SILDENAFIL- sildenafil citrate 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:
KAISER FOUNDATION HOSPITALS
INN (International Name):
SILDENAFIL CITRATE
Composition:
SILDENAFIL 20 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Sildenafil is 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 was added to background epoprostenol therapy [see Clinical Studies (14)] . Studies establishing effectiveness were short-term (12 to 16 weeks), 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 is contraindicated in patients with: - 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)] . - Known hypersensitivity to sildenafil or any component of the tablet. Hypersensitivity, inc
Product summary:
Sildenafil tablets are supplied as white, film-coated, round tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: Recommended Storage for Sildenafil Tablets: Store at controlled room temperature 20°C – 25°C (68°F – 77°F) ; excursions permitted to 15°C – 30°C (59°F –86°F) [see USP Controlled Room Temperature].
Authorization status:
New Drug Application Authorized Generic
Authorization number:
0179-0160-08, 0179-0160-24, 0179-0160-40

SILDENAFIL- sildenafil citrate tablet, film coated

KAISER FOUNDATION HOSPITALS

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use sildenafil safely and effectively. See full

prescribing information for sildenafil.

Sildenafil tablets, for oral use

Initial U.S. Approval: 1998

RECENT MAJOR CHANGES

INDICATIONS AND USAGE ( 1)

1/2014

WARNINGS AND PRECAUTIONS, Visual Loss ( 5.5)

3/2014

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

Tablets: 20 mg three times a day, 4–6 hours apart ( 2)

DOSAGE FORMS AND STRENGTHS

Tablets: 20 mg ( 3)

CONTRAINDICATIONS

Use with organic nitrates ( 4)

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

WARNINGS AND PRECAUTIONS

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)

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 Greenstone LLC Professional Information Services at

1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

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)

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

Revised: 9/2014

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

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 Labor and Delivery

8.3 Nursing Mothers

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

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Sildenafil is 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 was added to background epoprostenol therapy [see Clinical Studies (14)] .

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

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

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)] .

2 DOSAGE AND ADMINISTRATION

Sildenafil Tablets

The recommended dose of sildenafil is 20 mg three times a day. Administer sildenafil doses 4–6 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

White, film-coated, round tablets engraved with SDF20 containing sildenafil citrate equivalent to 20 mg

of sildenafil.

4 CONTRAINDICATIONS

Sildenafil is contraindicated in patients with:

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)] .

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.

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 co-administering 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

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.

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 2.5-11.8 cases per 100,000 males aged ≥ 50 per year in

the general population. An observational study evaluated whether recent, episodic use of PDE5

inhibitors (as a class), typical of erectile dysfunction treatment, was associated with acute onset of

NAION. The results suggest an approximately 2-fold increase in the risk of NAION within 5 half-lives

of PDE5 inhibitor use. It is not possible to determine whether these events are related directly to the

use of PDE-5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a

combination of these factors, or to other factors. 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.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:

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)]

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, %

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 at the recommended 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)

Epopros tenol

(n = 131)

(Sildenafil + Epoprostenol) minus

Epoprostenol

%

Headache

Edema

Dyspepsia

Pain in extremity

Diarrhea

Nausea

Nasal congestion

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

includes peripheral edema

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.

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 co-administered 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 co-administering blood pressure lowering drugs with sildenafil [see

Warnings and Precautions (5.2)] .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of sildenafil in pregnant women. 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 68-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 Labor and Delivery

The safety and efficacy of sildenafil during labor and delivery have not been studied.

8.3 Nursing Mothers

It is not known if sildenafil or its metabolites are excreted in human breast milk. Because many drugs are

excreted in human milk, caution should be exercised when sildenafil is administered to a nursing woman.

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 1:

Figure 1: 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 CLcr < 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, 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

for erectile dysfunction.

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 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: Sildenafil is formulated as white, film-coated round tablets for oral administration.

Each tablet contains sildenafil citrate equivalent to 20 mg of sildenafil. In addition to the active

Each tablet contains sildenafil citrate equivalent to 20 mg of sildenafil. In addition to the active

ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline

cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate,

hypromellose, titanium dioxide, lactose monohydrate, and triacetin.

