Sildenafil & Vigraz
Sildenafil is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula:
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 cyclic guanosine monophosphate(cGMP),producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus 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 sexual stimulation causes local release of NO,inhibition of PDE5 by Sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum.Sildenafil at recommended doses has no effect in the absence of sexual stimulation. (PDR 2002)
Sildenafil 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 potent cytochrome 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.Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes(median 60 minutes)of oral dosing in the fasted state.Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma Proteins.Protein binding is independent of total drug concentrations.
After either oral or intravenous 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 administered oral dose ) . (PDR 2002)
Pharmacokinetics in Special Populations:
Geriatrics:Healthy elderly volunteers (65 years or over ) had a reduced clearance of Sildenafil,with free plasma concentrations approximately 40% greater than those seen in healthy younger volunteers ( 18-45 years )
: In volunteers with mild and moderate renal impairment , the pharmacokinetics of a single oral dose of Sildenafil (50 mg) were not altered .In volunteers with severe renal impairment , Sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment.
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, hepatic impairment 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. (PDR 2002)
Sildenafil is indicated for the treatment of erectile dysfunction. (PDR 2002)
Erectile dysfunction that is medication – induced or caused by endocrine problems , such as hypogonadism or hypothyroidism, or hyperthyroidism should be evaluated and appropriately treated before Sildenafil treatment is considered. (USP DI 2001)
Consistent with its known effects on the nitric oxide /cGMP pathway Sildenafil 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 , it is unknown when nitrates , if necessary , can be safely administered . Sildenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet . (PDR 2002)
There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore , treatments for erectile dysfunction, including Sildenafil should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.
Sildenafil has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure 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 physicians should carefully consider whether their patients with underlying cardiovascular disease 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 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 resting hypotension ( BP <90/50 ) or hypertension (BP> 170/110).
Patients with cardiac failure 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 . 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, penile tissue damage and permanent loss of potency could result.
The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of Sildenafil (11–fold increase in AUC) . If Sildenafil is prescribed to patients taking ritonavir, caution should be used . Data from subjects exposed to high systemic levels of Sildenafil are limited. Visual disturbances occurred more commonly at higher levels of Sildenafil exposure. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of Sildenafil ( 200-800 mg ) . To decrease the chance of adverse events in patients taking ritonavir, a decrease in Sildenafil dosage is recommended.
Pregnancy , Nursing Mothers and Pediatric Use:
Sildenafil is not indicated for use in newborns , children , or women .
Healthy elderly volunteers ( 65 years of 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. ( PDR 2002)
The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assesment. Before prescribing Sildenafil , it is important to note the following : Patients on multiple antihypertensive medications were included in the pivotal clinical trials for Sildenafil . In a separate drug interaction study , when amlodipine, 5 mg or 10 mg , and Sildenafil , 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted. Controlled studies of drug interactions between Sildenafil and other antihypertensive medications have not been performed. The safety of Sildenafil is unknown in patients with bleeding disorders and patients with active peptic ulceration.
Sildenafil 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 with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
In humans, Sildenafil has no effect on bleeding time when taken alone or with aspirin. ( PDR 2002)
Information for patients:
Physicians should discuss with patients the contraindication of Sildenafil with regular and / or intermittent use of organic nitrates.
Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk 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 . 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, penile tissue damage and permanent loss of potency may result.
The use of Sildenafil 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. (PDR 2002)
Concurrent use of other impotence therapy agents is not presently recommended. (USP DI 2001)
Cimetidine (800 mg),a nonspecific CYP inhibitor , caused a 56% increase in plasma Sildenafil concentrations when coadministered with Sildenafil (50 mg ) to healthy volunteers . When a single 100 mg dose of Sildenafil was administered with erythromycin,a specific CYP3A4 inhibitor, at steady state (500 mg bid for 5 days) , there was a 182% increase in Sildenafil systemic exposure ( AUC ) . In addition , in a study performed in healthy male volunteers, coadministration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor , at steady state (1200 mg tid ) with Sildenafil (100 mg single dose ) resulted in a 140% increase in Sildenafil Cmax and a 210% increase in Sildenafil AUC. Sildenafil 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) . In another study in healthy male volunteers, coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with Sildenafil(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 effect on a broad range of P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics.
Although the interaction between other protease inhibitors and Sildenafil has not been studied, their concomitant use is expected to increase Sildenafil levels.
It can be expected that concomitant administration 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 .
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 calcium channel 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. When Sildenafil 100 mg oral was coadministered with amlodipine, 5 mg or 10 mg oral , to hypertensive patients , the mean additional reduction on supine blood pressure 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 (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg) .
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08% . In a study of healthy male volunteers, Sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir , both of which are CYP3A4 substrates. Sildenafil potentiates the hypotensive effect of nitrates including nitroglycerin. (PDR 2002)
Pre – Marketing Experience:
The adverse events were generally transient and mild to moderate in nature.
In fixed–dose studies, the incidence of some adverse events increased with dose . The nature of the adverse events in flexible-dose studies, which more closely reflect the recommended dosage regimen,was similar to that for fixed–dose studies.When Sildenafil was taken as recommended in flexible dose, the following adverse events were reported:
Headache, flushing, dyspepsia, nasal congestion, urinary tract infection, abnormal vision, diarrhea , dizziness , rash. In fixed–dose studies , dyspepsia (17%) and abnormal vision (11%) were more common at 100 than at lower doses.At doses above the recommended dose rang, adverse events were similar to those detailed above but generally were reported more frequenly . (PDR 2002)
Post – Marketing Experience:
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack and hypertension,have been reported post – marketing in temporal association with the use of Sildenafil .
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, without sexual activity. Others were reported to have occurred hours to days after the use of Sildenafil and sexual activity .
Other events reported post–marketing to have been observed in temporal association with Sildenafil and not listed in the pre–marketing adverse reactions section above include.
Seizure and anxiety .
Prolonged erection , priapism and hematuria.
Diplopia,temporary vision loss/decreased vision ocular redness or bloodshot appearance , ocular burning ocular swelling/pressure, increased intraocuar pressure,retinal vascular disease or bleeding,vitreous detachment/traction and paramacular edema. (PDR 2002)
Dosage and Administration:
Usual adult dose:
50 mg (base) one hour (range , one half to four hours) before sexual intercourse once a day if needed .As tolerated, subsequent doses may be increased to 100 mg or decreased to 25 mg once a day .
Usual adult prescribing limits :
100 mg once a day .
Usual geriatric dose:
Oral , 25 mg (base) one hour ( range,one half to four hours ) before sexual intercourse once a day if needed , as tolerated , subsequent doses may be increased . (USP DI 2001)
Store below at 30 º C .
Sildenafil 100 mg is available as blue,scored, barrel–shaped , film coated tablets in boxes of 2 .
1- PDR 2002
2-USP DI 2001