INSTRUCTIONS FOR MEDICAL USE
NIVAGRA
Trade name of the drug: Nivagra
Active substance (INN): Sildenafil citrate.
Dosage form: Coated tablets.
Contents:
1 coated tablet contains:
Active ingredient: sildenafil 25 mg, 50 mg or 100 mg.
Excipients: microcrystalline cellulose, calcium phosphate (as dihydrate), lactose, polyvinylpyrolidone, talc, magnesium or calcium stearate, aerosil, sodium starch glycolate, corn starch, methylhydroxybenzoate, propylhydroxybenzoate
Excipients in the shell: hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol 4000, indigo carmine dye.
Description: Blue, diamond-shaped, biconvex, coated tablets.
Pharmacotherapeutic group: Agents for potency correction.
ATX code: G04BE03
Pharmacological properties
Sildenafil citrate is a potent and selective inhibitor of specific phosphodiesterase type 5 (FDE5).
The physiological mechanism of penile erection involves the release of nitric oxide (NO) in the cavernous body during sexual stimulation. Nitric oxide activates the enzyme guanylate cyclase, which leads to increased levels of cyclic guanosine monophosphate (cGMP) and, accordingly, relaxation of the smooth muscles of the cavernous body, resulting in increased blood flow in the penis.
Sildenafil has no direct relaxing effect on the isolated human cavernous body, but it actively enhances the relaxing effect of NO on this tissue by inhibiting FDE5, which is responsible for the breakdown of cGMP in the cavernous body.
This leads to an increase in ts HMF levels, resulting in relaxation of smooth muscles and increased blood flow in the corpora cavernosa.
Therefore, the use of sildenafil in the recommended doses is ineffective in the absence of sexual stimulation.
Effect of sildenafil on erectile dysfunction:
In a double-blind, placebo-controlled crossover study of patients with erectile dysfunction of various etiologies (organic, psychogenic, mixed) the result of sexual stimulation was the onset of a prolonged erection sufficient for sexual intercourse after sildenafil administration compared to placebo.
Effect of sildenafil on blood pressure:
When the drug was administered orally at a dose of 100 mg, the maximum reduction in systolic blood pressure (BP) in the supine position averaged 8.4 mm Hg, and diastolic BP in the supine position averaged 5.5 mm Hg. A more pronounced but similarly transient effect on BP was observed in patients receiving nitrates at the same time.
Effect of sildenafil on hemodynamics:
A single administration of sildenafil at a dose of 100 mg caused no clinically significant changes in ECG in healthy volunteers.
Effect of sildenafil on vision:
Mild and transient impairment of color vision (blue/green) was detected in some patients 1 h after administration of the drug at doses of 100 and 200 mg; 2 h after administration, these changes were absent. Inhibition of FDE 6, which is involved in the transmission of light to the retina, is considered to be the established mechanism of color vision impairment.
Sildenafil has no effect on visual acuity, contrast sensitivity, intraocular pressure or pupil diameter.
Pharmacokinetics
The pharmacokinetics of sildenafil depend on the dose ranges administered orally.
The drug is metabolized mainly in liver (mainly by cytochrome Р450 3A4 isoenzyme) to form an active metabolite with properties similar to those of sildenafil.
The drug is quickly absorbed through the gastrointestinal tract. After oral administration on an empty stomach, maximum concentration (Cmax) is reached within 30-120 minutes (on average 60 minutes). Absolute bioavailability averages 41% (25-63%). When taking sildenafil in combination with fatty food, absorption rate is reduced; time to reach maximum concentration (Tmax) is increased by 60 min, and Cmax is reduced by 29% on average.
The volume of distribution (Vd) of sildenafil in the equilibrium state is on average 105 liters, indicating its distribution in the tissues. Sildenafil and its main circulating N-desmethyl metabolite are approximately 96% bound to plasma proteins. Binding to proteins is independent of the total concentration of sildenafil. In healthy volunteers receiving sildenafil, less than 0.0002% (mean 188 ng) of the dose was detected in semen 90 min after administration.
