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Infliximab (Systemic)


VA CLASSIFICATION
Primary: GA400
Secondary: MS109

Commonly used brand name(s): Remicade.

Another commonly used name is
cA2 {01}.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Inflammatory bowel disease therapy agent—

antirheumatic agent—

Indications

General considerations
Since tumor necrosis factor-alpha (TNF-alpha) mediates inflammation and modulates cellular immune response, infliximab (and other anti–TNF-alpha therapies) may affect normal immune responses {01}. At this time, it is not known whether long-term use of tumor necrosis inhibitors such as infliximab increases the incidence of infection {08} {13} or malignancy {08} {12} {13}.

Accepted

Crohn's disease (treatment) {01} {06} {07} {10} {11} {12}—Infliximab is indicated to reduce the symptoms of moderately to severely active Crohn's disease in patients who have an inadequate response to conventional therapy {01} {06} {07}. Also, infliximab is indicated to reduce the number of draining enterocutaneous fistula(s) in patients with fistulizing Crohn's disease {01} {11}.

Rheumatoid arthritis (treatment)—Infliximab, in combination with methotrexate, is indicated to reduce the signs and symptoms of rheumatoid arthritis in patients who have had an inadequate response to methotrexate.{13} {14} {15} {16} {17} {18} {19} {20} {21}{24}

[Ankylosing spondylitis (treatment) ]1—Infliximab is indicated for the treatment of ankylosing spondylitis in patients with evidence of inflammatory disease. {27}{28}{29}{30}{31}{32}{33}{34}{35}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: During premarketing clinical trials, no pharmacokinetic differences were observed in patient subgroups defined by gender, age, weight, or hepatic or renal function. {01}


Physicochemical characteristics:
Source—
    Infliximab is a chimeric human-murine immunoglobulin (IgG1– kappa) monoclonal antibody composed of human constant and murine variable regions {01} {03}.
Molecular weight—
    Approximately 149,100 daltons {01}

Mechanism of action/Effect:

Infliximab is a chimeric human-murine immunoglobulin (IgG1– kappa) {01} {14} {15} monoclonal antibody that binds specifically to tumor necrosis factor-alpha (TNF-alpha) {01} {06}, a proinflammatory cytokine {12}. Infliximab neutralizes the biological activity of TNF-alpha {01} {06} {12}; by binding to the soluble and transmembrane forms of TNF-alpha, it inhibits the binding of TNF-alpha to its receptors {01} {04}. Biological activities attributed to TNF-alpha include induction of proinflammatory cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6) {01} {06}; enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells {01} {06} and leukocytes {01}; stimulation of neutrophil and eosinophil functions {01}; and induction of acute phase and other liver proteins {01}. Cells expressing transmembrane TNF-alpha bound by infliximab can be lysed in vitro by complement {01} {12} or effector cells {01}. Antibodies to TNF-alpha reduce disease activity in a cotton-top tamarin colitis model {01} {03}. Infliximab inhibits the functional activity of TNF-alpha in a wide variety of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils, B and T lymphocytes, and epithelial cells {01}.

Mucosa {06} and stools {01} from patients with Crohn's disease have been found to contain elevated concentrations of TNF-alpha, correlating with increased disease activity {01}. Treatment with infliximab reduces both infiltration of inflammatory cells and TNF-alpha production in inflamed areas of the intestine, and also reduces the proportion of mononuclear cells from the lamina propria able to express TNF-alpha and interferon gamma {01} {05}. After treatment with infliximab, patients with Crohn's disease have decreased levels of serum IL-6 and C-reactive protein (CRP) when compared with baseline {01}. However, peripheral blood lymphocytes from infliximab-treated patients show no decrease in proliferative responses to in vitro mitogenic stimulation when compared with cells from untreated patients {01}.

Infliximab does not neutralize the biological activity of TNF-beta (lymphotoxin alpha), a related cytokine that utilizes the same receptors as TNF-alpha. {01} {03}


Other actions/effects:

Since TNF-alpha mediates inflammation and modulates cellular immune response, infliximab (and other anti-TNF therapies) may affect normal immune responses {01}. In addition, some patients treated with infliximab develop human antichimeric antibodies (HACA), which may predispose them to infusion reactions {01}. Anti-TNF therapy also may result in the formation of autoimmune antibodies {01}, such as antibodies against double-stranded deoxynucleic acid (dsDNA).

