SILDENAFIL tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
SILDENAFIL CITRATE (UNII: BW9B0ZE037) (SILDENAFIL - UNII:3M7OB98Y7H)
Available from:
Proficient Rx LP
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil tablets were added to background epoprostenol therapy [see Clinical Studies (14) ]. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%). Limitation of Use : Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity [see Clinical Studies (14) ]. Sildenafil tablets are contraindicated in patients with: Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcom
Product summary:
Sildenafil Tablets USP, 20 mg are supplied as white, film-coated, unscored, round biconvex tablets, debossed with “TEVA” on one side of the tablet and “5517” on the other side, in bottles of 30 (NDC 71205-509-30), 60 (NDC 71205-509-60), and 90 (NDC 71205-509-90). Recommended Storage: Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
Authorization status:
Abbreviated New Drug Application
Authorization number:
71205-509-30, 71205-509-60, 71205-509-90

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SILDENAFIL- sildenafil tablet, film coated

Proficient Rx LP

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use SILDENAFIL TABLETS safely and

effectively. See full prescribing information for SILDENAFIL TABLETS.

SILDENAFIL tablets, for oral use

Initial U.S. Approval: 1998

INDICATIONS AND USAGE

Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH)

(WHO Group I) in adults to improve exercise ability and delay clinical worsening. Studies establishing effectiveness were

short-term (12 to 16 weeks), and included predominately patients with NYHA Functional Class II-III symptoms. Etiologies

were idiopathic (71%) or associated with connective tissue disease (25%). (1)

Limitation of Use: Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity. (1, 14)

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

Most common adverse reactions greater than or equal to 3% and more frequent than placebo were epistaxis, headache,

dyspepsia, flushing, insomnia, erythema, dyspnea, and rhinitis. (6.1, 6.2)

To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 11/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Sildenafil Tablets

Tablet: 20 mg three times a day, 4 to 6 hours apart (2.1)

Tablets: 20 mg (3)

Use with organic nitrates or riociguat (4)

History of hypersensitivity reaction to sildenafil or any component of the tablet (4)

Increased mortality with increasing doses in pediatric patients. Not recommended for use in pediatric patients. (5.1)

Vasodilation effects may be more common in patients with hypotension or on antihypertensive therapy. (5.2)

Use in pulmonary veno-occlusive disease may cause pulmonary edema and is not recommended. (5.3)

Hearing or visual impairment: Seek medical attention if sudden decrease or loss of vision or hearing occurs. (5.5, 5.6)

Pulmonary hypertension secondary to sickle cell disease: Sildenafil may cause serious vaso-occlusive crises. (5.9)

Concomitant alpha-blockers or amlodipine: Note additive blood pressure lowering effects. (7)

Use with ritonavir and other potent CYP3A inhibitors: Not recommended. (7, 12.3)

Concomitant PDE-5 inhibitors: Avoid use with Viagra or other PDE-5 inhibitors. (5.7)

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Mortality With Pediatric Use

5.2 Hypotension

5.3 Worsening Pulmonary Vascular Occlusive Disease

5.4 Epistaxis

5.5 Visual Loss

5.6 Hearing Loss

5.7 Combination With Other PDE-5 Inhibitors

5.8 Priapism

5.9 Vaso-Occlusive Crisis in Patients With Pulmonary Hypertension Secondary to Sickle Cell

Anemia

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients With Hepatic Impairment

8.7 Patients With Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

Sildenafil Tablets USP 20 mg 90s Label Text

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in

adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was

demonstrated when sildenafil tablets were added to background epoprostenol therapy [see Clinical

Studies (14)].

Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately

patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic

etiology (71%) or associated with connective tissue disease (CTD) (25%).

Sections or subsections omitted from the full prescribing information are not listed.

Limitation of Use: Adding sildenafil to bosentan therapy does not result in any beneficial effect on

exercise capacity [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Sildenafil Tablets

The recommended dose of sildenafil tablets is 20 mg three times a day. Administer sildenafil tablet

doses 4 to 6 hours apart.

