Levitra, 20 mg

Levitra is an erectile function enhancer.

Pharmacodynamics

Per penile erection is a hemodynamic process based on relaxation of the smooth muscles of the cavernous bodies and the arterioles located in them. During sexual stimulation nitric oxide (NO) is released from the nerve endings of the cavernous bodies, and this activates the enzyme guanylate cyclic guanosine monophosphate (cGMP), which results in an increase in cavernous body content. As a result, the smooth muscles of the cavernous bodies relax, which contributes to the increase of blood flow in the penis. The level of cGMP is regulated, on the one hand, by guanylate cyclase synthesis, and on the other hand, by degradation (cleavage) of cGMP by hydrolysis of FDE. The best known FDE is cGMF-specific FDE-5.

Blocking FDE-5, which is involved in the cleavage of cGMP, vardenafil helps to increase the local action of endogenous nitric oxide (NO) in the cavernous bodies during sexual stimulation.

The increase in cGMP levels by inhibiting FDE-5 leads to relaxation of the smooth muscles of the cavernous bodies and an increase in blood flow in them.

This effect is the reason for Levitra®’s ability to enhance natural responses to sexual stimulation.

Vardenafil is a potent and highly selective inhibitor of FDE-5 (average inhibitory concentration towards FDE-5 is 0.7 nM). Inhibitory activity of vardenafil on FDE-5 is more pronounced than on other known FDEs (15 times more than on FDE-6, 130 times more than on FDE-1, 300 times more than on FDE-11 and 1000 times more than on FDE-2, -3, -4, -7, -8, -9, -10). Vardenafil increased cGMP in the isolated cavernous body, resulting in relaxation of the smooth muscles. Vardenafil causes penile erection, which depends on endogenous nitric oxide and is stimulated by nitric oxide donors.

The administration of vardenafil at a dose of 20 mg in some men caused an erection (sufficient for penetration) in as little as 15 min. Complete response was achieved after 25 min.

Pharmacokinetics

Absorption

After oral administration, it is rapidly absorbed. When taken on an empty stomach, early peak Cmax can be reached after 15 min, but in 90% of cases, on average, Cmax is reached after 60 min (30 to 120 min). Absolute bioavailability is about 15%.

Owing to the significant first-pass effect, absolute bioavailability is about 15%. In the recommended dose range (5-20 mg) the AUC and Cmax increase in proportion to the dose.

If vardenafil is taken concomitantly with a high-fat (57%) diet, the absorption rate decreases with an increase in Tmax to 60 min, and the Cmax value decreases by 20% on average without significant change in AUC. When taken with normal food containing no more than 30% fat, pharmacokinetic parameters of vardenafil (Cmax,Tmax, PPK) do not change. Based on these data, vardenafil can be prescribed regardless of food intake.

Distribution

The average Vss of vardenafil is 208 L, which demonstrates its good distribution in tissues. Vardenafil and its main metabolite (M1) bind well to plasma proteins (up to 95%), and this property is reversible and independent of the total drug concentration.

No more than 0.00012% of the dose taken can be detected in the semen of healthy patients 90 minutes after taking vardenafil.

Metabolism

Vardenafil is metabolized primarily by hepatic enzymes involving the CYP3A4 cytochrome system, but also by CYP3A5 and CYP2C9 isoforms.

The average T1/2 of vardenafil is 4-5 hours, and the main metabolite M1 (formed by de-ethylation of the piperazine part of the molecule) is about 4 hours.

The blood contains glucuronide in the form of a conjugate (glucuronic acid), which is part of the M1 metabolite.

The concentration of the rest of the M1 metabolite (non-glucuronic) is 26% of the active substance concentration. The selectivity profile with respect to FDEs of M1 is similar to that of vardenafil; in vitro ability to inhibit FDE-5 is 28% compared to vardenafil, which corresponds to 7% efficiency of the drug.

Elimination. Total clearance of vardenafil is 56 l/h, the final T1/2 is about 4-5 h. After oral administration vardenafil as metabolites is eliminated mainly through the gastrointestinal tract (91-95% of the dose), to a lesser extent – by the kidneys (2-6% of the dose).

Patients in the elderly. The hepatic clearance of vardenafil is decreased in healthy elderly men (≥65 years) compared to younger individuals (≤45 years). On average, AUC is increased by 52% in elderly individuals.

In patients 65 years of age and older when taking oral dispersible tablets (10 mg), there was an increase in AUC from 31% to 39% and Cmax from 16% to 21% compared to patients 45 years of age and younger. No plasma accumulation of vardenafil was noted when a single oral dispersible tablet (10 mg) was taken for 10 days in patients under 45 years of age and 65 years of age and older.

There is, however, no difference in efficacy and safety of the drug in elderly and younger patients.

