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primobolan side effects

Penile erection is a hemodynamic process based on the relaxation of smooth muscles of cavernous bodies and located in its arterioles. During sexual stimulation of the nerve endings of the cavernous bodies released nitric oxide (of NO), activates the enzyme guanylate cyclase, which leads to higher content in the cavernous bodies of cyclic guanosine monophosphate (cGMP). The result is relaxation of smooth primobolan side effects muscles of cavernous bodies, which increases blood flow to the penis. CGMP level is adjusted, on the one hand, the synthesis of guanylate cyclase, and on the other hand – the degradation (cleavage) hydrolysis of cGMP by phosphodiesterases (PDEs). The best-known PDE is the cGMP-specific phosphodiesterase type 5 (PDE5). By blocking PDE5, which participates in the cleavage of cGMP, thereby vardenafil enhances the local action of endogenous nitric oxide (NO) in the cavernous bodies during sexual stimulation. Increasing the level of cGMP by inhibiting PDE5 leads to relaxation of smooth muscles of the corpus cavernosum and increases blood flow to them.
This effect leads to the ability of vardenafil enhances the natural response to sexual stimulation.

Vardenafil is a potent and highly selective inhibitor of PDE5 (mean inhibitory concentration with respect to the PDE5 – 0.7 nM). Vardenafil inhibitory activity on PDE5 is more pronounced than in other known PDE (15 times more than the PDE6, 130 times greater than FDE1, 300 times greater than FDE11 and 1000 times greater than FDE- 2,3,4,7,8,9,10). Vardenafil increased cGMP in isolated corpus cavernosum, resulting in smooth muscle relaxation. Vardenafil causes penile erection is dependent on endogenous nitric oxide and nitric oxide donators stimulated.

Vardenafil 20 mg for some men causes an erection (enough for penetration) in 15 minutes. Complete response was achieved in 25 minutes (statistically significant and comparable to placebo).

 

. Metabolism Vardenafil is metabolised predominantly by hepatic enzymes with the participation of isoenzyme of cytochrome P450 (CYP) – CYP3A4, and CYP3A5 and of CYP2C9. The average half-life (T1 / 2) after administration of vardenafil dispersible tablets in the mouth (10 mg) of 4-6 hours, and the main metabolite M1 (formed by dezetilirovaniya piperazine moiety) – from 3 to 5 hours. The blood contained in the form of a glucuronide conjugate (glucuronic acid), which is part of the M1 metabolite. Concentration of the rest of the M1 metabolite (neglyukuronovoy) is 26% of the concentration of the active substance.Selectivity profile against phosphodiesterase from M1 is similar to that of vardenafil; in vitro ability to inhibit PDE5 is 28% compared to vardenafil, which corresponds to 7% efficacy.

Excretion. The total clearance of vardenafil is 56 l / h. After oral administration of vardenafil metabolites excreted mainly gastrointestinal tract (91 to 95% dose), less kidneys (6.2% of dose).

Elderly patients. Patients aged 65 years or older at the pill-dispersible oral (10 mg) showed an increase in AUC from 31 to 39% and Cmax from 16 to 21%, compared to patients aged 45 years and younger.When receiving one orally disintegrating tablet (10 mg) for 10 days to patients at the age of 45 years and 65 years of age or older were noted vardenafil accumulation in the plasma.

There were no differences in efficacy or safety of the drug in elderly and younger patients.

 

In patients on hemodialysis, the pharmacokinetics of vardenafil has not been studied.

Abnormal liver function. In patients with mild to moderate hepatic impairment, the clearance of vardenafil function decreases in proportion to the degree of liver dysfunction. Mild hepatic insufficiency (stage A by Child-Pugh) noted an increase in the AUC and 1.2 fold (AUC by 17% and Cmax by 22%), but at a moderate (stage B according to Child-Pugh) – AUC 2.6 (160 %) and Opah 2.3 (130%) times, respectively, compared to healthy subjects.

Safety of dispersible tablets in the mouth (10 mg) has not been studied in patients with moderate hepatic impairment (stage B by Child-Pugh), therefore not recommended to use in these patients.

In patients with severe hepatic insufficiency (C stage by Child-Pugh), the pharmacokinetics of vardenafil has not been studied.

Indications

Erectile dysfunction (inability to achieve and maintain an erection necessary for sexual intercourse).

