xerophthalmia
Sildenafil (Viagra) Adverse Reactions
During clinical trials worldwide, sildenafil was administered to over 3700 patients (aged 19 - 87 years). Over 550 patients were treated for longer than one year. In placebo-controlled clinical studies, the discontinuation rate due to adverse events for sildenafil (2.5%) was not significantly different from placebo (2.3%). Adverse events were generally transient and mild to moderate in nature. Adverse events reported by >= 2% of patients treated with sildenafil and which were more frequent on drug than placebo in as needed flexible-dose phase II/III studies include headache (16% vs. 4%), flushing (10% vs. 1%), dyspepsia (7% vs. 2%), nasal congestion (4% vs. 2%), urinary tract infection (3% vs. 2%), diarrhea (3% vs. 1%), dizziness (2% vs. 1%), and rash (unspecified) (2% vs. 1%). In fixed-dose studies, dyspepsia (17%) was more common at 100 mg doses than at lower doses. At doses above the recommended dose range, adverse events were similar to those detailed above but generally were reported more frequently. Other adverse reactions that occurred at a rate of > 2%, but were equally common in patients receiving placebo, include respiratory tract infection, back pain, flu syndrome, and arthralgia.
In clinical trials, no cases of priapism were reported with sildenafil. However, reports of priapism related to sildenafil have been reported in post-marketing surveillance. Painful erections have lasted greater than 6 hours in duration. Because of the potential for permanent tissue damage, priapism is a medical emergency and patients on sildenafil should report any erections lasting greater than 4 hours and seek medical attention.
During the marketing of sildenafil from late March through November 1998, more than 6 million outpatient prescriptions were dispensed. As of November 1998, 128 deaths had been reported to the FDA in association with sildenafil use. The cause of death was unknown for 48 patients. Three patients experienced a stroke and 77 patients had cardiovascular events. Cardiovascular events related to sildenafil included myocardial infarction, cardiac arrest, angina, ventricular tachycardia, hypertension, and other cardiac symptoms. Sixteen patients had received nitroglycerin or a nitrate, which is contraindicated with the use of sildenafil. Ninety of the 128 patients (70%) had one or more risk factors for cardiovascular or cerebrovascular disease. Forty-four (34%) of the 128 patients died or had onset of symptoms leading to death within 4 - 5 hours of drug use. Twenty-seven of these patients had died during or immediately after sexual intercourse. Other events were reported hours to days after use of sildenafil and participation in sexual activity. A combination of factors, including cardiac risk profile, sildenafil use, and sexual activity may have had a role in these events, but limited information makes it impossible at this time to make direct correlations. In controlled clinical trials of sildenafil, adverse reactions occurring in < 2% of patients and affecting the cardiovascular system included abnormal electrocardiogram, angina pectoris, AV block, cardiac arrest, cardiomyopathy, cerebral thrombosis, heart failure, hypotension, migraine, myocardial ischemia, palpitations, postural hypotension, syncope, and tachycardia. A causal relationship to sildenafil therapy is uncertain. Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Single oral doses of sildenafil (100 mg) produced an average decrease of about 10 mmHg in blood pressure of normal volunteers, similar to the effect in patients with ischemic heart disease given 40 mg of sildenafil IV. Larger but similarly transient effects on blood pressure were recorded among patients receiving concomitant nitrates. These effects are possibly related to the effects of sildenafil on PDE5 in vascular smooth muscle. In a study conducted at the Mayo Clinic, sildenafil was shown to have limited cardiovascular effects during exercise in men with known or probable coronary artery disease. The study reported that sildenafil had no effect on exercise capacity or the hemodynamic response to exercise. Systolic blood pressure was reduced an average of 7 mmHg compared to baseline. After chronic dosing (80 mg PO TID) in healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively. Post-marketing serious cardiovascular, cerebrovascular, and vascular adverse events were reported in temporal association with sildenafil use and include myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage.
Adverse reactions affecting the body as whole and occurring in < 2% of patients in controlled clinical trials of sildenafil include abdominal pain, accidental fall, accidental injury, allergic reaction, asthenia, chest pain, chills, face edema, pain, photosensitivity reaction, and shock. A causal relationship to sildenafil therapy is uncertain.
The following adverse reactions affecting the hemic, lymphatic, metabolic, and nutritional systems occurred in < 2% of patients in controlled clinical trials of sildenafil: anemia, edema, gout, hyperglycemia, hyperuricemia, hypoglycemic reaction, hypernatremia, leukopenia, peripheral edema, thirst, and unstable diabetes mellitus. A causal relationship to sildenafil therapy is uncertain.
