Tadalafil

When ATH:
G04BE08

Selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5).

The crystalline solid. Practically insoluble in water, very slightly soluble in ethanol. Molecular weight 389,41.

Pharmacological action.
Improve erectile function.

Application.

Hypersensitivity; simultaneous reception of organic nitrates in any form (cm. "Pharmacology", The effect on blood pressure when taken with nitrates); concomitant treatment with alpha-blockers (Besides 0,4 mg tamsulosin 1 once a day) (cm. "Interaction").

Tadalafil is not indicated for use in women, children (Tadalafil was not evaluated in patients under the age of 18 years), Newborn.

– unstable angina or angina, occurring during sexual intercourse;

– heart failure (class II or above of the NYHA classification), evolved in the past 6 Months;

– uncontrolled cardiac arrhythmia, hypotension (FROM<90/50 mm Hg. Art.) or uncontrolled hypertension;

Diagnosed hereditary degenerative retinal diseases, including retinitis pigmentosa.

A predisposition to priapism (drepanocytemia, mnozhestvennaya myeloma, leukemia), anatomical deformity of the penis (angulation, kavyernoznyi fibrosis, Peyronie's disease).

During the period of clinical trials around the world took over tadalafil 5700 of men aged 19-87 years (average age 59 years), above 1000 patients within 1 year and more, above 1300 patients- 6 months or more. In placebo-controlled clinical trials Phases 3 the proportion of patients, receiving 10 or 20 mg of tadalafil and interrupted treatment because of side effects, made 3,1% compared to 1,4% placebo.

The table below shows adverse effects, were observed in patients, tadalafil treated at the recommended doses (10 or 20 mg), during 8 major placebo-controlled clinical trials of Phases 3, including a study in patients with diabetes (specified adverse effects, marked at least 2% patients and the frequency of occurrence exceeding those in the placebo group).

Side effects, observed in placebo-controlled clinical trials

Back pain or myalgia were observed with a frequency, shown in Table. In clinical trials, Cialis back pain or myalgia, usually, manifested 12-24 hours after administration and usually resolves within 48 no. Back pain / myalgia, associated with taking tadalafil, characterized as bilateral diffuse pain in the lower lumbar, gluteal, femoral or torakolyumbarny muscular discomfort and aggravation in the supine position. Typically, the pain was mild or moderate severity and held without medical treatment, severe back pain are rare (<5% All posts). If necessary, treatment is usually effective proved paracetamol or NSAIDs, However, in a few cases it was used codeine. Generally, about 0,5% All patients, prinimavshih tadalafil, stopped treatment because of back pain / myalgia. Diagnostic Study, including the assessment of inflammation, muscle injury, or renal damage, found no significant medical data, underlying pathology.

For all studies with any dose of tadalafil change messages in color vision were rare (<0,1% patients).

In addition, the effects were noted, Register less frequently (<2%), than in controlled clinical trials. The relationship of these effects with tadalafil is not installed.

Body as a Whole: asthenia, swelling of the face, fatiguability, pain.

Cardio-vascular system: angina, chest pain, gipotenziya, hypertension, myocardial infarction, orthostatic hypotension, heartbeat, syncope, tachycardia.

From the digestive tract: change in the functional liver samples, diarrhea, dry mouth, dysphagia, esophagitis, hastroэzofahealnыy reflux, gastritis, increase the level of gamma-glutamyl, loose stools, nausea, pain at the top of the stomach, vomiting.

On the part of the musculoskeletal system: arthralgia, pain in the neck.

From the nervous system: dizziness, gipesteziya, insomnia, paraesthesia, drowsiness, vertigo.

From the respiratory system: dyspnoea, nose bleed, pharyngitis.

For part of the view: blurred vision, changes in color vision, conjunctivitis (including conjunctival hyperemia), sore eyes, increasing lacrimation, swelling of the eyelids.

With the genitourinary system: increased erections, spontaneous erection.

Tadalafil is metabolized primarily by CYP3A4. PM, which inhibit CYP3A4, may increase the effect of tadalafil (cm. "Dosage and administration").

Ketoconazole (400 mg daily) is selective and potent inhibitor of CYP3A4 is increased AUC cialis (20 mg dose) on 312% and C_max on 22% compared with the reception only of tadalafil in the same dose. Ketoconazole (200 mg daily) increased tadalafil AUC (10 mg dose) on 107% and C_max on 15% compared with the reception only of tadalafil in the same dose.

HIV protease inhibitor — ritonavir (200 mg twice a day), is an inhibitor of CYP3A4, CYP2C9, CYP2C19 and CYP2D6, increased tadalafil AUC (20 mg dose) on 124% without affecting the C_max. Although specific interactions have not been studied, We can assume, that other HIV protease inhibitors may increase the activity of tadalafil (cm. "Dosage and administration").

