effects side ocular induced-Drug • 7 Part

7. Trichomegaly

8. Ocular pain

Possible

1. Retinal and optic nerve ischemia (with total body radiation)

a.Cotton wool spots

b.Hemorrhages

c.Lipid deposits

2. Increased lymphoproliferative ocular disease

3. Intracranial hypertension

Local ophthalmic use or exposure

Certain

1. Irritation

a.Burning sensation

b.Pain, itching

Possible

1. Cornea

a.Superficial punctate keratitis

b.Superficial deposits (Fig. 7.12b) 2. Eyelids and conjunctiva

a.Edema

b.Hyperemia

Clinical significance

This drug is used systemically for medical conditions of some complexity where multiple medications and procedures (i.e. bone marrow transplants, total body radiation, leukemias, etc.) are complicating factors in determining specific drug side effects. However, with the drug now in clinical use for over 30 years, drug-induced ocular side effects are fairly well understood.

Bone marrow transplantation patients seem to have some unique ocular toxicity due to ciclosporin and associated drugs. Avery et al (1991) describe eight cases of optic disc edema which resolved after discontinuing or decreasing the dosage of this drug. Optic disc edema due to ciclosporin may be a direct toxic effect of the drug on the optic nerve or papilledema secondary to increased intracranial pressure. This drug rarely affects the optic nerve in renal transplant patients (Rodriguez et al 1992) but it is not uncommon in bone marrow transplantation (Walter et al 2000). Bernauer et al (1991) described retinal and optic nerve ischemia in 13 patients, including bilateral disc edema, cotton wool spots, retinal hemorrhages and lipid deposits. This occurred within the first 6 months of ciclosporin therapy after bone marrow transplantation and was reversible in nine of the 13 cases after the drug was discontinued. The authors concluded that this adverse event was due to a combined effect of ciclosporin along with total body radiation. In this group of patients and others

A B

Fig. 7.12b  Dense white deposits after topical ocular ciclosporin treatment­ . Photo courtesy of Kachi S, et al: Unusual corneal deposit after the topical use of cyclosporine as eyedrops. Am J Ophthalmol 130: 667—669, 2000.

ciclosporin has a neurotoxic effect. This includes cortical blindness, increased intracranial pressure and papilledema. There are a few reports of intracranial hypertension (Cruz et al 1996; Büschen et al 2004) with this drug, but a clear-cut cause-and- effect relationship is not proven. There are four cases (Openshaw et al 1997; Openshaw 2001) of unilateral or bilateral 6th nerve palsy with or without ptosis in patients on both ciclosporin and ganciclovir. An MRI showed this was due to abnormalities in the region of the sixth nerve nucleus rather than a localized ocular neuromuscular event. The palsies reverted to normal in a matter of days once ciclosporin was stopped. The MRI findings also resolved. Ocular flutter in bone marrow transplant patients taking ciclosporin has been described by Apsner et al (1997). Porges et al (1998) reported a case of ciclosporin-induced optic neuropathy, ophthalmoplegia and nystagmus in a patient with Crohn’s disease. Palmer et al (1995) showed that in renal allograft patients, systemic ciclosporin increased tear flow even when no lacrimal autoimmune disease exists. This drug may cause trichomegaly.

Ciclosporin causes a syndrome with various degrees of visual loss, including blindness, encephalopathy, white matter changes and seizures. The presentation of these findings is termed a ‘posterior leukoencephalopathy’. These changes usually return to near normal after stopping ciclosporin. There are at least 40 well-documented cases of this syndrome, primarily in bone marrow or liver transplant cases, but also in patients with leukemia or aplastic anemia. Visual abnormalities have a variable presentation, but most commonly occur within the first 2 months after starting ciclosporin. The retinal exam is negative, although Estel et al (1996) described yellow retinal exudates. When this syndrome is discovered, one must reduce or discontinue the drug. Recovery of vision is often directly proportional to the severity of the syndrome (DeGroen et al 1987). While complete recovery is the standard, there are cases of permanent blindness (Estel et al 1996; Casanova et al 1997). There have been reports of positive rechallenge (Knower et al 2003).