The following adverse reactions affecting the nervous and respiratory systems occurred in < 2% of patients in controlled clinical trials of sildenafil: abnormal dreams, asthma, ataxia, bronchitis, cough increased, depression, dyspnea, hypertonia, hypesthesia, insomnia, laryngitis, neuralgia, neuropathy, paresthesia, pharyngitis, reflexes decreased, sinusitis, somnolence, sputum increased, tremor, vertigo. A causal relationship to sildenafil therapy is uncertain. Additionally, MedWatch, the FDA’s voluntary adverse reaction reporting system, lists over 274 reports implicating sildenafil as the primary suspect for emotional, neurological, and psychological disturbances during the time period January 4, 1998, through February 21, 2001. These adverse effects included abnormal dreams, abnormal thinking, aggression, agitation, amnesia, anxiety, attempted suicide, attention disturbance, confusion, delirium, delusion, depersonalization, depression, disorientation, dizziness, emotional lability, euphoria, hostility, hallucinations, irritability, loss of consciousness, mania, nervousness, paranoia, personality disorders, suicide, and suicidal ideation. Sildenafil usage has also been listed as a potential factor in a significant number of murder, physical assault, and rape cases. Since sildenafil does cross the blood-brain barrier, it is possible that sildenafil may be associated with these adverse effects. Further investigation is necessary to prove or disprove the role of sildenafil in these disturbances. Two cases of tonic-clonic seizures have also been reported with sildenafil use.
Adverse reactions occurring in <2% of patients in controlled clinical trials of sildenafil and affecting the digestive and urogenital systems include abnormal ejaculation, anorgasmia, breast enlargement, colitis, cystitis, dysphagia, esophagitis, gastritis, gastroenteritis, genital edema, gingivitis, glossitis, abnormal liver function tests, nocturia, rectal hemorrhage, stomatitis, urinary frequency, urinary incontinence, vomiting, and xerostomia. A causal relationship to sildenafil therapy is uncertain.
Adverse reactions affecting the musculoskeletal system and occurring in < 2% of patients in controlled clinical trials of sildenafil include arthritis, arthrosis, bone pain, myalgia, myasthenia, synovitis, tendon rupture, and tenosynovitis. A causal relationship to sildenafil therapy is uncertain.
Adverse reactions affecting the skin and appendages and occurring in < 2% of patients in controlled clinical trials of sildenafil include contact dermatitis, diaphoresis, exfoliative dermatitis, herpes simplex, pruritus, skin ulcer, and urticaria. A causal relationship to sildenafil therapy is uncertain.
Adverse reactions affecting hearing or otic special senses and occurring in < 2% of patients in controlled clinical trials of sildenafil include hearing loss, otalgia, and tinnitus. A causal relationship to sildenafil therapy is uncertain.
A thorough ophthalmic examination, in addition to cardiovascular risk assessment, should be considered for patients prior to prescribing phosphodiesterase inhibitors. Ophthalmic adverse events reported by >= 2% of patients treated with sildenafil and which were more frequent on drug than placebo in as needed flexible-dose phase II/III studies include visual impairment including mild and transient color tinge to vision, photophobia, or blurred vision (3% vs. 0%). In these studies, only one patient discontinued drug due to abnormal vision. In fixed-dose studies, abnormal vision (11%) was more common at 100 mg doses than at lower doses. Other ophthalmic adverse reactions occurring in < 2% of patients in controlled clinical trials of sildenafil include cataracts, conjunctivitis, mydriasis, ocular hemorrhage, ocular pain, photophobia, and xerophthalmia. A causal relationship to sildenafil therapy is uncertain. Post-marketing reports have included diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular irritation/burning, ocular swelling/pressure, increased intraocular pressure (ocular hypertension), retinal vascular disease or retinal hemorrhage, vitreous detachment/traction, and paramacular edema and epistaxis. Nonarteritic ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors. It is thought that the vasoconstrictive effect of phosphodiesterase inhibitors may decrease blood flow to the optic nerve, especially in patients with a low cup to disk ratio. Symptoms, such as blurred vision and loss of visual field in one or both eyes, are usually reported within 24 hours of use. Most, but not all, of these patients who reported this adverse effect had underlying anatomic or vascular risk factors for development of NAION. These risk factors include, but are not limited to: low cup to disc ratio (’crowded disc’), age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Additionally, two patients had retinal detachment and one patient had hypoplastic optic neuropathy. It is not yet possible to determine if these adverse 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.
[ Last revised: 12/2/2005 11:39:00 AM ]
References
. Arruda-Olson AM, Mahoney DW, Nehra A, et al. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease. JAMA 2002;287:719 - 25.
. Milman HA, Arnold SB. Neurologic, psychological, and aggressive disturbances with sildenafil. Ann Pharmacother 2002;36:1129 - 34.
. Gilad R, Lampl Y, Eshel Y, Sadeh M. Tonic-clonic seizures in patients taking sildenafil. BMJ 2002;325;869.
. Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (Viagra): a report of seven new cases. J Neuroophthalmol 2005;25:9 - 13.
. Escaravage GK Jr., Wright JD Jr., Givre SJ. Tadalafil associated with anterior ischemic optic neuropathy. Arch Ophthalmol 2005;123(3):399 - 400.
. Bollinger K, Lee MS. Recurrent visual field defect and ischemic optic neuropathy associated with tadalafil rechallenge. Arch Ophthalmol 2005;123(3):400 - 1.
. Peter NM, Singh MV, Fox PD. Tadalafil-associated anterior ischaemic optic neuropathy. Eye 2005;19(6):715 - 7.
. Revatio™ (sildenafil citrate) package insert. New York, NY: Pfizer; 2005 Aug.
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