Infliximab and the Risk of Hepatotoxicity - Other Published Medical Literature
A review of the published literature identified 18 postmarketing case reports and 14 from clinical studies of hepatotoxicity occurring with the use of infliximab. A causal relationship between infliximab and these events has not been established.
The majority of reports of hepatotoxicity from infliximab clinical studies were in patients with psoriasis (7), psoriatic arthritis (4), ankylosing spondylitis (2), and Crohn’s disease (1). There were 7 cases reported in males and 1 case reported in a female along with several patients (n=6) where the gender was not identified. The data reported in the publications indicate the majority of patients had normal liver function prior to therapy. In several cases, hepatotoxicity resolved upon the discontinuation of infliximab.
With regard to information collected from published postmarketing reports, 5 cases were reported in rheumatoid arthritis patients, 3 in patients with ankylosing spondylitis; there appeared to be equal distribution among Crohn’s disease, ulcerative colitis, psoriasis, and psoriatic arthritis, with 2 additional cases being reported in other patients treated with infliximab. There were 12 cases reported in females and 6 cases reported in males. The majority of patients reportedly had comorbid conditions and were on other immunomodulator or steroid therapy. The reports of hepatotoxicity were reported anywhere from shortly after the first dose to several years after treatment, with most of the cases occurring within the first year of therapy. In most cases, hepatotoxicity resolved upon the discontinuation of infliximab. The information included in this section is summarized from published cases reported by the author(s) and has not been independently verified. The inclusion of published literature in this section should not be read to rule out the existence of other case reports of hepatotoxicity, published or otherwise.
| Age Gender Disease State (AS, CD, PsA, PsO, RA, UC) Publication | Infliximab Dosage/ Regimen Duration of Infliximab Therapy | Other Immuno- suppressant Medication/ Treatment History | Prior to Initiation of Infliximab | Following Administration of Infliximab |
|---|---|---|---|---|
|
Age and Gender not reported AS Haibel 200411514 |
|
Not reported |
Not reported |
One serious event of toxic hepatitis was reported |
|
Age and Gender not reported AS Perez-Guijo 200711509 |
Not reported |
Concomitant: MTX |
Not reported |
LFTs increased and abdominal ultrasound revealed hepatic steatosis Infliximab therapy was discontinued The authors did not consider the event to be serious |
|
Patient 1 (Age and Gender not reported) CD Gonzaga 200912453 |
Not reported |
Not reported |
Not reported |
Developed Hepatotoxicity |
|
Patient 1 (Age not reported) Male PsA Feletar 200411602 |
|
Concomitant: MTX |
Three months prior to study: ALT was Patient reported alcohol
intake as |
At Wk 6, the patient presented with increased
LFTs Infliximab therapy was discontinued and MTX was continued The LFTs returned to normal over several mo |
|
Patient 2 (Age not reported) Male PsA Feletar 200411602 |
|
Concomitant: MTX |
Normal liver function reported prior to start of study Patient consumed 4-5 standard drinks of alcohol daily |
At Wk 17, patient had elevated Infliximab therapy was discontinued Four wks later, LFTs returned to normal; no liver biopsy was performed An ultrasound showed an enlarged fatty liver. Viral hepatitis serology was negative |
|
Patient 3 (Age not reported) Male PsA Feletar 200411602 |
|
Concomitant: MTX |
Not reported |
The patient developed transaminitis. At
Wk 24, infliximab therapy was discontinued with elevated ALT Transaminases returned to normal |
|
Patient 7 (Age not reported) Male PsA Feletar 200411602 |
|
History of: MTX |