With systemic administration, severe ocular pain may occur for unexplained reasons with or without evidence of an ocular abnormality. This may occur while taking the drug, or when the drug is discontinued. Various irritative reactions may occur around the eye, but these are seldom of major clinical significance. Visual hallucinations may be so severe that they require ciclosporin to be discontinued. Cho et al (2001) suggested the possibility that ciclosporin may increase post-transplant lymphoproliferative disorder uveitis and iris nodules. These four cases were without systemic involvement.

Commercial topical ocular ciclosporin (0.05%) may, in up to 17% of patients, cause some burning or stinging on application. Occasionally patients may develop lid irritation, superficial punctate keratitis and erythema of the lids and/or conjunctiva. Sall et al (2000) reported few ocular side effects other than burning and stinging. Kachi et al (2000) reported a patient developing corneal deposits bilaterally within 5 days of starting topical ocular ciclosporin (2%) three times daily. She had severe disturbances of her corneal epithelial and decrease tear production. After 12 months, other than some peripheral clearing, no improvement in the density of the opacities was seen. Barber et al (2005) found no associated systemic side effects when using a 0.1% ophthalmic emulsion for up to 3 years.

References And Further Reading

Ahern MJ, et al. A randomized double-blind trial of cyclosporin and azathioprine in refractory rheumatoid arthritis. Aust N Z J Med 21: 844–849, 1991.

Apsner R, Schulenburg A, Steinhoff N, et al. Cyclosporin A induced ocular flutter after marrow transplantation. Bone Marrow Transplant 20(3): 255–256, 1997.

Avery R, et al. Optic disc edema after bone marrow transplantation. Ophthalmology 98: 1294–1301, 1991.

Barber LD, Pflugfelder SC, Tauber J, et al. Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion administered twice daily to dry eye disease patients for up to 3 years. Ophthalmology 112: 790–1794, 2005.

BenEzra D, et al. Cyclosporine eyedrops for the treatment of severe vernal keratoconjunctivitis. Am J Ophthalmol 101: 278, 1986.

Bernauer W, Gratwohl A, Keller A, et al. Microvasculopathy in the ocular fundus after bone marrow transplantation. Ann Int Med 115(12): 925–930, 1991.

Büscher R, Vij O, Hudde T, et al. Pseudotumor cerebri following cyclosporine A treatment in a boy with tubulointerstitial nephritis associated with uveitis. Pediatr Nephrol 19: 558–560, 2004.

Casanova B, Prieto M, Deya E. Persistent cortical blindness after cyclosporine leukoencephalopathy. Liver Transplant Surg 3: 638–640, 1997.

Cho AS, Holland GN, Glasgow BJ, et al. Ocular involvement in patients with posttransplant lymphoproliferative disorder. Arch Ophthalmol 119: 183–189, 2001.

Cruz OA, Fogg SG, Roper-Hall G. Pseudotumor cerebri associated with cyclosporine use. Am J Ophthalmol 122(3): 436–437, 1996.

Dawson DG, Trobe JD. Blindness after liver transplant. Surv Ophthalmol 47: 387–391, 2002.

DeGroen PC, Aksamit AJ, Rakela J, et al. Central nervous system toxicity after liver transplantation: the role of cyclosporine and cholesterol. N Engl J Med 317: 861–866, 1987.

Estel RM, Gupta N, Garvin PJ. Permanent blindness after cyclosporine neurotoxicity in a kidney-pancreas transplant recipient. Clin Neuro­ pharmacol 19: 259–266, 1996.

Filipec M, et al. Topical cyclosporine A and corneal wound healing. Cornea 11: 546–552, 1992.

Ghalie R, et al. Cortical blindness: a rare complication of cyclosporine therapy. Bone Marrow Transplant 6: 147–149, 1990.

González-Vincent M, Díaz MA, Madero L. ‘Pseudotumor cerebri’ following allogeneic bone marrow transplantation (BMT). Ann Hematol 80: 236–237, 2001.

Kachi S, Hirano K, Takesue Y, et al. Unusual corneal deposit after the ­topical use of cyclosporine as eyedrops. Am J Ophthalmol 130: 667–669, 2000.

Katirji MB. Visual hallucinations and cyclosporine. Transplantation 43: 768, 1987.

Knower MT, Pethke SD, Valentine VG. Reversible cortical blindness after lunch transplantation. South Med J 96: 606–612, 2003.

