Pharmacotherapeutic group: a treatment for erectile dysfunction – PDE5 inhibitor
ATC code: G04BE08
The mechanism of action
Tadalafil is a reversible, selective inhibitor of specific phosphodiesterase type 5 (PDE-5) is a cyclic guanosine monophosphate (cGMP). When sexual arousal there is a local release of nitric oxide (NO) in the corpus cavernosum, inhibition of PDE5 tadalafil leads to increase of cGMP concentration in the corpus cavernosum. In turn, cGMP causes the relaxation of smooth muscles of blood vessels and, therefore, blood flow to the corpus cavernosum of the penis, which contributes to an erection. The pharmacological effect is achieved only if there is sexual stimulation.
Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5, which is an enzyme found in corpus cavernosum smooth muscle, smooth muscle in blood vessels internal organs, skeletal muscle, platelets, kidneys, lungs and cerebellum. Effects of tadalafil for PDE5 is more active than other phosphodiesterase. Tadalafil is 10,000 times more potent against PDE5 than against PDE 1, PDE-2 and PDE-4 which are localized in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle and in other organs. Tadalafil 10,000 times more active blocks PDE5 than PDE-3 – enzyme that is found in the heart and blood vessels. This selectivity for PDE5 as compared to PDE-3 is significant, because 3-PDE is an enzyme participating in the reduction of the heart muscle. Furthermore, tadalafil is about 700 times more active against PDE5 than against PDE-6 found in the retina and is responsible for fotoperedachu. Tadalafil also shows effect is 10,000 times more potent for PDE5 compared with its effect on PDE-7 – PDE-10
In applying tadalafil in healthy persons were observed significant changes in systolic and diastolic blood pressure (BP) in the supine position (maximum mean decrease of 1.6 / 0.8 mm Hg. V., Respectively), and standing (mean maximum decrease 0.2 / 4.6 mm Hg. v., respectively), as well as significant changes in heart rate (HR).
Admission Tadalafil does not cause changes in the recognition of colors (blue / green), due to low affinity to PDE-6. In addition, there was no effect of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size.
With a daily intake of Tadalafil was not observed undesirable effects on sperm morphology and motility. It reported a decrease in the average concentration of
sperm, which was associated with a higher incidence of ejaculation. In addition, there was no adverse effect on the average concentration of sex hormones, testosterone, luteinizing hormone and follicle-stimulating hormone when taking tadalafil.
Suction. After intake of rapidly absorbed. Maximum plasma concentration (Cmax) achieved in the fasting state for 120 min, but when administered absolute bioavailability of tadalafil is not defined.
The rate and extent of absorption of tadalafil are not dependent on food intake, so tadalafil can be taken without regard to meals. Reception hours (morning or evening) had no clinically significant effect on the rate and extent of absorption.
Distribution. The average volume of distribution is approximately 63 liters, indicating that tadalafil is distributed in body tissues. At therapeutic concentrations, 94% of tadalafil in plasma is associated with proteins. Protein binding is not changed by impaired renal function.
In healthy persons less than 0.0005% of the administered dose was found in semen.
Metabolism. Tadalafil is mainly metabolized involving CYP3A4 isoenzyme of cytochrome P450. The main circulating metabolite is metilkateholglyukuronid. This metabolite is 13 000 times less active against PDE5 than tadalafil. Consequently, the concentration of this metabolite is not clinically significant.
Withdrawal. In healthy individuals the average clearance of tadalafil ingestion of 2.5 l / h, and the average half-life – 17.5 hours Tadalafil appears mainly in the form of inactive metabolites, mainly in the feces (about 61% of the dose) and to a lesser extent by the kidneys. (about 36% of the dose).
Linear dependence of the time, and the clinical effect of tadalafil is in a dosage range from 2.5 mg to 20 mg. The equilibrium state of the concentration of tadalafil in plasma is 5 days upon receipt of 1 times a day.
