NOLVADEX

Sildenafil tablets, USP, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Sildenafil citrate, is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H -pyrazolo[4,3 - d ]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7.

Sildenafil tablets

USP are formulated as pale blue to blue film-coated tablets equivalent to 25 mg, 50 mg and 100 mg of sildenafil for oral administration.

Sildenafil tablets 50 mg and 100 mg are caplet shaped whereas sildenafil tablets 25 mg are round shaped.

In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dicalcium phosphate anhydrous, FD&C Blue # 2 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, titanium dioxide and triacetin. sildenafil-citrate-structure.

• either in adjuvant treatment (preventive treatment of recurrences),.

• or advanced forms with local and/or metastatic progression.

The effectiveness of this therapy is more important in women whose tumour contains estradiol and/or progesterone receptors.

The risk of developing a drug is reduced by the presence of a drug.

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 enhances the effect of

NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum.

Sildenafil has no direct relaxant effect on isolated human 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.

Studies in vitro have shown that sildenafil is selective for PDE5.

Its effect is more potent on

PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11).

Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3.

PDE3 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 which is involved in the phototransduction pathway of the retina.

This lower selectivity is thought to be the basis for abnormalities related to color vision.

In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle.

The inhibition of

PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo. 12.2 Pharmacodynamics Effects of sildenafil on Erectile Response: In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan ® ), after sildenafil administration compared with placebo.

Most studies assessed the efficacy of sildenafil approximately 60 minutes post dose.

The erectile response, as assessed by RigiScan ® , 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 on Blood Pressure

Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg).

The decrease in sitting blood pressure was most notable approximately 1-2 hours after dosing, and was not different than placebo at 8 hours.

Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range.

Larger effects were recorded among patients receiving concomitant nitrates.

Effects of sildenafil on Blood Pressure When Nitroglycerin is Subsequently Administered: Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL).

In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be to 8 times higher than those seen in healthy volunteers.

Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point.

Effects of sildenafil on Blood Pressure When Co-administered with Alpha-Blockers: Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of sildenafil with doxazosin, an alpha-adrenergic blocking agent.

Study 1: Sildenafil with Doxazosin In the first study, a single oral dose of sildenafil 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH).

Following at least 14 consecutive daily doses of doxazosin, sildenafil 100 mg or matching placebo was administered simultaneously with doxazosin.

Following a review of the data from these first 4 subjects (details provided below), the sildenafil dose was reduced to 25 mg. Thereafter, 17 subjects were treated with sildenafil 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects).

The mean subject age was 66.5 years.

For the 17 subjects who received sildenafil 25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) sildenafil citrate 25 mg Supine 7.4 (-0.9, 15.7) Standing 6.0 (-0.8, 12.8) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg sildenafil or matching placebo are shown in Figure 2.

Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after sildenafil or matching placebo.

Outliers were defined as subjects with a standing systolic blood pressure of <85 mmHg or a decrease from baseline in standing systolic blood pressure of >30 mmHg at one or more timepoints.

There were no subjects treated with sildenafil 25 mg who had a standing SBP < 85mmHg.

There were three subjects with a decrease from baseline in standing systolic BP >30mmHg following sildenafil 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil and placebo.

No severe adverse events potentially related to blood pressure effects were reported in this group.

Of the four subjects who received sildenafil 100 mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with sildenafil with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing).

There were no reports of syncope among these patients.

For these four subjects, the placebo-subtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were 14.8 mmHg and 21.5 mmHg, respectively.

Two of these subjects had a standing SBP < 85mmHg.

Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension.

Study 2: Sildenafil with Doxazosin In the second study, a single oral dose of sildenafil 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH.

Following at least 14 consecutive days of doxazosin, sildenafil 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects).

The mean subject age in this study was 63.9 years.

Twenty subjects received sildenafil 50 mg, but only 19 subjects received matching placebo.

One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with sildenafil 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study.

For the 19 subjects who received both sildenafil and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure(mm Hg) sildenafil citrate 50 mg(95% CI) Supine 9.08 Standing 11.62 The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg sildenafil or matching placebo are shown in Figure 3.

Blood pressure was measured after administration of sildenafil at the same times as those specified for the first doxazosin study.

There were two subjects who had a standing SBP of < 85 mmHg.

In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of sildenafil 50 mg and resolving after approximately 7.5 hours.

There was one subject with a decrease from baseline in standing systolic BP >30mmHg following sildenafil 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil 50 mg and placebo.

There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study.

Study 3: Sildenafil with Doxazosin In the third study, a single oral dose of sildenafil 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH.

In dose period 1, subjects were administered open-label doxazosin and a single dose of sildenafil 50 mg simultaneously, after at least 14 consecutive days of doxazosin.

If a subject did not successfully complete this first dosing period, he was discontinued from the study.

Subjects who had successfully completed the previous doxazosin interaction study (using sildenafil 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1.

Treatment with doxazosin continued for at least 7 days after dose period 1.