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.

Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5

than on other known phosphodiesterases (10-fold for PDE-6, greater than 80-fold for PDE-1, greater

than 700-fold for PDE-2, PDE-3, PDE-4, PDE-7, PDE-8, PDE-9, PDE-10, and PDE-11). The

approximately 4,000-fold selectivity for PDE-5 versus PDE-3 is important because PDE-3 is involved

in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to

PDE-6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This

lower selectivity is thought to be the basis for abnormalities related to color vision observed with

higher doses or plasma levels [see Clinical Pharmacology (12.2)] .

In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in

other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in

these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric

oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.

12.2 Pharmacodynamics

Effects of Sildenafil on Hemodynamic Measures

Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial

pressure (mPAP) compared to those on placebo in a study with no background vasodilators [ Study 1 in

Clinical Studies (14)] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day

and placebo dosing regimens is displayed in Table 3. The relationship between these effects and

improvements in 6-minute walk distance is unknown.

Table 3. Changes from Baseline in Hemodynamic Parameters at Week

12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and

Placebo Group

Placebo

(n = 65)

Sildenafil 20 mg three

times a day

(n = 65)

mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular

resistance; SVR = systemic vascular resistance; RAP = right atrial pressure;

CO = cardiac output; HR = heart rate

mPAP (mmHg)

0.6 (-0.8, 2.0)

-2.1 (-4.3, 0.0)

PVR (dyn·s/cm

)

49 (-54, 153)

-122 (-217, -27)

SVR (dyn·s/cm

)

-78 (-197, 41)

-167 (-307, -26)

RAP (mmHg)

0.3 (-0.9, 1.5)

-0.8 (-1.9, 0.3)

CO (L/min)

-0.1 (-0.4, 0.2)

0.4 (0.1, 0.7)

HR (beats/min)

-1.3 (-4.1, 1.4)

-3.7 (-5.9, -1.4)

*

*

The number of patients per treatment group varied slightly for each parameter due

5

5

In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [Study 3 in Clinical Studies

(14)], there were no significant differences in the effects on hemodynamic variables between doses.

Effects of Sildenafil on Blood Pressure

Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine

blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The

decrease in blood pressure was most notable approximately 1–2 hours after dosing, and was not

different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and

100 mg doses 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 [see

Contraindications (4)] .

Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant

effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically

relevant effects on ECG were reported.

After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean

change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0

mmHg and 8.4 mmHg, respectively.

After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the

mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and

9.1 mmHg, respectively.

After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than

above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).

Effects of Sildenafil on Vision

At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination

(blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of

peak plasma levels. This finding is consistent with the inhibition of PDE-6, which is involved in

phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no

effects of sildenafil on visual acuity, intraocular pressure, or pupillometry.

12.3 Pharmacokinetics

Absorption and Distribution

Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25–

63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60

minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of

absorption is reduced, with a mean delay in T

of 60 minutes and a mean reduction in C

of 29%.

The mean steady state volume 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.

Metabolism and Excretion

Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (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 phosphodiesterase

selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the

parent drug. In healthy volunteers, 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. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both

sildenafil and the active metabolite have terminal half-lives of about 4 hours.

to missing assessments.

sildenafil and the active metabolite have terminal half-lives of about 4 hours.

After oral administration, sildenafil is excreted as metabolites predominantly in the feces (approximately

80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the

administered oral dose).

Population Pharmacokinetics

Age, gender, race, and renal and hepatic function were included as factors assessed in the population

pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset

available for the population pharmacokinetic evaluation contained a wide range of demographic data and

laboratory parameters associated with hepatic and renal function. None of these factors had a significant

impact on sildenafil pharmacokinetics in patients with PAH.

In patients with PAH, the average steady-state concentrations were 20–50% higher when compared to

those of healthy volunteers. There was also a doubling of C

levels compared to healthy volunteers.

Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients

with pulmonary hypertension compared to healthy volunteers.

