Pharmacodynamics
Cialis is a reversible selective inhibitor of specific phosphodiesterase type 5 (PDE5) of cyclic guanosine monophosphate (cGMP). When sexual arousal causes local release of nitric oxide, inhibition of PDE5 by Cialis leads to an increase in the concentration of cGMP in the cavernous body of the penis. The consequence is relaxation of the smooth muscles of the arteries and blood flow to the tissues of the penis, which causes an erection. Cialis has no effect in the absence of sexual arousal.In vitro studies have shown that Cialis is a selective PDE5 inhibitor. PDE5 is an enzyme found in the smooth muscles of the corpus cavernosum, in the smooth muscles of the vessels of the internal organs, in skeletal muscles, platelets, kidneys, lungs and cerebellum. The effect of Cialis on PDE5 is more active than on other phosphodiesterases.Cialis is 10,000 times more potent for PDE5 than for PDE1, PDE2, PDE4 and PDE7, which are localized in the heart, brain, blood vessels, liver, leukocytes, skeletal muscles and other organs. Cialis is 10,000 times more active in blocking PDE5 than PDE3, an enzyme found in the heart and blood vessels.This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac muscle contraction. In addition, Cialis is about 700 times more active against PDE5 than against PDE6, which is found in the retina and is responsible for phototransmission.Cialis also has an effect 9000 times more potent against PDE5 than its effect on PDE8, PDE9 and PDE10, and 14 times more potent against PDE5 than PDE11. Tissue distribution and physiological effects of PDE8-PDE11 inhibition have not yet been clarified.Cialis improves erection and increases the ability to have a full sexual intercourse.Cialis in healthy individuals does not cause significant changes in systolic and diastolic pressure in comparison 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). Cialis does not cause a significant change in heart rate.Cialis does not cause changes in color recognition (blue / green), which is explained by its low affinity for PDE6. In addition, there is no effect of Cialis on visual acuity, electroretinogram, intraocular pressure and pupil size. Several studies have been conducted to evaluate the effect of daily Cialis intake on spermatogenesis. None of the studies showed an undesirable effect on sperm morphology and motility. One study found a decrease in mean sperm concentration 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 mean concentration of sex hormones, testosterone, LH and FSH when taking Cialis compared with placebo.An improvement in erection was noted in patients with erectile dysfunction of all severity when taking Cialis 1 time / day.
Mechanism of action in patients with benign prostatic hyperplasia (BPH). Inhibition of PDE5 by Cialis, 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 gland, bladder and blood vessels that supply them. Relaxation of vascular smooth muscles leads to an increase in blood perfusion in these organs, and, as a consequence, to a decrease in the severity of BPH symptoms. Relaxation of smooth muscle of the prostate and bladder can further enhance vascular effects.
Pharmacokinetics
Suction
After oral administration, Cialis is rapidly absorbed. Average Cmax in plasma is achieved on average 2 hours after oral administration. The speed and degree of absorption of Cialis do not depend on food intake, therefore, Cialis can be used regardless of food intake. The time of intake (morning or evening) does not affect the rate and extent of absorption.
The pharmacokinetics of Cialis 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. Css in plasma is reached within 5 days when taking the drug 1 time / day.
The pharmacokinetics of Cialis in patients with erectile dysfunction is similar to the pharmacokinetics of the drug in patients without erectile dysfunction. Distribution. The average Vd is about 63 L, which indicates that Cialis is distributed in body tissues. At therapeutic concentrations, 94% of Cialis in plasma binds to proteins. Protein binding does not change with impaired renal function. In healthy volunteers, less than 0.0005% of the administered dose was found in semen.
