SILDENAFIL CITRATE (Page 3 of 9)

6 ADVERSE REACTIONS

The following are discussed in more detail in other sections of the labeling:

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Cardiovascular [ see Warnings and Precautions (5.1) ]

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Prolonged Erection and Priapism [ see Warnings and Precautions (5.2) ]

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Effects on the Eye [ see Warnings and Precautions (5.3) ]

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Hearing Loss [ see Warnings and Precautions (5.4) ]

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Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives [ see Warnings and Precautions (5.5) ]

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Adverse Reactions with the Concomitant Use of Ritonavir [ see Warnings and Precautions (5.6) ]

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Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies [ see Warnings and Precautions (5.7) ]

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Effects on Bleeding [ see Warnings and Precautions (5.8) ]

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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 was administered to over 3700 patients (aged 19-87 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 (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 Treated with sildenafil and More Frequent than Placebo in Fixed-Dose Phase II/III Studies

Adverse Reaction	25 mg (n=312)	50 mg (n=511)	100 mg (n=506)	Placebo (n=607)
Headache	16%	21%	28%	7%
Flushing	10%	19%	18%	2%
Dyspepsia	3%	9%	17%	2%
Abnormal vision†	1%	2%	11%	1%
Nasal congestion	4%	4%	9%	2%
Back pain	3%	4%	4%	2%
Myalgia	2%	2%	4%	1%
Nausea	2%	3%	3%	1%
Dizziness	3%	4%	3%	2%
Rash	1%	2%	3%	1%

† 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 was 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 at least once weekly, and the following adverse reactions were reported:

Table 2. Adverse Reactions Reported by ≥2% of Patients Treated with sildenafil and More Frequent than Placebo in Flexible-Dose Phase II/III Studies

Adverse Reaction	SILDENAFIL CITRATE	PLACEBO
	N=734	N=725
Headache	16%	4%
Flushing	10%	1%
Dyspepsia	7%	2%
Nasal Congestion	4%	2%
Abnormal Vision †	3%	0%
Back pain	2%	2%
Dizziness	2%	1%
Rash	2%	1%

† 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 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 with and without anti-hypertensive medication. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions.