Tadalafil-Induced Subretinal and Choroidal Hemorrhage in a Patient With an Unsuspected Uveal (Choroidal and Ciliary Body) Melanoma

Tadalafil (Cialis; Lilly ICOS LLC, Bothell, Wash) is a Food and Drug Administration–approved phosphodiesterase type 5 (PDE5) enzyme inhibitor approved for the treatment of erectile dysfunction. Although preclinical testing of tadalafil and sildenafil citrate (Viagra; Pfizer Inc, New York, NY) included an extended eye examination, electroretinography, and postmortem histologic analysis and no adverse effects were seen, a variety of studies have subsequently highlighted ophthalmic problems with both agents. Transient changes in vision, transient and mild impairment in color discrimination, eye pain, eyelid swelling, electroretinographic abnormalities,^1-3 abnormal histopathologic findings,⁴ pupil-sparing third nerve palsy,⁵ and central serous choroidopathy have been reported.⁶

We recently observed a male patient who suddenly developed a painful red eye and loss of vision after taking tadalafil and was found to have ruptured blood vessels in and on the surface of an ocular melanoma. The acute bleeding may be related to the vasodilatory effects of the drug on the ocular circulation in a patient taking aspirin.

A 63-year-old man with erectile dysfunction was awakened by severe pain in his left eye a few hours after taking a single tadalafil tablet (20 mg). He went back to sleep, but in the morning he awakened with limited sight in his left eye. His initial examination that morning by an ophthalmologist demonstrated a markedly red eye, and he was treated with topical ketorolac tromethamine eyedrops (Acular; Allergan, Irvine, Calif) for what was initially diagnosed as noninfectious conjunctivitis. His medical history included prostate cancer, for which he was surgically treated 3 years earlier.

One week after initial treatment the redness had subsided, but his vision had not improved, and he sought additional evaluation. His right eye was normal, but his left eye had vision of counting fingers; a shallow anterior chamber was identified, and early nuclear sclerosis was seen. A malignant melanoma of the choroid was identified. The melanoma extended anterior to the equator to the optic nerve and had clumps of orange pigment in it. The tumor was shaped like a fried egg, and the elevated central part had a collection of dark blood beneath the retina. Hemorrhages were also noted in the tumor itself.

B-scan ultrasound demonstrated a fried egg–shaped choroidal tumor (Figure 1), and on A-scan, characteristic medium to low reflectivity was seen. A diagnosis of choroidal melanoma with recent hemorrhage was made. A systemic evaluation revealed no evidence of metastatic disease. Enucleation was performed. Pathological analysis revealed a malignant melanoma of the ciliary body and choroid that measured 18 × 19 mm (Figure 2). The Bruch membrane was thick and vascularized, and subretinal pigment epithelial hemorrhage was identified in addition to hemorrhages in the tumor (Figure 3). There was marked vascular congestion in the tumor.

Three selective PDE inhibitors (sildenafil, vardenafil hydrochloride, and tadalafil) have been approved by the Food and Drug Administration for the treatment of erectile dysfunction. They are all selective for PDE5 inhibition, but vardenafil has the highest potency and the greatest selectivity. Sildenafil and vardenafil have a shorter duration of action (approximately 4 hours), whereas tadalafil may last up to 36 hours. These agents do not directly cause penile erections, but they do affect the response to sexual stimulation. They enhance the effect of nitric oxide in the corpus cavernosum by inhibiting PDE5, which is responsible for degradation of cyclic guanosine monophosphate in the corpus cavernosum, causing smooth muscle relaxation and inflow of blood into the corpus cavernosum. These agents are considered safe, and millions of doses have been prescribed. The most common adverse effects are related to vasodilation, including headache (11%-15%), dyspepsia (4%-10%), flushing (2%-3%), and nasal congestion (1%-3%).⁷ Although highly selective, tadalafil may also inhibit PDE11, PDE3, and PDE6; PDE6 is found only in the retina and functions in visual transduction.

Tadalafil has been shown to cause systemic vasodilation with a slight reduction in systolic and diastolic blood pressure. Studies of ocular perfusion have suggested that these agents cause vasodilation. Histopathologic studies⁸ of long-term use of sildenafil in rats demonstrated dilation and congestion of choroidal capillaries. There was a suggestion of similar findings in humans using a single dose (200 mg) of sildenafil.⁹ Using lower doses (50 mg) of sildenafil in healthy adults demonstrated a change in pulsatile ocular blood flow.¹⁰ In a double-masked, randomized crossover trial¹¹ using 100 mg of sildenafil on 2 separate days, results were less clear. Many other studies^12-14 have demonstrated a measurable vasodilatory effect of sildenafil on retinal arterioles and venuoles.

We believe that the painful red eye, subretinal and intratumoral hemorrhage, and intratumoral vascular congestion seen in this patient may have been related to the vasodilatory effect of tadalafil in a patient who was also taking aspirin. The vasodilation may have caused the red eye and transient swelling of the choroid, contributing to the rupture of a neovascular membrane that was present beneath the retinal pigment epithelium–Bruch membrane complex. The presence of aspirin may also have contributed to the acute bleeding from this membrane.

Correspondence: Dr Abramson, 70 E 66th St, New York, NY 10021 (abramsod@mskcc.org).

Financial Disclosure: None reported.

This article was corrected on 1/15/07, prior to publication of the correction in print.