Contraindications

– Hypersensitivity to any component of the product;
– the simultaneous use with nitrates or drugs, which are nitric oxide donators;
– simultaneous use with moderately active or potent inhibitors of CYP3A4, such as ketoconazole, itraconazole, ritonavir, indinavir, erythromycin and clarithromycin;
– safety of the drug has not been studied and is not obtained relevant data, its use is not recommended in patients

Precautions should use the drug in patients with anatomical deformation of the penis (curved, cavernous fibrosis, Peyronie’s disease), diseases predisposing to priapism (sickle-cell anemia, multiple myeloma, leukemia).In patients with a tendency to bleeding and exacerbation of peptic ulcer disease, the drug should be used only after assessment of the benefit-risk.

Application of pregnancy and during breastfeeding

The drug is not indicated for use in women, infants and children.

Dosing and Administration

Levitra ® taken orally with or without food.

Tablets are taken immediately after removing it from its packaging. The tablet should be kept in the language until its complete dissolution and then swallowed without water liquid.

At the beginning of treatment the recommended dose is 10 mg (approximately 25-60 minutes before sexual intercourse). The maximum recommended dose is 1 0 1 mg once a day.

In order to ensure an adequate response to treatment requires sexual stimulation. Levitra ® has shown to be effective when taking 4-5 hours before sexual intercourse.

Elderly patients (over 65 years) No dose adjustment in elderly patients is not required.

Abnormal liver function
in patients with minor hepatic impairment (step A by Child-Pugh) changes in the dosing regimen is required.
Use of the drug is not recommended in patients with moderate hepatic impairment (stage B by Child-Pugh).

 

 

Infectious and parasitic diseases: Rare: conjunctivitis.

Violations of the immune system:

Uncommon: allergic edema and angioedema.

Rare: allergic reactions.

Disorders of the nervous system: Very common: . Headache Common: dizziness.

Uncommon: sensitivity disorder, somnolence, insomnia. Rare: syncope, amnesia, seizures.

Violations of the organ of vision:

Uncommon: . Blurred vision, redness of the conjunctiva of the eyeball, color vision disorders, pain in the eyeballs, and discomfort in the eyes, photophobia Rare: increased intraocular pressure.

Violations of the organ of hearing and labyrinth disorders: Uncommon: tinnitus, vertigo.

Violations of the heart: Uncommon: palpitations, tachycardia.

Rare: angina pectoris, myocardial infarction, ventricular tachyarrhythmias.

Violations of the vessels: Common: . Vasodilatation Rare: hypotension.

Disorders of the respiratory system, organs, thoracic and mediastinal disorders: Common: nasal congestion.

Uncommon: shortness of breath, nasal sinuses.

Disorders of the gastrointestinal tract: Common: dyspepsia.

Uncommon: nausea, abdominal pain, dry mouth, diarrhea, gastro-esophageal reflux disease, gastritis, vomiting.

Disorders of the liver and biliary tract: Uncommon: increase in transaminases.

Disorders of the skin and subcutaneous tissue disorders: Uncommon: erythema, rash.

Violations of the musculoskeletal and connective tissue disorders:

Uncommon: back pain, increased levels of creatine phosphokinase (CPK), increased

muscle tone and spasms, myalgia.

Violations of the genital organs and the breast: Uncommon: increase in erection. Rare: priapism.

General disorders and administration site at: Uncommon: feeling unwell. Rare: chest pain.

It reported cases of myocardial infarction, associated in time with taking vardenafil and sexual activity, but not established whether this condition is directly connected with the use of vardenafil, or sexual activity, or with concomitant diseases, or a combination of these factors. There are rare reports of cases of anterior ischemic optic neuropathy (PINZN), leading to impaired vision (including permanent loss of vision), associated in time with taking PDE5 inhibitors, including the drug Levitra ® , patients, many of which are related risk factors for this condition, such as an anatomical defect of the optic nerve, age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It not determined whether PINZN development is connected directly with PDE5 inhibitors or with existing patient associated cardiovascular risk factors and anatomical defect, or a combination of these factors, or other causes.

Reported cases of visual disturbances , including temporary or permanent loss of vision, which are linked in time with taking PDE5 inhibitors, including Levitra ® . Not determined whether these cases directly to the reception of PDE5 inhibitors or concomitant cardiovascular risk factors, or other causes.

We noted a few cases of sudden hearing loss or deafness with preparations from the group of PDE5 inhibitors, including . Not determined whether these cases directly with the reception, with associated risk factors for hearing loss, with a combination of these factors, or other reasons.