Metabolism. Cialis is mainly metabolized with the participation of the isoenzyme CYP3A4 of cytochrome P450. The main circulating metabolite is methylcatechol glucuronide. This metabolite is at least 13,000 times less active against PDE5 than Cialis. Therefore, the concentration of this metabolite is not clinically relevant.Withdrawal.In healthy volunteers, the average clearance of Cialis when taken orally is 2.5 l / h, and the average T1 / 2 is 17.5 hours.Cialis is excreted mainly in the form of inactive metabolites, mainly through the intestines (about 61% of the dose) and, to a lesser extent, by the kidneys (about 36% of the dose).Pharmacokinetics in special patient groups. Healthy volunteers aged 65 years and older had a lower oral clearance of Cialis, which was expressed in an increase in AUC by 25% compared with healthy volunteers aged 19 to 45 years. This difference is not clinically significant and does not require dose adjustment.In patients with mild renal failure (CC from 51 to 80 ml / min) and moderate severity (CC from 31 to 50 ml / min), as well as in patients with end-stage renal failure on hemodialysis, exposure to Cialis (AUC) approximately doubled. In patients on hemodialysis, Cmax was 41% higher than in healthy volunteers. The elimination of Cialis by hemodialysis is negligible.The pharmacokinetics of Cialis in patients with mild to moderate hepatic impairment (class A and B according to the Child-Pugh classification) is comparable to that in healthy volunteers. Insufficient data are available for patients with severe hepatic impairment (Child-Pugh class C). When prescribing the drug Cialis to patients with severe hepatic impairment, it is necessary to first assess the risks and benefits of using the drug. In patients with diabetes mellitus while using Cialis, the AUC was approximately 19% less than in healthy volunteers. This difference does not require dose adjustment.
Contraindications
The use of preparations containing any organic nitrates;
The presence of contraindications to sexual activity in patients with diseases of the cardiovascular system: myocardial infarction within the last 90 days, unstable angina pectoris, the occurrence of an attack of angina pectoris during intercourse, chronic heart failure class II or higher according to the NYHA classification during the last 6 months, 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 use of PDE5 inhibitors);
Concomitant use with doxazosin, other PDE5 inhibitors, other treatment options for erectile dysfunction, with guanylate cyclase stimulants such as riociguat;
Chronic renal failure (CC less than 30 ml / min);
Age up to 18 years;
Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
Hypersensitivity to Cialis or to any substance that is part of the drug.
Carefully. Since there are insufficient data on patients with severe hepatic impairment (class C according to the Child-Pugh classification), caution should be exercised when prescribing Cialis-C3 to this group of patients.Care must be taken when prescribing Cialis to patients taking alpha1-blockers, since the simultaneous use of these drugs can lead to symptomatic arterial hypotension in some patients. When using a single dose of Cialis, there is no symptomatic arterial hypotension when used simultaneously with tamsulosin, a selective alpha1-blocker.The drug Cialis should be used with caution in patients with a predisposition to priapism (with sickle cell anemia, multiple myeloma or leukemia) or in patients with anatomical deformity of the penis (angular curvature, cavernous fibrosis or Peyronie's disease).You should also be careful while taking with CYP3A4 isoenzyme inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, clarithromycin, erythromycin, grapefruit juice), antihypertensive drugs, 5-alpha reductase inhibitors.
Pregnancy and lactation
Cialis is not intended for use in women.
Side effects
The most common adverse events in patients with erectile dysfunction and BPH are headache and dyspepsia, as well as back pain and myalgia.In accordance with the WHO classification, all reactions are distributed according to the organ system and the frequency of development: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rare (<1/10 000), the frequency is unknown (it is impossible to determine the frequency of occurrence of reactions from the available data).From the immune system: infrequently - hypersensitivity reactions; rarely - angioedema 2.
From the nervous system: often - headache; infrequently - dizziness; rarely - stroke1 (including acute cerebrovascular accident of hemorrhagic type), syncope, transient ischemic attacks1, migraine2, epileptic seizures2, transient amnesia.From the side of the organ of vision: infrequently - blurred vision, pain in the eyeball; rarely - visual field disturbance, eyelid swelling, conjunctival hyperemia, non-arterial anterior ischemic optic neuropathy2, retinal vascular occlusion2. From the side of the organ of hearing and labyrinthine disorders: infrequently - ringing in the ears; rarely - sudden hearing loss. From the heart1: infrequently - palpitations, tachycardia; rarely - myocardial infarction, ventricular arrhythmias2, unstable angina2.
