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Cialis instructions for use

Cialis indications for use

Erection disorders .

Clinical pharmacology

Tadalafil is a reversible selective inhibitor of specific PDE-5 cGMP. When sexual arousal causes local release of nitric oxide, inhibition of PDE-5 by 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. Tadalafil has no effect in the absence of sexual arousal.

In vitro studiesshowed that tadalafil is a selective PDE-5 inhibitor. PDE-5 is an enzyme found in cavernous body smooth muscle, visceral vascular smooth muscle, skeletal muscle, platelets, kidney, lung, and cerebellum. The action of tadalafil on PDE-5 is more active than on other PDEs. Tadalafil is 10,000 times more potent against PDE-5 than against PDE-1, PDE-2, PDE-4 and PDE-7, which are localized in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle and in other organs. Tadalafil is 10,000 times more active at 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 cardiac muscle contraction. Besides, tadalafil is about 700 times more active against PDE-5 than against PDE-6, found in the retina and responsible for phototransmission. Tadalafil is also 9000 times more potent against PDE-5 than its effect on PDE-8, PDE-9 and PDE-10 and 14 times more potent against PDE-5 than PDE-11. Distribution in tissues and physiological effects of inhibition of PDE-8 – PDE-11 have not yet been elucidated.

Tadalafil improves erection and increases the possibility of a full-fledged sexual intercourse.

Tadalafil in healthy subjects does not cause a significant change in SBP and diastolic blood pressure compared with placebo in the supine position (the average maximum decrease is 1.6 / 0.8 mm Hg, respectively) and in the standing position (the average maximum decrease is 0.2 / 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 the low affinity for PDE-6. In addition, there is no effect of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size.

Several studies have been conducted to evaluate the effect of daily tadalafil intake on spermatogenesis. No adverse effects on sperm morphology and motility were observed in any of the studies. One study found a decrease in mean sperm count compared to placebo. A decrease in sperm concentration was associated with a higher frequency of ejaculation. In addition, there was no undesirable effect on the average concentration of sex hormones, testosterone, LH and FSH when taking tadalafil compared with placebo.

The efficacy and safety of Cialis (at doses of 2.5 mg and 5 mg) was studied in clinical trials. There was an improvement in erection in patients with erectile dysfunction of all degrees of severity when taking tadalafil 1 time per day. In primary efficacy studies with tadalafil 5 mg, 62% and 69% of intercourse attempts were successful compared with 34% and 39% of placebo patients. Taking tadalafil at a dose of 5 mg significantly improved erectile function within 24 hours between doses.

The mechanism of action of tadalafil in patients with BPH – inhibition of PDE-5 by tadalafil, leading to an increase in the concentration of cGMP in the cavernous body of the penis, is also observed in the smooth muscles of the prostate, bladder and vessels that supply them with blood. Relaxation of vascular smooth muscles leads to an increase in blood perfusion in these organs and, as a result, to a decrease in the severity of BPH symptoms. Relaxation of the smooth muscles of the prostate and bladder may further enhance vascular effects.

Pharmacokinetics

Suction. After oral administration, tadalafil is rapidly absorbed. The average Cmax in plasma is achieved on average 2 hours after ingestion. The rate and degree of absorption of tadalafil do not depend on food intake, so Cialis can be used regardless of food intake. The time of administration (morning or evening) did not have a clinically significant effect on the rate and extent of absorption.

The pharmacokinetics of tadalafil in healthy individuals is linear with respect to time and dose. In the dose range from 2.5 to 20 mg, AUC increases in proportion to the dose.

The pharmacokinetics of tadalafil in patients with erectile dysfunction is similar to the pharmacokinetics of the drug in individuals without erectile dysfunction.

Distribution. ss in plasma are achieved within 5 days when taking the drug 1 time per day.

The average V d is about 63 liters, which indicates that tadalafil is distributed in body tissues.

At therapeutic concentrations, 94% of tadalafil in plasma is protein bound.

In healthy individuals, less than 0.0005% of the administered dose was found in semen.

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

Withdrawal. In healthy individuals, the average clearance of tadalafil when taken orally is 2.5 l / h, and the average half  -life is 17.5 hours. Tadalafil is excreted mainly in the form of inactive metabolites, mainly with feces (about 61% of the dose) and to a lesser extent degree with urine (about 36% of the dose).

Special populations

Elderly patients. Healthy elderly patients (65 years and over) had a lower oral clearance of tadalafil, which was expressed in a 25% increase in AUC compared with healthy individuals aged 19 to 45 years. This difference is not clinically significant and does not require dose adjustment.

Patients with renal insufficiency. In persons with mild to moderate renal insufficiency, dose adjustment is not required. Due to the increased exposure of tadalafil (AUC), Cialis is not recommended for patients with severe renal insufficiency.

