. Daily use (more than 2 times a week) of Tadalafil-Teva in patients with severe renal failure is not recommended.

In patients with mild and moderate hepatic impairment the recommended dose of Tadalafil-Teva is 10 mg. The use of a dose of more than 10 mg in patients with impaired liver function was not evaluated. Insufficient data on the use of the drug Tadalafil-Teva in severe hepatic insufficiency (on the scale Child-Pugh class C). Care should be taken when using Tadalafil-Teva in this group of patients.

Patients with diabetes mellitus

When used in patients with diabetes mellitus, dose adjustment is not required.

Side effects:

The most frequent adverse reactions in patients with erectile dysfunction who used tadalafil, are headache, dyspepsia, myalgia, back pain, most often they are unstable and mostly mild or moderately expressed. The most frequent reports of the onset of headache were observed in patients using tadalafil daily for 10-30 days from the beginning of taking the drug.

Adverse reactions are classified with the following frequency: very often (≥1 / 10); often - (≥1 / 100 to <1/10): infrequently - (≥1 / 1000 to <1/100); rarely - (≥1 / 10000 to <1/1000).

From the immune system: infrequently - hypersensitivity reactions; rarely - angioedema².

From the nervous system: often - headache; infrequently - dizziness; rarely - a stroke¹ (including hemorrhagic), syncope, transient ischemic attack¹, migraine², cluster convulsions, transient amnesia.

On the part of the organs of vision: infrequent - blurred vision, pain in the eyes; rarely - visual field defects, eyelid edema, conjunctival hyperemia, ischemic optic nerve neuropathy², occlusion of retinal vessels².

From the heart¹: infrequently - a tachycardia, a strong palpitation; rarely - myocardial infarction, unstable angina², ventricular arrhythmia².

From the side of the vessels: often - "tides" of blood to the face; infrequently - hypotension³, hypertension.

On the part of the respiratory system: often - nasal congestion; infrequently - shortness of breath, nosebleed.

From the gastrointestinal tract: often - dyspepsia, gastroesophageal reflux; infrequently - pain in the abdomen.

From the skin and subcutaneous tissues: infrequently - skin rash, hyperhidrosis (sweating); rarely - hives, Stevens-Johnson syndrome², exfoliative dermatitis².

From the side of the musculoskeletal and connective tissue: often - back pain, myalgia, pain in the limbs.

From the side of the kidneys and urinary tract: infrequently - hematuria.

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

Other: infrequently - chest pain; rarely - swelling of the face², sudden death^{1, 2}.

(1) Most patients had previous cardiovascular risk factors.

(2) Side effects are registered in the post-registration period.

(3) Reports of adverse reactions in patients taking tadalafil simultaneously with antihypertensive drugs.

Description of individual adverse reactions

It was reported changes in the electrocardiogram (sinus bradycardia) in patients who used tadalafil daily. These changes were not associated with adverse reactions.

Overdose:

With a single application in healthy volunteers tadalafil 500 mg and in patients with erectile dysfunction (repeatedly to 100 mg / day), the undesirable effects were the same as with the use of lower doses.

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

Interaction:

Inhibitors of the cytochrome P450 system

Tadalafil is mainly metabolized with the participation of isoenzyme CYP3A4. Selective inhibitor of isoenzyme CYP3A4 ketoconazole (200 mg / day) increases AUC tadalafil (10 mg once) in 2 times and C_mOh by 15%, and ketoconazole (400 mg / day) increases AUC tadalafil (20 mg once) 4 times and C_max on 22% in comparison with reception only tadalafila in the same dose. Ritonavir (200 mg twice daily), which is an inhibitor of isoenzymes CYP3A4, CYP2C9, CYP2C19 and CYP2D6, increased AUC tadalafil (20 mg) twice without changing C_mOh. Despite the fact that specific interactions have not been studied, it can be assumed that other protease inhibitors, such as, for example, saquinavir and other isoenzyme inhibitors CYP3A4, such as erythromycin, clarithromycin, intraconazole and grapefruit juice can increase the concentration of tadalafil in blood plasma, as well as increase the likelihood of adverse reactions, so caution should be exercised simultaneously with tadalafil.