From the side of the vessels: often - "hot flushes" of blood to the face; infrequently - a decrease in blood pressure, an increase in blood pressure. From the respiratory system: often - nasal congestion; infrequently - shortness of breath, nosebleeds.
From the digestive system: often - dyspepsia; infrequently - abdominal pain, gastroesophageal reflux, diarrhea in patients over 65 years of age, vomiting, nausea.On the part of the skin and subcutaneous tissues: infrequently - rash; rarely - urticaria, Stevens-Johnson syndrome2, exfoliative dermatitis2, hyperhidrosis. From the musculoskeletal system: often - back pain, myalgia, pain in the limbs. From the urinary system: infrequently - hematuria. From the genitals and mammary gland: infrequently - prolonged erection; rarely - priapism2, hematospermia, bleeding from the penis.Others: infrequently - chest pain1, peripheral edema, fatigue; rarely - facial edema2, sudden cardiac death1,2.
Interaction
Effect of other drugs on Cialis
Cialis is mainly metabolized with the participation of the CYP3A4 isoenzyme. Selective inhibitor of the isoenzyme CYP3A4 ketoconazole (400 mg / day) increases the exposure of a single dose of Cialis (AUC) by 312% and Cmax by 22%, and ketoconazole (200 mg / day) increases the exposure of a single dose of Cialis (AUC) by 107% and Cmax by 15% relative to AUC and Cmax values for Cialis alone.Ritonavir (200 mg 2 times / day), an inhibitor of isoenzymes CYP3A4, 2C9, 2C19 and 2D6, increases the exposure of a single dose of Cialis (AUC) by 124% without changing Cmax. Despite the fact that the specific interaction has not been studied, it can be assumed that other inhibitors of HIV protease, for example, saquinavir, as well as inhibitors of the isoenzyme CYP3A4, such as erythromycin, clarithromycin, itraconazole and grapefruit juice, may increase the concentration of Cialis in blood plasma. The role of vectors (eg, P-glycoprotein) in the distribution of Cialis is unknown. There is the possibility of drug interactions mediated by inhibition of vectors.A selective inducer of the CYP3A4 isoenzyme, rifampicin (at a dose of 600 mg / day), reduces the exposure of a single dose of Cialis (AUC) by 88% and Cmax by 46%, relative to AUC and Cmax values for Cialis alone. It can be assumed that the simultaneous use of other inducers of the isoenzyme CYP3A4 (such as phenobarbital, phenytoin or carbamazepine) should also reduce the concentration of Cialis in blood plasma.The simultaneous administration of an antacid (magnesium hydroxide / aluminum hydroxide) and Cialis reduces the rate of absorption of Cialis without changing the AUC for Cialis.An increase in gastric pH as a result of taking the histamine H2-receptor blocker nizatidine did not affect the pharmacokinetics of Cialis.The safety and efficacy of the combination of Cialis with other treatments for erectile dysfunction or other PDE5 inhibitors have not been studied, so the use of such combinations is not recommended.The effect of Cialis on other drugs. It is known that Cialis enhances the hypotensive effect of nitrates. This is due to the additive effect of nitrates and Cialis on the metabolism of nitric oxide II (NO) and cGMP. Therefore, the use of Cialis while taking nitrates is contraindicated. Cialis does not have a clinically significant effect on the clearance of drugs, the metabolism of which occurs with the participation of cytochrome P450. Studies have confirmed that Cialis does not inhibit or induce isoenzymes CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, CYP2E1.Cialis has no clinically significant effect on the AUC of S-warfarin or R-warfarin. Cialis does not affect the prothrombin time effect of warfarin. Cialis does not potentiate an increase in the duration of bleeding caused by the intake of acetylsalicylic acid.Cialis has systemic vasodilating properties and can enhance the effect of antihypertensive drugs aimed at lowering blood pressure. Additionally, in patients taking several antihypertensive drugs 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 Cialis should be given appropriate clinical guidelines. There was no significant decrease in blood pressure with the simultaneous use of Cialis and the selective alpha1A-blocker tamsulosin in healthy volunteers. The simultaneous use of Cialis with doxazosin is contraindicated. When Cialis was used by healthy volunteers who took doxazosin (4-8 mg / day), an alpha1-blocker, an increase in the hypotensive effect of doxazosin was observed. Some patients experienced BP-related symptoms, including fainting. The concomitant use of riociguat with PDE5 inhibitors, including Cialis, is contraindicated. riociguat enhances the hypotensive effect of PDE5 inhibitors. No drug interaction studies have been conducted between Cialis and 5-alpha-reductase inhibitors, and caution should be exercised when taking them simultaneously. Cialis causes an increase in the bioavailability of ethinyl estradiol when taken orally.