Sildenafil is metabolized mainly by P450 3A4 (main pathway) and P450 2C9 (additional pathway) liver microsomal isoenzymes. The main circulating metabolite, which is formed as a result of N-desmethylation of sildenafil, undergoes further metabolism. As for selectivity of action on FDE, the metabolite is comparable with sildenafil, and its activity against FDE5 in vitro is about 50% of sildenafil activity. Plasma concentrations of the metabolite are about 40% of those of sildenafil. Total clearance of sildenafil from the body is 41 l/h and half-life (T1/2) in the terminal phase is 3-5 hours. It is excreted as metabolites mainly in the faeces (about 80% of the oral dose) and to a lesser extent in the urine (about 13% of the oral dose).
Pharmacokinetics in special clinical cases:
The increase in plasma levels of sildenafil the area under the concentration-time curve (AUC) is influenced by the following factors:
- Age over 65 years (40% increase in AUC);
- Impaired liver function (e.g., cirrhosis, 84%);
- severe renal insufficiency (creatinine clearance (CK) <30 ml/min, 100%);
- concomitant use of cytochrome P450 3A4 inhibitor drugs (e.g., erythromycin, 182%, saquinavir, 210%).
Indications for use
Treatment of erectile dysfunction characterized by the inability to achieve or maintain a penile erection sufficient for satisfactory intercourse.
Sildenafil effective only in the presence of sexual arousal!
Dosage and administration
The drug is taken orally.
For most patients, the recommended dose is 50 mg, the drug is taken if necessary about 1 hour before sexual activity, and after taking a fatty meal – 1.5-2 hours before sexual activity. Depending on efficacy and tolerability, the dose may be increased to 100 mg or reduced to 25 mg. Maximum recommended frequency of use is 1 time per day.
Side effects
Undesired effects are usually transient and are mild or moderately expressed. The adverse events in the dose-finding studies were comparable to those in the fixed-dose studies, since these studies better reflect the recommended regimen. When sildenafil was used in the recommended fixed-dose, placebo-controlled clinical trials, the following side effects were noted: headache, hot flashes, dyspepsia, nasal hyperemia, eye pain, red eyes, dizziness, rash.
Other side effects were a little more than 2%, but were comparable to the placebo test: back pain, flu-like syndrome, and arthralgia. In fixed-dose studies, dyspepsia (17%) and visual disturbances (11%) were more common with doses greater than 100 mg; it was also observed that the incidence of side effects increased with increasing doses.
In controlled clinical trials in less than 2% of patients, the following clinically significant side effects were observed, as well as those events, the occurrence of which may have been associated with taking the drug:
Cardiovascular system: symptoms of vasodilation.
Gastrointestinal tract: diarrhea, abdominal pain, nausea.
Musculoskeletal system: back pain, arthralgia, myalgia.
Nervous system: dizziness, increased muscle tone, insomnia.
Respiratory system: nasal congestion, pharyngitis, rhinitis, sinusitis, respiratory tract infections, respiratory disorders.
Dermatological reactions: rash.
Senses: change in vision (mild and transient, mainly changes in the color of objects, as well as increased perception of light and impaired visual clarity), conjunctivitis.
Genitourinary system: urinary tract infections, prostate dysfunction.
In post-marketing observations there have been reports of cases of prolonged erection and/or priapism.
Contraindications
Hypersensitivity to the components of the drug.
The drug is contraindicated in patients receiving nitric oxide donators, organic nitrates or nitrates in any form, either continuously or intermittently, because sildenafil enhances the hypotensive effect of nitrates taken continuously or in emergency cases.
The drug is not intended for use in women and children. Adequate and well-controlled trials in pregnancy and lactation in women have not been performed.
Drug interactions
Effect of other drugs on sildenafil: cimetidine (800 mg), which is a non-specific inhibitor of cytochrome P450 3A4, in in vivo studies, when taken simultaneously with sildenafil, caused 56% increase of plasma concentration of the latter in healthy volunteers.
Simultaneous use of sildenafil at a dose of 100 mg with erythromycin, a specific inhibitor of cytochrome P450 3A4 (while taking erythromycin 2 times per day, by 500 mg for 5 days) during reaching a constant level of erythromycin in blood, increased sildenafil AUC by 182%. Also simultaneous administration of sildenafil at a dose of 100 mg and saquinavir, which is both HIV protease inhibitor and cytochrome P450 3A4 inhibitor (while taking saquinavir 3 times/day at a dose of 1200 mg) against reaching constant level of saquinavir in blood increased maximal sildenafil concentration in blood by 140%, and AUC increased by 210%. Sildenafil had no effect on the pharmacokinetic parameters of saquinavir.