In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses

higher than 20 mg three times a day is not recommended.

3 DOSAGE FORMS AND STRENGTHS

Sildenafil Tablets USP

Sildenafil Tablets USP are supplied as white, film-coated, unscored, round biconvex tablets, debossed

with “TEVA” on one side and “5517” on the other side containing sildenafil citrate, USP equivalent to

20 mg of sildenafil.

4 CONTRAINDICATIONS

Sildenafil tablets are contraindicated in patients with:

5 WARNINGS AND PRECAUTIONS

5.1 Mortality With Pediatric Use

In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil

dose was observed. Deaths were first observed after about 1 year and causes of death were typical of

patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children [see Use

in Specific Populations (8.4)].

5.2 Hypotension

Sildenafil has vasodilatory properties, resulting in mild and transient decreases in blood pressure.

Before prescribing sildenafil, carefully consider whether patients with certain underlying conditions

could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or

with resting hypotension [BP less than 90/50], fluid depletion, severe left ventricular outflow

obstruction, or autonomic dysfunction). Monitor blood pressure when coadministering blood pressure

lowering drugs with sildenafil.

5.3 Worsening Pulmonary Vascular Occlusive Disease

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary

veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil to

Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the

greater risk of hypotension [see Warnings and Precautions (5.2)].

Concomitant use of riociguat, a guanylate cyclase stimulator. PDE-5 inhibitors, including

sildenafil, may potentiate the hypotensive effects of riociguat.

Known hypersensitivity to sildenafil or any component of the tablet. Hypersensitivity, including

anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in

association with the use of sildenafil.

patients with veno-occlusive disease, administration of sildenafil to such patients is not recommended.

Should signs of pulmonary edema occur when sildenafil is administered, consider the possibility of

associated PVOD.

5.4 Epistaxis

The incidence of epistaxis was 13% in patients taking sildenafil with PAH secondary to CTD. This

effect was not seen in idiopathic PAH (sildenafil 3%, placebo 2%) patients. The incidence of epistaxis

was also higher in sildenafil-treated patients with a concomitant oral vitamin K antagonist (9% versus

2% in those not treated with concomitant vitamin K antagonist).

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

5.5 Visual Loss

When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a

cause of decreased vision including permanent loss of vision, has been reported postmarketing in

temporal association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, including sildenafil.

Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing

NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50,

diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. Based on published

literature, the annual incidence of NAION is 2.5 to 11.8 cases per 100,000 males aged ≥ 50 per year in

the general population.

An observational case-crossover study evaluated the risk of NAION when PDE-5 inhibitor use, as a

class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE-5 inhibitor

use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION,

with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk

estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded”

optic disc, may have contributed to the occurrence of NAION in these studies.

Neither the rare postmarketing reports, nor the association of PDE-5 inhibitor use and NAION in the

observational studies, substantiate a causal relationship between PDE-5 inhibitor use and NAION [see

Adverse Reactions (6.2)].

Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both

eyes while taking PDE-5 inhibitors, including sildenafil. Physicians should also discuss the increased

risk of NAION with patients who have already experienced NAION in one eye, including whether such

individuals could be adversely affected by use of vasodilators, such as PDE-5 inhibitors.

There are no controlled clinical data on the safety or efficacy of sildenafil in patients with retinitis

pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe sildenafil

with caution in these patients.

5.6 Hearing Loss

Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have

been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil. In some of

the cases, medical conditions and other factors were reported that may have played a role. In many

cases, medical follow-up information was limited. It is not possible to determine whether these reported

events are related directly to the use of sildenafil, to the patient’s underlying risk factors for hearing

loss, a combination of these factors, or to other factors.

Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing

while taking PDE-5 inhibitors, including sildenafil.

5.7 Combination With Other PDE-5 Inhibitors

Sildenafil is also marketed as VIAGRA . The safety and efficacy of combinations of sildenafil with

VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil not to take

VIAGRA or other PDE-5 inhibitors.

