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Ocular Safety of Sildenafil Citrate when Administered Chronically for Pulmonary Arterial Hypertension


One of the advantages of the large pharmaceutical companies is that they have the resources to do extensive clinical trials with their drugs. As drugs come off patent, there are just limited ways to perform additional safety and efficacy studies.


A study published in the British Medical Journal (2012;344:e554) was performed to assess the ocular effects and safety profile of chronic sildenafil oral dosing in patients with pulmonary arterial hypertension. The study was a 12-week, double masked, randomized, placebo controlled, phase III trial, with an open label extension, performed at 53 institutions worldwide.


Participants included 277 adults with idiopathic pulmonary arterial hypertension or pulmonary arterial hypertension associated with connective tissue disease or after congenital heart disease repair (mean pulmonary artery pressure >25 mm Hg; pulmonary capillary wedge pressure <15 mm Hg at rest).


During the double masked study, oral sildenafil 20 mg, 40 mg, or 80 mg or placebo (1:1:1:1) three times daily for 12 weeks was added to baseline drug treatment. In the extension study, the placebo, 20 mg and 40 mg groups received 40 mg three times daily titrated to 80 mg three times daily at week 6. After unmasking, the dose was titrated according to clinical need.


The main outcome measure was ocular safety (ocular examinations, visual function tests, participants’ reports of adverse events, and visual disturbance questionnaire completed by investigators) by treatment group at 12 weeks, 24 weeks, 18 months, and yearly.


Findings of the objective assessments of intraocular pressure and visual function tests (visual acuity, color vision, and visual field) were similar across groups. No clinically significant changes occurred between baseline and 12 weeks, except for an efficacy signal in contrast sensitivity for the sildenafil 40 mg three times daily group. In right eyes, changes in intraocular pressure from baseline to week 12 ranged from a mean of -0.5 mm Hg with placebo, -0.2 mm Hg with sildenafil 40 mg, and -0.1 mm Hg with 80 mg to 0.3 mm Hg with sildenafil 20 mg (the approved dose for pulmonary arterial hypertension). Mean changes from baseline to week 12 in contrast sensitivity in right eyes were -0.02 in the sildenafil 20 mg three times daily group compared with -0.05 in the placebo group (P=0.044).


Percentages of participants with deterioration in visual acuity (Snellen) from baseline to week 12 ranged from 10% (n=7) in the placebo group to 3% (n=2) in the sildenafil 20 mg three times daily group; the same percentages had visual field changes from normal to abnormal during the period in these two groups. The investigators did not deem any findings on color vision assessment to be clinically significant. Findings of the objective assessments in the 40 mg and 80 mg three times daily sildenafil treatment groups and in left eyes were not substantially different, nor were any measures different throughout the open label extension compared with week 12.


Incidence of ocular adverse events reported on the case report forms and assessed by the investigator was low with all doses, but a modest, dose related incidence of chromatopsia, cyanopsia, photophobia, and visual disturbance was reported with 80 mg three times daily consistent with the indicated dosing for erectile dysfunction. Retinal hemorrhages, captured on funduscopy, occurred in 2% (4/207) of sildenafil treated participants and none in the placebo group during the double masked study and in 4% (10/259) during the open label extension.


The authors concluded that sildenafil dosing up to 80 mg three times daily is safe and well tolerated from an ocular perspective in patients with pulmonary arterial hypertension, and that daily chronic dosing in this patient population was not associated with visual change and had no detrimental effect on best corrected visual acuity, contrast sensitivity, color vision, or visual field, or on slit lamp examinations, funduscopy, or intraocular pressure during the duration of this study.


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