Simultaneous use of sildenafil (once in a dose of 100 mg) and ritonavir, which is HIV protease inhibitor and strong enough cytochrome P450 inhibitor (in a dose of 500 mg twice per day) against steady ritonavir in blood, Cmax was increased by 300% (4 times) and AUC by 1000% (11 times). After 24 hours, the plasma level of sildenafil was 200 ng/ml (comparative concentration with a single use of sildenafil after 24 hours was 5 ng/ml). This is consistent with the effect of ritonavir on a number of drugs that are cytochrome P450 substrates. Sildenafil had no effect on the pharmacokinetic parameters of ritonavir.
Population pharmacokinetic analysis of clinical trial results demonstrated a decrease in sildenafil clearance when concomitant use of cytochrome P450 3A4 inhibitors (such as ketoconazole, itraconazole, erythromycin).
A single intake of antacid (magnesium hydroxide/aluminum hydroxide) had no effect on the bioavailability of sildenafil.
The results of pharmacokinetic studies of patients who participated in clinical trials of sildenafil showed that cytochrome P450 2C9 inhibitors (such as tolbutamide, warfarin), cytochrome P450 2D6 (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide-like diuretics, loop and potassium-saving diuretics, ACE inhibitors and calcium antagonists, had no effect on pharmacokinetic parameters of sildenafil.
Effect of sildenafil on other drugs: in patients with arterial hypertension there were no signs of interaction of sildenafil (100 mg) with amlodipine.
Sildenafil (50 mg) did not cause an additional increase in bleeding time when taking acetylsalicylic acid (150 mg).
Sildenafil (50 mg) did not increase the hypotensive effect of ethanol in healthy volunteers at a maximum blood ethanol level of 80 mg/mL on average.
Special indications
Sexual activity poses a certain risk in heart disease; therefore, a cardiovascular examination should be performed before starting therapy with sildenafil.
In clinical trials, sildenafil has had a systemic vasodilatory effect that leads to a transient decrease in BP. Before prescribing the drug, the physician should carefully weigh the risk of adverse vasodilatory effects in patients with various comorbidities, especially against the background of sexual activity. Increased susceptibility to vasodilators is seen in patients with left ventricular obstruction (e.g., aortic stenosis, hypertrophic cardiomyopathy) as well as rare multiple atrophy of various systems manifesting severe impairment of autonomous BP control.
Because of the lack of data on the safety of sildenafil use, the drug should be used with caution in the following groups of patients:
- Those who have had a myocardial infarction, suffering from impaired cerebral circulation, as well as life-threatening arrhythmias within the last 6 months;
- Patients with orthostatic hypotension (BP 90/50) or hypertension (BP 170/110);
- Patients with heart failure or coronary artery disease due to unstable angina pectoris;
- those with hereditary retinin pigmentation, having hereditary disorders related to retinal phosphodiesterase synthesis;
- in patients with an anatomical deformity of the penis (e.g., angulation, cavernous fibrosis, or Peyronie’s disease) and in patients with diseases that predispose to the development of priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
Drugs intended to treat erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable. In addition, safety and effectiveness of sildenafil when used in combination with other drugs intended for treatment of erectile dysfunction have not been studied, therefore, it is not recommended to use such combinations.
When using the drug in patients aged over 65 years, patients with hepatic impairment, patients with severe renal failure, as well as patients receiving concomitant drugs – cytochrome P450 3A4 inhibitors (such as erythromycin, saquinavir), increase in plasma sildenafil levels occurs. This may increase both the effectiveness of the drug and the possibility of side effects. It is reasonable to prescribe the drug in a dose of 25 mg/day to such groups of patients.
The drug may cause dizziness and visual impairment, therefore, patients should evaluate their reaction to the drug before driving a car or using machinery.
Overdose
In studies in healthy volunteers, when taking the drug once in doses up to 800 mg, the adverse effects were comparable with those when taking sildenafil in lower doses, but they occurred more frequently.
Treatment: if necessary, symptomatic therapy is carried out. Dialysis does not accelerate sildenafil clearance, as the latter is actively bound to plasma proteins and is not excreted in the urine.
Form of production
25 mg, 50 mg or 100 mg coated tablets in a carton pack.
Storage conditions
Store in a dry, dark place at a temperature not exceeding 25°C. Keep out of the reach of children!
Shelf life
3 years. Do not use after the expiration date.
Conditions of dispensing from pharmacies
Released by a doctor’s prescription.