Pharmacokinetics in special groups of patients
Healthy elderly volunteers (65 years or more) had a lower clearance tadalafil ingestion, resulting in increase in the area under “concentration-time” curve (AUC) is 25% as compared with healthy volunteers aged 19 to 45 years. This difference is not clinically significant and does not require a dose adjustment.
Patients with renal insufficiency
In single dose of tadalafil in a dose of from 5 to 20 mg AUC increased 2-fold in patients with mild renal impairment (creatinine clearance (CC) 51-80 ml / min) or medium (CC 31-50 ml / min) and severity patients with end-stage on dialysis. In patients on hemodialysis, the Cmax was 41% higher than in healthy volunteers. Hemodialysis contributes negligible excretion of tadalafil.
Patients with hepatic insufficiency
Pharmacokinetics tadalafil in patients with mild to moderate hepatic impairment comparable pharmacokinetics in healthy volunteers at a dose of 10 mg applied. Pharmacokinetics after receiving more than 10 mg of tadalafil in patients with impaired liver function was not assessed. There is insufficient data on the pharmacokinetics of tadalafil with severe hepatic insufficiency (according to Child-Pugh class C).
Patients with diabetes mellitus
Patients with diabetes mellitus during treatment with tadalafil AUC was lower by about 19% than in healthy volunteers. This difference does not require an individual dose adjustment.
Teva Pharmaceutical Enterprise Co., Ltd., Israel
1 tablet contains: active substance: Tadalafil 2.50 mg / 5.00 mg / 10.00 mg / 20.00 mg; 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 coating: Opadry II 85F32782 Yellow 2.00 mg / 4.00 mg / 7.00 mg / 15.00 mg (partially hydrolyzed polyvinyl alcohol 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 iron colorant oxide yellow (E 172) 0.156 mg / 0.312 mg / 0.546 mg / 1,170 mg.
- hypersensitivity to tadalafil or to any other component of the product.
- Concomitant use of tadalafil Nitrates and pharmaceuticals as tadalafil enhances hypotensive effects of nitrates due to NO / cGMP interaction.
- The presence of contraindications to sexual activity in patients with cardiovascular disease:
* Myocardial infarction within the last 90 days;
* Unstable angina and the occurrence of angina attack during sexual intercourse;
* Chronic heart failure class II-IV at NYHA classification;
* Uncontrollable arrhythmia, hypotension (blood pressure less than 90/50 mm Hg), uncontrolled hypertension;
* Ischemic stroke within the last 6 months.
- Loss of vision due nearterialnoy anterior ischemic optic neuropathy (irrespective of an inhibitor reception PDE5).
- Simultaneous reception of doxazosin, and drugs to treat erectile dysfunction.
- Daily (more than 2 times per week) use in patients with severe renal failure (creatinine clearance less than 30 mL / min).
- The lack of lactase, lactose intolerance, and glucose-galactose malabsorption.
- Children under 18 years of age.
In severe renal failure (creatinine clearance less than 30 mL / min), severe liver failure (in Child-Pugh class C.), the simultaneous use of alpha-blockers, patients with predisposition to priapism (for sickle cell anemia, multiple myeloma or leukemia ) or with anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie’s disease); while the use of potent inhibitors isoenzyme CYP3A4 (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), antihypertensives.
The most common adverse reactions in patients with erectile dysfunction who used tadalafil are headache, dyspepsia, myalgia, back pain, most often they were erratic and mostly mild to moderate. The most frequently reported symptoms like headaches were reported in patients treated with tadalafil daily for 10-30 days from the start of dosing.
