Keep Alert for These Drug-Related Adverse Effects

Here's a guide to the most common ones affecting ophthalmology patients.

By F.W. (Rick) Fraunfelder, MD

Adverse reactions to medications can come in the form of systemic effects from topically applied eye drops or, more commonly, from systemically applied medications affecting the visual system. The following adverse reactions are representative drug-related adverse effects pertinent to practicing ophthalmologists. For a more complete list of all known adverse ocular effects, interested readers are encouraged to refer to the book Clinical Ocular Toxicology.¹

What follows are a few representative drugs that most ophthalmologists should be aware of in their clinical practices. Where data is available, adverse ocular effects are classified according to the World Health Organization's Causality Assessment of Suspected Adverse Reactions Guide. This template helps categorize medications into side effect profiles. The definitions can be found in Table 1 (below).

For additional instruction, attendees of this year's AAO annual meeting may wish to take part in a course I will be giving on this subject: “Drug-Related Adverse Effects of Clinical Importance to the Ophthalmologist,” Course Number 194, Sunday, October 23, 2pm to 3pm.

Alpha-Adrenergic Antagonists

• Examples. Tamsulosin (Flomax), alfuzosin, doxazosin, terazosin.

• Primary Use. To treat benign prostatic hyperplasia and hypertension.

• Clinical Concerns. Intraoperative floppy iris syndrome (IFIS) associated with tamsulosin was first reported by Chang and Campbell in 2005.² They suggest IFIS diagnosis be based on three intraoperative findings: fluttering and billowing of the flaccid iris stroma; a propensity for iris prolapse; and progressive constriction of the pupil during surgery. Additional characteristics also include poor preoperative pupil dilation and elasticity of the pupil margin.

It is hypothesized that the alpha-1A blocking effect of tamsulosin is not purely selective for the prostate, as it may also selectively block the receptors in the iris dilator muscle. Tamsulosin has a relatively long half-life, and it is possible that long-term receptor blockade could result in a type of disuse atrophy of the iris dilator smooth muscle. This may explain why some patients have permanent IFIS, even after the medication is discontinued.

Boehringer Ingelheim has subsequently changed the labeling on tamsulosin to reflect the possibility of IFIS in patients who may require cataract surgery.

• WHO Classification. Certain: (1) floppy iris syndrome (primarily associated with tamsulosin), (2) amblyopia; (3) blurred vision.

• Management Guidelines. Inquire prior to cataract surgery whether or not a patient is taking an alpha-adrenergic inhibitor like tamsulosin and plan accordingly. Iris retractors or other pupil expansion devices will help enlarge pupil size for surgery in IFIS patients. Some ophthalmologists have suggested using Healon 5 with low aspiration parameters to maintain pupil size. Unfortunately, stopping the medicine does not always ensure IFIS will not occur.

Figure 1. IFIS, characterized by iris billowing and prolapse, can occur in patients taking Flomax or a similar drug.

Topiramate (Topamax)

• Primary Use. Various types of epilepsy and migraine headaches. It is also used off label as a “magic” weight reduction drug and in bipolar disorder and clinical depression.

• Clinical Concerns. Recent case reports by Banta et al., Rhee et al. and Sankar et al. have ballooned into almost 100 cases of a classic syndrome of acute angle-closure glaucoma.³ In the Registry series, patients ranged in age from 3.5 to 53 years of age, and time to onset of reaction ranged from three to 14 days after the start of oral therapy.

• WHO Classification. Certain: acute glaucoma (mainly bilateral), anterior chamber shallowing, ocular hyperemia, increased ocular pressure, mydriasis, suprachoroidal effusions, visual field defects/acute glaucoma, ocular pain, decreased vision, acute myopia (up to 6-8 diopters). Probable/Likely: blepharospasm, oculogyric crisis, retinal bleeds, uveitis. Possible: scleritis, teratogenic effects (including ocular malformations).

Before the syndrome was recognized, the majority of patients were treated with laser iridectomies or peripheral iridectomies, which we now know is not beneficial.

