Sildenafil - Preferred Pharmaceuticals Inc.

RECENT MAJOR CHANGES

RECENT MAJOR CHANGES SECTION

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

Sildenafil is indicated for the treatment of pulmonary arterial hypertension (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 New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%).

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

Sildenafil Tablets Sildenafil tablets are supplied as white, round shaped convex film-coated tablets debossed with “WPI” on one side and “3780” on the other side containing sildenafil citrate, USP equivalent to 20 mg of sildenafil.

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

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

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 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

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 citrate, 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 ® for erectile dysfunction. Sildenafil citrate, USP 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 is formulated as white, round shaped convex film-coated tablets for oral administration. Each tablet contains sildenafil citrate equivalent to 20 mg of sildenafil. In addition to the active ingredient, sildenafil citrate, USP, each tablet contains the following inactive ingredients: anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, opadry II blue and opadry II white. Opadry II blue contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, FD&C Blue # 2 aluminum lake and FD&C Yellow # 6 aluminum lake. Opadry II white contains: polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide.

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 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 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 dose groups were not different from each other (see Figure 9), 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 9. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in Study 1: Mean (95% Confidence Interval) Figure 10 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 10. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

Sildenafil tablets are supplied as white, round shaped convex film-coated tablets containing sildenafil citrate, USP equivalent to the nominally indicated amount of sildenafil as follows: Sildenafil Tablets Package Configuration Strength NDC Engraving on Tablet Bottle of 90 Bottle of 60 Bottle of 30 Bottle of 4 20 mg 68788-379-9 68788-7379-6 68788-7379-3 68788-7379-4 “WPI” on one side and “3780” on other side Recommended Storage for Sildenafil Tablets: Store at 20° to 25°C (68° to 77°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. This product’s label may have been updated. For current full prescribing information, please visit www.actavis.com Manufactured by: Watson Pharma Private Ltd. Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc . Parsippany, NJ 07054 USA Revised: September 2014 Repackaged By: Preferred Pharmaceuticals Inc.

SPL PATIENT PACKAGE INSERT SECTION

SPL PATIENT PACKAGE INSERT SECTION

Patient Information Sildenafil (sil-DEN-a-fil) Tablets 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 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 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 improve the ability to exercise and can slow down worsening changes in your physical condition. • Sildenafil tablets are 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 tablets contain 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? ” • 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 as 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 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? ” • 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 a 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 many 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, 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? Store sildenafil tablets at controlled room temperature, between 68° to 77°F (20° to 25°C). 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. For more information go to www.actavis.com or call 1-800-272-5525. What are the ingredients in sildenafil tablets? Active ingredients: sildenafil citrate, USP Inactive ingredients: anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, opadry II blue and opadry II white. Opadry II blue contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, FD&C Blue # 2 aluminum lake and FD&C Yellow # 6 aluminum lake. Opadry II white contains: polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. This product’s label may have been updated. For current full prescribing information, please visit www.actavis.com This Patient Information has been approved by the U.S. Food and Drug Administration. Rx only Manufactured by: Watson Pharma Private Ltd. Verna, Salcette Goa 403 722 INDIA Distributed by: Actavis Pharma, Inc . Parsippany, NJ 07054 USA Revised: September 2014 Repackaged By: Preferred Pharmaceuticals Inc.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 68788-7379 Sildenafil Tablets 20 mg PHARMACIST: PLEASE DISPENSE WITH THE PATIENT INFORMATION SHEET Watson Rx only Repackaged By: Preferred Pharmaceuticals Inc.