July 26, 2011

Petition Requesting Warnings on the Labels of Glucocorticosteroids Including Prednisone

February 8, 2024, FDA final response letter.

Margaret A. Hamburg, M.D.
Commissioner
U.S. Food and Drug Administration
Department of Health and Human Services
WO 2200
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002

Dear Dr. Hamburg:

Public Citizen, representing more than 225,000 members and supporters nationwide, hereby petitions the Food and Drug Administration (FDA), pursuant to the Federal Food, Drug, and Cosmetic Act 21 U.S.C. Section 352, and 21 C.F.R. 10.30 and 201.56, to immediately require that the labels for all brands of prednisone and other glucocorticosteroids currently on the market in the United States (U.S.) be revised to include central serous chorioretinopathy as one of the ophthalmic adverse reactions reported with these medications if not already included. At present, a substantial proportion of the labels for these products (87% of labels that we reviewed) do not contain a warning about this potentially serious adverse reaction. Furthermore, the FDA should review the labels for all such medications and, as appropriate, require additional label changes to ensure that other important information regarding the use and safety of these medications is presented in a consistent manner across all labels.

I. Statement of Grounds

A. Disclosure of the risk of central serous chorioretinopathy

Central serous chorioretinopathy is a common disease characterized by accumulation of edema fluid underneath the retina and subsequent retinal separation at the posterior pole of the fundus (the inner lining of the eye opposite the lens, located between the optic disc and the macula). This eye disorder can present with an acute decline in visual acuity and metamorphosia (a defect in vision in which objects appear to be distorted). Acute central serous chorioretinopathy usually remits spontaneously, with recovery of visual acuity, following cessation of the causative agent. However, recurrent episodes can lead to extensive retinal separation and permanent visual loss. Systemic, local, and even topical synthetic glucocorticosteroids are considered to be among the causes of this eye disorder.[1-6]

Glucocorticosteroids are widely used to treat many different diseases. In 2010, for example, there were 25.5 million prescriptions for oral prednisone and 13.7 million prescriptions for methylprednisolone tablets in the U.S.[7]

A review of the available labels for the brands of prednisone currently marketed in the U.S. reveals that labels for prednisone manufactured by the following companies appropriately list central serous chorioretinopathy as one of the ophthalmic adverse reactions reported for prednisone and other synthetic glucocorticosteroids:

• Mutual Pharmaceutical Company, Inc. (prednisone; 5-milligram [mg], 10-mg, and 20-mg tablets; revised December 2010[8]); and
• Roxane Laboratories, Inc. (prednisone; 1-mg, 2.5-mg, 5-mg, 10-mg, 20-mg, and 50-mg tablets, and 5-mg/milliliter (mL) and 5-mg/5-mL oral solutions; revised September 2009[9]).

In contrast, labels for prednisone manufactured by the following companies do not list central serous chorioretinopathy as one of the ophthalmic adverse reactions reported for prednisone and other synthetic glucocorticosteroids, even though there were other revisions to all of their labels in the past few years:

• Cadista Pharmaceuticals, Inc. (prednisone; 1-mg tablet; revised February 2007[10]);
• Qualitest Pharmaceuticals (prednisone; 1-mg, 2.5-mg, 5-mg, 10-mg, and 20-mg tablets; revised February 2011[11]);
• Watson Laboratories, Inc. (prednisone; 5-mg, 10-mg, and 20-mg tablets; revised September 2008[12]); and
• West-Ward Pharmaceutical Corp. (prednisone; 1-mg, 2.5-mg, 5-mg, 10-mg, and 20-mg tablets; revised August 2009[13] and November 2010[14]).

The FDA Orange Book indicates that Contract Pharmacal Corp. also markets prednisone (5-mg tablet) in the U.S., but we were unable to find the current label for this brand.

Furthermore, we reviewed a sample of the available labels for other types of synthetic glucocorticosteroids marketed in the U.S. and found that labels for the glucocorticosteroids manufactured by the following companies do not list central serous chorioretinopathy as one of the ophthalmic adverse reactions reported for prednisone and other synthetic glucocorticosteroids:

Cortisone acetate

• West-Ward Pharmaceutical Corp. (cortisone acetate; 25-mg tablet; revised July 2009[15]).

