those used in rheumatoid arthritis and Crohn's disease. Nine of these patients developed malignancies, including 1 lymphoma. The median duration of follow-up was 0.8 years (incidence 5.7% [95% CI 2.65% - 10.6%]. There was one reported malignancy amongst 77 control patients (median duration of follow-up 0.8 years; incidence 1.3% [95% CI 0.03% - 7.0%]). The majority of the malignancies developed in the lung or head and neck.
In addition, rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients with Crohn's disease and ulcerative colitis treated with Remicade, the majority of whom were adolescent or young adult males (see section 4.4).
Heart failure: In a phase II study aimed at eva luating Remicade in congestive heart failure (CHF), higher incidence of mortality due to worsening of heart failure were seen in patients treated with Remicade, especially those treated with the higher dose of 10 mg/kg (i.e. twice the maximum approved dose). In this study 150 patients with NYHA Class III-IV CHF (left ventricular ejection fraction 35%) were treated with 3 infusions of Remicade 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At 38 weeks, 9 of 101 patients treated with Remicade (2 at 5 mg/kg and 7 at 10 mg/kg) died compared to one death among the 49 patients on placebo.
There have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking Remicade. There have also been rare post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age.
Hepatobiliary events: In clinical studies, mild or moderate elevations of ALT and AST have been observed in patients receiving Remicade without progression to severe hepatic injury. Elevations of ALT 5 x Upper Limit of Normal (ULN) have been observed (see Table 2). Elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving Remicade than in controls, both when Remicade was given as monotherapy and when it was used in combination with other immunosuppressive agents. Most aminotransferase abnormalities were transient; however, a small number of patients experienced more prolonged elevations. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of Remicade, or modification of concomitant therapy. In post-marketing surveillance, very rare cases of jaundice and hepatitis, some with features of autoimmune hepatitis, have been reported in patients receiving Remicade (see section 4.4).
Table 2: Proportion of patients with increased ALT activity in clinical studies
Indication
Number of patients3
Median follow-up (wks)4
3 x ULN
5 x ULN
placebo
infliximab
placebo
infliximab
placebo
infliximab
placebo
infliximab
Rheumatoid arthritis1
375
1,087
58.1
58.3
3.2%
3.9%
0.8%
0.9%
Crohn's disease2
324
1034
53.7
54.0
2.2%
4.9%
0.0%
1.5%
Paediatric Crohn's disease
N/A
139
N/A
53.0
N/A
4.4%
N/A
1.5%
Ulcerative coliti |
