RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

Warnings and Precautions, Effects on the Eye (5.3) 08/2017

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INDICATIONS & USAGE SECTION

1 INDICATIONS & USAGE

Sildenafil tablets are indicated for the treatment of erectile dysfunction.

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USE IN SPECIFIC POPULATIONS SECTION

Highlight:

•Geriatric use: Consider a starting dose of 25 mg (2.5, 8.5)
•Severe renal impairment: Consider a starting dose of 25 mg (2.5,8.6)
•Hepatic impairment: Consider a starting dose of 25 mg(2.5,8.7)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary Sildenafil tablets is not indicated for use in females.
There are no data with the use of sildenafil tablets in pregnant women to inform any drug-associated risks for adverse developmental outcomes. Animal reproduction studies conducted with sildenafil did not show adverse developmental outcomes when administered during organogenesis in rats and rabbits at oral doses up to 16 and 32 times, respectively, the maximum recommended human dose (MRHD) of 100 mg/day on a mg/m2 basis (see Data).
Data
Animal Data
No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 16 and 32 times the MRHD on a mg/m2 basis in a 50 kg subject. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days, about 2 times the MRHD on a mg/m2 basis in a 50 kg subject.

8.2 Lactation

Risk Summary
Sildenafil tablets is not indicated for use in females.
Limited data indicate that sildenafil and its active metabolite are present in human milk. There is no information on the effects on the breastfed child, or the effects on milk production.

8.4 Pediatric Use

Sildenafil tablets are not indicated for use in pediatric patients. Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18 to 45 years) [see Clinical Pharmacology (12.3)].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 [see Clinical Pharmacology (12.3)].
Of the total number of subjects in clinical studies of sildenafil tablets, 18% were 65 years and older, while 2% were 75 years and older. No overall differences in safety or efficacy were observed between older (≥ 65 years of age) and younger (< 65 years of age) subjects.
However, since higher plasma levels may increase the incidence of adverse reactions, a starting dose of 25 mg should be considered in older subjects due to the higher systemic exposure [see Dosage and Administration (2.5)].

8.6 Renal Impairment

No dose adjustment is required for mild (CLcr=50 to 80 mL/min) and moderate (CLcr=30 to 49 mL/min) renal impairment. In volunteers with severe renal impairment (Clcr<30 mL/min), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (~2 fold), approximately doubling of Cmax and AUC. A starting dose of 25 mg should be considered in patients with severe renal impairment [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for Cmax and 85% for AUC). The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied. A starting dose of 25 mg should be considered in patients with any degree of hepatic impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

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ADVERSE REACTIONS SECTION

Highlight:

Most common adverse reactions (≥ 2%) include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness and rash (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 866-495-1995 or FDA at 1-800-FDA-1088 or****www.fda.gov/medwatch

6 ADVERSE REACTIONS

The following are discussed in more detail in other sections of the labeling:
•Cardiovascular [see Warnings and Precautions (5.1)]
•Prolonged Erection and Priapism [see Warnings and Precautions (5.2)]
•Effects on the Eye [see Warnings and Precautions (5.3)]
•Hearing Loss [see Warnings and Precautions (5.4)]
•Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives [see Warnings and Precautions (5.5)]
•Adverse Reactions with the Concomitant Use of Ritonavir [see Warnings and Precautions (5.6)]
•Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies [see Warnings and Precautions (5.7)]
•Effects on Bleeding [see Warnings and Precautions (5.8)]
•Counseling Patients About Sexually Transmitted Diseases [see Warnings and Precautions (5.9)]
The most common adverse reactions reported in clinical trials (≥ 2%) are headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash.

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 clinical practice.
Sildenafil tablets were administered to over 3700 patients (aged 19 to 87 years) during pre-marketing clinical trials worldwide. Over 550 patients were treated for longer than one year.
In placebo-controlled clinical studies, the discontinuation rate due to adverse reactions for sildenafil tablets (2.5%) was not significantly different from placebo (2.3%).
In fixed-dose studies, the incidence of some adverse reactions increased with dose. The type of adverse reactions in flexible-dose studies, which reflect the recommended dosage regimen, was similar to that for fixed-dose studies. At doses above the recommended dose range, adverse reactions were similar to those detailed in Table 1 below but generally were reported more frequently.

Table 1: Adverse Reactions Reported by ≥2% of Patients with Sildenafil Tablets and More Frequently than Placebo in Fixed-Dose Phase II/III Studies

† Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision.
When sildenafil tablets were taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials of two to twenty-six weeks duration, patients took sildenafil tablets at least once weekly, and the following adverse reactions were reported:
Table 2. Adverse Reactions Reported by ≥2% of Patients Treated with Sildenafil Tablets and More Frequent than Placebo in Flexible-Dose Phase II/III Studies

† Abnormal Vision: Mild and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision.
The following events occurred in <2% of patients in controlled clinical trials; a causal relationship to sildenafil tablets is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful:
Body as a Whole: face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury.
Cardiovascular: angina pectoris, AV block, migraine, syncope, tachycardia, palpitation, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy.
Digestive: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, liver function tests abnormal, rectal hemorrhage, gingivitis.
Hemic and Lymphatic: anemia and leukopenia.
Metabolic and Nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia.
Musculoskeletal: arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.
Nervous: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, reflexes decreased, hypesthesia.
Respiratory: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, cough increased.
Skin and Appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis.
Special Senses: sudden decrease or loss of hearing, mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, ear pain, eye hemorrhage, cataract, dry eyes.
Urogenital: cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence, abnormal ejaculation, genital edema and anorgasmia.
Analysis of the safety database from controlled clinical trials showed no apparent difference in adverse reactions in patients taking sildenafil tablets with and without anti-hypertensive medication. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of sildenafil tablets. 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. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors.
Cardiovascular and cerebrovascular
Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of sildenafil tablets. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil tablets without sexual activity. Others were reported to have occurred hours to days after the use of sildenafil tablets and sexual activity. It is not possible to determine whether these events are related directly to sildenafil tablets, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors [see Warnings and Precautions (5.1)and Patient Counseling Information (17)].
Hemic and Lymphatic: vaso-occlusive crisis: In a small, prematurely terminated study of REVATIO (sildenafil) in patients with pulmonary arterial hypertension (PAH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported in patients who received sildenafil than in those randomized to placebo. The clinical relevance of this finding to men treated with sildenafil tablets for ED is not known.
Nervous: seizure, seizure recurrence, anxiety, and transient global amnesia.
Respiratory: epistaxis
Special senses:
Hearing: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including sildenafil tablets. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. 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 tablets, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions (5.4) and Patient Counseling Information (17)].
Ocular: diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal edema, retinal vascular disease or bleeding, and vitreous traction/detachment.
Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post- marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil tablets. 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 [see Warnings and Precautions (5.3) and Patient Counseling Information (17)].
Urogenital: prolonged erection, priapism [see Warnings and Precautions (5.2)and Patient Counseling Information (17)], and hematuria.

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OVERDOSAGE SECTION

10 OVERDOSAGE

In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence rates and severities were increased.
In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

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