Sildenafil

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

Sildenafil tablets, USP 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 was 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 )].

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

Sildenafil Tablets White, film-coated, circular, biconvex tablets debossed with 'SC' on one side and '20' on other side containing sildenafil citrate equivalent to 20 mg of sildenafil.

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

Sildenafil tablets are 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 )]. • 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.

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

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 )]

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

Nitrates Concomitant use of sildenafil tablets with nitrates in any form is contraindicated [see Contraindications ( 4 )] . Ritonavir and other Potent CYP3A Inhibitors Concomitant use of sildenafil tablets 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 tablets [see Warnings and Precautions ( 5.2 )] .

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

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

DESCRIPTION SECTION

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, 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: Sildenafil tablets, USP is formulated as white, film-coated, circular, biconvex tablets for oral administration. Each tablet contains sildenafil citrate USP equivalent to 20 mg of sildenafil. In addition to the active ingredient, sildenafil citrate USP, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, hypromellose, hydroxypropyl cellulose, titanium dioxide, and polyethylene glycol.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

Studies of Adults with Pulmonary Arterial Hypertension Study 1 (Sildenafil tablets monotherapy (20 mg, 40 mg, and 80 mg three times a day)) A randomized, double-blind, placebo-controlled study of sildenafil tablets (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 tablets 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 the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45-50 meters were observed with all doses of sildenafil tablets. These increases were significantly different from placebo, but the sildenafil tablets dose groups were not different from each other (see 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 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 tablets. Without a control group, these data must be interpreted cautiously. Study 2 (Sildenafil tablets co-administered with epoprostenol) A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of 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 tablets (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%); and the mean age was 48 years, 80% were female, and 79% were Caucasian. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil tablets group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil tablets 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 tablets 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 tablets (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 tablets-treated patients and that sildenafil tablets -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 tablets (N = 134) Number of subjects with clinical worsening first event 23 8 First Event All Events First Event All Events Death, n 3 4 0 0 Lung Transplantation, n 1 1 0 0 Hospitalization due to PAH, n 9 11 8 8 Clinical deterioration resulting in: Change of Epoprostenol Dose, n Initiation of Bosentan, n 9 1 16 1 0 0 2 0 Proportion Worsened 95% Confidence Interval 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 tablets compared to placebo. More than twice as many sildenafil tablets-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study 3 (Sildenafil tablets 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 tablets: 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 tablets added to bosentan therapy – lack of effect on exercise cap...

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

Sildenafil tablets, USP are supplied as white, film-coated, circular, biconvex tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: NDC 68071-2602-1 BOTTLES OF 10 NDC 68071-2602-3 BOTTLES OF 30 Recommended Storage for Sildenafil Tablets: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

See FDA-approved patient labeling (Patient Information). Inform patients of contraindication of sildenafil tablets 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 tablets not to take VIAGRA or other PDE-5 inhibitors. Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil tablets. 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 tablets. These events may be accompanied by tinnitus and dizziness. Marketed by: Ajanta Pharma USA Inc. Bridgewater, NJ 08807. Made in India.

PATIENT INFORMATION

SPL PATIENT PACKAGE INSERT SECTION

Sildenafil (sil den' a fil) Tablets, USP Read this Patient Information before you start taking sildenafil tablets 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 tablets, ask your doctor or pharmacist. What is the most important information I should know about sildenafil tablets? Never take sildenafil tablets with any nitrate or guanylate cyclase stimulator 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) Guanylate cyclase stimulators include: Riociguat (Adempas) Ask your doctor or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine. What are sildenafil tablets? Sildenafil tablets are 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 tablets improves the ability to exercise and can slow down worsening changes in your physical condition. Sildenafil tablets is not for use in children Adding sildenafil tablets to another medication used to treat PAH, bosentan (Tracleer ® ), does not result in improvement in your ability to exercise. Sildenafil tablets contains the same medicine as VIAGRA ® (sildenafil), which is used to treat erectile dysfunction (impotence). Do not take sildenafil tablets with VIAGRA or other PDE-5 inhibitors. Who should not take sildenafil tablets? Do not take sildenafil tablets if you: take nitrate medicines. See “What is the most important information I should know about sildenafil tablets?” take guanylate cyclase stimulator medicines. See “What is the most important information I should know about sildenafil tablets?” are allergic to sildenafil or any other ingredient in Sildenafil tablets. See “What are the ingredients in sildenafil tablets?” at the end of this leaflet. What should I tell my doctor before taking sildenafil tablets? 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 tablets could harm your unborn baby. are breastfeeding. Sildenafil passes into your breast milk, it is not known if it could harm your baby. Tell your doctor about all of the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal products. Sildenafil tablets 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 tablets. Especially tell your doctor if you take Nitrate medicines. See “What is the most important information I should know about sildenafil tablets?” Riociguat (Adempas). See “What is the most important information I should know about sildenafil tablets?” 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 tablets? Take sildenafil tablets exactly as your doctor tells you. Sildenafil tablets may be prescribed to you as Sildenafil tablets 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 tablets at a time. Do not change your dose or stop taking sildenafil tablets on your own. Talk to your doctor first. If you take too much sildenafil tablets, call your doctor or go to the nearest hospital emergency room. What are the possible side effects of sildenafil tablets? 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 tablets. 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 tablets, 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 tablets 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 tablets. 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 tablets? Sildenafil tablets comes in a child-resistant package. Store sildenafil tablets at controlled room temperature, between 20°C to 25°C (68°F to 77°F). Keep sildenafil tablets and all medicines away from children. General information about sildenafil tablets Medicines are sometimes prescribed for purposes that are not in the patient leaflet. Do not use sildenafil tablets for a condition for which it was not prescribed. Do not give sildenafil tablets 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 tablets. If you would like more information about sildenafil tablets talk with your doctor. You can ask your doctor or pharmacist for information about sildenafil tablets that is written for health professionals. What are the ingredients in sildenafil tablets? Sildenafil tablets Active ingredients: sildenafil citrate Inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, hypromellose, hydroxypropyl cellulose, titanium dioxide, and polyethylene glycol This Patient Information has been approved by the U.S. Food and Drug Administration. Marketed by: Ajanta Pharma USA Inc. Bridgewater, NJ 08807. Made in India. Revised: 10/2019

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL