Cialis (Tadalafil)

Brand name of drug: Cialis.
Generic name: Tadalafil
Chemical name: pirazinol [1 ', 2', '1, 6] pyrido [3.4-b] indole-1 ,4-dione, 6 - (1,3-benzodioksol-5-yl) -2,3,6, 7,1-2,12 a-hexahydro-2-methyl-, (6R, 12aR) -
Pharmaceutical form: Tablets, film-coated.
Composition
Active ingredient: Tadalafil. Each tablet Cialis contains 20 mg of tadalafil.
Excipients: lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, magnesium stearate, a mixture of yellow dye Opadri II.
Description: Yellow tablet, film-coated. The tablets are almond-shaped and have one side the inscription "With 20".
Pharmacotherapeutic group: a treatment for erectile dysfunction, PDE5 inhibitor.
Code ATX [G04BE08].

Pharmacological properties

Pharmacodynamics

Tadalafil is an effective reversible selective inhibitor of specific phosphodiesterase type 5 (PDE5), cyclic guanosine monophosphate (cGMP). When sexual stimulation causes local release of nitric oxide, inhibition of PDE5 tadalafil leads to increased levels of cGMP in the cavernous body of penis. The consequence of this is the relaxation of smooth muscles of arteries and blood flow to the tissues of the penis, causing erection. Tadalafil has no effect in the absence of sexual stimulation.

In vitro studies have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in smooth muscles of cavernous bodies in vascular smooth muscle of the internal organs, skeletal muscle, platelets, kidney, lung, and cerebellum. The action of tadalafil on PDE5 is more active than other phosphodiesterase. Tadalafil is 10 000 times more potent for PDE5 than for FDE1, FDE2, FDE4 and FDE7, which are located in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle and other organs. Tadalafil 10 000 times more active blocks PDE5 than FDE3 - an enzyme that is found in the heart and blood vessels. This selectivity for PDE5 compared to FDE3 is important because FDE3 is an enzyme participating in the reduction of the heart muscle. In addition, tadalafil, approximately 700 times more potent for PDE5 than for FDE6 found in the retina and is responsible for fotoperedachu. Tadalafil is also showing the action in 9000 times more potent for PDE5 compared with its effect on FDE8, 9 and 10 and 14 times more potent for PDE5 compared to FDE11. Tissue distribution and physiological effects of inhibiting FDE8 - FDE11 so far not been clarified. Tadalafil improves erection and the possibility of successful sexual intercourse. The drug acts within 36 hours. The effect is already apparent 16 minutes after taking the drug in the presence of sexual arousal.

Tadalafil in healthy individuals does not cause significant changes in systolic and diastolic blood pressure compared with placebo in the prone position (mean maximum decrease of 1,6 / 0,8 mm Hg. Art., Respectively) and standing (mean maximum decrease of 0, 2 / 4, 6 mm Hg. Art., respectively). Tadalafil does not cause significant changes in heart rate. Tadalafil does not cause changes in the recognition of colors (blue / green), due to its low affinity to FDE6. In addition, no observed effect of tadalafil on visual acuity, electroretinogram, the intraocular pressure and pupil size.

Tadalafil does not cause changes in testosterone, luteinizing hormone and follicle-stimulating hormone in blood plasma.

There were no clinically significant effect on the characteristics of sperm in men who took daily doses of tadalafil for 6 months in placebo-controlled studies.

Pharmacokinetics

Suction

After oral administration, tadalafil is rapidly absorbed. The average maximum concentration (Cmax) in plasma is reached after an average of 2 hours after ingestion.

The speed and extent of absorption of tadalafil is not dependent on food intake, and the drug Cialis may be taken without regard to meals. Hours (morning or evening) had no clinically significant effect on the rate and extent of absorption.

Tadalafil pharmacokinetics in healthy subjects is linear with respect to time and dose. In the dose range from 2.5 to 20 mg of the area under the curve "concentration-time» (AUC) increased proportionally to dose. Equilibrium plasma concentrations are reached within 5 days while taking the drug one time and day.

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

Distribution

The average volume of distribution is about 63 liters, indicating that tadalafil is distributed in body tissues. At therapeutic concentrations, 94% of tadalafil in plasma is associated with proteins. Protein binding does not change with impaired renal function.

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

Metabolism

Tadalafil is mainly metabolized by CYP3A4 isoenzyme, with the participation of cytochrome P450. Main circulating metabolite is metilkateholglyukuronid. This metabolite, at least 13 000 times less active against PDE5 than tadalafil. Consequently, the concentration of this metabolite is not clinically significant.