5.8 Priapism

Use sildenafil with caution in patients with anatomical deformation of the penis (e.g., angulation,

cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions, which may predispose

them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection

that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism

(painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and

permanent loss of potency could result.

5.9 Vaso-Occlusive Crisis in Patients With Pulmonary Hypertension Secondary to Sickle Cell

Anemia

In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to

sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by

patients who received sildenafil than by those randomized to placebo. The effectiveness and safety of

sildenafil in the treatment of PAH secondary to sickle cell anemia has not been established.

6 ADVERSE REACTIONS

The following serious adverse events are discussed elsewhere in the labeling:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice.

Safety data of sildenafil in adults were obtained from the 12 week, placebo-controlled clinical study

(Study 1) and an open-label extension study in 277 sildenafil-treated patients with PAH, WHO Group I

[see Clinical Studies (14)].

The overall frequency of discontinuation in sildenafil-treated patients on 20 mg three times a day was

3% and was the same for the placebo group.

In Study 1, the adverse reactions that were reported by at least 3% of sildenafil-treated patients (20 mg

three times a day) and were more frequent in sildenafil-treated patients than in placebo-treated patients

are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature.

Table 1: Most Common Adverse Reactions in Patients With PAH in Study 1 (More Frequent in

Sildenafil-Treated Patients Than Placebo-Treated Patients and Incidence ≥ 3% in Sildenafil-

Treated Patients)

Placebo, %

(n = 70)

Sildenafil 20 mg

three times a day, %

(n = 69)

Placebo-Subtracted, %

Mortality with pediatric use [see Warnings and Precautions (5.1) and Use in Specific Populations

(8.4)]

Hypotension [see Warnings and Precautions (5.2)]

Vision loss [see Warnings and Precautions (5.5)]

Hearing loss [see Warnings and Precautions (5.6)]

Priapism [see Warnings and Precautions (5.8)]

Vaso-occlusive crisis [see Warnings and Precautions (5.9)]

Epistaxis

Headache

Dyspepsia

Flushing

Insomnia

Erythema

Dyspnea exacerbated

Rhinitis

Diarrhea

Myalgia

Pyrexia

Gastritis

Sinusitis

Paresthesia

At doses higher than the recommended 20 mg three times a day, there was a greater incidence of some

adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances

were identified as mild and transient, and were predominately color-tinge to vision, but also increased

sensitivity to light or blurred vision.

The incidence of retinal hemorrhage with sildenafil, 20 mg three times a day was 1.4% versus 0%

placebo and for all sildenafil doses studied was 1.9% versus 0% placebo. The incidence of eye

hemorrhage at both 20 mg three times a day and at all doses studied was 1.4% for sildenafil versus

1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including

concurrent anticoagulant therapy.

In a placebo-controlled fixed dose titration study (Study 2) of sildenafil (starting with recommended

dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous

epoprostenol in patients with PAH, the adverse reactions that were more frequent in the sildenafil +

epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2

[see Clinical Studies (14)].

Table 2: Adverse Reactions (%) in Patients With PAH in Study 2 (Incidence in Sildenafil +

Epoprostenol Group at Least 6% Greater Than Epoprostenol Group)

Sildenafil + Epoprostenol

(n = 134)

Epoprostenol

(n = 131)

(Sildenafil + Epoprostenol)

minus Epoprostenol

Headache

Edema

Dyspepsia

Pain in extremity

Diarrhea

Nausea

Nasal congestion

includes peripheral edema

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of sildenafil (marketed

for both PAH and erectile dysfunction). Because these reactions are reported voluntarily from a

population of uncertain size, it is not always possible to reliably estimate their frequency or establish a

causal relationship to drug exposure.

Cardiovascular Events

In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious

cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac

death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension,

pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal

association with the use of the drug. 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 use concurrent with sexual activity. It is not possible to

determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s

underlying cardiovascular disease, or to a combination of these or other factors.