Adverse events categorized with the following frequency: very often (≥1 / 10); often – (≥1 / 100 to < 1/10); infrequently – (≥1 / 1000 < 1/100); rarely – (≥1 / 10,000 to < 1/1000)
Immune system: rarely – hypersensitivity reactions; rarely -. angioedema otek2
From the nervous system: often – headache; rarely – dizziness; rarely – insult1 (including hemorrhagic), syncope, transient ischemic ataka1, migren2, cluster seizures, transient amnesia
On the part of the organs of vision: rarely – blurred vision, pain in the eyes; rarely – defects of fields of vision, eyelid edema, conjunctival hyperemia, ischemic optic neuropathy nerva2, occlusion of blood vessels setchatki2
On the part of serdtsa1: rarely – tachycardia, palpitations; rare – myocardial infarction, unstable stenokardiya2, ventricular aritmiya2
On the part of the vessels: often – “tides” of blood to the face; infrequently – gipotoniya3, hypertension
On the part of the respiratory system: often – nasal congestion; rarely – shortness of breath, nosebleeds
Gastro-intestinal tract: often – dyspepsia, gastroesophageal reflux disease; infrequently -. abdominal pain
Skin and subcutaneous tissue disorders: rare – skin rash, hyperhidrosis (sweating); rarely – urticaria, Stevens-Dzhonsona2 syndrome, exfoliative dermatit2
On the part of the musculoskeletal and connective tissue disorders: often – back pain, myalgia, pain in the limbs
On the part of the kidney and urinary tract: rarely – hematuria
On the part of the genital organs: rarely – bleeding from the penis, haemospermia; rare – prolonged erection priapizm2
Other: rarely – pain in the chest; rarely – swelling litsa2 sudden smert1,2
(1) The majority of patients had a previous cardiovascular risk factors.
(2) Side effects reported in post-registration period.
(3) reported adverse reactions in patients treated with tadalafil simultaneously with antihypertensive drugs.
Description of individual adverse reactions
It reported on the changes of electrocardiogram (sinus bradycardia) in patients treated with tadalafil daily. These changes were not associated with adverse reactions.
How to accept, acceptance rate and dosage
Inside, regardless of meals.
The recommended dose is 10 mg at the intended sexual intercourse.
Patients who DYNAMIC LONG preparation in a dose of 10 mg of an effective dose of 20 mg is used. DYNAMIC LONG drug should be taken at least 30 minutes before sexual activity.
The maximum frequency of dosing LONG DYNAMIC is 1 times a day.
Doses of 10 mg and 20 mg is used immediately before the sexual activity and is not recommended for daily use. For patients with frequent sexual activity (more than two times a week) it is recommended to use the drug DYNAMIC LONG 5 mg daily, one time per day at the same time. The daily dose can be reduced to 2.5 mg depending on the individual sensitivity. For patients with infrequent sexual activity (at least 2 times per week) recommended the use of the drug DYNAMIC LONG 20mg immediately before sexual activity. The maximum daily dose of 20 mg.
A special group of patients
In elderly patients, a dose adjustment is required.
In patients with mild or moderate renal impairment dose adjustment is required. The maximum dose in patients with severe renal failure is 10 mg. Daily use (more than 2 times per week) DYNAMIC LONG drug in patients with severe renal impairment is not recommended.
Patients with mild to moderate hepatic impairment recommended dose DYNAMIC LONG is 10 mg. Application of a 10 mg dose for patients with impaired liver function was not evaluated. Insufficient data on the use of the drug DYNAMIC LONG with severe hepatic insufficiency (according to Child-Pugh Class C). Caution should be exercised when using the drug DYNAMIC LONG in this group of patients.
Patients with diabetes mellitus
When used in patients with diabetes dose adjustment is required.
Store at a temperature not higher than 25 ° C.
Keep out of the reach of children.
Inhibitors of cytochrome P450
Tadalafil is mainly metabolized by CYP3A4 isoenzyme with. Selective inhibitor of isozyme CYP3A4 ketoconazole (200 mg / d) increases AUC tadalafil (10 mg dose) in 2 times and Cmax by 15%, and ketoconazole (400 mg / d) increases AUC tadalafil (20 mg dose) 4 times and Cmax for 22% compared with the reception of only tadalafil in the same dose.
Ritonavir (200 mg twice daily), which is an inhibitor of isozymes CYP3A4, CYP2C9, CYP2C19 and CYP2D6, increased AUC tadalafil (20 mg) was twice unchanged Cmax. Despite the fact that the specific interactions have not been studied, it can be assumed that
other protease inhibitors such as saquinavir and other inhibitors of isoenzyme CYP3A4, such as erythromycin, clarithromycin, itraconazole and grapefruit juice may increase the concentration of tadalafil in the blood plasma, and also increase the likelihood of adverse reactions, so care should be taken to use them in conjunction with tadalafil .
