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Vegarpi, 50 mg tablets

Drug formTablets

ATC categoryUrology, Nephrology

ATC subcategoryAgents for erectile dysfunction therapy

Brand nameVegarpi

Generic nameSildenafil

Composition

Each coated tablet contains:

active ingredient: sildenafil (as citrate) – 50.0 mg;
excipients: core – microcrystalline cellulose, lactose monohydrate, calcium hydrogen phosphate, povidone, sodium starch glycolate,magnesium stearate, talc purified;
coating – talc purified, brilliant blue, titanium dioxide , propylene glycol, hypromellose .

Chemical name and CAS number
1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy-phenyl]sulfonyl]-4-methylpiperazine citrate; 171599-83-0.
Pharmacological group and ATC code
Phosphodiesterase type-5 inhibitor; G04ВЕ.
Pharmacology

Vegarpi, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclicguanosine monophosphate (cGMP)-specific phosphodiesterasetype 5 (PDE5).

Mechanism of Action

The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclicguanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil has no direct relaxanteffect on isolated humancorpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexualstimulation causes localrelease of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth musclerelaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.

Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (>80-fold for PDE1, >1000-fold for PDE2, PDE3, and PDE4). The approximately 4000-fold selectivity for PDE5 versus PDE3 is important because that PDE is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina; this lower selectivity is thought to be the basis for abnormalities related to colorvision observed with higher doses or plasma levels.

In addition to humancorpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of plateletthrombusformationin vivo and peripheral arterial-venous dilatation in vivo.

Pharmacodynamics

Effects of Sildenafil Citrate on Erectile Response: In patients with either organic or psychogenicerectile dysfunction, sexual stimulation resulted in improved erections after sildenafil citrate administration compared with placebo. Most studies assessed the efficacy of sildenafil citrate approximately 60 minutes post dose. The erectile response, as assessed by penile plethysmography, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours.

Effects of Sildenafil Citrate on Blood Pressure: Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in supinebloodpressure (mean maximum decrease of 8.4/5.5 mmHg). The decrease in bloodpressure was most notable approximately 1-2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on bloodpressure were noted with 25 mg, 50 mg and 100 mg of sildenafil citrate, therefore the effects are not related to dose or plasma levels. Larger effects were recorded among patients receiving concomitant nitrates.

Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normalmale volunteers.

Studies have produced relevant data on the effects of sildenafil citrate on cardiac output.

Effects of Sildenafil Citrate on Vision: At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visualfunction at doses up to twice the maximum recommended dose revealed no effects of sildenafil citrate on visual acuity, electroretinograms, intraocular pressure, or pupillometry.

Pharmacokinetics
Sildenafil citrate is rapidly absorbed after oral administration, with absolute bioavailability of about 40%. Its pharmacokinetics are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil. The concomitant use of potentcytochrome P450 3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil. Both sildenafil and the metabolite have terminal half lives of about 4 hours.

Absorption and Distribution: Sildenafil citrate is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil citrate is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. The mean steady statevolume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.

Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.

Metabolism and Excretion: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects.

After oral administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).

Pharmacokinetics in Special Populations

Geriatrics: healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, with treeplasma concentrations approximately 40% greater than those seen in healthy younger volunteers (18-45 years).

Renal insufficiency: in volunteers with mild (CLcr= 50-80 ml/min) and moderate (CLcr= 30-49 ml/min) renal impairment, the pharmacokinetics of a single oraldose of sildenafil citrate (50 mg) were not altered. In volunteers with severe (CLcr= max compared to age-matched volunteers with no renal impairment.

Hepatic Insufficiency: in volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment.

Therefore, age >65, hepaticimpairment and severe renal impairment are associated with increased plasma levels of sildenafil. A starting oral dose of 25 mg should be considered in those patients.

Uses
Vegarpi is indicated for the treatment of erectile dysfunction.

Dosage and administration
For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, Vegarpi may be taken anywhere from 4 hours to 0.5 hour before sexual activity. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum recommended dosing frequency is once per day.

The Following Factors are Associated with Increased Plasma Levels of Sildenafil: age >65 (40% increase in AUC), hepatic impairment (e.g., cirrhosis, 80%), severe renalimpairment (creatinine clearance

Given the extent of the interaction with patients receiving concomitant therapy with ritonavir, it is recommended not to exceed a maximum single dose of 25 mg of sildenafil citrate in a 48 hours period.

Vegarpi was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors or nitrates in any form is therefore contraindicated.

Adverse effects

Adverse effects most commonly reported from Vegarpi are headache, flushing, and dyspepsia. There may be visual disturbances, dizziness, and nasal congestion. Other adverse effects reported include diarrhea, muscle pain, skin rashes, and urinary- or respiratory-tract infection. Priapism has also occurred. There have also been reports of serious cardiovascular events, including sudden cardiac death, associated with the use of Vegarpi.

Cardiovascular: serious cardiovascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack and hypertension, have been reported post-marketing in temporalassociation with the use of sildenafil citrate. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil citrate without sexual activity. Others were reported to have occurred hours to days after the use of sildenafil citrate and sexual activity. It is not possible to determine whether these events are related directly to sildenafil citrate, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors.

Nervous: seizure and anxiety.

Urogenital: prolonged erection, priapism and hematuria.

Ocular: diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinalvasculardisease or bleeding, vitreous detachment/traction and paramacular edema.