Dexamethasone

• ECR Pharmaceuticals (dexamethasone; 1.5-mg tablet; revised November 2008[16]);
• Roxane Laboratories, Inc. (dexamethasone; 0.5-mg, 0.75-mg, 1-mg, 1.5-mg, 2-mg, 4-mg, and 6-mg tablets, and 0.5-mg/mL and 0.5-mg/5-mL oral solutions; revised September 2007[17]); and
• Wockhardt USA, LLC (Baycadron [dexamethasone]; 0.5-mg/5-mL solution; issued December 2008[18]).

Hydrocortisone

• Pharmacia and Upjohn Company (Cortef [hydrocortisone]; 5-mg, 10-mg, and 20-mg tablets; revised July 2006[19]); and
• West-Ward Pharmaceutical Corp. (hydrocortisone; 20-mg tablet; revised July 2003[20]).

Methylprednisolone

• Pharmacia and Upjohn Company (Medrol [methylprednisolone]; 2-mg, 4-mg, 8-mg, 16-mg, and 32-mg tablets; revised November 2006[21]);
• Sandoz, Inc. (methylprednisolone acetate; 40-mg/ml and 80-mg/ml injectable; revised April 2010[22]); and
• Teva Parenteral Medicine, Inc. (methylprednisolone acetate; 40-mg/ml and 80-mg/ml injectable; issued May 2009[23]).

B. Additional discrepancies between labels

A review of the labels for the above-listed drugs reveals many other significant discrepancies in the information provided regarding risks and precautions. For example, the labels for prednisone manufactured by Mutual Pharmaceutical Company, Inc.,[8] and by Roxane Laboratories, Inc.,[9] include a warning about activation of latent infections due to special pathogens (including Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, and Toxoplasma), as well as a precaution about the possible development of Kaposi’s sarcoma. In contrast, such information is not provided in the labels for prednisone manufactured by Cadista Pharmaceuticals, Inc.,[10] or Qualitest Pharmaceuticals.[11]

There is also significant variation across the labels for the above-listed drugs regarding information about important drug interactions.

II. Summary of Requested Actions

Since synthetic glucocorticosteroid medications share similar mechanisms of action and risk profiles, it is important that the labels for these drugs communicate consistent information to health care providers and consumers regarding drug use and safety.

Given that (a) central serous chorioretinopathy is a well-described ophthalmic adverse reaction associated with the use of prednisone and other synthetic glucocorticosteroids,[1-6] and (b) this adverse reaction is included in the FDA-approved labels for the brands of prednisone marketed by Mutual Pharmaceutical Company, Inc., and Roxane Laboratories, Inc., we hereby petition the FDA to immediately require that the labels for all brands of prednisone and other synthetic glucocorticosteroids currently on the market in the U.S. be revised to include central serous chorioretinopathy as one of the ophthalmic adverse reactions reported with these medications.

Given the other significant discrepancies across the labels for synthetic glucocorticosteroids as well as the widespread use of these medications, we hereby petition the FDA to review the labels for all synthetic glucocorticosteroid medications currently marketed in the U.S. and, as appropriate, require additional label changes to ensure that other important information regarding the use and safety of these medications is presented in a consistent manner across all labels. As an initial, immediate step, the FDA should ensure that all labels for synthetic glucocorticosteroids include a warning about activation of latent infections due to special pathogens and a precaution about the possible development of Kaposi’s sarcoma.

III. Environmental Impact Statement

Nothing requested in this petition will have an impact on the environment.

IV. Certification

We certify that, to the best of our knowledge and belief, this petition includes all information and views on which this petition relies, and that it includes representative data and information known to the petitioners which are unfavorable to the petition.

Sincerely,

Michael Carome, M.D.
Deputy Director
Public Citizen’s Health Research Group

Sidney M. Wolfe, M.D.
Director
Public Citizen’s Health Research Group

Jonathan D. Trobe, M.D.
Professor of Ophthalmology and Neurology
University of Michigan

cc: Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research, FDA