A similar increase in bioavailability can be expected with terbutaline, but the clinical consequences have not been established.
Cialis did not affect the concentration of ethanol, as well as ethanol did not affect the concentration of Cialis. At high doses of alcohol (0.7 g / kg), taking Cialis did not cause a statistically significant decrease in the mean blood pressure. Some patients experienced postural dizziness and orthostatic hypotension. When taking Cialis 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 alone. Cialis does not have a clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline.
Dosage and administration
The drug is taken orally.
erectile dysfunction
For patients with frequent sexual activity (more than 2 times a week): the recommended frequency of administration is daily, 1 time / day, 5 mg, at the same time, regardless of food intake. The daily dose can be reduced to 2.5 mg (1/2 tab. 5 mg), depending on individual sensitivity. For patients with infrequent sexual activity (less than 2 times a week), it is recommended to prescribe the drug Cialis at a dose of 20 mg, immediately before sexual activity, according to the instructions for medical use of the drug. The maximum daily dose of Cialis is 20 mg.
BPH or Erectile Dysfunction / BPH
The recommended dose of the drug Cialis when administered 1 time / day is 5 mg; the drug should be taken at approximately the same time of the day, regardless of the time of sexual activity. The duration of treatment is determined by the doctor individually.In patients with mild renal failure (CC from 51 to 80 ml / min) and moderate severity (CC from 31 to 50 ml / min), dose adjustment is not required. In patients with severe renal insufficiency (CC <30 ml / min and on hemodialysis), the use of Cialis is contraindicated.
Overdose
With a single appointment of Cialis to healthy volunteers at a dose of up to 500 mg and to patients with erectile dysfunction - repeatedly up to 100 mg / day, the undesirable effects were the same as when using lower doses.
Treatment: in case of overdose, it is necessary to carry out standard symptomatic treatment. With hemodialysis, Cialis is practically not excreted.
Special instructions
Diagnosis of erectile dysfunction should include identification of the potential underlying cause, appropriate medical evaluation, and treatment.Sexual activity has a potential risk for patients with cardiovascular disease. Therefore, the treatment of erectile dysfunction, incl. Cialis should not be used in men with heart diseases in which sexual activity is not recommended.There have been reports of the occurrence of priapism with the use of PDE5 inhibitors, including Cialis. Patients should be informed of the need for immediate medical attention in case of an erection lasting 4 hours or more. Late treatment of priapism leads to damage to the tissues of the penis, resulting in irreversible impotence.The safety and effectiveness of the combination of Cialis with other PDE5 inhibitors and treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.Like other PDE5 inhibitors, Cialis has systemic vasodilating properties, which can lead to a transient decrease in blood pressure. Before prescribing the drug Cialis, you should carefully consider whether patients with cardiovascular disease will be exposed to unwanted effects due to such vasodilating effects.Non-arterial anterior ischemic optic neuropathy (NAPION) is a cause of visual impairment, including complete loss of vision. There are rare post-marketing reports of cases of NAPION development, in time associated with the intake of PDE5 inhibitors. It is currently impossible to determine whether there is a direct relationship between the development of NAPION and the use of PDE5 inhibitors or other factors.Patients should be advised to stop taking Cialis in case of sudden loss of vision and seek medical attention. Patients should be advised that people who have undergone NAPION have an increased risk of re-developing NAPION.Patients suspected of having BPH should be screened to rule out prostate cancer. The efficacy of Cialis in patients undergoing pelvic surgery or radical neurosaving prostatectomy is unknown.Influence on the ability to drive vehicles and mechanisms
During the period of treatment with Cialis, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.