Thereafter, sildenafil 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion.

The mean subject age in this study was 66.4 years.

Twenty-five subjects were screened.

Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label sildenafil 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using sildenafil 50 mg).

For the 20 subjects who received sildenafil 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure(mm Hg) sildenafil citrate 100 mg Supine 7.9 Standing 4.3 (-1.8,10.3) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg sildenafil or matching placebo are shown in Figure 4.

Blood pressure was measured after administration of sildenafil at the same times as those specified for the previous doxazosin studies.

There were three subjects who had a standi.

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

Administration of sildenafil tablets to patients using nitric oxide donors, such as organic nitrates or organic nitrites in any form.

Sildenafil tablets was shown to potentiate the hypotensive effect of nitrates Known hypersensitivity to sildenafil or any component of tablet Administration with guanylate cyclase (GC) stimulators, such as riociguat 4.1 Nitrates Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil tablets was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using nitric oxide donors such as organic nitrates or organic nitrites in any form either regularly and/or intermittently is therefore contraindicated.

After patients have taken sildenafil tablets, it is unknown when nitrates, if necessary, can be safely administered.

Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point. 4.2 Hypersensitivity Reactions Sildenafil tablets are contraindicated in patients with a known hypersensitivity to sildenafil, as contained in sildenafil tablets and REVATIO, or any component of the tablet.

Hypersensitivity reactions have been reported, including rash and urticaria. 4.3 Concomitant Guanylate Cyclase (GC) Stimulators Do not use sildenafil tablets in patients who are using a GC stimulator, such as riociguat.

PDE5 inhibitors, including sildenafil, may potentiate the hypotensive effects of GC stimulators.

For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity.

However, sildenafil tablets may be taken anywhere from 30 minutes to 4 hours before sexual activity Based on effectiveness and toleration, may increase to a maximum of 100 mg or decrease to 25 mg Maximum recommended dosing frequency is once per day 2.1 Dosage Information For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity.

However, sildenafil tablets may be taken anywhere from 30 minutes to 4 hours before sexual activity.

The maximum recommended dosing frequency is once per day. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. 2.2 Use with Food Sildenafil tablets may be taken with or without food. 2.3 Dosage Adjustments in Specific Situations Sildenafil tablets was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors such as organic nitrates or organic nitrites in any form is therefore contraindicated.

When sildenafil tablets are co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating sildenafil tablets treatment and sildenafil tablets should be initiated at 25 mg. 2.4 Dosage Adjustments Due to Drug Interactions Ritonavir The recommended dose for ritonavir-treated patients is 25 mg prior to sexual activity and the recommended maximum dose is 25 mg within a 48 hour period because concomitant administration increased the blood levels of sildenafil by 11-fold.

CYP3A4 Inhibitors Consider a starting dose of 25 mg in patients treated with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or saquinavir) or erythromycin.

Clinical data have shown that co-administration with saquinavir or erythromycin increased plasma levels of sildenafil by about 3 fold. 2.5 Dosage Adjustments in Special Populations Consider a starting dose of 25 mg in patients > 65 years, patients with hepatic impairment (e.g., cirrhosis), and patients with severe renal impairment (creatinine clearance <30 mL/minute) because administration of sildenafil tablets in these patients resulted in higher plasma levels of sildenafil.

Sildenafil tablets

USP are supplied as pale blue to blue, caplet shaped film-coated tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: For 25 mg.

• Pale blue to blue, round film-coated tablets, debossed with “25” on one side and “SL” on other side.

NDC 72789-404-30 Bottles of 30 Tablets NDC 72789-404-90 Bottles of 90 Tablets Recommended Storage: Store at 25°C (77°F); excursions permitted within 15-30°C (59-86°F) .

Sildenafil is not indicated for use in females.

There are no data with the use of sildenafil in pregnant women to inform any drug-associated risks for adverse developmental outcomes.

Animal reproduction studies conducted with sildenafil did not show adverse developmental outcomes when administered during organogenesis in rats and rabbits at oral doses up to and 32 times, respectively, the maximum recommended human dose (MRHD) of 100 mg/day on a mg/m 2 basis.

No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received oral doses up to 200 mg/kg/day during organogenesis.

These doses represent, respectively, about and 32 times the MRHD on a mg/m 2 basis in a 50 kg subject.

In the rat pre.

• and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days, about 2 times the MRHD on a mg/m 2 basis in a 50 kg subject.

Sildenafil is not indicated for use in pediatric patients.

Safety and effectiveness have not been established in pediatric patients.

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18-45 years) .

Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively.

Of the total number of subjects in clinical studies of sildenafil, 18% were 65 years and older, while 2% were 75 years and older.

No overall differences in safety or efficacy were observed between older (≥ 65 years of age) and younger (< 65 years of age) subjects.

However, since higher plasma levels may increase the incidence of adverse reactions, a starting dose of 25 mg should be considered in older subjects due to the higher systemic exposure.