Patients with liver failure. The pharmacokinetics of tadalafil in individuals with mild to moderate hepatic insufficiency is comparable to that in healthy individuals. No data are available for patients with severe hepatic impairment (Child-Pugh class C). When prescribing Cialis to patients with severe hepatic insufficiency, it is necessary to first assess the risks and benefits of using the drug.

Patients with diabetes. In diabetic patients treated with tadalafil, the AUC was approximately 19% lower than in healthy individuals. This difference does not require dose adjustment.

Release form and composition

1 film-coated tablet contains:
active ingredient : tadalafil 5 and 20 mg;
excipients: lactose monohydrate; lactose monohydrate (spray dried); hyprolosis; hyprolosis (extra thin); sodium lauryl sulfate; microcrystalline cellulose”; MCC; croscarmellose sodium; magnesium stearate (vegetable);
film barrel: Opadry yellow (Y-30-12863-A) (lactose monohydrate, hypromellose, titanium dioxide, triacetin, iron oxide yellow dye);
in a package of 1, 2, 4, 8, 14 and 28 tablets.

Special Instructions

Sexual activity poses a certain risk in the presence of heart disease, so it is strongly recommended to consult a doctor before using Cialis.

Interaction

Effect of other drugs on tadalafil

Tadalafil is mainly metabolized with the participation of the CYP3A4 isoenzyme. The selective inhibitor of the CYP3A4 isoenzyme ketoconazole (400 mg / day) increases the AUC of tadalafil in a single dose by 312% and C max by 22%, and ketoconazole (200 mg / day) increases the AUC of tadalafil in a single dose by 107% and C max by 15% relative to AUC and C max values ​​for only one tadalafil. Ritonavir (200 mg 2 times a day), an inhibitor of CYP3A4, 2C9, 2C19 and 2D6 isoenzymes, increases the AUC of tadalafil in a single dose by 124% without changing C max. Although specific interactions have not been studied, it can be assumed that other inhibitors of HIV protease, such as saquinavir, as well as inhibitors of the CYP3A4 isoenzyme, such as erythromycin and itraconazole, increase the activity of tadalafil.

The selective inducer of the CYP3A4 isoenzyme, rifampicin (600 mg / day), reduces the exposure of a single dose of tadalafil (AUC) by 88% and Cmax by 46% relative to AUC and Cmax values ​​for tadalafil alone. It can be assumed that the simultaneous use of other inducers of the CYP3A4 isoenzyme should also reduce plasma concentrations of tadalafil.

The simultaneous use of an antacid (magnesium hydroxide / aluminum hydroxide) and tadalafil reduces the rate of absorption of tadalafil without changing the area under the pharmacokinetic curve for tadalafil. An increase in gastric pH as a result of taking the H 2 -histamine receptor blocker nizatidine did not affect the pharmacokinetics of tadalafil.

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.

Tadalafil does not potentiate the increase in bleeding time caused by taking acetylsalicylic acid.

The effect of tadalafil on other drugs

It is known that tadalafil enhances the hypotensive effect of nitrates. This occurs as a result of the additive action of nitrates and tadalafil on nitric oxide (NO) and cGMP metabolism. Therefore, the use of tadalafil while taking nitrates is contraindicated.

Tadalafil does not have a clinically significant effect on the clearance of drugs, the metabolism of which proceeds with the participation of cytochrome P450. Studies have confirmed that tadalafil does not inhibit or induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, CYP2E1 isoenzymes.

Tadalafil does not have a clinically significant effect on the pharmacokinetics of S-warfarin or R-warfarin. Tadalafil does not affect the effect of warfarin on PV.

Tadalafil does not increase the duration of bleeding caused by acetylsalicylic acid.

Tadalafil has systemic vasodilating properties and may enhance the action of antihypertensive drugs aimed at lowering blood pressure.

Additionally, in patients taking multiple antihypertensive agents, in whom arterial hypertension was poorly controlled, a slightly greater decrease in blood pressure was observed. In the vast majority of patients, this decrease was not associated with hypotensive symptoms. Patients receiving treatment with antihypertensive drugs and taking tadalafil should be given appropriate clinical recommendations.

There was no significant decrease in blood pressure when using tadalafil in healthy individuals who took the selective alpha 1A -blocker tamsulosin in two clinical studies.

The simultaneous use of tadalafil with doxazosin is contraindicated. When using tadalafil to healthy volunteers who took doxazosin (4–8 mg / day), an alpha 1 -blocker, an increase in the hypotensive effect of doxazosin was observed. Some patients have experienced symptoms associated with a decrease in blood pressure, including syncope.