Distribution:

A single intravenous infusion of 5 mg per kg of body weight (mg/kg) resulted in a median volume of distribution (Vol D) of 3 L. Vol D was independent of the administered dose {01}.

Half-life:

A single intravenous infusion of 5 mg/kg of infliximab resulted in a terminal half-life of 9.5 days {01}.

Peak serum concentration:

A single intravenous infusion of 5 mg/kg of infliximab resulted in a median maximum serum concentration (C max) of 118 mcg/mL {01}. The C max and area under the concentration-time curve (AUC) showed a direct and linear relationship with the administered dose {01}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to any murine (mouse) proteins or other component of this product may be sensitive to infliximab also {01}.

Carcinogenicity

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of infliximab {01}.

Mutagenicity

No clastogenic or mutagenic effects of infliximab were observed in the in vivo mouse micronucleus test or the Ames test (Salmonella-Escherichia coli assay), respectively {01}. Chromosomal aberrations were not observed in an assay performed using human lymphocytes {01}.

Pregnancy/Reproduction
Fertility—
Long-term studies in animals have not been performed to evaluate the effects of infliximab on potential impairment of fertility in male and female animals {01}.

Pregnancy—
Studies have not been done in humans {01}.

Animal reproduction studies have not been conducted with infliximab since it does not cross-react with TNF-alpha in species other than humans and chimpanzees {01}. In a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNF-alpha, no evidence of maternal toxicity, embryotoxicity, or teratogenicity was found {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether infliximab is distributed into breast milk or absorbed by the nursing infant {01}. Because many immunoglobulins do appear in breast milk and because of the potential for serious adverse effects in the nursing infant, risk-benefit must be considered {01}.

Pediatrics

No information is available on the relationship of age to the effects of infliximab in pediatric patients. Safety and efficacy have not been established. {01}


Geriatrics


No information is available on the relationship of age to the effects of infliximab in geriatric patients {01}. However, the incidence of infections in the elderly population is higher in general; caution should be used in treating these patients, since the impact of infliximab treatment on the incidence of infections is not known {01}.

Drug interactions and/or related problems
Specific studies on drug interactions with infliximab have not been conducted {01}. The majority of patients in premarketing clinical trials received other concomitant medications commonly used in the treatment of Crohn's disease, including antibiotics, antivirals, corticosteroids, mercaptopurine, methotrexate {23}, azathioprine, and aminosalicylates {01}.

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medicine should not be used when the following medical problem exists::
» Congestive heart failure.     (infliximab should not be initiated in patients with congestive heart failure. Treatment should be discontinued in patients whose congestive heart failure is worsening, and treatment discontinuation should be considered in patients with stable concomitant congestive heart failure, especially in those who have not had a significant response to infliximab therapy {26}. )


» Hypersensitivity to any murine (mouse) proteins or other component of infliximab{25}
» Infections, invasive or
» Infections, opportunistic     (infliximab should not be administered to patients with a clinically important, active infection; caution should be exercised when considering the use of infliximab in patients with a chronic infection or a history of recurrent infection)

{25}
Risk-benefit should be considered when the following medical problem exists
» Tuberculosis, latent    (treatment of latent tuberculosis infection should be initiated prior to therapy with infliximab{25})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Cardiac status    (patients with stable concomitant congestive heart failure should have cardiac status closely monitored{26})


» Infection    (patients should be monitored for signs and symptoms of infection while on or after treatment with infliximab; new infections should be closely monitored )

{25}
» Tuberculin skin test    (patients should be evaluated for latent tuberculosis infection with a tuberculin skin test)