• Management Guidelines. (1) Patients should stop the medication. (2) Hyperosmotic therapy. (3) Cycloplegic. (4) Topical antiglaucoma medication.

Bisphosphonates

• Examples. Pamidronate disodium (Aredia), alendronic acid (Fosamax) ibandronate, zolendronate (Zometa), risedronate sodium (Actonel), clodronate (Bonefos), etidronate disodium (Didrocal), olpadronate.

• Primary Use. Pamidronate disodium inhibits bone resorption in the management of hypercalcemia of malignancy, osteolytic bone metastases of both breast cancer and multiple myeloma, and Paget's disease of the bone.

• Clinical Concerns. This class of drug has been reported to cause anterior uveitis and nonspecific conjunctivitis. There are case reports of episcleritis, nerve palsy, ptosis, retrobulbar neuritis and yellow vision. We previously reported a case of anterior scleritis and a case of posterior scleritis associated with pamidronate use, without rechallenge data.

Patients who are taking Fosamax or another bisphosphonate drug can develop anterior uveitis.

The most studied drug in this class, pamidronate, has caused 17 cases of unilateral scleritis and one case of bilateral scleritis. Onset is usually within six to 48 hours of intravenous drug administration. Six patients had positive rechallenge testing with the scleritis occurring after a repeat drug exposure. Other ocular side effects with positive rechallenge data associated with pamidronate disodium use include blurred vision, nonspecific conjunctivitis, ocular pain, bilateral anterior uveitis and episcleritis.

• WHO Classification. Certain: blurred vision, ocular irritation, non-specific conjunctivitis, pain, epiphoria, photophobia, anterior uveitis (rare – posterior), anterior scleritis (rare – posterior), episcleritis. Probable: periocular, lid and/or orbital edema. Possible: retrobulbar neuritis, yellow vision, diplopia, cranial nerve palsy, ptosis, visual hallucinations.

• Guidelines for Management. This is the only class of drug proven to cause scleritis. Bisphosphonates can cause vision-threatening diseases. The seriousness of these conditions may dictate discontinuation of the drug in some uveitis cases and, in this series, all cases of scleritis. Further guidelines are as follows:

1. If persistent decrease in vision or ocular pain occurs, the patient should see an ophthalmologist.
2. Nonspecific conjunctivitis seldom requires treatment, and usually decreases in intensity or may be absent on subsequent pamidronate injections. In rare instances, a non-steroidal anti-inflammatory eye drop may be needed.
3. Bilateral anterior uveitis or, rarely, posterior uveitis may occur and can vary markedly in severity. Many cases require intensive topical ocular or systemic medication. In some cases, the drug may need to be discontinued for the uveitis to resolve.
4. Episcleritis may require topical ocular medication; however, pamidronate may be continued.
5. In this series, for the scleritis to resolve, even on full medical therapy, the intravenous pamidronate had to be discontinued.

Phosphodiesterase Type 5 Inhibitors

• Examples. Sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra).

• Primary Use. Management of erectile dysfunction.

• Clinical Concerns. Sildenafil has been studied far more extensively than the two more recently released agents. In pre-marketing clinical trials, tadalafil and vardenafil have about the same type and incidence of visual side effects as sildenafil. In my opinion, to date there is no proof of any permanent damage to the visual system from any of these agents. Vascular effects may be rarely associated, but one cannot distinguish a drug side effect from increased physical exertion with increased blood pressure and pulse rate, which may occur with sexual activity.

Ocular side effects are common, dosage dependent and thus far have all been fully reversible. Reported side effects include changes in color perception (objects have colored tinges, usually blue or blue/green, though they may also be pink or yellow; diminished color vision on the Farnsworth-Munsell 100 Hue Test; and dark colors may appear darker). Patients have also reported blurred vision, sometimes with central haze and transitory decreased vision. These agents may cause changes in light perception, increased perception of brightness and/or a sensation of seeing flashing lights, especially when blinking.