Laibovitz RA, et al. Pilot trial of cyclosporine 1% ophthalmic ointment in the treatment of keratoconjunctivitis sicca. Cornea 12: 315–323, 1993.

Marchiori PE, Mies S, Scaff M. Cyclosporine A-induced ocular opsoclonus and reversible leukoencephalopathy after orthotopic liver transplantation. Clin Neuropharmacol 27: 195–197, 2004.

Meyers-Elliott RH, Chitjian PA, Billups CB. Effects of cyclosporine A on clinical and immunological parameters in herpes simplex keratitis. Invest Ophthalmol Vis Sci 28: 1170–1180, 1987.

Noll RB, Kulkarni R. Complex visual hallucinations and cyclosporine. Arch Neurol 41: 329, 1984.

Obermoser G, Weber F, Sepp N. Discoid lupus erythematosus in a patient receiving cyclosporine for liver transplantation. Acta Derm Venereol 81: 319, 2001.

Openshaw H. Eye movement abnormality associated with ciclosporin. J Neurol Neurosurg Psychiatry 70: 809, 2001.

Openshaw H, Slatkin NE, Smith E. Eye movement disorders in bone marrow transplant patients on cyclosporin and ganciclovir. Bone Marrow Transplant 19(5): 503–505, 1997.

Palmer SL, Bowen A II, Green K. Tear flow in cyclosporine recipients. ­Ophthalmology 102(1): 118–121, 1995.

Palmer SL, Bowen A II, Green K. Longitudinal tear study after cyclosporine in kidney transplant recipients. Ophthalmology 103(4): 670–673, 1996.

Porges Y, Blumen S, Fireman Z, et al. Cyclosporine-induced optic neuropathy, ophthalmoplegia, and nystagmus in a patient with Crohn’s disease. Am J Ophthalmol 126(4): 607–608, 1998.

Rodriguez E, Delucchi A, Cano F. Neurotoxicity caused by cyclosporine A in renal transplantation in children. Rev Med Child 120: 300–303, 1992.

Rubin AM, Kang H. Cerebral blindness and encephalopathy with cyclosporin A toxicity. Neurology 37: 1072, 1987.

Sall K, Stevenson OD, Mundorf TK, et al. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology 107: 631–639, 2000.

Stevenson D, Tauber J, Reis BL, et al. Efficacy and safety of cyclosporine A ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease. Ophthalmology 107: 967–974, 2000.

Stucrenschneider BJ, Meiler WF. Ocular findings following bone marrow transplantation. Ophthalmology 92(suppl): 152, 1992.

Tang-Liu DD, Acheampong A. Ocular pharmacokinetics and safety of ciclosporin, a novel topical treatment for dry eye. Clin Pharmacokinet 44: 247–261, 2005.

Uoshima N, Karasuno T, Yagi T, et al. Late onset cyclosporine-induced cerebral blindness with abnormal SPECT imagings in a patient undergoing unrelated bone marrow transplantation. Bone Marrow Transplant 26:

105–108, 2000.

Walter SH, Bertz H, Gerling J. Bilateral neuropathy after bone marrow transplantation and cyclosporine A therapy. Graefe’s Arch Clin Exp Ophthalmol 238: 472–476, 2000.

Weaver SE, et al. Cyclosporin A-induced reversible cortical blindness. J Clin Neuro-Ophthalmol 8: 215–220, 1988.

Generic name: Tacrolimus.

Proprietary names: Prograf, Protopic.

Primary use

Systemic

This potent immunosuppressant is used in the prophylaxis treatment of organ rejection.

Ophthalmic

Used off-label for graft rejection and other conditions helped by immunosuppression.

