Download Systemic Therapeutic Agents and Retinal Toxicity

Systemic Therapeutic Medications
and Retinal Toxicity
William F Mieler, MD
University of Illinois at Chicago
Chicago, IL
Financial Disclosures
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Consultant
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Genentech
Data and Safety Monitoring Committee
ThromboGenics (in the past)
 Acucela
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Introduction
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A number of systemic medications are capable of
impacting retinal function, even when employed at
therapeutic dosages
This presentation will review
Specific medications
 Classifications and impact of effects on the retina
 Mechanisms of toxicity when known
 Means of limiting risks
 Treatment when applicable
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Disruption of the RPE
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Chloroquine derivatives
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Chloroquine
Hydroxychloroquine
Phenothiazine derivatives
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Thioridazine
Chlorpromazine
Quinine sulfate
Disruption of the RPE
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Dideoxyinosine (DDI)
Clofazamine
Deferoxamine
Corticosteroid preparations
Chemotherapeutic agents
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Cisplatin and BCNU
(carmustine)
Denileukin diftitox (Ontak)
Vascular Damage or Occlusion
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Quinine sulfate (combined
retinal pigmentary change
and vascular occlusion)
Vascular Damage or Occlusion
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Ergot alkaloids
Oral contraceptives
Procainamide
Vascular Damage or Occlusion
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Gentamacin (intravitreal)
Vascular Damage or Occlusion
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Interferon A
Chemotherapeutic Agents
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Gemcitadine
Cisplatin and BCNU
(carmustine)
Macular and Retinal Edema
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Nicotinic Acid (Niacin)
Diuretics
Oral contraceptives
Glitazones (Actos and
Avandia)
Paclitaxel (Taxol) and
Docetaxel
Drug-Induced Myopia
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Idiosyncratic response to
various sulfur derivative
medications, including
diuretics and antibiotics, may
result in transient retinal and
choroidal folds
Crystalline Deposition
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Canthaxanthine
Tamoxifen
Methoxyflurane
Nitrofurantoin
Talc
Uveitis
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Rifabutin
Cidofovir
Miscellaneous
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Digoxin
Sildenafil
Methanol
Chemotherapeutic Agents
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Imatinib mesylate (Gleevec)
Interferon A
Gemcitabine
Denileukin diftitox (Ontak)
Paclitaxel (Taxol) and Docetaxel
Anandron
Tilorone
Cisplatin and BCNU (Carmustine)
Hydroxychloroquine
Background
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A Task Force assembled by
the American Academy of
Ophthalmology (AAO)
developed monitoring
guidelines (2002), which
were updated (2011)
Combination of SD-OCT,
FAF, and multifocal ERG
Dr. Fawzi will delineate
Marmor MF, Kellner U, Lai TYY, Lyons JS, Mieler WF: Revised recommendations on screening for chloroquine and hydroxychloroquine
retinal toxicity. Ophthalmol 118:1242-1252, 2011
Hydroxychloroquine
Monitoring
Marmor MF, Kellner U, Lai TYY, Lyons JS, Mieler WF: Revised recommendations on screening for chloroquine and hydroxychloroquine
retinal toxicity. Ophthalmol 118:1242-1252, 2011
Thioridazine (Mellaril)
Background
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Introduced in 1952 for the treatment of psychoses
Retinal pigmentary retinopathy reported in 1960
Thioridazine
Clinical Symptoms
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Visual blurring
Brownish discoloration of vision
Central or ring-shaped scotoma
Macular and Retinal Edema
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Oral Contraceptives
Nicotinic acid (Niacin)
Glitazones
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Actos and Avandia
Drug-induced myopia
Paclitaxel (Taxol) and Docetaxel
Drug-Induced Myopia
Background
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Reported with a variety of sulfur derivative
medications
Numerous diuretics including chlorthalidone,
acetazolamide, and hydrochlorothiazide
Appears to be an idiosyncratic response
Drug-Induced Myopia
Fundus Findings
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Transient macular edema
Possible retinal and/or choroidal folds
Changes are usually reversible
Drug-Induced Myopia
Fundus Findings
Chlorthalidone
Topirimate
Courtesy: William Tang, MD
T12
Topirimate (two weeks later)
Drug-Induced Myopia
Mechanism of Action
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Not fully known
May involve alteration of the
ciliary body with forward
movement of the lens-iris
diaphram
Shallow peripheral choroidal
detachments have also been
documented echographically
Tamoxifen (Nolvadex)
Background
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Non-steroidal anti-estrogen
agent used in the treatment
of metastatic breast
carcinoma, especially in cases
of positive estrogren
receptors
Also employed in the past in
a breast carcinoma
prevention clinical trial
(increased the risk of uterine
carcinoma)
Tamoxifen
Fundus Findings
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Bilateral refractile opacities
(crystalline deposition) at the
level of the retinal pigment
epithelium
Macular edema has also been
described
Changes limited to the
macular region, and appear
to be permanent
Tamoxifen
Dosage and Toxicity
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Initially employed at 60 to 100 mg/day, though now
more commonly at 10 to 20 mg/day
At the initial higher dosage level, crystalline deposition
was quite common
Cases still occur at the lower dosage levels
Tamoxifen
Newer Indication