Based on these results, patients, taking tadalafil together with strong inhibitors of CYP3A4, Do not exceed the dose of tadalafil 10 mg and take tadalafil more often, than 1 times during 72 no.

Other inhibitors of cytochrome P450. Although specific interactions have not been studied, It assumed, Inhibitors of CYP3A4, such as erythromycin, itraconazole, Grapefruit juice can increase tadalafil exposure.

Rifampicin (600 mg daily), being an inducer of CYP3A4, reduced tadalafil AUC (10 mg dose) on 88% and C_max on 46% compared with the reception only of tadalafil in the same dose. Although specific interactions have not been studied, It assumed, that other inducers of CYP3A4, such as carbamazepine, phenytoin, phenobarbital may decrease tadalafil exposure. No dosage adjustment is required.

N₂-antihistamines. Increasing the pH in the stomach while taking nizatidine had no significant effect on the pharmacokinetics of tadalafil.

Antacids. The simultaneous use of antacid (magnesium hydroxide / aluminum hydroxide) and tadalafil reduce the rate of absorption of tadalafil without altering the AUC.

Not expected, that tadalafil will cause clinically significant inhibition or induction of the clearance PM, metabolized by the cytochrome P450 isoforms different. Studies have shown, that tadalafil does not inhibit or induce cytochrome P450 isoforms: CYP1A2, CYP3A4, CYP2С9, CYP2C19, CYP2D6 and CYP2E1.

CYP1A2 substrate. Tadalafil has no clinically meaningful effect on the pharmacokinetics of theophylline. When patients receiving tadalafil, receiving theophylline, there was a small increase (3 u. / min) increase in heart rate, caused by theophylline.

Substrate CYP3A4. Tadalafil has no clinically significant effect on the AUC of midazolam and lovastatin.

Substrate CYP2C9. Tadalafil clinically significant does not affect the AUC S-warfarin / R-warfarin, It did not affect the action of warfarin on PT.

Alcohol and PDE5 inhibitors, including as tadalafil, are weak systemic vasodilators, when combined hypotensive effect of each compound may increase. Significant alcohol in combination with tadalafil may increase the likelihood of orthostatic signs and symptoms, including increased heart rate, decrease in blood pressure, dizziness and headache.

PDE5 inhibitors, including as tadalafil, are weak systemic vasodilators.

Doksazozin. When you receive healthy volunteers 20 mg of tadalafil with alpha₁-adrenoblokatorom doxazosin (8 mg daily) revealed a significant increase gipotenzivnogo effect doksazosine.

Tamsulozin. In clinical pharmacology issledovaniiu healthy volunteers in single dose 20 mg of tadalafil and daily intake 0,4 mg tamsulosin is a selective alpha_1A-adrenoblocker is not detected significant decrease AD. Based on the significant increase of the hypotensive effect of doxazosin (alpha₁-adrenoblokator) and no significant effect when taken daily 0,4 mg tamsulosin (alpha_1A-adrenoblokator), the use of tadalafil in patients, receiving any alpha-blocker (with the exception of 0,4 mg tamsulosin 1 once a day), contraindicated (cm. "Contra").

Amlodipine. A study was conducted to assess the interaction of amlodipine (5 mg daily) and 10 mg tadalafil. Tadalafil has no effect on blood levels of amlodipine, the effect of amlodipine on the plasma levels of tadalafil are not mentioned. The mean decrease in SBP / DBP in the "lying" after receiving 10 mg of tadalafil by patients, prinimayushtimi amlodipine, made 3/2 mm Hg. Article. vs placebo. In a similar study using a dose of tadalafil 20 mg clinically significant effect not observed.

Metoprolol. Study to evaluate the interaction of metoprolol sustained release (from 25 to 200 mg daily) and 10 mg tadalafil showed, that the average decline in SBP / DBP in the "lying" after receiving 10 mg of tadalafil by patients, receiving metoprolol, made 5/3 mm Hg. Article. vs placebo.

Bendrofluazid. A study was conducted to assess the interaction bendrofluazida (2,5 mg daily) and 10 mg tadalafil. The mean decrease in SBP / DBP in the "lying" after receiving 10 mg of tadalafil by patients, host bendrofluazid, made 6/4 mm Hg. Article. vs placebo.

Enalapril. Investigation of the interaction of enalapril (from 10 to 20 mg daily) and 10 mg tadalafil showed, that the average decline in SBP / DBP in the "lying" after receiving 10 mg of tadalafil by patients, receiving enalapril, made 4/1 mm Hg. Article. vs placebo.

Angiotensin II receptor blockers (and other anti-hypertensive drugs). A study was conducted to assess the interaction of angiotensin II receptor blockers and 20 mg tadalafil. In this study, patients were treated with a preparation from the group of angiotensin II receptor antagonists in the form of monocomponent or combined PM, in either complex antihypertensive therapy. Ambulatory BP measurement revealed a difference in SBP / DBP, is 8/4 mm Hg. Art., between tadalafil and placebo.