While sildenafil has been reported to cause ERG changes, Cordell et al. in a 15-center, six-month trial of daily use of either sildenafil or tadalafil versus placebo found no abnormal ERG or any other retinal function parameters. This drug may cause hyperemia and subconjunctival hemorrhages. Some patients report ocular pain and photophobia. There have also been reports of mydriasis, although this is probably not drug-related.

The above ocular side effects are dose-dependent with all three drugs, but with sildenafil occur at the following incidences:

50mg …………3%
100mg ……….10%
200mg ……….40-50%

Incidence is the same for all ages, and the incidence and severity of reported ocular side effects is directly proportional to blood drug levels. The side effects based on dosage with sildenafil start 15-30 minutes after ingestion of the drug, and usually peak 60 minutes after ingestion.

• WHO Classification. Certain: Changes in color perception (colored tinges that are usually blue or blue-green but may be pink or yellow; decreased color vision; dark colors appear darker), blurred vision (central haze; transitory decreased vision), changes in light perception (increased perception of brightness; flashing lights, especially when blinking), conjunctival hyperemia, ocular pain, photophobia. Possible: Subconjunctival hemorrhage, anterior ischemic optic neuropathy, macular edema, ocular rosacea. Conditional/unclassified: mydriasis (emotional effect?), retinal vascular accidents (secondary to exertion?).

Sildenafil has recently become a controversial drug due to the media spotlight on the risk of NAION. To date, the literature contains 14 case reports, including a single report of positive rechallenge (recurrence of NAION when drug therapy was restarted). Spontaneous reporting systems record 86 cases of visual disturbances associated with sildenafil therapy. From this poorly documented data, the association between sildenafil and NAION is “possible” according to WHO criteria, requiring that a clinical event occur within a reasonable time from drug administration. There is no well-researched explanation as to how sildenafil therapy could cause NAION. Over 27 million men have used sildenafil. Most are vasculopathic and fall into an age group in which they are already at risk for NAION.

There are four published cases of macular edema (Allibhai et al. 2004, Quiram et al. 2005) and another seven in the National Registry (Fraunfelder and Fraunfelder 2007). Four of these cases have positive rechallenge of serous macular edema associated with erectile dysfunction drugs at normal or elevated dosages. Included are cases of chronic macular edema, which would not resolve until the drug was stopped. While these data are suggestive, the nature of non-drug-induced serous macular edema is recurrent and transitory. Further data are necessary.

Ioannides et al. reported 10 men on erectile dysfunction agents who developed full blown acne rosacea. While ocular rosacea was not mentioned in this dermatologic study, this side effect should be considered.

• Management Guidelines. We feel that the only patients who should not take phosphodiesterase type 5 inhibitors are those who have previously suffered NAION in one eye or anyone who experiences transitory visual loss while on these medications. These patients may be more prone to developing NAION in the same or fellow eye if sildenafil or other medicines in this class are ingested. Also, the subset of patients who take phosphodiesterase type 5 inhibitors may have the highest risk of developing NAION, independent of an adverse effect, but this is not proven.

Hydroxychloroquine/Chloroquine (Plaquenil)

• Primary Use. Treatment of rheumatoid arthritis and lupus erythematosis, dermatologic conditions and various inflammatory disorders. Chloroquine is no longer available except for malaria treatment and is primarily used in the military.

• Clinical Concerns. From published reports, about one million patients have used hydroxychloroquine or chloroquine, yet only 20 cases of toxicity have been reported in the low-dose range (<6.5mg/kg/day). In addition, all cases occurred after five years of treatment. Still, retinal toxicity can be devastating and guidelines need to be available for screening. It should be emphasized that the recommendations that follow are aimed at detection and not prevention, as stopping the drug is the only way to prevent possible side effects and this is not an option for some patients.

Hydroxychloroquine crystals have been found in the tear film, which may aggravate k. sicca or be bothersome to contact lens wearers. If hydroxychloroquine is found to have caused skin, eyelid, corneal or hair changes, the clinician should suspect retinal changes.