Overdose

In the appointment of vardenafil at a dose of 80 mg per day was observed for serious adverse reactions. However, the application of vardenafil 40 mg 2 times a day had apparent pain without signs of toxic action on the muscular and nervous systems.

should be a standard maintenance therapy in cases of overdose. Since vardenafil is highly bound to plasma primobolan side effects proteins, and only a small amount of the drug is excreted by the kidneys, dialysis efficiency is unlikely.

Interaction with other drugs CYP inhibitors

Vardenafil is metabolised predominantly involving the liver enzyme cytochrome P450 (CYP), namely, isoform 3A4, as well as with the participation of some isoforms CYP3A5 and CYP2C9. Inhibitors of these enzymes may reduce vardenafil clearance.

Cimetidine (400 mg, 2 times daily) : nonspecific inhibitor of cytochrome P450 has no effect on the value of AUC and Cmax parameters vardenafil (20 mg) at their simultaneous use.

Levitra ® is contraindicated in concomitant use with active moderate or potent inhibitors of CYP3A4, such as ketoconazole, itraconazole, ritonavir, indinavir, clarithromycin and erythromycin.

The combined application of the drug Levitra ® with ketoconazole, itraconazole, ritonavir, indinavir, and (potential inhibitors of CYP3A4) can expect a significant increase in plasma concentrations of vardenafil.

Nitrates, donators of nitric oxide

Receiving vardenafil (10 mg) in a period of from 24 hours to 1 hour prior to receiving nitroglycerin (0.4 mg sublingual), it does not enhance the hypotensive effect when taking in healthy subjects. At a dose of 20 mg for 1-4 hours prior to receiving nitrate (0.4 mg sublingual) vardenafil enhances their hypotensive action, but if assigned vardenafil for 24 hours, the hypotensive effect of nitrates amplification does not occur while taking in healthy middle-aged subjects.

Nicorandil is a potassium channel activator, and contains a nitro group in its structure. The presence of the nitro group in the composition of nicorandil causes high probability of interaction with vardenafil.

However, there is insufficient information on the potential hypotensive effects of vardenafil while the use of nitrates. Therefore, this combination is contraindicated.

other

Vardenafil (20 mg) did not alter the parameters AUC and Cmax glibenclamide (glyburide 3.5 mg dose) for their joint administration. We also show that the pharmacokinetics of vardenafil does not change when an application with glibenclamide. Pharmacokinetic and pharmacodynamic interaction (effect on prothrombin time and coagulation factors II, VII, X) are not observed with sovmestnomprimenenii vardenafil (20 mg), warfarin(25 mg). Concomitant use with warfarin does not alter the pharmacokinetics of vardenafil.

There was no significant pharmacokinetic interaction between vardenafil (20 mg) and nifedipine (30 mg or 60 mg). Concurrent use of vardenafil and nifedipine did not lead to significant pharmacodynamic interaction: vardenafil is compared with placebo additional reduction in systolic and diastolic blood pressure (BP) when measured in the supine position by an average of 5.9 mm Hg. Art. and 5.2 mm Hg. Art. respectively.

Since it is known that alpha-blockers cause a reduction in blood pressure, especially postural hypotension and syncope, the question of the interaction of alpha-blockers and vardenafil when used together carefully studied.

Evaluation of blood pressure and heart rate during the 10 hours after administration of vardenafil at a dose of 5 mg or 10 mg, designated by 4 hours after the administration of alfuzosin, did not reveal any clinically significant further reduction in the maximum average blood pressure as compared to placebo. In one patient, there was a decrease in systolic blood pressure from baseline of more than 30 mm Hg. Art. standing after taking vardenafil 5 mg. The other patient had a systolic blood pressure decrease from baseline of more than 30 mm Hg. Art. standing after taking vardenafil 10 mg. Cases reducing systolic blood pressure in the standing position below 85 mm Hg. Art. in this case, it has been identified. Reported the presence of dizziness in two patients after administration of vardenafil 5 mg, one patient – receiving 10 mg vardenafil, and one – after placebo.So how to identify the maximum potential interactions has been selected 4-hour interval between doses doses of vardenafil and alfuzosin, observance of the time interval between drug administration is required. No cases of syncope in this case, and while the use of vardenafil with tamsulosin or terazosin have been identified.

