Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF blockers (initiation of therapy ≤18 years of age), including infliximab products. Approximately half of these cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.

Lymphomas

In the controlled portions of clinical trials of TNF blockers, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. Cases of acute and chronic leukemia have been reported with postmarketing TNF blocker use, including infliximab products. 

Hepatosplenic T-cell Lymphoma (HSTCL)

Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including infliximab products. These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. The majority of reported cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were in adolescent and young adult males. It is uncertain whether the occurrence of HSTCL is related to TNF blockers or TNF blockers in combination with these other immunosuppressants. When treating patients, consideration of whether to use ZYMFENTRA alone or in combination with other immunosuppressants such as azathioprine or 6-mercaptopurine should take into account a possibility that there is a higher risk of HSTCL with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with TNF blocker monotherapy from the clinical trial data [see Warnings and Precautions (5.7)]

Skin Cancer

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab products. Periodic skin examination is recommended for all patients during treatment with ZYMFENTRA, particularly those with risk factors for skin cancer. 

Cervical Cancer

Cases of invasive cervical cancer have been reported postmarketing in women who received infliximab products for other conditions. A causal relationship between infliximab products and cervical cancer cannot be excluded. Routine cervical cancer screening is recommended during treatment with ZYMFENTRA. 

Other Malignancies 

In the controlled portions of clinical trials of some TNF blockers, including infliximab products, more malignancies (excluding lymphoma and nonmelanoma skin cancer) have been observed in patients receiving those TNF blockers compared with control patients. The most common malignancies were breast, colorectal, and melanoma in these controlled trials of TNF blockers.

In controlled trials of TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater proportion of malignancies occurred in the TNF blocker group compared to the control group. Patients had a history of heavy smoking. Avoid ZYMFENTRA in patients with moderate to severe COPD. 

The potential role of TNF blockers in the development of malignancies is not known. Avoid ZYMFENTRA treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving ZYMFENTRA.