WARNINGS

There is a potential for cardiacrisk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including Vegarpi, should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.

Sildenafil citrate has systemic vasodilatory properties that resulted in transient decreases in supinebloodpressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg). While this normally would be expected to be of little consequence in most patients, prior to prescribing sildenafil citrate, physicians should carefully consider whether their patients with underlying cardiovasculardisease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.

There is no controlled clinical data on the safety or efficacy of sildenafil citrate in the following groups; if prescribed, this should be done with caution:

– patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months;

– patients with restinghypotension (BP <90/50) or hypertension (BP >170/110);

– patients with cardiacfailure or coronary artery disease causing unstable angina;

– patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).

Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of sildenafil citrate. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, peniletissue damage and permanentloss of potency could result.

Precautions
General

The evaluation of erectiledysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment.

Before prescribing sildenafil citrate, it is important to note the following:

– Patients on multipleantihypertensive medications were included in the pivotal clinical trials for sildenafil citrate. In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and sildenafil citrate, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressurereduction of 8 mmHg systolic and 7 mmHg diastolic were noted. Controlled studies of drug interactions between sildenafil citrate and other antihypertensive medications have not been performed.

The safety of sildenafil citrate is unknown in patients with bleeding disorders and patients with active peptic ulceration.

Vegarpi should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

The safety and efficacy of combinations of sildenafil citrate with other treatments for erectiledysfunction have not been studied. Therefore, the use of such combinations is not recommended.

In humans, sildenafil citrate has no effect on bleedingtime when taken alone or with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). The combination of heparin and sildenafil citrate had an additiveeffect on bleedingtime in the anesthetized rabbit, but this interaction has not been studied in humans.

Information for the Patient

Physicians should discuss with patients the contraindication of sildenafil citrate with regular and/or intermittent use of organic nitrates. Physicians should discuss with patients the potentialcardiacrisk of sexual activity in patients with preexisting cardiovascularrisk factors. Patients who experience symptoms (e.g., angina pectoris, dizziness, nausea) upon initiation of sexual activity should be advised to refrain from further activity and should discuss the episode with their physician. Physicians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of sildenafil citrate. In the event of an erection that persists longer than 4 hours, the patient should seek immediatemedical assistance. If priapism is not treated immediately, penile tissue damage and permanentloss of potency may result. The use of sildenafil citrate offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemicdrugexposure (AUCs) for unbound sildenafil and its major metabolite of 29- and 42-times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m2 basis.

Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mousemicronucleus assays to detect clastogenicity.

There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUCvalue of more than 25 times the humanmale AUC.

There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil citrate in healthy volunteers.

Pregnancy, Nursing Mothers, and Pediatric Use

Sildenafil citrate is not indicated for use in newborns, children, or women.

Pregnancy Category B: No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 20 and 40 times the MRHD on a mg/m2 basis in a 50 kg subject. In the rat pre- and postnataldevelopment study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days. In nonpregnant rat the AUC at this dose was about 20 times human AUC. There are no adequate and well-controlled studies of sildenafil in pregnant women.

Geriatric Use

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil. Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered.

Contraindications
Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil citrate was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates either regularly and/or intermittently in any form is therefore contraindicated.

After patients have taken sildenafil citrate, it is unknown when nitrates, if necessary, can be safely administered. Based on the pharmacokinetic profile of a single 100 mg oraldose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours postdose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). In the following patients: age >65, hepatic impairment (e.g., cirrhosis), severe renalimpairment (e.g., creatine clearance

Sildenafil citrate is contraindicated in patients with a known hypersensitivity to any component of the tablet.

Overdosage
In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but incidence rates were increased.

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

Drug interactions

Effects of Other Drugs on Sildenafil Citrate

In Vitro Studies: Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance.

In Vivo Studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when coadministered with sildenafil citrate (50 mg) to healthy volunteers.

When a single 100 mg dose of sildenafil citrate was administered with erythromycin, a specificCYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In addition, coadministration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with sildenafil citrate (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil citrate had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole would be expected to have still greater effects, and population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine).

Coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (400 mg bid) with sildenafil citrate (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir’s marked effects o n a broad range of P450 substrates. Sildenafil citrate had no effect on ritonavir pharmacokinetics.

It can be expected that concomitantadministration of CYP3A4 inducers, such as rifampin, will decrease plasma levels of sildenafil.

Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil citrate.

Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calciumchannel blockers. The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.

Effects of Sildenafil Citrate on Other Drugs

In Vitro Studies: Sildenafil is a weakinhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 mM). Given sildenafil peak plasma concentrations of approximately 1 mcM after recommended doses, it is unlikely that sildenafil citratewill alter the clearance of substrates of these isoenzymes.

In Vivo Studies: When sildenafil citrate 100 mg oral was coadministered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supinebloodpressure was 8 mmHg systolic and 7 mmHg diastolic.

No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.

Sildenafil citrate (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).

Sildenafil citrate (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with meanmaximumbloodalcohol levels of 0.08%.

Sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.

Identification

Blue colored, biconvex coated tablets.

Presentation

1 blister packet with 10 tablets in the cardboard box.

Expiry date

3 years. Do not use after the expiration date.

Prescription status

To be dispensed with prescription.

Storage conditions

Store at a room temperature (15-250C), in a dry place, out of the reach of children. Protect from light.