Maculopathy must be bilateral and reproducible by Amsler grid and visual field testing. Transient or unilateral defects are not sufficient reasons to implicate the drug, and are not necessarily an indication to stop therapy. A recent preliminary paper by Shroyer et al. suggests that individuals with an ABCR mutation (Stargardt's disease) may be predisposed to develop retinal toxicity when exposed to chloroquine/hydroxychloroquine.

• Management Guidelines. The goal in managing patients on hydroxychloroquine is to find early changes, i.e., relative scotomas. Disease in patients with early paracentral relative scotomas seldom advance when the drug is discontinued. Later findings include retinal changes, color vision loss, absolute scotoma or decreased vision. Even if the drug is stopped, once these changes occur they are irreversible, and many patients may continue to lose some vision and/or peripheral fields.

To date, there is no data to show that hydroxychloroquine toxicity worsens pre-existing macular degeneration. However, the best course in today's litigious environment may make informed consent and explanation of risk/benefit ratios necessary on an individual basis. Document in the patient's chart that you have explained that, in very rare instances, significant loss of vision can occur after only a few years of therapy, and that he or she may need to be examined if any visual abnormality occurs.

Patients at greatest risk are those on hydroxychloroquine for longer than five years and those with renal or liver disease (this drug is metabolized via the kidney and liver, and thus damage to these organs may increase levels of hydroxychloroquine in the blood). Elderly, thin patients may also be overdosed, as may obese patients. Dosing regimens are based on body weight, but hydroxychloroquine is primarily absorbed by cellular tissue. Since adipose tissue is relatively acellular, obese patients may be overdosed.

How best to follow patients on hydroxychloroquine was summarized in an article in the July 2002 issue of Ophthalmology. These recommendations follow the overall guidelines of the American Academy of Ophthalmology for seeing patients. Patients aged 20-29, one examination; ages 30-39, two examinations; 40-64, every two to four years; and patients aged 65 and over should be seen every one to two years.

Bull's eye maculopathy secondary to Plaquenil use.

Baseline Examinations: Within the first year after starting this drug, patients should have a complete dilated exam, including the informed consent mentioned above, warning of possible permanent visual problems in rare instances. This baseline exam should include visual acuity, Amsler grid (with instructions for monthly home use), and optional color vision testing (preferably including the blue-yellow axis, such as the pseudo-isochromatic plates for color by American Optical Corp.). If macular abnormalities are evident, it would be ideal to obtain fundus photographs. If any progressive ocular abnormality is suspected, consider a baseline Humphrey 10-2 or other automated perimetry. Multifocal ERG is optional.

Follow-up Examinations: For patients who are not obese, frail, elderly or extremely thin, are without significant renal or hepatic disease or macular disease of any type, and who are younger than 40, another complete exam is unnecessary for two to four years. Patients should be seen sooner if they experience any persistent visual symptoms or if their dosage exceeds 6.5 mg/kg.

Patients between 40 and 64 years: Same as above, with follow-up every two to four years,

Age 64 and older: Same as above, with more frequent follow-up (every one to two years).

Annual eye examinations should be considered if patients have been on hydrochloroxyquine therapy for longer than five years, if they are obese, or lean and small (especially in the case of elderly patients), or if they have progressive macular disease of any type, significant renal or liver disease, or their dosage exceeds 6.5 mg/kg.

Follow-up Examination Procedures: Repeat baseline examination; fundus photography if any macular abnormality noted; consider fluorescein angiography only in the presence of suspicious pigmentary changes; automated central visual fields (optional); multifocal ERG (selected cases).

For patients taking chloroquine, perform the tests listed above. See patients at least annually if dosage is less than 3.0 mg/kg of ideal body weight. See every six months if dosage is greater than 3.0 mg/kg body weight, or if patients are short, obese, or have renal and/or liver impairment.

HMG-COA Reductase Inhibitors (Statins)

• Primary Use. To lower cholesterol levels in patients at risk of cardiovascular disease. The enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is inhibited, thereby preventing the rate-limiting step in the mevalonate pathway of cholesterol synthesis. Clinical trials have documented the efficacy of statins in preventing coronary heart disease, cerebrovascular accidents and death from hypercholesterolemia-related disease. Although side effects are rare, myopathies are a well-known adverse reaction.