Selective isoenzyme CYP3A4 inducer rifampicin while the use of tadalafil reduces AUC tadalafil (10 mg dose) to 88%. This can lead to a decrease tadalafil exposure and reduce its effectiveness. The degree of reduction efficiency is unknown. It can be assumed that other inducers of CYP3A4 isoenzyme, such as carbamazepine, phenytoin, phenobarbital, may also reduce the concentration of tadalafil in plasma.
It is known that tadalafil (5 mg, 10 mg and 20 mg) enhances the hypotensive effects of nitrates. This is due to the additive effect of nitrates and tadalafil on the NO and cGMP metabolism. Therefore, the use of tadalafil in the treatment with nitrates is contraindicated. However, if necessary, nitrates may be used at least 48 hours after the last dose of tadalafil. In this situation, the nitrate intake should be done only under medical supervision and accompanied by monitoring of hemodynamic parameters.
Antihypertensive drugs, including blockers “slow” calcium channels
The simultaneous use of doxazosin (4 mg and 8 mg daily) with tadalafil (5 mg daily and 20 mg once daily) significantly enhances the antihypertensive effect of alpha-blockers. This effect lasts for at least 12 hours and can be accompanied by the appropriate symptoms, including fainting, and therefore the concomitant use of these drugs is not recommended. With simultaneous use of alfuzosin or tamsulosin with tadalafil on these reactions have not been reported, but it should be used with caution tadalafil in patients treated with alpha-blockers, particularly in elderly patients. Treatment should be started with the lowest dose and subsequently adjust the dose.
Tadalafil has systemic vasodilator properties and may enhance the antihypertensive effect of antihypertensive drugs, including such groups antihypertensive drugs as blockers “slow” calcium channel (amlodipine), angiotensin converting enzyme inhibitors (enalapril), beta blockers (metoprolol), thiazide diuretics (bendrofluazid) and angiotensin II receptor antagonists (various types and doses, alone or in combination with a thiazide diuretic, blockers “calcium” channel, beta-adrenergic blocker and and / or alpha-blockers).
Additionally, patients taking multiple antihypertensive agents that have hypertension, poorly controlled, there was a slightly greater blood pressure reduction. The vast majority of patients, this reduction was not associated with hypotensive syndrome. Patients receiving concomitant treatment with antihypertensive drugs with tadalafil, should be given appropriate clinical guidelines.
An inhibitor of 5-alpha-reductase
With simultaneous use of tadalafil (5 mg), finasteride (5 mg) to alleviate the symptoms of benign prostatic hyperplasia has not been reported for additional adverse reactions. However, the interaction of these drugs has not been studied fully and at the same time to use them with caution.
Substrate isoenzyme CYP1A2 (e.g., theophylline)
With simultaneous use of tadalafil (10 mg) and theophylline (a nonselective phosphodiesterase inhibitor) no reported adverse reactions, but there was a slight change in pharmacodynamic properties: increased 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 while the use of these drugs.
It was reported to increase the bioavailability of ethinylestradiol for oral administration, while the use tadalafil; such an increase can be expected with the use of oral terbutaline, although the clinical significance of this effect is insignificant.
Tadalafil did not affect the concentration of alcohol, as well as alcohol does not affect the concentration of tadalafil. Tadalafil (20 mg) did not enhance blood pressure reduction by alcohol (0.7 g / kg). Some patients experienced postural dizziness and orthostatic hypotension. When receiving tadalafil in conjunction with lower doses of alcohol (0.6 g / kg) decrease in blood pressure were not observed, and dizziness occurred with the same frequency as that of the reception without alcohol tadalafil. The effect of alcohol on cognitive function does not change when using simultaneously with tadalafil.
Drugs metabolized by the action of cytochrome P450
Tadalafil has no clinically significant effect on the clearance of drugs metabolized with isoenzyme CYP450. Studies have confirmed that tadalafil does not inhibit or induce isozymes CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and CYP2C19.
