Journal of Neuro-Ophthalmology, September 2004, Volume 24, Issue 3

Evidence for a Probable Causal Relationship Between Tretinoin, Acitretin, and Etretinate and Intracranial Hypertension

With the recognition that vitamin A and isotretinoin may cause intracranial hypertension, the authors reviewed 331 case reports of ocular side effects associated with the three other marketed retinoids: tretinoin, acitretin, and etretinate. The reports were drawn from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization (WHO), the Food and Drug Administration, and medical journals between 1979 and 2003. There were 21 cases of intracranial hypertension associated with these three retinoids, leading to an inference that they are probably causally related to intracranial hypertension by WHO criteria. The lack of positive rechallenge data precludes the inference of a definite causal relationship to intracranial hypertension by WHO criteria. The inference of an independent causal role of these retinoids is further cautioned by the fact that six patients were concurrently using tetracycline or minocycline. Even so, the data suggest that all retinoids may, in rare instances, cause intracranial hypertension.

ORIGINAL CONTRIBUTION Evidence for a Probable Causal Relationship Between Tretinoin, Acitretin, and Etretinate and Intracranial Hypertension Frederick W. Fraunfelder, MD and Frederick T. Fraunfelder, MD Abstract: With the recognition that vitamin A and isotre­tinoin may cause intracranial hypertension, the authors re­viewed 331 case reports of ocular side effects associated with the three other marketed retinoids: tretinoin, acitretin, and etretinate. The reports were drawn from the National Registry of Drug- Induced Ocular Side Effects, the World Health Organization ( WHO), the Food and Drug Admin­istration, and medical journals between 1979 and 2003. There were 21 cases of intracranial hypertension associated with these three retinoids, leading to an inference that they are probably causally related to intracranial hypertension by WHO criteria. The lack of positive rechallenge data pre­cludes the inference of a definite causal relationship to in­tracranial hypertension by WHO criteria. The inference of an independent causal role of these retinoids is further cau­tioned by the fact that six patients were concurrently us­ing tetracycline or minocycline. Even so, the data suggest that all retinoids may, in rare instances, cause intracran­ial hypertension. ( JNeuro- Ophthalmol 2004; 24: 214- 216) Retinoids are used to treat severe recalcitrant nodular acne, acne vulgaris, and severe recalcitrant psoriasis, and to induce remission of leukemia. Isotretinoin is the most widely prescribed medication in this class, used by an estimated five million Americans, and is a top seller for the pharmaceutical company Hoffman- LaRoche. There was a 250% increase in the number of dispensed prescriptions for isotretinoin in the United States between 1992 and 2000 ( 1). Casey Eye Institute, Oregon Health & Science University, Portland, Oregon; Collaborating Center for International Drug Monitoring, World Health Organization, Uppsala, Sweden; Food and Drug Administration, Rockville, Maryland, and the National Registry of Drug Induced Ocular Side Effects, Casey Eye Institute, Portland, Oregon. This study was supported in part by an unrestricted grant from Re­search to Prevent Blindness, New York, New York. Address correspondence to F. W. Fraunfelder, MD, Casey Eye Insti­tute, 3375 SW Terwilliger Blvd., Portland, OR 97201; E- mail: eyedrug@ ohsu. edu In 2003, isotretinoin was placed in the World Health Orga­nization ( WHO) " certain" category for inducing intracrani­al hypertension ( IH) because of positive rechallenge data, a characteristic pattern of rapid IH onset after exposure, and the fact that this agent is a degradative product of all- trans retinoic acid ( ATRA; vitamin A), a known contributor to IH ( 2- 6). Because ATRA and isotretinoin are now recognized as agents that can cause IH, we reviewed the case reports of ophthalmic side effects of other retinoids to ascertain if they too might cause IH. We selected all retinoids marketed in the United States for treatment of acne, as well as tretinoin, which is used to induce remission of leukemia. Only acitre­tin, tretinoin, and etretinate had complete case reports of associated IH. METHODS We hunted for case reports of ocular side effects re­lated to retinoid therapy among reported submitted by phy­sicians between 1979 and 2003 to the National Registry of Drug- Induced Ocular Side Effects ( Portland, OR), WHO ( Uppsala, Sweden), and the Food and Drug Admin­istration ( FDA; Rockville, MD). National Registry reports were sent spontaneously from physicians to the website ( www. eyedrugregistry. com) or via mail to the Casey Eye Institute. WHO data were available to the authors, who were acting as WHO consultants. FDA reports were avail­able through the Freedom of Information Act. We also re­viewed medical journals for reports of retinoid- associated ophthalmic side effects over the past 20 years by searching Medline using the retinoid generic name and either " intra­cranial hypertension" or " pseudotumor cerebri" as key­words. Reports related to ATRA ( vitamin A) and isotretin­oin were not included. We encountered 331 reports of ocular side effects and analyzed them for an association with IH. Tretinoin, acitre­tin, and etretinate were the only medications found to have an association with IH. We noted the age and gender of the patient, duration of therapy, dose of the retinoid, concurrent use of other medications, positive dechallenge ( IH abated 214 J Neuro- Ophthalmol, Vol. 24, No. 3, 2004 Intracranial Hypertension JNeuro- Ophthalmol, Vol. 24, No. 3, 2004 when the retinoid was discontinued), and positive rechal-lenge data ( IH recurred when the retinoid was restarted). RESULTS There were 21 case reports of retinoid- associated IH ( Table 1). For acitretin, one case report came from the WHO and two from the FDA. For tretinoin, two reports came from the WHO and nine from the FDA. Etretinate had one case report submitted to the National Registry, one to the WHO, two to the FDA, and three from the medical jour­nal literature. These data suggest that, in rare instances, retinoids may cause IH when used at prescribed therapeutic doses. Onset of symptoms ( blurred vision, headache) oc­curred an average of two to three months after patients com­menced therapy ( range, five days to two years). From the available information, all but three cases of IH resolved within a few months after retinoid use was discontinued. There are no follow- up data. In six reports, patients were concurrently taking a tetracycline, a class of agents previ­ously associated with IH. DISCUSSION Postmarketing surveillance systems suffer from underreporting, incomplete information, and lack of follow- up. These systems, however, provide information as to a temporal relationship, a pattern of presentation, TABLE 1. Drug Acitretin Tretinoin Etretinate Intracranial Source WHO FDA FDA FDA FDA FDA WHO FDA FDA FDA FDA WHO FDA FDA FDA WHO FDA NR Lit Lit Lit hypertension Age UNK 40 30 24 29 UNK 19 UNK 25 30 31 14 14 27 36 44 11 UNK 3313 67" 75" associated with retinoids Gender UNK F M M F F F F F F F UNK F F F F M F F F F Concurrent medications None None None Zidovudine Trazodone Pyridoxine HCl Epoetin alfa Insulin None Minocycline* Minocycline* Tetracycline* Tetracycline* Imipramine Naproxen Lorazepam Tetracycline* Lorazepam Oral contraceptive Tetracycline* Sulfamethoxazole Fluconazole Oral contraceptive None None Furosemide None None Floctafenine None Minocycline* Dose of retinoid 50mg/ d 50mg/ d 50mg/ d 45 mg/ m2/ d 45 mg/ m2/ d 45 mg/ m2/ d 45 mg/ m2/ d 45 mg/ m2/ d 45 mg/ m2/ d 45 mg/ m2/ d 45 mg/ m2/ d 45 mg/ m2/ d 45 mg/ m2/ d 45 mg/ m2/ d 0.75- 1 mg/ kg/ d 0.75- 1 mg/ kg/ d 0.75- 1 mg/ kg/ d 0.75- 1 mg/ kg/ d 0.50- 1 mg/ kg/ d 1.0 mg/ kg/ d 1.0 mg/ kg/ d Time from usage to onset of IH Unknown 515 d Unknown 53 d 45 d 257 d Unknown Unknown Unknown 82 d 730 d Unknown Unknown Unknown 5d 90 d Same day Unknown 90 d 30 d 180 d Dechallenge Unknown + + - Unknown Unknown Unknown + Unknown Unknown Unknown Unknown + + Unknown + + + + + * Drags reported to cause IH. UNK, unknown; +, positive dechallenge; -, negative dechallenge; NR, National Registry; WHO, World Health Organization; FDA, Food and Drag Administration; Lit, Medical journal literature. 