effects side ocular induced-Drug • 7 Part

of drugs. Fraunfelder and Fraunfelder (2003) reported that all bisphosphonates can cause blurred vision and photophobia. Supported by multiple cases in the literature and positive rechallenge data, almost all bisphosphonates can cause non-specific conjunctivitis, blurred vision and anterior uveitis. More rarely, they have been associated with posterior non-granulomatous uveitis, scleritis, episcleritis, ocular pain and photophobia. The authors suggest that probably any bisphosphonate can cause any of these adverse effects, but these adverse effects have not been proven for all bis­ phosphonates. There have been multiple papers supporting a causal­ relationship of these effects secondary to this class of drugs.

Non-specific conjunctivitis usually occurs within 6–48 hours after drug exposure. This conjunctivitis is transitory and seldom requires treatment. Cases of anterior or posterior uveitis (Haverbeke et al 2003) may occur unilaterally or bilaterally within 24–48 hours after drug exposure, and episcleritis or scleritis can occur as early as 1 to 6 days after. The onset is more rapid and intense with intravenous medication. Fraunfelder et al (2003) reported 17 cases of unilateral and one case of bilateral scleritis after IV pamidronate with the first positive rechallenge data for any drug causing scleritis. The cause of the uveitis, scleritis and episcleritis is conjecture but, since this is a high molecular weight drug, the potential for an immune complex formation has been suggested. The cause for the non-specific conjunctivitis is also unknown, but the pattern suggests that the drug is secreted into the tears by the lacrimal gland and then causes transitory irritation to the mucous membranes. If patients develop a uveitis, episcleritis or scleritis, one needs to monitor these patients more closely, and in some cases discontinue the drug. Xanthopsia (red vision-look up) occurs with positive rechallenge within 2 hours of drug exposure, but only in two single case reports. Des Grottes et al (1997) described a patient with porphyria who developed reversible retrobulbar neuritis after intravenous pamidronate. Ghose et al (1994) also reported a case with orbital pain, proptosis, ptosis, chemosis and partial 3rd and 4th nerve palsy. The patient had a negative neurologic work-up that resolved after a course of oral steroids. Stach and Tan (2006) reported a case of possible optic neuritis due to alendronte, however­ the National Registry has no other cases.

Subramanian et al (2003) reported two cases and Ryan and Sampath (2001) a third, which suggest intravenous pamidronate may cause unilateral or bilateral significant orbital inflammation. No rechallenge data are available. With the absence of another clinical cause and close temporal relation with positive dechallenge, the authors suggest this drug as the probable cause. Each case developed diplopia. Meaney et al (2004) reported a case with positive rechallenge of a possible early phase orbital inflammation with bilateral chemosis, lid edema, erythema and vertical diplopia 2 hours after intravenous pamidronate.

Recommendations

1. Any patients on this group of drugs who report any change in vision or ocular pain should see an ophthalmologist.

2. Non-specific conjunctivitis seldom requires treatment and usually decreases in intensity with repeat exposure to the drug. Use of preservative-free artificial tears may give temporary relief.

3. One needs to be aware that multiple ocular side effects may occur in the same patients so a complete dilated ophthalmic exam is necessary. In some instances the drug may need

to be discontinued for severe uveitis to resolve, but in the main uveitis can be controlled with topical steroids.

4. In our experience, for the slceritis to resolve, even with the patient on full medical therapy, the bisphosphonate must be discontinued.

References And Further Reading

Adverse Drug Reactions Advisory Committee. Bisphosphonates and ocular inflammation. Aust Adv Drug React Bull 23: 7–8, 2004.

Coleman CI, Perkerson KA, Lewis A. Alendronate-induced hallucinations and visual disturbance. Pharmacotherapy 24: 799–802, 2004.

De S, Meyer P, Crisp AJ. Pamidronate and uveitis (letter to the editor). Br J Rheumatol 34(5): 479, 1995.

Des Grottes JM, Schrooyen M, Dumon JC, et al. Retrobulbar optic neuritis after pamidronate administration in a patient with a history of cutaneous porphyria. Clin Rheum 16(1): 93–95, 1997.

Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular inflammation. N Engl J Med 348: 1187–1188, 2003.

Fraunfelder FW, Fraunfelder FT, Jensvold B. Scleritis and other ocular side effects associated with pamidronate disodium. Am J Ophthalmol 135: 219–222, 2003.

Ghose K, Waterworth R, Trolove P, et al. Uveitis associated with ­pamidronate. Aust N Z J Med 24: 320, 1994.

Haverbeke G, Pertile G, Claes C, et al. Posterior uveitis: an underrecognized­ adverse effect of pamidronate: 2 case reports. Bull Soc Belge Ophtalmol 290: 71–76, 2003.

Leung S, Ashar BH, Miller RG. Bisphosphonates-associated scleritis: a case report and review. South Med J 98: 733–735, 2005.

Macarol V, Fraunfelder FT. Disodium pamidronate and adverse ocular drug reactions. Am J Ophthalmol 118: 220–224, 1994.

Mbekeani JN, Slamovits TL, Schwartz BH, Sauer HL. Ocular inflammation associated with alendronate therapy. Arch Ophthalmol 117: 837–838, 1999.

Meany TPJ, Musadiq M, Corridan PGJ. Diplopia following intravenous administration of pamidronate. Eye 18: 103–104, 2004.

MHRA. Final report on TGN1412 clinical trial. Media release: 25 May 2006. Available from: http://www.mhra.gov.uk.

Morton AR, et al. Disodium pamidronate (APD) for the management of single-dose versus daily infusions and of infusion duration. In: Disodium Pamidronate (APD) in the Treatment of Malignancy-Related Disorders, Hans Huber Publishers, Toronto, pp 85–100, 1989.

O’Donnell NP, Rao GP, Aguis-Fernandez A. Paget’s Disease: ocular ­complications of disodium pamidronate treatment. Br J Clin Pract 49(5): 272–273, 1995.

Ryan PJ, Sampath R. Idiopathic orbital inflammation following intravenous pamidronate. Rheumatology 40: 956–957, 2001.

Siris ES. Bisphophonates and iritis. Lancet 342: 436–437, 1993. Stach R, Tarr K. Drug-induced optic neuritis and uveitis secondary to

bisphosphonates. N Z Med J 119: 74–76, 2006.

Stewart GO, Stuckey BG, Ward LC, et al. Iritis following intravenous ­pamidronate. Aust N Z J Med 26(3): 414–415, 1996.

Subramanian PS, Kerrison JB, Calvert PC, et al. Orbital inflammatory disease after pamidronate treatment for metastatic prostate cancer. Arch Ophthalmol 121: 1335–1336, 2003.

Vinas G, Olive A, Holgado S, et al. Episcleritis secondary to risedronate. Med Clin 118: 598–599, 2002.

Class: Chelating Agents

Generic name: Deferoxamine mesilate.

Proprietary name: Desferal.

Primary use

Systemic

This chelating agent is used in the treatment of iron-storage ­diseases and acute iron poisoning.

Ophthalmic

This topical agent is used in the treatment of ocular siderosis and hematogenous pigmentation of the cornea.

Ocular side effects

Systemic administration

Certain

1. Decreased vision

2. Problems with color vision

3. Decreased dark adaptation

4. Retina

a.Pigment epithelium (Fig. 7.12a)

i.Opacitification

ii.Loss of transparency

iii.Molting

b.Bullege maculopathy

c.Vitellifrom maculopathy

d.Cystoid macular edema

5. Optic nerve

a.Disc edema

b.Pallor

c.Atrophy

6. Abnormal – ERG, EOG or VEP

7. Visual field defects

a.Scotoma – central, centrocecal and ring

b.Constriction

8. Eyelids and conjunctiva

a.Allergic reactions

b.Urticaria

c.Angioneurotic edema

Possible

1. Cataracts

2. Optic neuritis

Local ophthalmic use or exposure

Certain

1. Eyelids or conjunctiva

a.Allergic reactions

b.Hyperemia

Clinical significance

Deferoxamine has been used clinically for almost 40 years and with expanded therapeutic uses, additional ocular toxicity reports are occurring. Ocular toxicity usually occurs with long-term therapy, although acute toxicity may occur with rechallenge exposure

Fig. 7.12a  Late flourescein angiogram showing foveal RPE pigment clumping after deferoxamine treatment. Photo courtesy of Haimovici R, et al. The expanded clinical spectrum of deferoxamine retinopathy. Ophthalmology 109: 164—171, 2002.

(Bene et al 1989; Yaqoob et al 1991; Mehta et al 1994), in dialysis patients (Blake et al 1985) or in endstage renal disease (Davies et al 1983; Rubinstein et al 1985; Cases et al 1988). The acute reactions are no different to those found in patients on long-term deferoxamine therapy and may be irreversible, even with only a single dose (Bene et al 1989; Pengloan et al 1990). While ocular toxicity is rare, it varies from minimal reversible changes in approximately­ two-thirds of cases to irreversible changes, including blindness, in approximately one-third of cases. Acute adverse ocular effects are seen most frequently in high dosages while lowdose chronic exposure over a 20-year period does not appear to appear to show retinal toxicity (Elison et al 2005).

No clear-cut relationship between drug dosage and retinopathy has been established for deferoxamine, a drug for which there are no alternative medications. The earliest signs of retinal toxicity include blurred or decreased night vision. Retinal pigment epithelial mottling changes are only seen after the onset of visual color abnormalities or after nyctalopia occurs. Hiamovici et al (2002) reported that the earliest fundus findings are subtle opacifications or loss of transparency of the outer retina and retinal pigment epithelium. Fluorescein angiography in the earliest stage of toxicity is variable. During the transition stage, there is often block fluorescence and then late fluorescence in the late stage. This occurs before retinal pigment epithelium molting. If vitelliform maculopathy develops, permanent visual loss may occur (Mehta et al 1994; Gonzales et al 2004). Gonzales et al (2004) pointed out that persistent hyperfluorescence within the macula may represent a poor prognostic finding due to irreversible retinal pigment epithelium damage. This molting is primarily foveal, but with time may extend to the paramacular, papullomacular and peripapillar areas. Electrophysiologic studies suggest widespread retinal involvement, not just focal areas as seen on funduscopic examination (Haimovici et al 2002). Albalate et al (1996) studied 24 patients and controls on dialysis with chronic renal failure with aluminum intoxication. Thirty-three per cent had macular changes, often with good vision. After 1 year the retinal changes persisted, but only one patient continued to have a significant decrease in vision that did not improve. These pigmentary changes may be progressive for many months, even if the drug is discontinued. ERG, EOG and dark adaptation may also be abnormal.

Toxic cerebral and optic neuropathy with central or centrocecal scotomas and peripheral constriction of visual fields has also been reported in patients receiving deferoxamine (Lakhanpal et al 1984; Blake et al 1985; Pinna, et al 2001). Various symmetrical or asymmetrical disc changes have been described, including edema and atrophy. While these events may well be drug related, there are a few with no clear pattern or mechanism. While this drug can cause cataracts in animals, there are few reports of this in humans (Jacobs et al 1965; Ciba 1969; Bloomfield et al 1978). These reports were before 1978; more recently Popescu et al (1998) suggested that deferoxamine may even be protective against cataracts. To date therefore there is no evidence that this drug is cataractogenic in humans, and at worst there is possibly only a weak association. The exact mechanism of deferoxamine toxicity to the eye is unknown and varies, in part, according to the condition that is being treated. However, in some cases it is probably due to the drug’s capacity to chelate the essential trace elements required for normal enzymatic activity and cellular function.

Recommendations

There are no universally accepted ophthalmic guidelines for following patients on deferoxamine. It is clear that with low doseages, very few ocular side effects are seen. However, in patients

agents miscellaneous and antagonist metal Heavy • 12 Section

effects side ocular induced-Drug • 7 Part

Local ophthalmic use or exposure – inadvertent ocular exposure­

Certain

1. Irritations

a.Conjunctivitis

b.Lacrimation

c.Hyperemia

d.Photophobia

e.Burning sensation 2. Decreased vision

3. Cornea

a.Keratitis

b.Edema

Clinical significance

Hexachlorophene is toxic by the oral route, and in overdose situations can be toxic to any and all areas of the visual system. Case reports, both published and in the National Registry, confirm a predilection of the toxic effect for the optic nerve. There are large numbers of reports in animals (rats, dogs, sheep, calves, monkeys) of hexachlorophene producing cerebral edema, papilledema, mydriasis, no pupillary reaction to light and optic nerve atrophy. Histologically, widespread ‘status spongiosus’, vacuolation of the white matter of the central nervous system, was evident in animals and in one human case (Martinez et al 1974). The clinical finding in animals was identical to a human outbreak of hexachlorophene nervous system toxicity when given orally (Martinez et al 1974; Slamovits et al 1980), from systemic absorption through excoriated skin (Goutieres and Aicardi 1977; Martin-Bouyer et al 1982) or by infant exposure when this agent is used as a vaginal disinfectant (Strickland et al 1983). This agent, in toxic amounts, can cause selective damage to any and all parts of the visual systems from the retina to the cerebral cortex. There is a dose-response curve with reversibility in mild exposure to irreversibility in high doses or chronic exposure.