Geriatric Patients

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in

approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl

metabolite, respectively, compared to those seen in healthy younger 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.

Renal Impairment

In volunteers with mild (CLcr = 50–80 mL/min) and moderate (CLcr = 30–49 mL/min) renal impairment,

the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with

severe (CLcr < 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in

approximately doubling of AUC and C

compared to age-matched volunteers with no renal

impairment. In addition, N-desmethyl metabolite AUC and C

values were significantly increased

200 % and 79 %, respectively, in subjects with severe renal impairment compared to subjects with

normal renal function.

Hepatic Impairment

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance

was reduced, resulting in increases in AUC (84%) and C

(47%) compared to age-matched

volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C)

have not been studied.

Drug Interaction Studies

In vitro studies

Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route)

cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance

and inducers of these isoenzymes may increase sildenafil clearance.

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A

(IC50 >150 µM).

Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these

CYP enzymes at clinically relevant concentrations.

In vivo studies

The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure

to other drugs are shown in Figure 2 and Figure 3, respectively.

Figure 2. Effects of Other Drugs on Sildenafil Pharmacokinetics

Figure 3 Effects of Sildenafil on Other Drugs

CYP3A Inhibitors and Beta Blockers

Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately

30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A

inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-

blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is

shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers

the same increased sildenafil exposure observed in specifically-designed drug interaction studies with

CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir).

CYP3A4 inducers including bosentan

Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in

plasma levels of sildenafil.

Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-

fold the sildenafil clearance when it was co-administered with mild CYP3A inducers.

Epoprostenol

The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with

epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations.

Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered

clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known.

No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which

are metabolized by CYP2C9.

Alcohol

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean

maximum blood alcohol levels of 0.08%.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose

resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37

times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day.

Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months,

respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD

on a mg/m

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 mouse micronucleus assays to detect

clastogenicity.

There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose

producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19 and 38

times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day.

14 CLINICAL STUDIES

Studies of Adults with Pulmonary Arterial Hypertension

Study 1 (Sildenafil monotherapy (20 mg, 40 mg, and 80 mg three times a day))

A randomized, double-blind, placebo-controlled study of sildenafil (Study 1) was conducted in 277

patients with PAH (defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg at

rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were predominantly World

Health Organization (WHO) functional classes II–III. Allowed background therapy included a

combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of

prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not

permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left

ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were

not studied.

Patients were randomized to receive placebo (n=70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80

mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension

(PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right

congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean

age of 49 years (range: 18–81 years) and baseline 6-minute walk distance between 100 and 450 meters

(mean 343).

The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last

dose) in 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45–50 meters

were observed with all doses of sildenafil. These increases were significantly different from placebo,

but the sildenafil dose groups were not different from each other (Figure 4), indicating no additional

clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was

apparent after 4 weeks of treatment and was maintained at week 8 and week 12.

Figure 4. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in

Study 1: Mean (95% Confidence Interval)

Figure 5 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk

Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age,

and secondary hemodynamic parameters.

Figure 5. Placebo Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week

12 by study subpopulation in Study 1: Mean (95% Confidence Interval)

Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary

hypertension;

PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times

daily.

Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study. At the end of 1 year,

94% of these patients were still alive. Additionally, walk distance and functional class status appeared

to be stable in patients taking sildenafil. Without a control group, these data must be interpreted

cautiously.

Study 2 (Sildenafil co-administered with epoprostenol)

A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with

PAH who were stabilized on intravenous epoprostenol. Patients had to have a mean pulmonary artery

pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP)

less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization,

and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to

450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil (in a fixed titration

starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous

epoprostenol therapy.

At baseline patients had PPH (80%) or PAH secondary to CTD (20%); WHO functional class I (1%), II

(26%), III (67%), or IV (6%) at baseline. The mean age was 48 years, 80% were female, and 79% were

Caucasian.