Combined appointment of vardenafil and alpha-blockers is permissible only in the presence of stable rates of blood pressure in patients receiving alpha-blockers, with vardenafil should be administered with a minimum recommended dose is 5 mg. However, the drug Levitra ® in the form of dispersible tablets in the mouth (10 mg) should not be administered as an initial dose in concurrent therapy with alpha-blockers. Vardenafil should not be taken in the same time with alpha-blockers, except alfuzosin and tamsulosin, which may be the same reception time with the reception
Levitra ® . Between taking vardenafil and other alpha-blockers should be observed time interval. When concomitant administration of terazosin and vardenafil should be observed 6-hour interval between drug administration. The simultaneous use of digoxin (0.375 mg) and vardenafil (20 mg) every other day for 14 days is not accompanied by their interaction.

A single dose of antacid (hydroxide / aluminum magnesium hydroxide) did not affect the performance of vardenafil AUC and Cmax.

Bioavailability vardenafil (20 mg) was also not affected by its combination with H2-receptor antagonists ranitidine (150 mg, 2 times a day).

Vardenafil (10 mg and 20 mg) did not affect the duration of bleeding when used as monotherapy and in combination with acetylsalicylic acid at a low dose (2 tablets of 81 mg).

Vardenafil (20 mg) did not potentiate the hypotensive effect of alcohol (0.5 g / kg body weight), the pharmacokinetics of vardenafil is not disturbed.

Aspirin, ACE inhibitors, beta-blockers, diuretics, and antidiabetic drugs (sulfonylureas and metformin), CYP3A4 inhibitors weaknesses do not affect the pharmacokinetics of vardenafil.

special instructions

Prior to the appointment of drugs used to treat erectile dysfunction, the physician should evaluate the state of the cardiovascular system, as there is a risk of developing complications from the heart during sexual activity.Vardenafil has vasodilator properties, which may be accompanied by minor or moderate decrease in blood pressure. Patients with obstruction of the outflow tract of the left ventricle, eg, aortic stenosis, idiopathic hypertrophic subaortal stenosis, can be sensitive to the action of vasodilators, including PDE5 inhibitors.

For men who do not show sexual activity due to concomitant cardiovascular disease, drugs to treat erectile dysfunction, should not be used.

When using  therapeutic (10 mg) or sverhterapevticheskih (80 mg) doses marked prolongation of the interval QT. The simultaneous use of vardenafil with other drugs, providing a similar effect on the QT interval, resulting in a summation of the effects on the duration of QT interval compared with the reception of each of these drugs alone. It dolzhnouchityvatsya while the appointment of the drug  in patients with QT prolongation in history or in patients who are taking drugs prolonging QT interval. In this regard, the appointment of the drug  should be avoided in patients with congenital prolongation of the QT interval and in patients taking primobolan side effects anti-arrhythmic drugs class bA (quinidine, procainamide), or class III (amiodarone, sotalol).

The safety and efficacy of vardenafil in combination with other treatments for erectile dysfunction has not been studied, so their combined use is not recommended.

Safety of dispersible tablets in the mouth (10 mg) has not been studied in patients with moderate hepatic impairment (stage B by Child-Pugh), therefore not recommended to use in these patients.

Against the background of the drug Levitra ® and other PDE5 inhibitors have been reported cases of transient visual loss and nearteriitnoy ischemic optic neuropathy. In the event of a sudden loss of vision should stop taking Levitra ® and immediately consult your doctor. Combined therapy of alpha-blockers and vardenafil may be accompanied by the development of arterial hypotension with the appropriate clinical picture, because these drugs have vasodilating effects. Combined appointment of vardenafil and alpha-blockers is permissible only in the presence of stable rates of blood pressure in patients receiving alpha-blockers, with vardenafil should be administered in the minimum recommended dose of 5 mg. Patients receiving treatment with alpha-blockers should not be used as an initial dose of drug Levitra ® in the form of dispersible tablets in the mouth (10 mg).Vardenafil should not be taken at the same time with alpha-blockers, except alfuzosin or tamsulosin, which may be the same reception time with the reception of vardenafil. Between taking vardenafil and other alpha-blockers should be observed time interval. In the case of receiving selected dose of vardenafil therapy of alpha-blockers should be started with the lowest dose. The gradual increase in the dose of alpha-blockers in patients receiving drugs from the group of PDE5 inhibitors, may lead to a further decrease in blood pressure.

Orally disintegrating tablet containing 1.8 mg of aspartame, phenylalanine source, which should be considered when the patient has phenylketonuria.

Orally disintegrating tablet containing 7.96 mg of sorbitol. Patients with rare hereditary disorders of fructose intolerance should not take this drug. hoeveel calorie?n verbrand ik met hardlopen