Selective inductor of isoenzyme CYP3A4 rifampicin when used simultaneously with tadalafil reduces AUC tadalafil (10 mg once) by 88%. This can lead to a reduction in the effect of tadalafil and reduce its effectiveness. The degree of loss of effectiveness is unknown. It can be assumed that other isoenzyme inducers CYP3A4, such as carbamazepine, phenytoin, phenobarbital, can also reduce the concentration of tadalafil in blood plasma.

Other medications

It is known that tadalafil (5 mg, 10 mg and 20 mg) enhances the hypotensive effect of nitrates. This occurs as a result of the additive effect of nitrates and tadalafil on metabolism NO and cGMP.Therefore, the use of tadalafil against the background of the use of nitrates is contraindicated. However, if necessary, nitrates can be used at least 48 hours after the last dose of tadalafil. In this situation, nitrates should be taken only under the supervision of a doctor and accompanied by monitoring of hemodynamic parameters.

Hypotensive drugs, including blockers of "slow" calcium channels

The simultaneous use of doxazosin (4 mg and 8 mg daily) with tadalafil (5 mg daily and 20 mg once) significantly increases the antihypertensive effect of alpha-blockers. This effect lasts at least 12 hours and can be accompanied by appropriate symptoms, including syncope, and therefore simultaneous reception of these drugs is not recommended. With the simultaneous use of alfuzosin or tamsulosin with tadalafil, these reactions have not been reported, but caution should be exercised tadalafil in patients treated with alpha-blockers, especially in elderly patients. Treatment should begin with a minimal dose and later adjust the dose.

Tadalafil has a systemic vasodilator property and can enhance the antihypertensive effect of antihypertensive drugs,including such groups of antihypertensive drugs as blockers of "slow" calcium channels (amlodipine), angiotensin-converting enzyme inhibitors (enalapril), beta-blockers (metoprolol), thiazide diuretics (bendroflaizide) and angiotensin II receptor antagonists (various types and doses, alone or in combination with thiazide diuretics, calcium channel blockers, beta-blockers and / or alpha-blockers).

In addition, in patients taking several antihypertensive drugs, in whom hypertension was poorly controlled, there was a slightly greater reduction in blood pressure. In the vast majority of patients, this decrease was not associated with an antihypertensive syndrome. Patients receiving simultaneous treatment with antihypertensive drugs with tadalafil should be given appropriate clinical recommendations.

5-alpha-reductase inhibitor

With the simultaneous use of tadalafil (5 mg) with finasteride (5 mg), no additional adverse reactions were reported to alleviate the symptoms of benign prostatic hyperplasia. However, the interaction of these drugs is not fully understood and should be applied with caution.

Isoenzymatic substrate CYP1A2 (for example theophylline)

With the simultaneous use of tadalafil (10 mg) and theophylline (non-selective phosphodiesterase inhibitor), no adverse reactions were reported, but there was a slight change in pharmacodynamic properties: an increase in the heart rate by 3.5 beats per minute. This effect is regarded as insignificant and has no clinical significance, but it should be taken into account when these medications are used simultaneously.

Ethinyl estradiol and terbutaline

An increase in the bioavailability of ethinylestradiol for oral administration has been reported with simultaneous use with tadalafil; a similar increase can be expected with terbutaline for oral administration, although the clinical significance of this effect is not significant.

Alcohol

Tadalafil did not affect the concentration of alcohol, as well as alcohol did not affect the concentration of tadalafil. Tadalafil (20 mg) did not increase the decrease in blood pressure caused by alcohol (0.7 g / kg). 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 as when taking alcohol without tadalafil.The effect of alcohol on cognitive functions does not change when applied simultaneously with tadalafil.

Drugs metabolized by the cytochrome P450 system

Tadalafil has no clinically significant effect on the clearance of drugs metabolized with the participation of isoenzyme CYP450. Research has confirmed that tadalafil Does not inhibit or induce isoenzymes CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and CYP2C19.

Isoenzymatic substrate CYP2C19 (e.g., R-varmarin)

Tadalafil in a dose of 10 mg and 20 mg does not have a clinically significant effect on AUC S-warfarin or R/ RTI & gt; Tadalafil as does the effect of warfarin on prothrombin time.