Breeding

In healthy individuals the average clearance of tadalafil ingestion of 2,5 l / h, and the average half-life - 17.5 hours. Tadalafil is excreted mainly as inactive metabolites mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (about 36% of the dose).

Special Populations

Elderly patients

Healthy elderly (65 years and over) had a lower clearance of tadalafil when taken orally, which was reflected in the increase in the area under the curve "concentration-time" by 25% compared with healthy people aged 19 to 45 years. This difference is not clinically significant and does not require dose adjustment.

Patients with renal insufficiency

In patients with renal insufficiency, including patients on hemodialysis, the area under the curve "concentration-time was greater than in healthy individuals.

Patients with liver failure

Pharmacokinetics of tadalafil in patients with mild to moderate to severe hepatic impairment is comparable with that in healthy individuals. With regard to patients with severe hepatic impairment (classified Child-Pugh class C) is not available.

Patients with diabetes

Patients with diabetes mellitus during treatment with tadalafil area under the curve "concentration-time was less than about 19% higher than in healthy individuals. This difference does not require dose adjustment.

Indications for Use

Erectile dysfunction.

Contraindications

Installed hypersensitivity to tadalafil or any substance that is part of the drug;

In the case of the drugs containing any organic nitrates;
Application of persons under 18 years of age.
Precautions

Since there is no data in patients with severe hepatic insufficiency (classified Child-Pugh Class C), caution must be exercised in the appointment of Cialis to this group of patients.

Caution must be exercised in the appointment of Cialis to patients taking alpha [1]-blockers such as doxazosin, as the simultaneous use can lead to symptomatic hypotension in some patients. In a study of clinical pharmacology in 18 healthy volunteers who received a single dose of tadalafil, there was no symptomatic hypotension while the introduction of tamsulosin, an alpha [1A]-blocker (see "Interaction with other drugs).

Dosing and Administration

For ingestion.

The recommended maximum dose of Cialis is 20 mg. Cialis is taken before anticipated sexual activity, regardless of the meal. The drug should be taken at least 16 minutes prior to anticipated sexual activity.

Patients may attempt to carry out sexual intercourse at any time within 36 hours after taking the drug in order to establish the optimal response time for the drug.

The maximum recommended frequency of administration - one time per day.

Side effects

The most frequently reported adverse events were headache and dyspepsia (11 and 7%, respectively). Adverse events associated with taking tadalafil were generally mild or moderate in severity, transient and diminished with continued use of the drug.

Other common adverse effects include back pain, myalgia, nasal congestion and "tides" of blood to the face.

Rarely - edema of the eyelids, eye pain, conjunctival hyperemia, and dizziness.

Very rarely - hypersensitivity reactions (including rash, urticaria and facial edema, Stevens-Johnson syndrome and exfoliative dermatitis); hypotension (in patients who have already taken antihypertensive drugs); hypertension and syncope, abdominal pain and gastroesophageal reflux, hyperhidrosis (excessive sweating), and the delay in erection priapism, blurry vision, no arterial anterior ischemic optic neuropathy, retinal vein occlusion; violation of the visual fields.

Myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations and tachycardia were observed in patients who previously had cardiovascular risk factors. However, it is impossible to pinpoint whether these phenomena directly with these risk factors with tadalafil, sexual excitement, or a combination of these or other factors.

Overdose

With a single appointment healthy individuals tadalafil at a dose of 500 mg and patients with erectile dysfunction (many times up to 100 mg / day), adverse effects were the same as when using lower doses. In case of overdose should be carried out standard symptomatic treatment. When dialysis nearly tadalafil is not displayed.

Interaction with other drugs

The influence of other drugs on tadalafil

Tadalafil is mainly metabolized with participation of the enzyme CYP3A4. Selective inhibitor of CYP3A4, ketoconazole (400 mg / day) increases the impact of a single dose of tadalafil (AUC) at 312% and Cmax by 22% and ketokonazop (200 mg / day) increases the impact of a single dose of tadalafil (AUC) by 107% and Cmax by 15% with respect to AUC and Cmax values ??for only one of tadalafil.

Ritonavir (200 mg twice daily), an inhibitor of CYP3A4, 2C9, 2S1E and 2D6, increases the impact of a single dose of tadalafil (AUC) by 24% without changing the C max. Despite the fact that the specific interactions were not investigated, suggests that other HIV protease inhibitors such as saquinavir, as well as SURZA4 inhibitors such as erythromycin and intrakonazol, increases the activity of tadalafil.