Renal insufficiency. In patients with mild (creatinine Cl 55-80 ml/min) and moderate (creatinine Cl 30-50 ml/min) renal dysfunction, the pharmacokinetic parameters of vardenafil are comparable to those of healthy subjects. With severe renal impairment (Cl creatinine max decreases by 23%. There is no significant correlation between creatinine clearance and plasma concentrations of vardenafil (AUC and Cmax).

The pharmacokinetics of vardenafil has not been studied in patients on hemodialysis.

Hepatic impairment. In patients with mild to moderate hepatic impairment, vardenafil clearance decreases in proportion to the degree of hepatic impairment. In mild hepatic impairment (Child-Pugh stage A), there is a 1.2-fold increase in IPC and Cmax (17% IPC and 22% Cmax), and 2.6 (160%) and 2.3 (130%) times higher in moderate (Child-Pugh stage B) patients, respectively, than in healthy volunteers.

In patients with severe hepatic impairment (Child-Pugh stage B) the pharmacokinetics of vardenafil has not been studied.

Indications

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

Active ingredient

Composition

Active ingredient:

Vardenafil 20 mg;

Associates:

crospovidone, 8.85 mg;

magnesium stearate, 1.77 mg;

MCC, 141.797 mg;

Colloidal silicon dioxide – 3.385 mg;

Capsule film:

Macrogol 400, 1.128 mg; hypromellose, 3.385 mg; titanium dioxide, 0.925 mg; iron oxide yellow dye, 0.188 mg; iron oxide red dye, 0.015 mg

How to take, the dosage

Ingestion, regardless of meals.

In the beginning of treatment, the recommended dose is 10 mg (about 25-60 minutes before sexual intercourse).

However, Levitra® has also been shown to be effective when taken 4-5 hours before sexual activity.

The maximum frequency of taking the drug is once a day.

The dose can be increased to 20 or decreased to 5 mg/day depending on efficacy and tolerability of treatment.

The maximum recommended dose is 20 mg once daily.

Sexual stimulation is necessary to ensure adequate response to treatment.

Interaction

Vardenafil is metabolized primarily with participation of hepatic cytochrome Р450 enzymes, namely isoform 3A4, and with some participation of isoforms 3A5 and 2C9. Inhibitors of these enzymes can decrease clearance of vardenafil.

Cimetidine (400 mg 2 times/day): non-specific cytochrome P450 inhibitor has no effect on the AUC and Cmax values of vardenafil (20 mg) when used simultaneously.

The drug Levitra® CCT is contraindicated when used concomitantly with moderately active or potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, erythromycin and clarithromycin. When combining Levitra® CCT with ketoconazole, itraconazole, indinavir, and ritonavir (potential CYP3A4 inhibitors), a significant increase in plasma vardenafil concentrations can be expected.

Nitrates, nitric oxide donors: Taking vardenafil (10 mg) between 24 h and 1 h prior to taking nitroglycerin (0.4 mg sublingually) does not increase its hypotensive effect when taken in healthy subjects. At a dose of 20 mg 1-4 h prior to nitrate administration (0.4 mg sublingually), vardenafil enhances their hypotensive effects, but if vardenafil is administered 24 h, there is no enhancement of the hypotensive effects of nitrates when taken in healthy middle-aged subjects.

Nicorandil is a potassium channel activator and contains a nitro group. The presence of the nitro group in nicorandil makes it highly likely to interact with vardenafil.

Contraindications

Side effects

Infectious and parasitic diseases: rarely – conjunctivitis.

Immune system disorders: infrequent – allergic edema and angioedema; rarely – allergic reactions.

Mental disorders: infrequent – sleep disorders.

Nervous system disorders: very common – headache; common – dizziness; infrequent – paresthesia and dysesthesia, somnolence; rare – syncope, amnesia, seizures.

VIight disorders: infrequent – visual disturbances, conjunctival hyperemia, color perception disorders, pain in the eyeballs and a feeling of discomfort in the eyes, photophobia; rarely – IOP increase.

Hearing and labyrinth disorders: infrequent – tinnitus, vertigo.

Chronic disorders: infrequent – palpitation, tachycardia; rarely – angina pectoris, myocardial infarction, ventricular tachyarrhythmia.

Vascular disorders: often – vasodilation; rarely – hypotension.

Respiratory system, thoracic and mediastinal disorders: frequently – nasal congestion; infrequently – dyspnea, congestion of the paranasal sinuses.

Gastrointestinal disorders: frequently – dyspepsia; infrequently – nausea, abdominal pain, dry mouth, diarrhea, gastro-oesophageal reflux disease, gastritis, vomiting.

Liver and biliary tract disorders: infrequent – increased transaminase activity.

Skin and subcutaneous tissue disorders: infrequent – erythema, rash.

Muscular and connective tissue disorders: infrequent – back pain, increased CPK level, increased muscle tone and cramps, myalgia.

Gender and mammary gland disorders: infrequent – enhancement of erection; rarely – priapism.

General disorders and disorders at the site of administration: infrequent – malaise; rarely – pain in the chest.