Substrate isoenzyme CYP2C19 (e.g., R-warfarin)
Tadalafil 10 mg and 20 mg has no clinically significant effect on AUC S-warfarin or R-warfarin. Tadalafil does not affect the action of warfarin on prothrombin time.
Tadalafil 10 mg and 20 mg of an increased duration of bleeding caused by acetylsalicylic acid.
Specific interaction studies with antidiabetic drugs was conducted.
Prior to the application of tadalafil
Before using the product DYNAMIC LONG need to diagnose erectile dysfunction, determine possible causes, and the selection of adequate treatment, to evaluate the medical history and a physical examination.
Prior to the treatment of erectile dysfunction drug DYNAMIC LONG, a doctor must examine the state of the cardiovascular system of a patient, as with her hand, there is a certain degree of risk of developing disorders associated with sexual activity. Preparation DYNAMIC LONG has vasodilating properties, whereby there may be a moderate decrease of blood pressure and periodic, which can enhance the hypotensive effects of nitrates.
The effectiveness of tadalafil in patients who underwent surgery in the pelvis, pelvic inflammatory disease or nerve-sparing radical prostatectomy, is not known.
Serious adverse reactions from the cardio-vascular system, such as myocardial infarction, sudden death, angina, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and tachycardia, – have been reported in the post-registration period, and in clinical trials. Most patients who have observed these reactions previously had cardiovascular risk factors. However, to determine the relationship of these reactions to tadalafil, cardiovascular risk factors, sexual activity, or a combination of these or other factors is impossible.
In patients receiving combination therapy with antihypertensive drugs and drug DYNAMIC LONG, the latter may cause a decrease in blood pressure. With daily use of the drug DYNAMIC LONG may need a dose adjustment of antihypertensive
In some patients, the simultaneous use of alpha-blockers with DYNAMIC LONG drug may cause a decrease in blood pressure. The simultaneous use of these drugs is not recommended.
Violations by the organ of vision
It reported on the development of disorders of the organ of vision and ischemic optic neuropathy in connection with the use of tadalafil and other PDE5 inhibitors. You must stop using the product DYNAMIC LONG in the event of a violation on the part of the organ of vision and seek immediate medical attention.
Renal and hepatic insufficiency
Due to the increased AUC tadalafil limited clinical experience with its use, as well as the limited efficacy on reducing clearance hemodialysis tadalafil daily drug application DYNAMIC LONG not recommended in patients with severe renal failure patients.
No information about the daily use of the drug DYNAMIC LONG patients with severe hepatic insufficiency (according to Child-Pugh Class C). Caution should be used tadalafil in these patients.
Priapism and anatomical deformation of the penis
Patients who have an erection persists for more than 4 hours should seek immediate medical attention. Delays in treatment of priapism can damage the penile tissue and loss of potency.
DYNAMIC LONG drug 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 the development of priapism (sickle-cell anemia, multiple myeloma, leukemia).
The use of inhibitors of CYP3A4 isoenzyme
Should be used with caution preparation DYNAMIC LONG simultaneously with potent inhibitors isoenzyme CYP3A4 (ritonavir, saquinavir, ketoconazole, itraconazole and erythromycin), due to a possible increase in AUC tadalafil.
Application along with other treatments for erectile dysfunction
Not simultaneous application of the drug is recommended DYNAMIC LONG with other drugs used to treat erectile dysfunction, as efficacy and safety of combination therapy has not been studied.
Effects on ability to drive vehicles and mechanisms
Caution should be exercised when using the drug DYNAMIC LONG due to the fact that dizziness can occur, which may affect the ability to drive vehicles and work with potentially dangerous machinery.
When a single application in healthy volunteers tadalafil 500 mg in patients with erectile dysfunction (repeatedly to 100 mg / day) undesirable effects were the same as when using lower doses.
In case of overdose should be carried out standard symptomatic treatment. Hemodialysis tadalafil virtually displayed.