Tadalafil did not affect the concentration of alcohol, nor did 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 mean blood pressure. Some patients experienced postural dizziness 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 at the same frequency as when taking alcohol alone.

Tadalafil does not have a clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline.

Overdose

With a single appointment of tadalafil in healthy individuals at a dose of up to 500 mg and in patients with ED – repeatedly up to 100 mg / day, undesirable effects were the same as when using lower doses.

Treatment: in case of overdose, standard symptomatic treatment should be carried out. With hemodialysis, tadalafil is practically not excreted.

How to take, course of administration and dosage

The use of the drug Cialis according to the indication of ED. For patients with frequent sexual activity (more than 2 times a week): the recommended frequency of administration is daily, 1 time per day, 5 mg, at the same time, regardless of food intake. The daily dose may be reduced to 2.5 mg depending on individual sensitivity.

For patients with infrequent sexual activity (less than 2 times a week): it is recommended to prescribe Cialis at a dose of 20 mg, immediately before sexual activity, according to the instructions for the medical use of the drug. The maximum daily dose of Cialis is 20 mg.

Use of Cialis for BPH or ED/BPH. The recommended dose of Cialis when used once a day is 5 mg; the drug should be taken at approximately the same time of day, regardless of the time of sexual activity. The duration of treatment is determined by the doctor individually. In patients with mild renal insufficiency (Cl creatinine from 51 to 80 ml / min) and moderate severity (Cl creatinine from 31 to 50 ml / min), dose adjustment is not required.

In patients with severe renal insufficiency (Cl creatinine <30 ml / min and hemodialysis): the use of Cialis once a day is not recommended.

Contraindications

  • hypersensitivity to tadalafil or any substance that is part of the drug Cialis;
  • taking drugs containing any organic nitrates;
  • use in persons under 18 years of age;
  • the presence of contraindications to sexual activity in patients with CVD diseases (myocardial infarction within the last 90 days, unstable angina pectoris, the occurrence of an angina attack during intercourse, chronic heart failure II–IV classes according to the NYHA classification, uncontrolled arrhythmias, arterial hypotension (BP 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 administration of doxazosin, as well as drugs for the treatment of erectile dysfunction;
  • frequent (more than 2 times a week) use in patients with chronic renal failure (Cl creatinine <30 ml / min);
  • lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution: since there are no data on patients with severe hepatic insufficiency (Child-Pugh class C), caution should be exercised when prescribing Cialis to this group of patients.

Caution must be exercised when prescribing the drug to Cialis patients taking alpha 1 – blockers, since simultaneous use can lead to symptomatic arterial hypotension in some patients. In a clinical pharmacology study in 18 healthy volunteers taking a single dose of tadalafil, symptomatic arterial hypotension was not observed with the simultaneous administration of tamsulosin alfa 1A -blocker (see “Interaction”).

Diagnosis of erectile dysfunction should include identification of a potential underlying cause, appropriate medical evaluation, and determination of treatment tactics.

Cialis should be used with caution in patients with a predisposition to priapism (with sickle cell anemia, multiple myeloma or leukemia) or with an anatomical deformity of the penis (angular curvature, cavernous fibrosis or Peyronie’s disease). Caution should also be exercised when taken simultaneously with potent inhibitors of the CYP3A4 isoenzyme (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), antihypertensive drugs.

special instructions

Sexual activity has a potential risk for patients with cardiovascular disease. Therefore, the treatment of ED, incl. Cialis should not be used in men with heart conditions for which sexual activity is not recommended.

There are reports of the occurrence of priapism with 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 safety and efficacy of the combination of Cialis with other PDE5 inhibitors and ED treatments have not been studied. Therefore, the use of such combinations is not recommended.

Like other PDE-5 inhibitors, tadalafil has systemic vasodilating properties, which can lead to a transient decrease in blood pressure. Before prescribing Cialis, physicians should carefully consider whether patients with cardiovascular disease will be adversely affected by such vasodilating effects.

NAPION causes visual impairment, including complete loss of vision. There are rare post-marketing reports of cases of NAPION development, temporally associated with the use of PDE-5 inhibitors. It is currently impossible to determine whether there is a direct relationship between the development of NAPION and the use of PDE-5 inhibitors or other factors. Physicians should advise patients in the event of sudden loss of vision to stop taking tadalafil and seek medical attention. Physicians should also tell patients that people who have had NAPION are at increased risk of developing NAPION again.

Patients with a suspected diagnosis of BPH should be screened to rule out prostate cancer.

The efficacy of Cialis in patients undergoing pelvic surgery or radical neurosparing prostatectomy is unknown.

Influence on the ability to drive a car and perform work that requires an increased speed of psychomotor reactions. Despite the fact that the incidence of dizziness against the background of placebo and tadalafil is the same, during the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

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