No prior history of liver disease |
LFTs rose slowly; peaked at Wk 32 |
|
44-yr-old Male PsO Smith 200611720 |
|
History of: PUVA Cyclosporine MTX Fumaric acid esters |
LFTs normal prior to therapy; however, the patient had fatty liver reportedly secondary to MTX and alcohol |
After the 4th infusion,
elevated LFTs Infliximab therapy was discontinued and values decreased within 2
mo of discontinuation. Autoimmune hepatitis was considered because
of the autoantibody profile The patient was switched to another anti-TNF therapy and liver function tests have remained normal |
|
Patient A (Age and Gender not reported) PsO Smith 200611720 |
|
Unknown |
Patient had prior liver morbidity, followed by possible DMARD and/or alcohol excess (fatty liver only), Roenigk stage 2 hepatitic fibrosis, and cirrhosis |
Patient had elevations in LFTs |
|
Patient B (Age and Gender not reported) PsO Smith 200611720 |
|
Unknown |
Patient had prior liver morbidity, followed by possible DMARD and/or alcohol excess (fatty liver only), Roenigk stage 2 hepatitic fibrosis, and cirrhosis |
Patient had elevations in LFTs |
|
Patient C (Age and Gender not reported) PsO Smith 200611720 |
|
Unknown |
Patient had prior liver morbidity, followed by possible DMARD and/or alcohol excess (fatty liver only), Roenigk stage 2 hepatitic fibrosis, and cirrhosis |
Patient had elevations in LFTs |
|
56-yr-old Male PsO Ahmad & Rogers 200611715 |
|
History of: PUVA UVB Acitretin MTX Cyclosporine |
Normal liver function reported prior to the start of study |
Infliximab therapy was discontinued because
patient had elevated AST and |
|
52-yr-old Female PsO Ahmad & Rogers 200611715 |
|
History of: PUVA PUVB Acitretin MTX Cyclosporine Hydroxyurea |
Normal liver function reported prior to the start of study |
Infliximab therapy was discontinued because
patient had elevated AST and |
|
46-yr-old Male PsO Ahmad & Rogers 200611715 |
|
History of: PUVA PUVB MTX Cyclosporine |
Normal liver function reported prior to start of study |
Infliximab therapy was discontinued because
patient had elevated AST and |
|
ALT=alanine aminotransferase; ANA=anti-nuclear antibody; anti-TNF=anti tumor necrosis factor; AST=aspartate aminotransferase; AS=ankylosing spondylitis; ASMA=anti-smooth muscle antibodies; CD=Crohn’s disease; DMARD=disease-modifying antirheumatic drug;; γGT=gamma glutamyl transferase; IU/L=international units per liter; ULN=upper limit of normal; LFT=liver function tests; mg/kg=milligrams per kilogram; MTX=methotrexate; NR=not reported; NSAIDs=non-steroidal anti-inammatory drugs; PsA=psoriatic arthritis; PsO=psoriasis; PUVA=psoralen with ultraviolet A; PUVB=psoralen with ultraviolet B; RA=rheumatoid arthritis; ULN=upper limit of normal; UVB=ultraviolet B. . | ||||
| Age Gender Disease State (AS, CD, PsA, PsO, RA, UC) Publication | Dose of Infliximab/ Regimen/ Duration of Infliximab Therapy | Other Immuno- suppressant Medication Treatment History | Prior to Initiation of Infliximab | Following Administration of Infliximab |
|---|---|---|---|---|
|
48-yr-old Male AS Thiefin 200811771 |
|
Concomitant: NSAIDs History of: NSAIDs MTX |
No history of liver disease LFTs normal, and tests for hepatitis B and C were negative Reportedly the patient was not exposed to IV drugs or alcohol abuse |
LFTs were elevated after the Two additional Infliximab infusions given and LFTs continued to rise Liver biopsy revealed interportovenular bridging necrosis and moderate portal inflammation LFTs returned to normal 1 mo after last dose of infliximab |
|
48-year-old Male AS García Aparicio 200710655 (Contin. below) |
|
Concomitant: NSAIDs History of: Immunomod- ulators |
Baseline liver enzymes normal Patient reportedly did not consume any alcohol |
Slight increase in ALT level Asymptomatic rise in liver enzymes After the 4th infliximab dose,
ALT was Hepatitis B and C tests were negative |