Ocular side effects

Systemic administration – oral or injection

Certain

1. Decreased vision

2. Visual hallucination

3. Photophobia

4. Eyelids or conjunctiva

a.Photosensitivity

b.Increased susceptibility to bacterial, viral or fungal infections­

Probable

1. Cortical blindness

Possible

1. Optic nerve

a.Neuritis

b.Neuropathy

2. Abnormal visual evoked potential

3. Increase incidence of malignancies (especially lymphoma)

4. Eyelids or conjunctiva

a.Stevens-Johnson syndrome

b.Toxic epidermal necrolysis

Conditional/Unclassified

1. Downward gaze deviation

2. Internuclear ophthalmoplegia

agents miscellaneous and antagonist metal Heavy • 12 Section

effects side ocular induced-Drug • 7 Part

Local ophthalmic use of exposure – ointment 0.1–0.3%

Certain

1. Irritation

a.Burning

b.Itching

Conditional/Unclassified

1. Mucosal pigmentary changes

2. Hypertrichosis – skin

3. Reactivation of herpes simplex

Clinical significance

This potent agent is often given with ciclosporin. Cortical blindness is consistently associated with tacrolimus from the drug, causing bilateral occipital white matter lesions or a leukoencephalopathy (Shutter et al 1993; Devine et al 1996; Steg et al 1999). Once the drug is stopped, vision usually improves within 1–2 weeks. Devine et al (1996) reported three cases of cortical blindness that followed a pattern similar to ciclosporin-induced cortical blindness, with early onset in the course of therapy, no direct correlation to blood levels of the drug and continued improvement while still on the drug. MRI findings appeared to lag behind the clinical improvements.

Three cases of bilateral optic neuropathy have been attributed to tacrolimus. One was reversible 1 month after discontinuing treatment (Kessler et al 2005), one showed continued deterioration even when the drug was stopped (Brazis et al 2000) and two of the three occurred at the normal or low therapeutic dose range (Brazis et al 2000; Lake and Poole 2003). There are 11 cases of poorly documented optic neuritis in the WHO database. There are isolated reports of downward gaze deviation in tacrolimus-induced mutism (Sokol et al 2003), reversible bilateral internuclear opthalmoplegia (Lai et al 2004) and decreased vision with MRI cerebral abnormalities (Bova et al 2000). Lauzurica et al (2002) reported severe bilateral noninfectious corneal ulcers after oral tacrolimus. The authors postulated either a direct toxic effect or a drug-induced vasculitic response. There are no other cases of corneal ulcers in the National Registry or reported to the manufacturer. Plosker and Foster (2000) pointed out, as with most immunosuppressive therapy, an increased rate of malignancy can happen, especially with lymphomas.

Freeman et al (2004) and Russell (2002), when treating 20 patients with atopic eyelid disease using 0.1% tacrolimus ointment, found that 60–80% reported burning and 25–50% reported itching on application of the ointment, but neither reaction was severe enough to stop the drug. Kang et al (2001), in treating dermatitis in children, found up to an 11% increase in skin infections after topical tacrolimus in the form of herpes simplex, varicella and eczema herpeticum. Joseph et al (2005) reported a patient developing herpes simplex corneal ulcer 1 week after starting topical ocular tacrolimus, but at the time the patient was also on steroids. Russell (2002) felt there was a higher incidence of recurrence of herpes after this drug is applied to or around the eye. Shen and Pedvis-Leftick (2004) reported hyperpigmentation of the oral mucosa after topical tacrolimus. Caelles et al (2005) reported a case and there are an additional five cases in the WHO database of hypertrichosis in the area where tacrolimus ointment was applied. There are reports (Rikker et al 2003) that find no significant adverse ocular events due to tacrolimus ointment applied to the eyelids. The FDA has terminated topical ocular application of this drug in solution form for ocular sicca (Sucampo Pharmaceuticals Inc. 2005).

References And Further Reading

Bova D, Shownkeen H, Goldberg K, et al. Delayed transient neurologic toxicity due to tacrolimus: CT and MRI. Neuroradiology 42: 666–668, 2000.

Brazis PW, Spivey JR, Bolling JP, et al. A case of bilateral optic neuropathy in a patient on tacrolimus (FK506) therapy after liver transplantation. Am J Ophthalmol 129: 536–538, 2000.

Caelles IP, Pinto PH, Casado ELD, et al. Focal hypertrichosis during topical tacrolimus therapy for childhood vitiligo. Pediatr Dermatol 22: 86–87, 2005.

Devine SM, Newman NJ, Siegel JL, et al. Tacrolimus (FK506)-induced cerebral blindness following bone marrow transplantation. Bone Marrow Transplant 18: 569–572, 1996.

Freeman AK, Serle J, VanVeldhuisen P, et al. Tacrolimus ointment in the treatment of eyelid sermatitis. Cutis 73: 225–227, 2004.