There was a statistically significant greater increase in 6-minute walk distance at Week 16 (primary

endpoint) for the sildenafil group compared with the placebo group. The mean change from baseline at

Week 16 (last observation carried forward) was 30 meters for the sildenafil group compared with 4

meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2)

(p = 0.0009).

Patients on sildenafil achieved a statistically significant reduction in mPAP compared to those on

placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil

(95% CI: -5.7, -2.1) (p = 0.00003).

Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence

of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical

deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with

clinical worsening events in Study 2. Kaplan-Meier estimates and a stratified log-rank test demonstrated

that placebo-treated patients were 3 times more likely to experience a clinical worsening event than

sildenafil-treated patients and that sildenafil-treated patients experienced a significant delay in time to

clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical

worsening is presented in Figure 6.

Table 4. Clinical Worsening Events in Study 2

Placebo

(N = 131)

Sildenafil

(N = 134)

Number of subjects with clinical

worsening first event

First Event

All Events

First Event

All Events

Death, n

Lung Transplantation, n

Hospitalization due to PAH, n

Clinical deterioration resulting in:

Change of Epoprostenol Dose, n

Initiation of Bosentan Therapy, n

Proportion Worsened

95% Confidence Intervals

0.187

(0.12 – 0.26)

0.062

(0.02 – 0.10)

Figure 6. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in Study 2

Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil

compared to placebo. More than twice as many sildenafil-treated patients (36%) as the placebo group

(14%) showed an improvement of at least one functional New York Heart Association (NYHA) class

for PAH.

Study 3 (Sildenafil monotherapy (1 mg, 5 mg, and 20 mg three times a day))

A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. This

study was prematurely terminated with 129 subjects enrolled. Patients were required to have a mPAP

greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart

catheterization within 12 weeks before randomization, and a baseline 6-minute walk test distance greater

than or equal to 100 meters and less than or equal to 450 meters (mean 345 meters). Patients were

randomized to 1 of 3 doses of sildenafil: 1 mg, 5 mg, and 20 mg, three times a day.

At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III

(41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were

Asian (67%), and 28% were Caucasian.

The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last

dose) in the 6-minute walk distance. Similar increases in walk distance (mean increase of 38–41 meters)

were observed in the 5 and 20 mg dose groups. These increases were significantly better than those

observed in the 1 mg dose group (Figure 7).

Figure 7. Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 – ITT

Population Sildenafil Protocol A1481244

Study 4 (Sildenafil added to bosentan therapy – lack of effect on exercise capacity)

A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who

were on bosentan therapy for a minimum of three months. The PAH patients included those with primary

PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three

times a day) in combination with bosentan (62.5–125 mg twice a day). The primary efficacy endpoint was

the change from baseline at Week 12 in 6MWD. The results indicate that there is no significant

difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan

and bosentan alone.

16 HOW SUPPLIED/STORAGE AND HANDLING

Sildenafil tablets are supplied as white, film-coated, round tablets containing sildenafil citrate

equivalent to the nominally indicated amount of sildenafil as follows:

Sildenafil Tablets

Package Configuration

Strength

Engraving on Tablet

Bottle of 40 Tablets

20 mg

0179-0160-40

SDF20

Bottle of 24 Tablets

20 mg

0179-0160-24

SDF20

Bottle of 8 Tablets

20 mg

0179-0160-08

SDF20

Recommended Storage for Sildenafil Tablets: Store at controlled room temperature 20°C – 25°C (68°F

– 77°F) ; excursions permitted to 15°C – 30°C (59°F –86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling ( Patient Information)

Inform patients of contraindication of sildenafil with regular and/or intermittent use of organic

nitrates.

Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise patients

taking sildenafil not to take VIAGRA or other PDE-5 inhibitors.

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

both eyes while taking sildenafil. Such an event may be a sign of NAION.

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

while taking sildenafil. These events may be accompanied by tinnitus and dizziness.

This product's label may have been updated. For current full prescribing information, please visit

www.greenstonellc.com.