|
Abdominal ultrasound was normal Infliximab was discontinued and 10 wks later, liver tests had returned to normal Other anti-TNF therapy began, and 5 mo later the liver tests remained normal | ||||
|
56-yr-old Female AS Ozorio 200711510 (Contin. below) |
|
History of: NSAIDs Leflunomide Concomitant medications not reported |
Patient had a history of smoking, but reportedly did not drink alcohol Normal LFTs and a negative ANA reported prior to infliximab therapy Routine serology including LFT’s, done every 3 mo during infliximab treatment |
Three mo after 1st dose minor elevations in LFTs were observed Patient developed epigastric discomfort, jaundice, pale stools, and further elevations in LFTs after the 6th infliximab infusion and it was discontinued At the
time infliximab was stopped, transaminases |
|
CT scan showed diffusely non-homogeneous liver texture consistent with chronic liver disease with no duct dilatation Liver biopsy revealed marked inflammatory infiltrate with neutrophils, lymphoid, and plasma cells, bridging necrosis and piecemeal necrosis consistent with autoimmune chronic active hepatitis Corticosteroid therapy was initiated and the patient’s condition improved after 3 mo | ||||
|
45-yr-old Female CD Moum 20078110 |
|
History of: Corticosteroids Other anti-TNF therapy Concomitant medications not reported |
Ileocolonoscopy revealed Crohn’s lesions in terminal ileum and large bowel before initiation of infliximab therapy No history of alcohol consumption |
Transaminases increased after 3rd infliximab infusion and peaked after Wk 8 The patient experienced transitory mild discomfort in the upper abdomen without additional symptoms Infliximab therapy was discontinued following the elevated LFTs A liver ultrasound revealed no features indicating steatosis or structural disorders Serological tests were negative for hepatitis A, B, and C Liver biopsy revealed extensive centrilobular, as well as peripheral necrosis. Moderate inflammatory infiltration with mononuclear and granulocytes were seen without any indication of fibrosis The LFTs returned to normal The patient then underwent treatment with glucocorticoids and was switched to another anti-TNF therapy |
|
44-yr-old Female CD Menghini & Arora 200111052 (Contin. below) |
|
Concomitant: Immunomodu- lators Corticosteroids Medication history not reported |
Blood tests 1 mo prior to infliximab therapy
were normal except for a gamma-glutamyl transpeptidase level of Patient denied excessive alcohol use |
Fatigue, malaise, anorexia and nausea developed 19 days after infliximab infusion. Jaundice followed Elevated transaminases Peak levels included
bilirubin Tests for other potential causes of hepatic dysfunction were negative |
|
Ultrasound showed no dilated biliary ducts Laboratory tests were negative for hepatitis A, B, and C A liver biopsy indicated "bland" cholestasis. The patient was treated conservatively with an immunomodulator, and steroid treatments continued. Patient was reportedly asymptomatic with normal LFTs 1 mo later | ||||
|
63-yr-old Male PsA De Leonardis 200811716 |
Unknown (~ 3 yrs) |
Concomitant: MTX Medication history not reported |
Not reported |
On admission, the patient was positive for hepatitis Infliximab was discontinued upon admission A liver biopsy indicated possible autoimmune hepatitis The patient was treated with immunomodulator and corticosteroid therapy LFTs reportedly returned to normal |
|
53-yr-old Female PsA Germano 200510713 |
|
Concomitant: MTX Corticosteroids History of: Cyclosporine |
Not reported |
Elevated transaminases developed; MTX and infliximab were discontinued ALT was Serologic tests for hepatitis viruses, CMV, and EBV were negative Liver biopsy revealed intense and diffuse portal lymphoplasmacytic, granulocytic inflammation and severe interface hepatitis Corticosteroids started as treatment for autoimmune hepatitis Several months later, the transaminases were reportedly normal and ASMA were negative, although ANA remained positive |
