Corticosteroids: Belated Safety Labeling Changes Prompted by a Public Citizen Petition

Made by the adrenal glands, corticosteroids (a term for steroid hormones that includes glucocorticosteroids, also called glucocorticoids) impact carbohydrate, fat and protein metabolism, as well as other body functions.[1] Synthetic corticosteroids are available in systemic (oral and injectable) formulations (see the Table, below, for examples) as well as inhaled, nasal, ophthalmic (eye) and topical forms. Because of their ability to suppress inflammatory and immune responses, corticosteroids are used widely to treat many conditions (such as asthma, inflammatory bowel disease and rheumatoid arthritis) and to prevent organ rejection in transplant recipients.

The use of corticosteroids is associated with many adverse effects that are included in the labels of these drugs, such as high blood pressure, high blood sugar levels, gastrointestinal ulcers and osteoporosis (bone loss).[2]

In July 2011 Public Citizen’s Health Research Group petitioned the Food and Drug Administration (FDA) to require certain additional safety warnings on the labels of glucocorticosteroids.[3] In February 2024 the FDA finally granted our petition in part.[4]

Hereafter, this article uses the term corticosteroids, consistent with how the FDA refers to this drug class.

Table: Examples of Common Systemic Corticosteroids

Public Citizen’s petition and related labeling changes

In our 2011 petition we requested that the FDA require the revision of labels for all synthetic corticosteroids to include warnings regarding the increased risk of Kaposi’s sarcoma (a type of cancer that forms lesions in the gastrointestinal tract, lungs or skin) and activation of latent (dormant) infections caused by various pathogens (including Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis and Toxoplasma).[5]

Similarly, we asked the agency to require universal warnings on the labels of corticosteroids about a potential eye-related adverse effect called central serous chorioretinopathy (which is characterized by fluid accumulation under the retina that can cause blurred central vision and may even detach the retina). Particularly, we found that this adverse effect was not listed in 87% of the labels that we reviewed, including those for prednisone formulations.

Finally, we asked the FDA to review the labels of all corticosteroids, as appropriate, and to require further labeling changes to ensure that other important information regarding the use and safety of these medications is presented in a consistent manner.

In its February 2024 response letter, the FDA granted our requests regarding the risks of Kaposi’s sarcoma and activation of latent infections.[6] Since June 2024, therefore, standardized warnings regarding these risks have been incorporated into the labels of systemic corticosteroid products (see the Text Box below for these new warnings).[7] The agency did not require these warnings for corticosteroids that are administered by localized routes of administration (such as topically or by inhalation).

Although we welcome these new safety warnings prompted by our petition, we are troubled by the FDA’s extreme tardiness. Indeed, the agency easily could have required the safety labeling changes outlined in our petition more than a decade ago to warn the public about the risks of these widely used medications.

Importantly, the FDA denied our request regarding the risk of central serous chorioretinopathy and also declined to review all other pertinent labels to ensure that other important information regarding the use and safety of corticosteroids is presented in a consistent manner.

Table: Examples of Common Systemic Corticosteroids

Corticosteroids suppress the immune system and increase the risk of infection with any pathogen (including viral, bacterial, fungal, protozoan or helminthic pathogens). Corticosteroids can reduce resistance to new infections, exacerbate existing infections, increase the risk of spread of infections, increase the risk of reactivation or exacerbation of latent infections, and mask some signs of infection.

Corticosteroid-associated infections can be mild but also can be severe and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages.

Monitor for the development of infection and consider corticosteroid drug withdrawal or dosage reduction as needed.

Do not administer corticosteroids by injection in a bursal cavity, joint, tendon or lesion in the presence of acute local infection.

Tuberculosis: If a corticosteroid drug is used to treat a condition in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation. During prolonged corticosteroid therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis.

Varicella zoster (shingles) and measles viral infections: Varicella and measles can have a serious or even fatal course in non-immune patients taking corticosteroids. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles:

• If a corticosteroid-treated patient is exposed to varicella, prophylaxis with varicella zoster immune globulin may be indicated. If varicella develops, treatment with antiviral agents may be considered.
• If a corticosteroid-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated.

Hepatitis B virus reactivation: Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection.

Screen patients for hepatitis B infection before initiating immunosuppressive (such as prolonged) treatment with corticosteroids. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy.

Fungal infections: Corticosteroids may exacerbate systemic fungal infections; therefore, avoid use of corticosteroids in the presence of such infections unless corticosteroid therapy is needed to control drug reactions. For patients on chronic corticosteroid therapy who develop systemic fungal infections, corticosteroid withdrawal or dosage reduction is recommended.

Amebiasis: Because corticosteroids may activate latent amebiasis, it is recommended to rule out latent amebiasis or active amebiasis before initiating corticosteroid therapy in patients who have spent time in the tropics or those with unexplained diarrhea.

Strongyloides (threadworm) infestation: Corticosteroids should be used with great care in patients with known or suspected Strongyloides infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia (a condition in which bacteria enters the bloodstream).

Cerebral malaria: Avoid corticosteroids in patients with cerebral malaria.

Kaposi’s sarcoma: Kaposi’s sarcoma has been reported in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma.

*Paraphrased from the FDA’s language. Note, the agency required modified warnings for Alkindi Sprinkle and Tarpeyo.

What You Can Do

If you are currently taking or considering taking corticosteroids, discuss their potential risks and benefits with your clinician. To reduce your risks, try to use the lowest effective corticosteroid dose for the shortest time and try to use non-systemic forms, if possible.

References

[1] Adrenal steroids. Worst Pills, Best Pills News. July 9, 2007. https://www.worstpills.org/chapters/view/18. Accessed November 4, 2024.

[2] Edenbridge Pharmaceuticals. Label: dexamethasone (HEMADY). June 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/211379s006lbl.pdf. Accessed November 4, 2024.

[3] Public Citizen. Petition requesting warnings on the labels of glucocorticosteroids including prednisone. July 26, 2011. https://www.citizen.org/article/petition-requesting-warnings-on-the-labels-of-glucocorticosteroids-including-prednisone/. Accessed November 4, 2024.

[4] Food and Drugs Administration. Response to Public Citizen’s 2011 petition regarding requesting warnings on the labels of glucocorticosteroids. February 8, 2024. https://www.citizen.org/wp-content/uploads/FDA-2011-P-0604-0006_attachment_1.pdf. Accessed November 4, 2024.

[5] Public Citizen. Petition requesting warnings on the labels of glucocorticosteroids including prednisone. July 26, 2011. https://www.citizen.org/article/petition-requesting-warnings-on-the-labels-of-glucocorticosteroids-including-prednisone/. Accessed November 4, 2024.

[6] Food and Drugs Administration. Response to Public Citizen’s 2011 petition regarding requesting warnings on the labels of glucocorticosteroids. February 8, 2024. https://www.citizen.org/wp-content/uploads/FDA-2011-P-0604-0006_attachment_1.pdf. Accessed November 4, 2024.

[7] Ibid.