Joseph MA, Kaufman HE, Insler M. Topical tacrolimus ointment for treatment of refractory anterior segment inflammatory disorders. Cornea 24: 417–420, 2005.

Kang S, Luck AW, Pariser D, et al. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol 44(Suppl 1): S58–S64, 2001.

Kessler L, Lucescu C, Pinget M. Tacrolimus-associated optic neuropathy after pancreatic islet transplantation using a sirolimus/tacrolimus immunosuppressive regimen. Tansplantation 81: 636–637, 2005.

Lai MM, Kerrison JB, Miller NR. Reversible bilateral internuclear ophthalmolplegia associated with FK506. J Neurol Neurosurg Psychiatr 75: 776–778, 2004.

Lake DB, Poole TRG. Tacrolimus. Br J Ophthalmol 87: 121–122, 2003. Lauzurica R, Loscos J, Diaz-Couchod P, et al. Tacrolimus-associated severe bilat­

eral corneal ulcer after renal transplantation. Trans 73: 1006–1007, 2002. Nakamura M, Fuchinouc S, Sato S, et al. Clinical and radiological features

of two cases of tacrolimus-related posterior leukoencephalopathy in living related liver transplantation. Transplant Proc 30: 1477–1478, 1998.

Oliverio PJ, Lucas R, Mitchell SA, et al. Reversible tacrolimus-induced neurotoxicity isolated to the brain stem. Am J Neuroradiol 21: 1251–1254, 2000.

Plosker GL, Foster RH. Tacrolimus: a further update of its pharmacology and therapeutic use in the management of organ transplantation. Drugs 59: 323–389, 2000.

Rikker SM, Holland GN, Drayton GE, et al. Topical tacrolimus treatment of atopic eyelid disease. Am J Ophthalmol 135: 297–302, 2003.

Russell JJ. Topical tacrolimus: a new therapy for atopic dermatitis. Am Fam Physician 66: 1899–1902, 2002.

Shen JT, Pedvis-Leftick A. Mucosal staining after using topical tacrolimus to treat erosive oral lichen planus. J Am Acad Dermatol 50: 326, 2004.

Shutter LA, Green JP, Newman NJ, et al. Cortical blindness and white matter lesions in a patient receiving FK506 after liver transplantation. Neurology 43: 2417–2418, 1993.

Sokol DK, Molleston JP, Filo RS, et al. Tacrolimus (FK560)-induced mutism after liver transplant. Pediatr Neurol 28: 156–158, 2003.

Steg RE, Kessinger A, Wszolek ZK. Cortical blindness and seizures in a patient receiving FK506 after bone marrow transplantation. Bone Marrow Transplant 23: 956–962, 1999.

Sucampo Pharmaceuticals Inc. Sucampo voluntarily halts tacrolimus eye drops development, files complaint against business partner. Media Release, 24 Jun 2005. Available from: http://www.sucampo.com.

Class: Retinoids

Generic name: Isotretinoin.

Proprietary names: Accutane, Amnesteem, Claravis, Sotret.

Primary use

These retinoids are used in the treatment of psoriasis, cystic acne and various other disorders of the skin.

Ocular side effects

Systemic administration

Certain

1.Eyelids or conjunctiva

a.Blepharoconjunctivitis

b.Erythema

c.Edema

d.Conjunctivitis – non-specific

e.Photosensitivity

f.Angioneurotic edema

g.Pruritus

2.Decreased or blurred vision

3.Meibomian glands

a.Meibomitis

b.Increased viscosity of secretion

c.Atrophy

d.Associated increased staphyloccus

4.Lacrimation – variable

5.Tears

a.Decreased osmolarity

b.Decreased tear film break-up times

c.Drug found in tears

d.Sicca-evaporative form

6.Cornea

a.Superficial opacities – fine, rough

b.Superficial punctate keratitis

c.Ulceration

7.Decreased dark adaptation

a.Night blindness

b.Permanent night blindness

8.Myopia – transitory

9.Abnormal ERG (scopic)

