Side Effects of Viagra (sildenafil)

Viagra (sildenafil) is a phosphodiesterase inhibitor (PDE-5 inhibitor) used to treat impotence (or erectile dysfunction, ED, the inability to attain or maintain a penile erection). 

Erection of the penis occurs when the penis fills with blood. Filling occurs because blood vessels that bring blood to the penis increase in size and deliver more blood to the penis, and blood vessels that take blood away from the penis decrease in size and remove less blood from the penis. 

Sexual stimulation that leads to an erection causes the production and release of nitric oxide in the penis. Nitric oxide causes an enzyme, guanylate cyclase, to produce cyclic guanosine monophosphate (cGMP) that is primarily responsible for increasing and decreasing the size of blood vessels carrying blood to and from the penis and causing an erection.

When the cGMP is destroyed by the phosphodiesterase-5 enzyme, the erection ends. Viagra prevents phosphodiesterase-5 from destroying cGMP so cGMP stays around longer, which leads to a more prolonged erection. 

Common side effects of Viagra include:

• facial flushing,
• headaches,
• stomach pain,
• nasal congestion,
• nausea,
• dizziness,
• rash,
• urinary tract infections (UTIs),
• diarrhea, and
• an inability to differentiate between the colors green and blue.

Serious side effects of Viagra include low blood pressure and abnormal ejaculation. Viagra may cause prolonged erections or priapism (painful erections lasting more than 6 hours). 

Drug interactions of Viagra include other PDE5 inhibitors. Viagra can increase the blood pressure-lowering effects of other pressure-lowering medications, including nitrates.

Cimetidine, erythromycin, ketoconazole, itraconazole, atazanavir, and mibefradil cause marked increases in the amount of Viagra in the body. Rifampin will decrease blood levels of Viagra and probably reduce its effectiveness. 

Although extensive testing in animals has demonstrated no negative effects on the fetus, Viagra has not been studied in pregnant women. There is no effect on sperm count or motility of sperm in men. 

It is not known whether Viagra is excreted into breast milk. Consult your doctor before breastfeeding. 

Approximately 15% of persons taking Viagra experience side effects. The most common side effects are:

• facial flushing (1 in 10),
• headaches (1 in 6),
• stomach pain,
• nasal congestion,
• nausea,
• dizziness,
• rash,
• urinary tract infections (UTIs)
• diarrhea, and
• an inability to differentiate between the colors green and blue.

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

• Cardiovascular
• Prolonged Erection and Priapism
• Effects on the Eye
• Hearing Loss
• Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives
• Adverse Reactions with the Concomitant Use of Ritonavir
• Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies
• Effects on Bleeding
• Counseling Patients About Sexually Transmitted Diseases

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.

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.

Viagra 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 Viagra (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 Viagra and More Frequent than Placebo in Fixed-Dose Phase II/III Studies

When Viagra 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 Viagra at least once weekly, and the following adverse reactions were reported:

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

The following events occurred in < 2% of patients in controlled clinical trials; a causal relationship to Viagra 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 Viagra with and without anti-hypertensive medication. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Viagra. 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 Viagra. 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 Viagra without sexual activity. Others were reported to have occurred hours to days after the use of Viagra and sexual activity. It is not possible to determine whether these events are related directly to Viagra, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors.

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 Viagra 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 Viagra. 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 Viagra, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors.

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 Viagra. 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. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.

Urogenital: prolonged erection, priapism, and hematuria.

Nitrates

Administration of Viagra with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Consistent with its known effects on the nitric oxide/cGMP pathway, Viagra was shown to potentiate the hypotensive effects of nitrates.

Alpha-blockers

Use caution when co-administering alpha-blockers with Viagra because of potential additive blood pressure-lowering effects. When Viagra is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating Viagra treatment and Viagra should be initiated at the lowest dose.

Amlodipine

When Viagra 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.

Ritonavir And Other CYP3A4 Inhibitors

Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC). It is therefore recommended not to exceed a maximum single dose of 25 mg of Viagra in a 48 hour period.

Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in a 160% and 182% increases in sildenafil Cmax and AUC, respectively. Co-administration of saquinavir, a strong CYP3A4 inhibitor, resulted in 140% and 210% increases in sildenafil Cmax and AUC, respectively. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir. A starting dose of 25 mg of Viagra should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itraconazole).

Alcohol

In a drug-drug interaction study sildenafil 50 mg given with alcohol 0.5 g/kg in which mean maximum blood alcohol levels of 0.08% was achieved, sildenafil did not potentiate the hypotensive effect of alcohol in healthy volunteers.