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Tamoxifen is occasionally employed at high dosage in
the treatment of advanced high-grade recurrent
glioblastoma
Crystalline retinopathy reported similar to when the
agent was originally introduced in the mid-1970s
Tamoxifen
Treatment of Glioblastoma
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Used at dosages up to 200
mg BID, and may be
employed for several years
In addition to crystalline
retinopathy, profound CME
may develop as well
Tamoxifen
Treatment of Glioblastoma
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Tamoxifen discontinued
Patient treated with intravitreal bevacizumab for the
CME (OD x 3, OS x 5)
Resultant VA 20/20 OD, and 20/40 OS
Before
After
Before
After
Before
After
Before
After
20/100 OD
Pre-Avastin
20/20 OD
Post-Avastin
20/70 OS
20/40 OS
Sildenafil (Viagra)
Background
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Impotence drug with potential complications in
patients with underlying vascular disease
Selective inhibitor of phosphodiesterase-5 (PDE5),
though 10% as effective in blocking PDE6 as well
Sildenafil (Viagra)
Background
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May modify the transduction cascade in the
photoreceptor outer segments, causing a
pharmacologically induced rise in c-GMP
Defects in PDE6 gene (allowing a permanently high
level of c-GMP) cause a type of autosomal recessive
retinitis pigmentosa in rats and dogs
Sildenafil (Viagra)
Background
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Induces smooth muscle
relaxation
Increases vascular
engorgement (including the
choroid)
Sildenafil (Viagra)
Ocular Effects
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Increases ophthalmic artery blood flow
Alters choroidal perfusion and congestion
Increases retinal arterial and venous pressure
308 u
365 u
383 u
EDI Post-Viagra
Vance, Freund Retina 2011
Sildenafil
Clinical Symptoms
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Patients report a bluish tinge or haze to their vision,
generally peaking one to two hours after taking the
medication
Seen in 3% of patients taking 25 to 50 mg, in 11% of
those taking 100 mg, and in excess of 50% of those
ingesting medication over the prescribed level
Sildenafil
Clinical Symptoms
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No permanent visual effects have been reported at the
present time, though long-term concerns do exist,
especially in patients with pre-existing vascular disease
or in those with retinitis pigmentosa
Sildenafil
Possible Associations
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Several reports of nonarteritic anterior ischemic
optic neuropathy (NAION),
though not necessarily out of
proportion to age-matched
controls
Recent reports of a case of
ICSC, and of a serous
macular detachment
Sildenafil
Ancillary Tests
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Depression in ERG has been noted within one hour of
ingesting the medication, though this change does not
appear to be permanent
Even in young healthy volunteer patients given 100 mg
of medication, transient ERG changes have been
documented
Long-term effects not known
Sildenafil
Treatment
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Advise patients that long-term potential risks of the
medication are not fully known at the present time
Chemotherapeutic Agents
Background
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Thousands of agents, yet relatively few direct ocular
complications
Retinal toxicity seen more frequently when combined
with radiation therapy, such as in the setting of bone
marrow transplantation (BMT)
Often difficult to verify that the complication is a sole
manifestation of the medication
Interferon Alpha-2a
Ocular Manifestations
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Important to keep in mind that it is often difficult to
distinguish a side effect from manifestations of the
underlying disease process, or as an effect from
concurrently administered therapy
Peyman (1987, 1992) failed to show any retinal
abnormalities with intravitreal injection of interferon
alpha-2a in rabbits (up to 640,00 IU/0.1 cc)
Interferon Alpha-2a
Possible Ocular Manifestations
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Cotton-wool spots
Retinal hemorrhages
Venous occlusive disease
Isolated cases of optic neuropathy
Visual field abnormalities
Visual evoked potential (VEP) modifications
Interferon Alpha-2a
Mechanism of Action
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Used in the treatment of lymphoma, leukemia, and
melanoma
Delivered subcutaneously
It is a cytokine with pleiotrophic cellular function,
including anti-viral, anti-proliferative,
immunomodulatory, and anti-angiogenic
Courtesy: Joseph Maguire
One Week Later
4/30/10
5/7/10
6/18/10
20/30
20/25 +1
Paclitaxel
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Approved in the treatment of metastatic breast and
ovarian carcinoma, and in Kaposi’s sarcoma
Mitotic inhibitor, interferes with microtubule
breakdown
Ocular side effects may include a form of cystic
maculopathy without leakage on fluorescein
angiography
Findings appear to be reversible with cessation of the
medication
Courtesy: David Weinberg, MD
Milwaukee, WI
January 2010
January 2010
October 2010
October 2010
OD
OS
baseline
3 weeks
6 weeks
Summary
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Thousands of therapeutic medications available on the
market
Relatively few cause retinal complications
Important to recognize the usual patterns of toxicity,
and be alert for possible new associations in the future
Summary
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Most recent reference
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Mittra RA, Mieler WF: Drug Toxicities of the Posterior
Segment, in RETINA, 5th Edition, Ryan SJ, Editor, CV
Mosby, Section 5, Chapter 89, pp 1532-1554, 2013
The National Registry of Drug-Induced Ocular Side
Effects serves as a source of adverse ocular drug
reactions
Data Base and Website
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www.eyedrugregistry.com
Thank You