Oral Itraconazole and Terbinafine: Too Dangerous for Fungal Nail Infections

Fungal infections of the toenails and fingernails, a condition known as onychomycosis, are common. These infections typically begin as a white or yellow spot under the tip of the nail and then progress deeper, leading to nail discoloration, thickening and crumbling at the edge.[1] Importantly, a fungal nail infection is primarily a cosmetic condition that is not life-threatening and does not require urgent treatment.

Because fungal nail infections generally respond more slowly to topical therapy, doctors often prescribe oral antifungal drugs to treat the condition. Two drugs have been approved by the Food and Drug Administration (FDA) for such use: itraconazole (ONMEL,[2] SPORANOX[3]) and terbinafine (LAMISIL).[4]

Oral itraconazole was originally approved by the FDA in 1992 to treat certain serious fungal infections involving the lungs or other internal organs.[5] In 1995, it was approved for fungal toenail infections. Terbinafine was initially approved in 1992 for topical use only to treat fungal skin infections, such as athlete’s foot, jock itch and ringworm.[6] An oral prescription tablet form was subsequently approved in 1996 to treat fungal toenail and fingernail infections.[7] Oral terbinafine is not approved for other uses. For both drugs, a course of oral treatment for fungal toenail infections lasts 12 weeks. For many years, the oral forms of both medications were heavily promoted directly to consumers for treatment of fungal nail infections, but manufacturers have retreated from these promotional efforts.

For 20 years, Public Citizen’s Health Research Group has recommended against using oral itraconazole or terbinafine for treatment of fungal nail infections because these drugs have serious, potentially fatal risks that far outweigh the benefit of treating a minor cosmetic condition.[8]

Adverse effects of itraconazole[9]

The labeling for itraconazole includes a black-box warning — the strongest warning that the FDA can require — against using the drug to treat fungal nail infections in patients who have evidence of heart failure or a history of heart failure. The drug has been shown to depress heart function when administered by injection into a vein in dogs and healthy humans. The black-box warning also lists more than two dozen drugs that should never be taken in combination with itraconazole because of the risk of life-threatening drug interactions, including a risk of fatal abnormal heart rhythms in some cases.

Itraconazole also has been linked to rare cases of serious liver damage, including liver failure and death. In some of these cases, the patients did not have liver disease or any serious underlying medical condition prior to use of the drug. Some patients developed liver damage within a week of starting itraconazole.

Additional adverse effects of itraconazole include neuropathy (nerve damage), which can cause numbness or tingling sensations in the hands or feet; hearing loss, which in some patients can be permanent; nausea and vomiting; and pancreatitis (inflammation of the pancreas).

Adverse effects of oral terbinafine[10]

As with itraconazole, terbinafine can cause liver damage, particularly in patients with chronic or active liver disease. Cases of liver failure, leading to liver transplantation or death, have occurred in patients using oral terbinafine. The labeling for oral terbinafine recommends that patients undergo blood tests to monitor liver function before and while taking the drug.

Taste disturbances (including taste loss) and smell disturbances (including loss of smell) have been reported in patients taking oral terbinafine. In some cases, the taste loss was severe enough to cause decreased food intake, weight loss, anxiety and symptoms of depression. According to the labeling for the drug, taste loss may resolve within several weeks of stopping terbinafine but may last longer than a year or even be permanent. Smell disturbances likewise may be prolonged or permanent.

Use of oral terbinafine has been linked to dangerously low levels of white blood cells known as neutrophils. Neutrophils are a type of white blood cell that are essential for protecting against bacterial and fungal infections. Patients with severely decreased neutrophil levels are highly susceptible to life-threatening infections.

Another type of blood disorder rarely reported in patients using terbinafine is thrombotic microangiopathy. This condition is characterized by blood clots forming in small blood vessels, which may lead to low blood platelet levels, anemia, bleeding and kidney failure. Some cases of this disorder in patients treated with terbinafine were fatal.

There also have been reports of terbinafine-treated patients developing serious hypersensitivity reactions, such as Stevens-Johnson syndrome — a rare, sometimes fatal disorder that causes severe, blistering lesions

Other adverse effects of oral terbinafine include symptoms of depression, headache, diarrhea, stomach upset, nausea, abdominal pain and itching.

What You Can Do

The possibly fatal outcome of using oral terbinafine or itraconazole for a cosmetic, non-health-threatening nail infection is not rational. Therefore, you should not take oral itraconazole or terbinafine to treat fungal nail infections. You should use itraconazole only to treat serious fungal infections, never for fungal nail infections.

If you have a fungal nail infection, talk to your doctor about safer treatment alternatives, including topical antifungal therapies or surgical removal of the nail.
 

References

[1] Mayo Clinic. Nail fungus. January 3, 2019. https://www.mayoclinic.org/diseases-conditions/nail-fungus/symptoms-causes/syc-20353294. Accessed July 2, 2019.

[2] Merz Pharmaceuticals. Label: itraconazole (ONMEL). November 2012. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=fb8a2e5b-fd23-4977-81de-a95f4af168e2&type=display. Accessed July 2, 2019.

[3] Janssen Pharmaceuticals. Label: itraconazole (SPORANOX). March 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020083s063lbl.pdf. Accessed July 2, 2019.

[4] Novartis Pharmaceuticals. Label: terbinafine (LAMISIL). March 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020539s033lbl.pdf. Accessed July 2, 2019.

[5] Food and Drug Administration. Approval package for NDA 020694. 1996. https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/020694ap.pdf. Accessed July 2, 2019. PDF page 12.

[6] Food and Drug Administration. Approval package for NDA 020193/S003. January 21, 1997. https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020192_S003.pdf. Accessed July 2, 2019. PDF page 18.

[7] Novartis Pharmaceuticals. Label: terbinafine (LAMISIL). March 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020539s033lbl.pdf. Accessed July 2, 2019.

[8] Worst Pills, Best Pills. Drug profile: itraconazole and terbinafine. April 30, 2019. https://worstpills.org/member/drugprofile.cfm?m_id=279. Accessed July 2, 2019.

[9] Janssen Pharmaceuticals. Label: itraconazole (SPORANOX). March 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020083s063lbl.pdf. Accessed July 2, 2019.

[10] Novartis Pharmaceuticals. Label: terbinafine (LAMISIL). March 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020539s033lbl.pdf. Accessed July 2, 2019.