10.Decreased tolerance to contact lenses

11.Papilledema secondary to intracranial hypertension

Probable

1. Color vision – decreased

Possible

1. Optic neuritis

Ocular teratogenic effects

Certain

1. Microphthalmia

2. Optic nerve hypoplasia

3. Orbital hypertelorism

4. Cortical blindness

Possible

1. Cataracts

2. Keratoconus

Clinical significance

Ocular side effects are dose related and probably the most frequent adverse drug reactions are blepharoconjunctivitis, subjective complaints of dry eyes and transient blurred vision. Acute refractive changes, especially myopic shifts, are transitory and well documented. The drug is secreted in the tears via the lacrimal gland, which may be the cause of an irritative or drug-induced conjunctivitis. Bozkurt et al (2002) and Mathers et al (1991) believe if given in low doses and not in multiple cycles, the sicca is reversible, but in rare instances it may be permanent (Fraunfelder et al 2001). Some of these signs and symptoms are secondary to isotretinoin’s direct effect of decreasing meibomian gland function with resultant increased tear evaporation and tear osmolarity. In some patients, isotretinoin causes keratoconjunctivitis sicca (Fraunfelder et al 2001). This again confirms that drugs that cause oral dryness have the potential to cause ocular sicca as well (Bots et al 2003). Aragona et al (2005) discussed the problems of ocular surface

disease in patients on isotretinoin and its management. Miles et al (2006) pointed out the problems of doing laser assisted in situ keratomileusis (LASIK) in patients on isotretinoin and recommend not using this drug for 6 months post surgery. Fine, rounded, subepithelial opacities found in the central and peri­ pheral corneas of patients treated with this medication rarely interfere with vision. They may be of variable sizes, white to gray in color, and disappear within 2–10 months after discontinuation of the drug. This probably occurs partially by changes in tear film along with the drug being secreted in the tears. These factors also affect patients who are contact lens wearers. Some recommend not fitting patients with lenses while on the drug. Approximately 20% of previously successful wearers may need to discontinue their contact lens use, decrease their wearing time or use additional preservative-free lubricating eye drops while on isotretinoin.

There are well-documented cases of decreased ability to see at night in patients after taking this agent (Fraunfelder et al 2001). This may occur as early as after a few weeks or after prolonged drug exposure. This may be irreversible. Retinal dysfunction is probably due to the competition for binding sites between retinoic acid and retinol (vitamin A). The risk of a photosensitizing drug, such as isotretinoin, enhancing the effects of light on the macula and retina is unclear. While there are cases in the National Registry of retinal pigmentary changes, these are few in number and may be unrelated.

Fraunfelder et al (2004) report on 179 cases of intracranial hypertension in patients on isotretinoin. The mean onset was 2.3 months after starting the drug. Six patients in this series had positive rechallenges. Isotretinoin is a synthetic derivative of vitamin A that has well-documented data as being a cause of intracranial hypertension. It is felt this class of drugs alters the lipid concentration of the arachnoid villi, thereby impeding absorption of cerebrospinal fluid (Roytman et al 1988).

The role of isotretinoin as a cataractogenic agent is not yet defined. Although there are a number of reports of cataracts in the National Registry, as well as in a publication by Herman and Dyer (1987), there are little data to prove that isotretinoin is a cataractogenic agent. This drug has been in widespread use for more than two decades and very few cataracts are reported, which suggests that this agent is at worst a very weak cataractogenic agent. Drug exposure is often short-term (i.e. a number of months), indicating the reports are a chance event or consist of a subset of individuals whose lenses are highly sensitive to the drug. Regardless, there is no clear-cut pattern to the cataracts. There are a few cases in the National Registry of a subset of patients in high-light environments who have taken multiple cycles of isotretinoin, developing multiple, small, cortical punctate opacities of various sizes.

Optic neuritis, unilateral and bilateral, has been seen shortly after starting isotretinoin. Since most of these patients are in the multiple sclerosis age group, it is difficult to be confident as to a cause-and-effect relationship. To our knowledge, no case has been rechallenged. However, there are cases that suggest a possible relationship therefore the manufacturer recommends stopping the drug if this occurs.

While keratoconus has been reported with isotretinoin usage, the drug is used in atopic individuals. Keratoconus is seen in 4–6% of atopics. We doubt keratoconus is caused by this agent. Fraunfelder (2001) reviewed 2449 spontaneous isotretinoin ocular side effects and gives the most complete overview.

Offspring of mothers exposed to these drugs during preg­ nancy may have numerous congenital abnormalities involving the eyes (Guirgis et al 2002).

agents miscellaneous and antagonist metal Heavy • 12 Section