Acetylsalicylic acid. Tadalafil did not potentiate the increase in bleeding time, caused by acetylsalicylic acid.

Overdose.

Symptoms: When you assign a healthy volunteers single doses up to 500 MG patients with erectile dysfunction multiple doses up to 1000 mg undesirable effects were the same, as the lower dose.

Treatment: standard supportive therapy. Hemodialysis is making a minor contribution to the elimination of tadalafil.

Inside, regardless of the meal, the initial dose - 20 mg. Patients may carry an attempt sexual intercourse during 36 h after administration to determine the optimum response time to the drug. Maximum recommended frequency reception is 1 once a day.

In older men (65 and older) No dosage adjustment is required.

Renal failure. Patients with impaired renal function minor changes dosing regime is not required.

In moderate renal insufficiency (CL creatinine 31-50 mL/min) the initial recommended dose is no more 5 mg per day, the maximum dose is not more than 10 mg every 48 no. In severe renal failure in patients on hemodialysis, the maximum recommended dose is no more 5 mg per day (cm. "Pharmacology", Reduced renal function).

Abnormal liver function. When liver failure mild and moderate degree maximum dose is 10 mg 1 once a day. In severe hepatic impairment is not recommended to use the drug, since there are no data from controlled clinical trials on the safety of (cm. "Pharmacology", Reduced liver function).

Soputstvuyushtaya therapy: patients, receiving strong CYP3A4 inhibitors (as ketoconazole, ritonavir and the like.) the maximum recommended dose is 10 mg not more, than 1 once every 72 no (cm. "Pharmacology", Pharmacokinetics).

Concomitant treatment with nitrates or any alpha-blockers (Besides 0,4 mg tamsulosin 1 once a day) contraindicated (cm. "Contra", "Interaction").

Before taking to diagnose erectile dysfunction, determining its possible causes and the selection of adequate treatment is necessary to collect and evaluate medical history of the patient.

It will be appreciated, that the sexual activity is a potential risk for patients with cardiovascular diseases. Therefore, treatment of erectile dysfunction, incl. using tadalafil, should not be performed in men with cardiovascular disease, in which sexual activity is not recommended.

It is necessary to take into account, that obstruction of left ventricular (for example aortalnыy stenosis and idiopathic hypertrophic stenosis subaortalnыy) patients may respond to the action of vasodilators, including PDE5 inhibitors.

Some groups of patients with cardiovascular disease were not included in the clinical trial the efficacy and safety of Cialis and therefore its use in these patients is not recommended until further information (cm. "Restrictions on the use").

There are rare reports of the occurrence of an erection, continuing more 4 no, and priapism (painful erection, lasting more 6 no) when using this class of compounds. Delays in treatment of priapism can lead to permanent damage to the tissues of the penis. When, If an erection lasts more than 4 no, the patient should seek medical advice immediately.

Before the appointment of Cialis is necessary to pay attention to the following:

Renal failure (cm. "Dosage and administration"). Against the background of tadalafil in patients with renal insufficiency moderately (CL creatinine 31-50 mL/min) more common back pain compared to patients with mild renal insufficiency (Creatinine CL 51-80 mL/min) or with healthy volunteers.

The clinical and pharmacological studies (N=28) at a dose of tadalafil 10 mg in patients with renal insufficiency moderately (CL creatinine 31-50 mL/min) more common back pain compared to patients with mild renal insufficiency (Creatinine CL 51-80 mL/min) or with healthy volunteers. At a dose of 5 mg frequency and severity of back pain were not significantly different from those in the general population. Patients on hemodialysis, receiving 10 or 20 mg tadalafil, cases of back pain has not been reported.

Abnormal liver function and soputstvuyushtaya therapy potent inhibitors of CYP3A4 of cytochrome P450 (cm. "Dosage and administration").

As with other PDE5 inhibitors, Tadalafil has vasodilator properties of weak system, which can lead to short-term reduction in blood pressure (cm. "Pharmacology", The effect on blood pressure).

The safety and efficacy of tadalafil when taken with other drugs to treat erectile dysfunction, I have not been studied, simultaneously is not recommended.

Tadalafil has not been used in patients with an increased tendency to bleeding or active peptic ulcer. Although tadalafil does not increase bleeding time in healthy volunteers, when used in patients with an increased tendency to bleeding, or active peptic ulcer is necessary to evaluate the risk / benefit ratio.

Use in elderly patients. In clinical studies, tadalafil about 25% the men were over the age of 65 years. In general, there was no difference in efficacy and safety between older and younger patients. However, some older men observed great sensitivity to drugs (cm. "Pharmacology", Advanced age).