Inadvertent ocular exposure of this agent can produce severe keratitis involving all layers of the human cornea. A marked reduction of visual acuity has been reported to occur initially, but seldom are these changes irreversible.

References And Further Reading

Goutieres F, Aicardi J. Accidental percutaneous hexachlorophene intoxication in children. BMJ 2: 663, 1977.

Leopold IH, Wong EK Jr. The eye: Local irritation and topical toxicity. In: Cutaneous Toxicity, Drill VA, Lazar P (eds), Raven Press, New York, pp 99–108, 1984.

MacRae SM, Brown B, Edelhauser HF. The corneal toxicity of presurgical skin antiseptics. Am J Ophthalmol 97: 221, 1984.

Martin-Bouyer G, et al. Outbreak of accidental hexachlorophene poisoning in France. Lancet 1: 91, 1982.

Martinez AJ, Boehm R, Hadfield MG. Acute hexachlorophene encephalopathy: clinico-neuopathological correlation. Acta Neuropathol 28: 93, 1974.

Slamovits TL, Burde RM, Klingele TG. Bilateral optic atrophy caused by chronic oral ingestion and topical application of hexachlorophene. Am J Ophthalmol 89: 676, 1980.

Strickland D, et al. Vaginal absorption of hexachlorophene during labor. Am J Obstet Gynecol 147: 769, 1983.

Generic name: Methoxsalen.

Proprietary names: 8-Mop, Oxsoralen, Oxsoralen-Ultra, Uvadex.

Primary use

This psoralen is administered orally or topically for the treatment of psoriasis. The drug is administered before long-wave (320—400 nm) ultraviolet light source exposure (PUVA therapy).

Ocular side effects

Systemic administration or absorption from topical application without uv blocking goggles

Certain

1. Eyelids

a.Hyperpigmentation

b.Erythema

c.Phytodermatitis

2. Conjunctival hyperemia

3. Keratitis

4. Photophobia

Probable

1. Eyelids and periocular skin – increased incidence of malignancies

Possible

1. Eyelids – hypertrichosis

2. Decreased lacrimation

3. Cataracts

Conditional/Unclassified

1. Pigmentary glaucoma

Clinical significance

This medication is given orally as a photosensitizing agent prior to ultraviolet A therapy (PUVA) for treatment of various skin disorders. Wrap-around UV protecting sunglasses are given to the patient during and for at least 12 hours post treatment. To date, this regimen has had little to no ocular side effects other than a photosensitizing effect on the periocular skin. Most ocular adverse effects are transitory and reversible, and have been due to inadvertent light exposure or not wearing protective lenses. Other than the typical photosensitivity reaction of the anterior segment (conjunctival hyperemia, keratitis photophobia), occasionally a patient may also complain of sicca-like symptoms for 48–72 hours following therapy. In a study of 82 patients who refused goggles and post-treatment UV blocking lenses over a 2- to 4-year period, about one-quarter had transitory conjunctival hyperemia and decreased lacrimation. Souêtre et al (1989) reported increased sensitivity of the retina to visible light. Reported visual field changes (Fenton and Wilkinson 1983) are transitory and probably functional rather than drug related. There are a few case reports of pigmentary glaucoma after PUVA therapy in the National Registry, but this is not a proven drug-related event. Since this therapy causes proliferation of pigment epithelial cells, this association may not be coincidental. The increased incidence of skin cancers is probable (Forman et al 1989; Lever and Farr 1994).

The area of greatest controversy is whether PUVA therapy causes cataracts. It has been shown in animals without UV ocular protection that systemic psoralens can cause anterior inferior cortical cataracts. Lerman et al (1980) detected methoxsalen in the lens for at least 12 hours after oral administration. Lerman et al (1980) as well as Woo et al (1985) state that this drug is photobound in the lens and may be cumulative with additional therapy. Van Deenen and Lamers (1988) reported transitory punctiform opacities in the nucleus and cortex of patients undergoing PUVA treatment. There have been numerous reports both supporting and denying lens changes in patients with

agents miscellaneous and antagonist metal Heavy • 12 Section