Selective inducer of CYP3A4, rifampin (rifampicin, 600 mg / day), reduces the impact of a single dose of tadalafil (AUC) by 88% and Cmax by 46% with respect to AUC and Cmax values ??for only one of tadalafil. We can assume that the simultaneous administration of other inducers of CYP3A4 should also reduce the concentration of tadalafil in plasma.

Simultaneous treatment with an antacid (magnesium hydroxide / aluminum hydroxide) and tadalafil reduced the rate of absorption of tadalafil without altering the area under the pharmacokinetic curve for tadalafil.

Increasing the pH of the stomach as a result of receiving H2-antagonist nizatidina, had no effect on the pharmacokinetics of tadalafil.

Effect of tadalafil on other drugs

It is known that tadalafil enhances the hypotensive effect of nitrates. This is due to the additive effect of nitrates and tadalafil on the metabolism of nitric oxide and cGMP. Therefore, use of tadalafil on the background of the use of nitrates is contraindicated.

Tadalafil has no clinically significant effect on clearance of drug metabolism of which proceeds with the participation of isoenzyme of cytochrome P450. Studies have confirmed that tadalafil does not inhibit or induce isozymes CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, CYP2E1.

Tadalafil has no clinically significant effect on the pharmacokinetics of 5-warfarin or R-warfarin. Tadalafil does not affect the action of warfarin on prothrombin time.

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

Tadalafil has a systemic vasodilating properties and may exacerbate the effects of antihypertensive drugs to lower blood pressure. Additionally, patients taking multiple antihypertensive agents that have hypertension, poorly controlled, we observed a somewhat larger reduction in blood pressure. The vast majority of these patients reduction was not associated with hypotensive symptoms. Patients treated with antihypertensive drugs and receiving tadalafil, should be given appropriate clinical advice.

There were no significant reduction in blood pressure when using tadalafil makers selective alpha [1A]-blocker, tamsulosin.

In the application of tadalafil in healthy volunteers who took doxazosin (8 mg / day), alpha [1]-blocker, were increased hypotensive action of doxazosin. Some patients experienced dizziness. Cases of syncope were not observed. Lower doses of doxazosin were not studying. Tadalafil does not affect the concentration of alcohol, as well as alcohol does not affect the concentration of tadalafil. At high doses of alcohol (0.7 g / kg), receiving Tadalafil does not cause a statistically significant reduction in average blood pressure. Some patients experienced postural dizziness and orthostatic hypotension. The introduction of tadalafil in combination with lower doses of alcohol (0.6 g / kg), hypotension was not observed, and dizziness occurred at the same frequency as in the admission of only one alcohol.

Tadalafil has no clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline.

Cautions

Sexual activity is a potential risk for patients with cardiovascular disease. Therefore, treatment of erectile dysfunction, including those using Cialis, you should not hold for men with heart disease, for whom sexual activity is not recommended. Should take into account the potential risk of complications in sexual activity in patients with cardiovascular disease:

myocardial infarction within the last 90 days

unstable angina or angina occurring during sexual intercourse
heart failure class 2 and higher NYHA, evolved during the last 6 months
uncontrolled cardiac arrhythmias, hypotension (with BP <90/50 mmHg. cent.) or uncontrolled hypertension
stroke, moved in the past 6 months.
Cialis should be used with caution in patients predisposed to priapism (eg sickle cell anemia, multiple myeloma, leukemia FPI) or patients with anatomical deformation of the penis (such as angulations, cavernous fibrosis or Peyronie's disease). There are reports of occurrence of priapism using PDE5 inhibitors, including tadalafil. Patients should be informed of the need for immediate treatment for medical assistance in the event of an erection lasts for 4 hours or more. Delayed treatment leads to priapism penile tissue damage, resulting in a loss may occur long-term potency.

Safety and efficacy of a combination of Cialis with other treatments erectile dysfunction was not investigated. Therefore, the use of such combinations is not recommended.

As with other PDE5 inhibitors, tadalafil has a systemic vasodilating properties, which can lead to transient reduction in blood pressure. Prior to the appointment of Cialis, physicians should carefully consider the question - not whether the patients with their existing cardiovascular disease undergo undesirable effects due to these vasodilator effects.

Impact on the ability of driving and using machinery

No special requirements.

Use during pregnancy and lactation

Cialis is not intended for use in women.

Form release

Tablets, film-coated 20 mg and 1, 2, 4 or 8 tablets per pack.

Storage conditions

Store at temperatures below 30 ° C in the original packaging.
Keep out of reach of children.

Expiration date

3 years. Do not use later than the date on the package.

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