|
46-yr-old Female PsO Kluger 200912445 |
|
Concomitant: none reported History of: Topical corticosteroids PUVA DMARDs |
Blood tests were normal prior to initiation of infliximab Patient denied any history of recent alcohol intake |
Prior to receiving 5th infusion of infliximab patient’s blood tests came back abnormal AST was Laboratory tests were negative for hepatitis A, B and C Infliximab therapy was discontinued and LFTs were back into normal range after 6 wks |
|
64-yr-old Male PsO Wahie 200610552 |
|
Concomitant: MTX History of: PUVA DMARDs |
Reportedly consumed 2.5 alcoholic beverages per wk Liver enzymes were normal at baseline Four liver biopsies performed while the patient was receiving MTX showed only mild steatosis without evidence of fibrosis or cirrhosis |
One wk after 2nd infliximab infusion, ALT was Patient did not alter alcohol intake Liver ultrasound was normal; autoantibodies and hepatitis A, B and C were all negative. No further infliximab was given. Laboratory tests returned to normal 4 wks later |
|
38-yr-old Female RA Carlsen 200912446 |
|
Concomitant: MTX Folic Acid History of: DMARDs Corticosteroids |
Normal liver enzymes No history of alcohol abuse |
Patient discontinued methotrexate and folic acid without notifying physician within 3 wks of starting infliximab as symptoms improved After the 7th infusion of infliximab transaminases and lactate dehydrogenase were elevated and infliximab was discontinued ALT was Liver biopsy revealed acute toxic hepatitis without methotrexate related fibrosis. LFTs returned to normal after Methotrexate and folic acid were restarted
and other LFTs have been in normal range for approx 3 yrs |
|
41-yr-old Female RA Becker 200811772 |
|
Concomitant: MTX Corticosteriods Folic Acid History of: DMARD |
Negative for hepatitis A, B, C Normal liver enzymes |
LFTs were elevated after 3 years of infliximab therapy All medications were discontinued except corticosteroid therapy Patient was negative for hepatitis, but liver biopsy revealed lymphoplasmacytic inflammatory cell infiltration, hepatocytic necrosis, and mild periportal fibrosis LFTs reportedly returned to normal
within 4 wks and were followed for |
|
39-yr-old Female RA Tobon 200710412 (Contin. below) |
|
History of: Anti-malarial therapy NSAIDs Corticosteroids Other medication reported but not delineated as concomitant or historical Leflunomide |
LFTs normal prior to infliximab therapy No history of hepatic diseases, exposure to hepatotoxic drugs, illicit drugs, alcohol abuse, or blood transfusions |
Patient developed fatigue, malaise and jaundice several wks after last dose of infliximab and was hospitalized Tests for hepatitis A, B and C were negative
Liver biopsy showed "severe ductal proliferation, surrounded by mononuclear cells and neutrophils, hepatocytes were collapsed and enucleated, and perivenular necrosis and severe cholestasis were evident" |
|
A presumptive diagnosis of autoimmune hepatitis was made and oral methylprednisolone was started The patient developed hepatic encephalopathy and a successful liver transplantation was performed 45 days after hospital admission. Surgical pathology on the explanted liver was interpreted as "severe autoimmune hepatitis." The patient recovered after the transplant operation | ||||
|
54-yr-old Female RA Tobon 200710412 |
|
Concomitant: MTX Corticosteroids NSAIDs Other medications reported but not delineated as concomitant or historical Cyclosporine Sulfasalazine |
Normal LFTs and ANA levels were reported prior to the start of infliximab Patient denied alcohol or drug abuse |
Patient presented with nausea, vomiting, malaise, and anorexia 17 mo post 1st infliximab dose.