LAB-0562-3.0

PATIENT INFORMATION

Sildenafil tablets

Read this Patient Information before you start taking sildenafil and each time you get a refill. There may

be new information. This information does not take the place of talking with your doctor about your

medical condition or treatment. If you have any questions about sildenafil, ask your doctor or

pharmacist.

What is the most important information I should know about sildenafil?

Never take sildenafil with any nitrate medicines. Your blood pressure could drop quickly to an

unsafe level. Nitrate medicines include:

Medicines that treat chest pain (angina)

Nitroglycerin in any form including tablets, patches, sprays, and ointments

Isosorbide mononitrate or dinitrate

Street drugs called "poppers" (amyl nitrate or nitrite)

Ask your doctor or pharmacist if you are not sure if you are taking a nitrate medicine.

What is sildenafil?

Sildenafil is a prescription medicine used in adults to treat pulmonary arterial hypertension (PAH). With

PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your

lungs.

Sildenafil improves the ability to exercise and can slow down worsening changes in your physical

condition.

Sildenafil is not for use in children

Adding sildenafil to another medication used to treat PAH bosentan (Tracleer

), does not result in

improvement in your ability to exercise.

Sildenafil contains the same medicine as VIAGRA

(sildenafil), which is used to treat erectile

dysfunction (impotence). Do not take sildenafil with VIAGRA or other PDE-5 inhibitors.

Who should not take Sildenafil?

Do not take sildenafil if you:

take nitrate medicines. See " What is the most important information I should know about

s ildenafil?"

are allergic to sildenafil or any other ingredient in sildenafil tablets. See " What are the

ingredients in sildenafil?" at the end of this leaflet.

What should I tell my doctor before taking sildenafil?

Tell your doctor about all of your medical conditions, including if you

have heart problems such as angina (chest pain), heart failure, irregular heartbeats, or have had a

heart attack

have a disease called pulmonary veno-occlusive disease (PVOD)

have high or low blood pressure or blood circulation problems

have an eye problem called retinitis pigmentosa

have or had loss of sight in one or both eyes

have any problem with the shape of your penis or Peyronie's disease

have any blood cell problems such sickle cell anemia

have a stomach ulcer or any bleeding problems

are pregnant or planning to become pregnant. It is not known if sildenafil could harm your unborn

baby.

are breastfeeding. It is not known if sildenafil passes into your breast milk or if it could harm your

baby.

Tell your doctor about all of the medicines you take, including prescription and non-prescription

medicines, vitamins, and herbal products. Sildenafil and certain other medicines can cause side

effects if you take them together. The doses of some of your medicines may need to be adjusted while

you take sildenafil.

Especially tell your doctor if you take

Nitrate medicines. See " What is the most important information I should know about

s ildenafil?"

Ritonavir (Norvir

) or other medicines used to treat HIV infection

Ketoconazole (Nizoral

Itraconazole (Sporanox)

High blood pressure medicine

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist

when you get a new medicine.

How should I take sildenafil?

Take sildenafil exactly as your doctor tells you.

Take sildenafil tablet 3 times a day about 4 to 6 hours apart.

Take sildenafil tablets at the same times every day.

If you miss a dose, take it as soon as you remember. If it is close to your next dose, skip the missed

dose, and take your next dose at the regular time.

Do not take more than one dose of sildenafil at a time.

Do not change your dose or stop taking sildenafil on your own. Talk to your doctor first.

If you take too much sildenafil, call your doctor or go to the nearest hospital emergency room.

What are the possible side effects of sildenafil?

low blood pressure. Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel

faint or dizzy.

more shortness of breath than usual. Tell your doctor if you get more short of breath after you

start sildenafil. More shortness of breath than usual may be due to your underlying medical

condition.

decreased eyesight or loss of sight in one or both eyes (NAION). If you notice a sudden

decrease or loss of eyesight, talk to your doctor right away.

sudden decrease or loss of hearing. If you notice a sudden decrease or loss of hearing, talk to

your doctor right away. It is not possible to determine whether these events are related directly to

this class of oral medicines, including sildenafil, or to other diseases or medicines, to other factors,

or to a combination of factors.

heart attack, stroke, irregular heartbeats, and death. Most of these happened in men who already

had heart problems.

erections that last several hours. If you have an erection that lasts more than 4 hours, get medical

help right away. If it is not treated right away, priapism can permanently damage your penis.