Acetylsalicylic acid

Tadalafil in a dose of 10 mg and 20 mg does not increase the duration of bleeding caused by acetylsalicylic acid.

Antidiabetic drugs

Specific studies of interaction with antidiabetic drugs have not been conducted.

Special instructions:

Before the application of tadalafil

Before using the drug Tadalafil-Teva, it is necessary to diagnose erectile dysfunction, to identify possible causes and selection of adequate methods of treatment, to evaluate a medical history and to conduct a physical examination.

Before the treatment of erectile dysfunction with Tadalafil-Teva, the doctor should examine the patient's cardiovascular system, since there is a certain degree of risk of developing disorders related to sexual activity. Tadalafil-Teva has vasodilating properties, as a result of which there can be a moderate and periodic decrease in blood pressure, which can enhance the hypotensive effect of nitrates.

The efficacy of tadalafil in patients who underwent pelvic surgery, pelvic organs, or nerve-sparing radical prostatectomy is not known.

Cardiovascular complications

Severe cardiovascular side effects, such as myocardial infarction, sudden death, angina pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and tachycardia, were recorded both during the post-marketing period and during clinical tests. Most patients who had these reactions had previously had cardiovascular risk factors.Nevertheless, it is impossible to determine the relationship of these reactions with the administration of tadalafil, with cardiovascular risk factors, sexual activity, or a combination of these or other factors.

In patients receiving co-therapy with antihypertensive drugs and Tadalafil-Teva, the latter can cause a decrease in blood pressure. With daily use of the drug Tadalafil-Teva, you may need to adjust the dose of the antihypertensive drug.

In some patients, simultaneous use of alpha-adrenergic blockers with the drug Tadalafil-Teva can cause a decrease in blood pressure. Simultaneous use of these drugs is not recommended.

Disturbances on the part of the organ of sight

There was reported the development of a violation of the visual organ and ischemic neuropathy of the optic nerve in connection with the use of tadalafil and other PDE-5 inhibitors. It is necessary to stop the use of the drug Tadalafil-Teva in case of signs of a violation of the organ of vision and immediately consult a doctor.

Renal and hepatic impairment

In connection with the increase AUC tadalafil, the limited clinical experience of its use,as well as the limited effectiveness of hemodialysis to reduce the clearance of tadalafil, daily use of the drug Tadalafil-Teva is not recommended in patients with severe renal failure.

There is no data on the daily use of the drug Tadalafil-Teva in patients with severe hepatic insufficiency (on the Child-Pugh class C). It is necessary to use caution tadalafil in these patients.

Priapism and anatomical deformities of the penis

Patients who have an erection for more than 4 hours should immediately consult a doctor. Untimely treatment of priapism can lead to damage to the tissues of the penis and to a loss of potency.

Tadalafil-Teva should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie's disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia).

Use with isoenzyme inhibitors CYP3A4

It should be used with caution Tadalafil-Teva at the same time with potent inhibitors of isoenzyme CYP3A4 (ritonavir, saquinavir, ketoconazole, itraconazole and erythromycin), in connection with a possible increase AUC tadalafil.

Application simultaneously with other treatments for erectile dysfunction

It is not recommended simultaneous use of the drug Tadalafil-Teva with other drugs used to treat erectile dysfunction, tk. the efficacy and safety of the combined treatment has not been studied.

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

Care should be taken when using Tadalafil-Teva because dizziness may develop, which can affect the ability to drive vehicles and work with potentially dangerous mechanisms.

Form release / dosage:Tablets, film-coated, 2.5 mg / 5 mg / 10 mg / 20 mg.

Packaging:

For 10 tablets in a blister of PVC / ACLAR / PVC / / aluminum foil (or in a blister of aluminum (OPA / aluminum / PVC) foil, or in the blister of PVC / ACLAR / PVDC / PVC KRMAC // aluminum foil).

1 blister together with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003558

Date of registration:11.04.2016

Date of cancellation:2021-04-11

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

TEVA Pharmaceutical Industries, Ltd. Israel

Representation: & nbspTeva Teva Israel

Information update date: & nbsp16.06.2016

Illustrated instructions

Instructions

Tadalafil-Teva (Tadalafil-Teva)