{25}


Side/Adverse Effects

Note: Tuberculosis (frequently disseminated or extrapulmonary), invasive fungal infections, and other opportunistic infections have been observed in patients receiving infliximab. Some of these infections have been fatal. If a patient develops a serious infection, infliximab therapy should be discontinued.{25}
Cases of histoplasmosis, listeriosis, pneumocytosis, and tuberculosis have been observed in patients receiving infliximab. For patients residing in regions where histoplasmosis is endemic, the benefits and risks of infliximab treatment should be carefully considered before initiation of infliximab therapy.{25}
Human antichimeric antibody (HACA) development may occur secondary to infliximab therapy {01} {10} {12}. The majority of the HACA-positive patients were at low titer (£ 1:20) {01}. Patients who were HACA-positive were more likely to experience an infusion reaction to the administration of infliximab {01}. However, the incidence of positive HACA responses was lower among Crohn's disease patients who were receiving immunosuppressant therapies (such as 6-mercaptopurine, azathioprine, or corticosteroids) than among patients not receiving such therapies {01}. Also, the clinical significance of HACA formation has been questioned since HACA-positive patients who received repeated treatment with infliximab have demonstrated sustained clinical benefit and have tolerated such treatment well {23}.
Anti-TNF therapy may result in the formation of autoimmune antibodies and, rarely, the development of a lupus-like syndrome {01}. If a patient develops symptoms suggestive of a lupus-like syndrome and is positive for antibodies against double-stranded deoxynucleic acid (dsDNA), infliximab treatment should be discontinued {01}. In premarketing clinical trials, discontinuation of infliximab therapy in these patients resulted in resolution of symptoms and disappearance of the anti-dsDNA {01}.
Patients with chronic Crohn's disease and long-term exposure to immunosuppressant therapies are more likely to develop infections and lymphomas {01} {08}. However, the effect of infliximab treatment on the incidence of infections or lymphomas is not known {01}.
Caution should be used in the re-treatment of patients with infliximab following an extended period without treatment {09}. In one study, 25% of patients who received infliximab 2 to 4 years following previous infliximab therapy presented with delayed adverse events including myalgia; rash; fever; polyarthralgia (including temporomandibular arthralgia); pruritus; facial, hand, or lip edema; dysphagia; urticaria; sore throat; and headache {09}. Adverse effects appeared to be related to development of an immune response to infliximab {09}. It is not clear if the formulation of the previous dose that most of these patients received initially, which differs from the current product formulation, contributed in a causal manner to the adverse reactions {09}.
In a phase 2 trial of 150 patients with moderate to severe (NYHA class III-IV) congestive heart failure (CHF), higher incidences of mortality and hospitalization for worsening heart failure were seen in patients treated with infliximab, especially those treated with the higher dose of 10 mg/kg. At present, there are insufficient data to determine optimal patient management. However, it is recommended that treatment with infliximab be discontinued in patients with worsening CHF and treatment should not be initiated in patients with congestive heart failure {26}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Abdominal pain {01} {10} {12}
    
bronchitis {01} {10} (cough; shortness of breath ; tightness in chest; troubled breathing ; wheezing)
    
fatigue {01} {07} {12} (unusual tiredness or weakness)
    
infusion-related reactions, including fever {01}
chills {01}
pruritus {01} (itching), urticaria {01} {19} (hives), chest pain {08}
dyspnea {08} (troubled breathing), facial flushing {08}
headache {08}
hypotension {08} (dizziness; fainting)
    
myalgia {07} (muscle pain)
    
nausea {01} {07} {10} {12}
    
upper respiratory tract infection {01} {07} {10} {12} (cough; fever; nasal congestion ; runny nose; sneezing; sore throat)
    
vomiting {01} {07}

Note: Infusion-related reactions are more likely to occur in patients who have developed human antichimeric antibodies (i.e., HACA-positive).


Incidence less frequent
    
Back pain {01}
    
cardiopulmonary reactions {01} , including chest pain {01} {07}
dyspnea {01} {07} (troubled breathing ), hypertension {01} (headache; high blood pressure), or hypotension {01} (dizziness; fainting; low blood pressure)
    
cough {01}
    
diarrhea {01}
    
fever {01}
    
headache {01} {07} {10} {12}
    
moniliasis {01} {02} , including dermal candidiasis {01} {02} (skin rash; cracks in skin at the corners of mouth; soreness or redness around fingernails and toenails), thrush {01} {02} (soreness or irritation of mouth or tongue; white patches in mouth and/or on tongue), and vaginitis {01} {02} (vaginal burning or itching and discharge)
    
pain {01} {07}
    
pharyngitis {01} {10} (sore throat)
    
pruritus {01} ( itching)
    
rhinitis {01} {07} (runny nose)
    
sinusitis {01} (pain or tenderness around eyes and cheekbones; fever; headache; nasal congestion)
    
urinary tract infection {01} (difficult or painful urination; frequent urge to urinate; bloody or cloudy urine)