Nervous system

Seizure, seizure recurrence

Ophthalmologic

NAION [see Warnings and Precautions (5.5) and Patient Counseling Information (17)].

7 DRUG INTERACTIONS

Nitrates

Concomitant use of sildenafil with nitrates in any form is contraindicated [see Contraindications (4)].

Ritonavir and other Potent CYP3A Inhibitors

Concomitant use of sildenafil with ritonavir and other potent CYP3A inhibitors is not recommended [see

Clinical Pharmacology (12.3)].

Other drugs that reduce blood pressure

Alpha blockers. In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-

blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic

hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional

reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg,

respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4

mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients

who experienced symptomatic postural hypotension. These reports included dizziness and light-

headedness, but not syncope.

Amlodipine. 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.

Monitor blood pressure when coadministering blood pressure lowering drugs with sildenafil [see

Warnings and Precautions (5.2)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited published data from randomized controlled trials, case-controlled trials, and case series do not

report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or

fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from

untreated pulmonary arterial hypertension (see Clinical Considerations). Animal reproduction studies

conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to

32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits,

respectively (See Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In

the U.S. general population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke,

preterm delivery, and maternal and fetal death.

Data

Animal Data

No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits

dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m basis, 32- and 65-

times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and

postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-

times the RHD on a mg/m basis).

8.2 Lactation

Risk Summary

Limited published data from a case report describe the presence of sildenafil and its active metabolite in

human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and

no information on the effects of sildenafil on milk production. Limited clinical data during lactation

preclude a clear determination of the risk of sildenafil to an infant during lactation.

8.4 Pediatric Use

In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study,

234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized,

on the basis of body weight, to three dose levels of sildenafil, or placebo, for 16 weeks of treatment.

Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III

(15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-

to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or

placebo was administered three times a day.

The primary objective of the study was to assess the effect of sildenafil on exercise capacity as

measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the

test (n = 115). Administration of sildenafil did not result in a statistically significant improvement in

exercise capacity in those patients. No patients died during the 16 week controlled study.

After completing the 16 week controlled study, a patient originally randomized to sildenafil remained on

his/her dose of sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or

high-dose sildenafil. After all patients completed 16 weeks of follow-up in the controlled study, the

blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were

followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by

originally assigned dose, is shown in Figure 6:

Fig ure 6: Kaplan-Meier Plot of Mortality by Sildenafil Dose

During the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to

titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil

doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to

low dose was 3.9, p = 0.007. Causes of death were typical of patients with PAH. Use of sildenafil,

particularly chronic use, is not recommended in children.

8.5 Geriatric Use

Clinical studies of sildenafil did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently from younger subjects. Other reported clinical experience

has not identified differences in responses between the elderly and younger patients. In general, dose

selection for an elderly patient should be cautious, reflecting the greater frequency of decreased

hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical

Pharmacology (12.3)].

8.6 Patients With Hepatic Impairment

No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied

[see Clinical Pharmacology (12.3)].

8.7 Patients With Renal Impairment

No dose adjustment is required (including severe impairment CL < 30 mL/min) [see Clinical

Pharmacology (12.3)].

10 OVERDOSAGE

In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those

seen at lower doses but 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.

11 DESCRIPTION

Sildenafil Tablets USP, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a

selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5

(PDE-5). Sildenafil is also marketed as VIAGRA (sildenafil citrate tablets) for erectile dysfunction.

Sildenafil citrate, USP 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:

H N O SC H O M.W. 666.7

Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in

water.

Sildenafil citrate, USP is formulated as white, film-coated, unscored, round biconvex tablets equivalent

to 20 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, USP,

each tablet contains the following inactive ingredients: croscarmellose sodium, dibasic calcium

phosphate anhydrous, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl

alcohol - partially hydrolyzed, talc, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of

the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore,

increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with

PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation

in the systemic circulation.

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