Hepatitis A, B, and C tests were negative Liver biopsy disclosed an altered lobular structure with strong chronic inflammation and the formation of collagen bands The patient was started on prednisone and AZA and recovered, within 1 mo. Laboratory tests also returned to normal |
|
53-yr-old Female RA Gosserand 20078109 (Contin. below) |
|
Concomitant: Corticosteroids MTX Medication history not reported |
No history of chronic liver disease, and all baseline laboratory studies including LFTs were within normal limits |
Two wks post 4th infusion, progressively worsening jaundice developed Total bilirubin Infliximab therapy was discontinued. Liver biopsy indicated marked bile duct damage, diffuse ballooning degeneration of hepatocytes with lobular disarray and cholestasis with a scattered mixed inflammatory infiltrate |
|
The patient’s condition continued to deteriorate (total bilirubin 19.9) and hepatic encephalopathy developed requiring an orthotopic liver transplantation (10 wks after the last infliximab infusion). The explants showed submassive necrosis with large areas of hepatocyte dropout, collapse of hepatic lobules and marked bile ductular proliferation with cholestasis The patient was well 6 mo after transplant | ||||
|
34-yr-old Female UC Marques 200811718 |
|
History of: Corticosteroids Mesalamine DMARD Concomitant medications not reported |
Previous liver biopsy completed and revealed mild chronic hepatitis, with focal intralobular activity without fibrosis potentially related to DMARD therapy which was discontinued LFTs were reportedly normal when infliximab started |
LFT’s after 4th infliximab infusion : Patient had abdominal pain, fever, malaise, and polyarthralgias Viral infection serological markers were negative Liver biopsy revealed features of chronic hepatitis, with numerous plasmacytes in portal tracts, interface hepatitis, with mild intralobular activity and mild portal fibrosis Infliximab therapy was discontinued and corticosteroid therapy initiated LFTs reportedly returned
to normal: |
|
28-yr-old Male UC Ierardi 200610080 |
|
Concomitant: Coticosteroids Mesalazine Medication history not reported |
Liver enzymes normal prior to infliximab Patient denied alcohol abuse |
Patient presented with jaundice and elevated
transaminases Multiple tests for etiology of hepatitis were negative MCRP revealed no evidence of primary sclerosing cholangitis All medications were discontinued; 6 wks later the patient’s liver tests had reportedly returned to normal Immunomodulator therapies were reintroduced with no change in liver enzymes |
|
25-yr-old Male OTH Satapathy 200811719 |
OTH |
Not reported |
No history of hepatic diseases, and reportedly no exposure to hepatotoxic drugs, illicit drugs or alcohol abuse |
On admission, the patient had elevated Tests for hepatitis (A, B, C, E and G) were negative. Criteria for autoimmune hepatitis type 1 were met and patient was treated with prednisone for progressive hepatic failure On the 5th day of hospital admission, the patient developed hepatic encephalopathy and required a liver transplant |
|
22-yr-old Female OTH Fairhurst 200711717 |
|
History of: Topical therapy PUVA Cyclosporine MTX Concomitant medications not reported |
At baseline, the patient had normal LFT’s and was negative for hepatitis B and C |
ALT was elevated to Hepatitis screening tests were negative A liver biopsy was performed and autoimmune hepatitis was diagnosed Corticosteroids and another DMARD were started and the condition improved |
|
ALT=alanine aminotransferase; AMA=antimitochondrial antibodies; ANA=anti-nuclear antibody; AS=ankylosing spondylitis; ASMA=anti-smooth muscle antibodies; AST=aspartate aminotransferase; AZA=azathioprine; CD=Crohn’s disease; CMV=cytomegalovirus; CRP=C-reactive protein; DMARD=disease-modifying antirheumatic drug; EBV=Epstein-Barr virus; ESR=erythrocyte sedimentation rate; HBV=hepatitis B virus; γGT=gamma glutamyl transferase; IU/L=international units per liter; LDH=lactate dehydrogenase; LFT=liver function tests; mg/dl=milligrams per deciliter; MTX=methotrexate; NR=not reported; NSAIDs=nonsteroidal anti-inammatory drugs; PsA=psoriatic arthritis; PsO=psoriasis; PT=prothrombin time; PUVA=psoralen in combination with ultraviolet light A; RA=rheumatoid arthritis; ULN=upper limit of normal; OTH=diagnosis/dosing other than those for which REMICADE is approved (please see published case report for details) . | ||||
Content on this page was last reviewed on January 01, 2010.
Content on this page was last changed on April 01, 2010.
