Background

FDA Drug Safety Communication

On August 29, 2018, the FDA issued a Drug Safety Communication (DSC) informing of a rare but serious infection, called necrotizing fasciitis of the perineum, also known as Fournier’s gangrene (FG), that has been identified in 12 cases submitted to the FDA Adverse Event Reporting System (FAERS) or reported in the medical literature between March 2013-May 2018 in patients taking a sodium-glucose cotransporter inhibitor (SGLT2i).¹

• In the 12 cases (7 males; 5 females; age range 38-78 years), FG developed within several months of initiating therapy (mean 9.2 months) and all patients required hospitalization and surgery.¹
  • Five patients required additional surgeries, one required a skin graft, and four patients experienced complications which prolonged their hospitalization, and lead to death for one patient.
  • The SGLT2i was discontinued in eight of the cases; one patient died; and information on drug continuation or discontinuation in three cases was not available.
• In October 2018, a warning regarding post marketing reports of necrotizing fasciitis of the perineum (FG) was added to the prescribing information and Medication Guides of all SGLT2i products, including INVOKANA^®.^{1, 2}

SGLT2 Inhibitors class review

A search of the FAERs database from March 1, 2013 through January 31, 2019 was conducted to identify cases of patients receiving an FDA-approved SGLT2i at the time of FG diagnosis with a reported necrotizing infection of the perineum (vulva/vagina or scrotum or buttocks) and surgical debridement in response to the infection. A search of medical literature during the same time frame did not identify any additional unique case reports.³

A total of 55 unique cases of FG in patients receiving an SGLT2i (INVOKANA 21; dapagliflozin 16; empagliflozin 18) were identified.³

• The median patient age was 56 years; 39 cases were male; the average time to event from SGLT2i initiation was 9 months (median 4.5 months; range 5 days to 49 months).
• Complications occurred for some patients during hospitalization, including diabetic ketoacidosis (n=8), sepsis or septic shock (n=9), acute kidney injury (n=4); necrotizing fasciitis of a lower extremity (n=2); gangrenous toes requiring bypass procedure (n=1); death (n=3). Some patients may have had more than 1 complication.
• The SGLT2i was discontinued in at least 22 of the 52 surviving patients.

INVOKANA Clinical trial data

The Janssen Research and Development (JRD) Safety Management Team (SMT) reviewed the safety data from fourteen^4-21 completed Phase 3^4-18 & Phase 4^19-21 randomized controlled clinical trials of INVOKANA in which a total of 18,248 subjects diagnosed with type 2 diabetes mellitus (T2DM) received study drug and were included in the safety analysis dataset.  Results for all fourteen trials have been published.^4-21

Among the 18,248 subjects, there were three cases of FG (two subjects randomized to placebo and one subject randomized to INVOKANA 100 mg).  All three cases occurred in one trial.^{18, 22} No cases occurred in the other thirteen trials.  None of the three subjects were on study drug at the time of the FG diagnosis.  The subject randomized to INVOKANA 100 mg had been withdrawn from study drug on Day 1006, five months prior to presentation with painful swollen scrotum on Day 1160 which was diagnosed as fasciitis necroticans (accelerated FG).  Blood cultures were positive for Escherichia coli and a recto-scrotal fistula was discovered as the source of infection.²²

Systematic examination of eight^23-32 additional published Phase 2^23-27 and Phase 3^28-32 clinical trials (N=3557) as well as the serious adverse event data posted on www.clinicaltrials.gov for each of these eight INVOKANA clinical trials^33-40 did not identify any more cases of Fournier’s gangrene.

In the CREDENCE trial (N=4397 in the safety population), which was designed to assess the effects of INVOKANA on renal outcomes in patients with T2DM and chronic kidney disease vs placebo, there was one report of FG in a 49 year old male.⁴¹

published case reports

• Several case reports of FG in patients being treated with an SGLT2i have been published.^42-48

patient management

• Health care professionals are advised to assess patients for FG if they present with tenderness, erythema, swelling in the genital or perineal area, fever, malaise, and have pain out of proportion to the physical exam.  These symptoms can worsen quickly and require immediate treatment with broad-spectrum antibiotics and surgical debridement if necessary. SGLT2i therapy should be discontinued, and blood glucose should be closely monitored.¹
• Patients are advised to seek immediate medical attention if they experience tenderness, redness, swelling of the genital or the area from the genitals back to the rectum, and have a fever >100.4°F or a general feeling of being unwell.^{1, 2}
  • Information for patients regarding possible side effects of INVOKANA^®, including necrotizing fasciitis of the area between and around the anus and genitals (perineum) has been added to the Medication Guide.²
• The DSC explained to patients that FG is a bacterial infection of the tissue under the skin that surrounds muscles, nerves, fat, and blood vessels of the perineum. The bacteria usually get into the body through a cut or break in the skin, where they quickly spread and destroy the tissue they infect. 
• The DSC highlights that SGLT2i can also cause local genital fungal infections, also known as yeast infections or genital mycotic infections, which are different from necrotizing fasciitis of the perineum (FG) because they cause limited local symptoms like vaginal or penile discharge, itching, or redness, and are not associated with fever or generally feeling unwell.¹ An over-the-counter antifungal medicine is suggested to treat a yeast infection of the vagina or penis.²

fournier’s gangrene

FG is a rare form of polymicrobial necrotizing fasciitis of the perineal, perianal, or genital regions with marked symptoms of intoxication. It occurs in men more than women (10:1 ratio), with an estimated incidence of 1.6 cases per 100,000 men each year, mostly between 50-79 years of age.⁴⁹ Ulceration in the balanus, prepuce, skin of the penis or scrotum occur with progression from erythema to necrosis within hours. Symptoms include genital discomfort and erythema, pruritis, scrotal edema and pain, fever, painful urination, necrosis of the skin, subcutaneous tissue and muscles, accompanied by sepsis, multi-organ failure, leading to death.^{50, 51}

• Predisposing conditions include diabetes, alcohol abuse, obesity, chronic kidney disease, congestive heart failure, severe sepsis, coagulopathy, cirrhosis, trauma to the genital area, steroid use, chemotherapy, human immunodeficiency virus (HIV), malignant neoplasms, and low socioeconomic status.^{1, 50-52}
  • Diabetes was identified as one of the most frequent comorbidities with Fournier’s gangrene, and linked with a higher rate of death.^51-53
• Localized infection adjacent to a portal of entry is the inciting event in the development of FG. Wound cultures from patients with FG reveal that it is a polymicrobial infection, with Escherichia coli, anaerobic Streptococcus species, Staphylococcus aureus, Enterobacter species, Bacteroides, Pseudomonas aeruginosa, Proteus species, Clostridia species, and mixed microorganisms being identified as the most frequent organisms.^{51, 52} Infections with Proteus Mirabilis were found to have a greater risk of death.^{50, 51}
• Radiography, ultrasound, computed tomography, and magnetic resonance imaging are used for diagnosis.⁵⁰
• Treatment includes emergency surgical intervention along with antibacterial and detoxification therapy.⁵⁰

Literature Search

A literature search of MEDLINE^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted through 18 July 2022.