215 JNeuro- Ophthalmol, Vol. 24, No. 3, 2004 Fraunfelder and Fraunfelder TABLE 2. World Health Organization Causality Assessment of Suspected Adverse Drug Reactions7 Certain: A clinical event, including laboratory test abnormality, occurring in a plausible time relationship to drug administration, which cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug ( dechallenge) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary. Probable/ likely: A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, which follows a clinically reasonable response on withdrawal ( dechallenge). Rechallenge information is not required to fulfill this definition. Possible: A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear. Unlikely: A clinical event, including laboratory test abnormality, with a temporal relationship to drug administration that makes a causal relationship improbable, and in which other drugs, chemicals, or underlying disease provide plausible explanations. Conditional/ unclassified: A clinical event, including laboratory test abnormality, reported as an adverse reaction, about which more data are essential for a proper assessment or the additional data are undergoing examination. Nonassessible/ unclassifiable: A report suggesting an adverse reaction that cannot be judged because information is insufficient or contradictory, and that cannot be supplemented or verified. and dechallenge and rechallenge data that may suggest pos­sible, probable, or certain causation of an adverse drug event ( 7). Based on our review, the temporal relationship of tre­tinoin, acitretin, and etretinate to symptoms and the overall pattern of IH in patients receiving these retinoids is similar to that described for isotretinoin and ATRA in previous published reports ( 2- 6,8). The positive dechallenge data allow inference of a " probable" causal relationship of IH for these three agents, according to WHO criteria ( Table 2). A " certain" causal relationship cannot be inferred because there is a paucity of rechallenge data. An independent cau­sal relationship for these three retinoids must also be in­ferred with caution, because six of the patients were also using tetracycline or minocycline, agents previously caus­ally implicated in IH ( 9,10). For patients receiving retinoids, we suggest the fol­lowing management guidelines: 1) prompt ophthalmologic consultation to rule out papilledema in patients using reti­noid therapy in whom otherwise unexplained headaches or blurred vision develops; 2) periodic ophthalmologic con­sultation to rule out papilledema even in asymptomatic pa­tients using retinoid therapy for six months or more because IH can develop without symptoms; and 3) avoidance of concomitant use of tetracyclines or vitamin A because they may potentiate the development of IH ( 11,12). Acknowledgment The authors are indebted to the national centers men­tioned in this study that contributed data. The opinions and conclusions, however, are not necessarily those either of the various centers or of the WHO. REFERENCES 1. Wysowski DK, Swann J, Vega A. Use of isotretinoin ( Accutane) in the United States: Rapid increase from 1992 through 2000. J Am Acad Dermatol 2002; 46: 505- 9. 2. Fraunfelder FW, Fraunfelder FT, Corbett JJ. Isotretinoin- Associ-ated Intracranial Hypertension. Ophthalmology 2004; 111: 1248- 50. 3. Fraunfelder FT, Fraunfelder FW, Edwards R. Ocular side effects possibly associated with isotretinoin usage. Am J Ophthalmol 2001; 132: 299- 305. 4. Schroeter T, Lanvers C, Herding H, Suttorp M. Pseudotumor cere­bri induced by all- trans- retinoic acid in a child treated for acute pro-myelocytic leukemia. MedPeiatr Oncol 2000; 34: 284- 6. 5. Sano F, Tsuji K, Kunika N, et al. Pseudotumor cerebri in a patient with acute promyelocytic leukemia during treatment with all- trans-retinoic acid. Intern Med 1998; 37: 546- 9. 6. Tiamkao S, Sirijirachai C. Pseudotumor cerebri caused by all- trans-retinoic acid: a case report. J Med Assoc Thai 2000; 83: 1420- 3. 7. Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Sa/ T994; 10: 93- 102. 8. Guirgis MF, Lueder GT. Intracranial hypertension secondary to all-trans retinoic acid treatment of leukemia: diagnosis and manage­ment. JAAPOS 2003; 7: 432- 4. 9. Gardner K, Cox T, Digre KB. Idiopathic intracranial hypertension associated with tetracycline use in fraternal twins: case reports and review. Neurology 1995; 45: 6- 10. 10. Meacock DJ, Hewer RL. Tetracycline and benign intracranial hy­pertension [ Letter]. Br Med J 1981; 282: 1240. 11. Lee AG. Pseudotumor cerebri after treatment with tetracycline and isotretinoin for acne. Cutis 1995; 55: 165- 8. 12. Donahue SP. Recurrence of idiopathic intracranial hypertension af­ter weight loss: the carrot craver. Am J Ophthalmol 2000; 130: 850- 1. 13. Bonnetblanc JM, Hugon J, Dumas M, et al. Intracranial hyperten­sion with etretinate [ Letter]. Lancet 1983; 2: 974. 14. Viraben R, Mathieu C, Fontan B. Benign intracranial hypertension during etretinate therapy for mycosis fiingoides. J Am AcadDerma-tol 1985; 13: 515- 7. 216 © 2004 Lippincott Williams & Wilkins