The most common side effects with sildenafil include:

Nosebleed, headache, upset stomach, getting red or hot in the face (flushing), trouble sleeping, as well

as fever, erection increased, respiratory infection, nausea, vomiting, bronchitis, pharyngitis, runny nose,

and pneumonia in children.

Tell your doctor if you have any side effect that bothers you or doesn't go away.

These are not all the possible side effects of sildenafil. For more information, ask your doctor or

pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store sildenafil?

Store sildenafil tablets at controlled room temperature, between 20°C –25°C (68°F to 77°F).

Keep sildenafil and all medicines away from children.

General information about sildenafil

Medicines are sometimes prescribed for purposes that are not in the patient leaflet. Do not use

sildenafil for a condition for which it was not prescribed. Do not give sildenafil to other people, even

if they have the same symptoms you have. It could harm them.

This patient leaflet summarizes the most important information about sildenafil. If you would like more

information about sildenafil talk with your doctor. You can ask your doctor or pharmacist for

information about sildenafil that is written for health professionals.

For more information go to www.greenstonellc.com or call 1-800-438-1985.

What are the ingredients in sildenafil?

Sildenafil tablets

Active ingredients: sildenafil citrate

Inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose

sodium, magnesium stearate, hypromellose, titanium dioxide, lactose monohydrate, and triacetin

This product's label may have been updated. For current full prescribing information, please visit

www.greenstonellc.com.

LAB-0563-4.0

April 2014

Trademarks are the property of their respective owners.

PRINCIPAL DISPLAY PANEL - 20 mg- 40 Tablets Bottle Label

NDC 0179-0160-40

40 Tablets

GREENSTONE

BRAND

Repackaged by: KAISER FOUNDATION HOSPITALS

Livermore, CA 94551

sildenafil

tablets

20 mg*

Rx only

PRINCIPAL DISPLAY PANEL - 20 mg- 24 Tablets Bottle Label

NDC 0179-0160-24

24 Tablets

GREENSTONE

BRAND

Repackaged by: KAISER FOUNDATION HOSPITALS

Livermore, CA 94551

sildenafil

tablets

20 mg*

®

®

Rx only

PRINCIPAL DISPLAY PANEL - 20 mg- 8 Tablets Bottle Label

NDC 0179-0160-08

8 Tablets

GREENSTONE

BRAND

Repackaged by: KAISER FOUNDATION HOSPITALS

Livermore, CA 94551

sildenafil

tablets

20 mg*

Rx only

SILDENAFIL

sildenafil citrate tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 179 -0 16 0 (NDC:59 76 2-0 0 33)

Route of Administration

ORAL

®

KAISER FOUNDATION HOSPITALS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

SILDENAFIL CITRATE (UNII: BW9 B0 ZE0 37) (SILDENAFIL - UNII:3M7OB9 8 Y7H)

SILDENAFIL

20 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ANHYDRO US DIBASIC CALCIUM PHO SPHATE (UNII: L11K75P9 2J)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

TRIACETIN (UNII: XHX3C3X6 73)

Product Characteristics

Color

white

S core

no sco re

S hap e

ROUND

S iz e

Flavor

Imprint Code

SDF20

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 179 -0 16 0 -40

40 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /19 /20 14

0 7/31/20 20

2

NDC:0 179 -0 16 0 -24

24 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /19 /20 14

0 7/31/20 20

3

NDC:0 179 -0 16 0 -0 8

8 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /19 /20 14

0 7/31/20 20

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA autho rized generic

NDA0 218 45

0 9 /19 /20 14

0 7/31/20 20

Labeler -

KAISER FOUNDAT ION HOSPIT ALS (053052619)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

KAISER FOUNDATION HOSPITALS

0 530 526 19

re pa c k(0 179 -0 16 0 )

Revised: 11/2018

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