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| 8110. | Moum B, Konopski Z, Tufteland KF, Jahnsen J. Occurrence of hepatotoxicity and elevated liver enzymes in a Crohn’s disease patient treated with infliximab. Inflamm Bowel Dis . 2007;13(12):1584-1586. |
| 10080. | Ierardi E, Valle ND, Nacchiero MC, De Francesco V, Stoppino G, Panella C. Onset of liver damage after a single administration of infliximab in a patient with refractory ulcerative colitis. Clin Drug Investig. 2006;26(11):673-676. |
| 10412. | Tobon GJ, Cañas C, Jaller JJ, Restrepo JC, Anaya JM. Serious liver disease induced by infliximab. Clin Rheumatol. 2007;26(4):578-581. |
| 10552. | Wahie S, Alexandroff A, Reynolds NJ. Hepatitis: a rare, but important, complication of infliximab therapy for psoriasis. Clin Exp Dermatol. 2006;31(3):460-461. |
| 10655. | Garcia Aparicio AM, Rey JR, Sanz AH, Alvarez JS. Successful treatment with etanercept in a patient with hepatotoxicity closely related to infliximab. Clin Rheumatol. 2007;26(5):811-813. |
| 10713. | Germano V, Picchianti Diamanti A, Baccano G, et al. Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann Rheum Dis. 2005;64(10):1519-1520. |
| 11052. | Menghini VV, Arora AS. Infliximab-associated reversible cholestatic liver disease. Mayo Clin Proc. 2001;76(1):84-86. |
| 11509. | Pérez-Guijo VC, Cravo AR, Castro Mdel C, Font P, Muñoz-Gomariz E, Collantes-Estevez E. Increased efficacy of infliximab associated with methotrexate in ankylosing spondylitis. Joint Bone Spine . 2007;74(3):254-258. |
| 11510. | Ozorio G, McGarity B, Bak H, Jordan AS, Lau H, Marshall C. Autoimmune hepatitis following infliximab therapy for ankylosing spondylitis. Med J Aust . 2007;187(9):524-526. |
| 11514. | Haibel H, Rudwaleit M. Multicenter open label study with infliximab in active ankylosing spondylitis over 24 weeks in daily praxis. Ann Rheum Dis. 2004;63(Supp 1):SAT0046. |
| 11602. | Feletar M, Brockbank JE, Schentag CT, Lapp V, Gladman DD. Treatment of refractory psoriatic arthritis with infliximab: a 12 month observational study of 16 patients. Ann Rheum Dis . 2004;63(2):156-161. |
| 11715. | Ahmad K, Rogers S. Three years’ experience with infliximab in recalcitrant psoriasis. Clin Exp Dermatol . 2006;31(5):630-633. |
| 11716. | De Leonardis F, Lo Monaco A, Govoni M, et al. Visceral leishmaniasis in a patient with psoriatic arthritis treated with infliximab. Clin Exp Rheumatol . 2008; 26(Suppl 48):S-92. |
| 11717. | Fairhurst D, Sheehan-Dare R. Infliximab-associated autoimmune hepatitis in a patient with palmoplantar pustular psoriasis. Br J Dermatol . 2007;157(Suppl 1):23-73. |
| 11718. | Marques M, Magro F, Cardoso H, et al. Infliximab-induced lupus-like syndrome associated with autoimmune hepatitis. Inflamm Bowel Dis . 2008;14(5):723-725. |
| 11719. | Satapathy S, Aloman C, Ward S, et al. Fulminant autoimmune hepatitis induced by infliximab therapy: a rare case report. Am J Gastroenterol . 2008;103(Suppl S):S153-S154. |
| 11720. | Smith CH, Jackson K, Bashir SJ, et al. Infliximab for severe, treatment-resistant psoriasis: a prospective, open-label study. Br J Dermatol . 2006;155(1):160-169. |
| 11771. | Thiéfin G, Morelet A, Heurgué A, et al. Infliximab-induced hepatitis: absence of cross-toxicity with etanercept. Joint Bone Spine . 2008;75(6):737-739. |
| 11772. | Becker H, Willeke P, Domschke W, et al. Etanercept tolerance in a patient with previous infliximab-induced hepatitis. Clin Rheumatol . 2008;27(12):1597-1598. |
| 12445. | Kluger N, Girard C, Guillot B, Bessis D. Efficiency and safety of entanercept after acute hepatitis induced by infliximab for psoriasis [letter to the editor]. Acta Derm Venereol. 2009;89(3):332-334. |
| 12446. | Carlsen K, Riis L, Madsen O. Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept. Clin Rheumatol . 2009;28(8):1001-1003. |
| 12453. | Gonzaga JE, Ananthakrishnan AN, Issa M, et al. Durability of infliximab in Crohn’s disease: A single-center experience. Inflamm Bowel Dis. 2009; 15(12):1837-1843. |
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Prescribing Information and Medication Guide
REMICADE® (infliximab) Indications and Important Safety Information
INDICATIONS AND USAGE
Crohn’s Disease
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy.