• Clinical Concerns. The myopathy most often associated with statin therapy affects skeletal muscle and, to date, there is a single published case report of a myopathy of the skeletal musculature around the eye, a case of unilateral blepharoptosis (ptosis), presumably due to levator palpebrae superioris myositis in a patient taking 10 mg of atorvastatin daily. When atorvastatin was discontinued, the ptosis resolved within four days and did not reoccur.

Due to multiple reports of diplopia and ptosis associated with statin therapy received at the National Registry of Drug-Induced Ocular Side Effects, an association between statins and adverse events of this type was investigated.⁷

We found 256 case reports of diplopia, ptosis or ophthalmoplegia associated with statins in the spontaneous reporting databases. Patients included 143 men and 91 women. In 22 case reports, gender was not specified. The average age was 64.5 +/− 10 years (range 34-89 years). Dosage varied, but the average was within the range recommended for each. A total of 108 patients were taking no medications except the statin. Concurrent medications in the other 148 patients included high blood pressure medications such as beta-blockers, diuretics and calcium-channel blockers. Seven of these patients were taking a second statin drug and five were taking gemfibrozil. Women frequently were taking estrogen replacement therapy, and many patients took an aspirin daily. Nine patients had diabetes and 91 had hypertension.

The average time from the start of statin therapy to the appearance of the ADR was 8.3 months +/− 1.5 months (range one day to 84 months). A total of 23 case reports described total ophthalmoplegia. Ptosis was reported alone 20 times and in conjunction with diplopia 13 times. There were 62 reports of positive dechallenge and 14 positive rechallenge case reports.

• WHO Classification. Possible: Diplopia, ptosis, ophthalmoplegia, exacerbate myasthenia gravis, cataracts.

• Management Guidelines. There is a known mechanism for these ADRs: localized myositis in the extraocular muscles or levator palpebrae superioris. Systemic myopathy is commonly associated with statin therapy. Perhaps most compelling are the positive rechallenge case reports.

Myositis due to statin therapy is estimated to occur in approximately 0.1% of patients, increases to 0.5%−2.5% if gemfibrozil is administered at the same time. It is possible that a localized myositis occurred in the extraocular muscles or the levator muscles on and around the eye, leading to the ADRs reported here. In the single published case report of ptosis related to statin therapy, magnetic resonance imaging showed an enlarged right levator muscle. Enhanced with gadolinium, these images suggest myositis.

From the data presented, it appears that statin-associated diplopia, ptosis and ophthalmoplegia are completely reversible on discontinuation of the statin as evidenced by the 62 positive dechallenge case reports. It is possible that toxicity results from many months of therapy, but the data, so far, are inconclusive. The reversibility of the ADR coincides with published literature on statin-associated myopathy and the single case report from the ophthalmic literature. OM

References

1. Fraunfelder FT, Fraunfelder FW, Chambers WA. Clinical Ocular Toxicology. Elsevier, Philadelphia, PA. 2008.
2. Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated with tamsulosin. J. Cataract Refract. Surg 2005;31:664-673.
3. Fraunfelder FW, Keates EU, Fraunfelder FT: Topiramate-associated acute, bilateral, secondary angle-closure glaucoma. Ophthalmology 2004;111(1):109-111.
4. Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular side effects. N Engl J Med 2003;348:1187-8.
5. Fraunfelder FT, Laties A. Visual side effects possibly associated with sildenafil (Viagra). J Toxicol Cut Ocular Toxicol 2000;19:21-25.
6. Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler WF. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. American Academy of Ophthalmology. Ophthalmology. 2011 Feb;118(2):415-22.
7. Fraunfelder FW, Richards AB. Diplopia, blepharoptosis, and ophthalmoplegia and 3-hydroxy-3 methyl-glutaryl-CoA reductase inhibitor use. Ophthalmology. 2008 Dec;115(12):2282-5.