REMICADE is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease.
Ulcerative Colitis
REMICADE is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
Rheumatoid Arthritis
REMICADE, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.
Ankylosing Spondylitis
REMICADE is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
Psoriatic Arthritis
REMICADE is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.
Plaque Psoriasis
REMICADE is indicated for the treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. REMICADE should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.
IMPORTANT SAFETY INFORMATION
RISK OF INFECTIONS
Patients treated with REMICADE® (infliximab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue REMICADE® if a patient develops a serious infection or sepsis.
Reported infections include:
- Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with REMICADE®. 1,2 Treatment for latent infection should be initiated prior to treatment with REMICADE®.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
- Bacterial, viral, and other infections due to opportunistic pathogens.
The risks and benefits of treatment with REMICADE® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with REMICADE®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.
In clinical trials, other serious infections observed in patients treated with REMICADE® included pneumonia, cellulitis, abscess, and skin ulceration.
MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including REMICADE®. 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 after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.
Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including REMICADE®. These cases have had a very aggressive disease course and have been fatal. All reported REMICADE® cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with REMICADE® at or prior to diagnosis. Carefully assess the risks and benefits of treatment with REMICADE®, especially in these patient types.
In clinical trials of all TNF inhibitors, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF inhibitors, including REMICADE®, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with REMICADE® was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. As the potential role of TNF inhibitors in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).
CONTRAINDICATIONS
REMICADE® is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have been observed in these patients. REMICADE® should be used with caution and only after consideration of other treatment options. Patients should be monitored closely. Discontinue REMICADE® if new or worsening CHF symptoms appear. REMICADE® should not be (re)administered to patients who have experienced a severe hypersensitivity reaction or to patients with hypersensitivity to murine proteins or other components of the product.
HEPATITIS B REACTIVATION
TNF inhibitors, including REMICADE®, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating REMICADE®. Exercise caution when prescribing REMICADE® for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with REMICADE®. Discontinue REMICADE® in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of REMICADE® and monitor patients closely.
HEPATOTOXICITY
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported rarely in patients receiving REMICADE® postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥ 5 times the upper limit of normal) develop, REMICADE® should be discontinued, and a thorough investigation of the abnormality should be undertaken.
HEMATOLOGIC EVENTS
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to REMICADE® therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of REMICADE® in patients who develop significant hematologic abnormalities.
HYPERSENSITIVITY
REMICADE® has been associated with hypersensitivity reactions that differ in their time of onset. Acute urticaria, dyspnea, and hypotension have occurred in association with infusions of REMICADE®. Serious infusion reactions including anaphylaxis were infrequent. Medications for the treatment of hypersensitivity reactions should be available.
NEUROLOGIC EVENTS
TNF inhibitors, including REMICADE®, have been associated with rare cases of new or exacerbated symptoms of demyelinating disorders including multiple sclerosis, optic neuritis, and Guillain-Barré syndrome, seizure, and CNS manifestations of systemic vasculitis. Exercise caution when considering REMICADE® in all patients with these disorders. Consider discontinuation for significant CNS adverse reactions.
AUTOIMMUNITY
Treatment with REMICADE® may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.
ADVERSE REACTIONS
In clinical trials, the most common REMICADE® adverse reactions occurring in >10% of patients included infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.
USE WITH OTHER DRUGS
The concomitant use of a TNF blocker and anakinra was associated with a higher risk of serious infections, therefore the use of REMICADE® in combination with anakinra is not recommended. Live vaccines should not be given with REMICADE®. Bring pediatric Crohn's patients up to date with all vaccinations prior to initiating REMICADE®.
Please see full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion.
References: 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221–S247. 2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.