Incidence rare
    
Abdominal hernia {01} {12} (bulge of tissue through the wall of the abdomen)
    
abscess {01} ( swollen, red, tender area of infection containing pus)
    
adult respiratory distress syndrome {01} (shortness of breath; tightness in chest; troubled breathing; wheezing)
    
cholecystitis {01} (stomach pain, severe; nausea ; vomiting)
    
dysuria {01} (difficult or painful urination)
    
falls {01}
    
infection {01} {12}
    
intestinal obstruction {01} {12} (abdominal pain, severe; constipation ; nausea; vomiting)
    
intestinal perforation {01} (abdominal pain, severe; troubled breathing; vomiting)
    
intestinal stenosis {01} (abdominal pain ; nausea; vomiting)
    
kidney infarction {01} (back or side pain; nausea; vomiting )
    
lupus erythematosus syndrome {01} (skin rash, hives, or itching; fever; sore throat; swollen or painful glands; bone or joint pain; unusual tiredness or weakness)
    
lymphoma {01} {12} (swollen glands; weight loss; general feeling of illness; black, tarry stools; yellow skin and eyes)
    
palpitations {01} (irregular or pounding heartbeat)
    
pneumonia {01} ( cough; shortness of breath; troubled breathing ; tightness in chest; wheezing)
    
proctalgia {01} (pain in rectum)
    
skin rash {01}
    
splenic infarction {01} (abdominal pain; pain spreading to left shoulder)
    
splenomegaly {01} (abdominal pain; feeling of fullness)
    
syncope {01} (fainting)
    
tendon injury {01}
    
thrombocytopenia {01} (usually asymptomatic; rarely, unusual bleeding or bruising; black, tarry stools ; blood in urine or stools; pinpoint red spots on skin)
    
ureteral obstruction {01} (back or side pain, severe; nausea; vomiting)





Overdose
Single infliximab doses of up to 20 mg per kg of body weight (mg/kg) have been administered without any direct toxic effect {01}.

For information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
The patient should be monitored for any signs or symptoms of adverse reactions or effects, and appropriate symptomatic treatment instituted immediately {01}.

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Infliximab (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to any murine (mouse) proteins or other component of infliximab

Pregnancy—Risk-benefit must be considered





Breast-feeding—Risk-benefit must be considered





Use in the elderly—Caution should be used, since the effect of infliximab treatment on the incidence of infections is not known
Other medical problems, especially congestive heart failure, invasive or opportunistic infections, or latent tuberculosis infection

Proper use of this medication

» Proper dosing

» Proper storage

Precautions while using this medication
Check with doctor or nurse if chest pain, fever, chills, facial flushing, itching, hives, or troubled breathing occurs within a few hours after receiving infliximab

Importance of evaluating for latent tuberculosis infection with a tuberculin skin test

Importance of evaluating cardiac status with concomitant congestive heart disease


Side/adverse effects
Signs of potential side effects, especially abdominal pain, bronchitis, fatigue, infusion-related reactions (including fever, chills, pruritus, urticaria, chest pain, dyspnea, facial flushing, headache, and hypotension), myalgia, nausea, upper respiratory tract infection, vomiting, back pain, cardiopulmonary reactions (including chest pain, dyspnea, hypertension, and hypotension), cough, diarrhea, fever, headache, moniliasis (including dermal candidiasis, thrush, and vaginitis), pain, pharyngitis, pruritus, rhinitis, sinusitis, urinary tract infection, abdominal hernia, abscess, adult respiratory distress syndrome, cholecystitis, dysuria, falls, infection, intestinal obstruction, intestinal perforation, intestinal stenosis, kidney infarction, lupus erythematosus syndrome, lymphoma, palpitations, pneumonia, proctalgia, skin rash, splenic infarction, splenomegaly, syncope, tendon injury, thrombocytopenia, and ureteral obstruction


General Dosing Information
Reconstituted infliximab and diluted infliximab infusion solutions are incompatible with plasticized polyvinylchloride (PVC) equipment or devices. Diluted infliximab solutions should be prepared only in glass infusion bottles or polypropylene or polyolefin infusion bags and administered through polyethylene-lined administration sets. {01}

Infliximab infusion solutions must be administered via a polyethylene-lined infusion set with an in-line, sterile, nonpyrogenic, low–protein-binding filter with a pore size £ 1.2 micrometers (microns). {01}

Caution should be used in the re-treatment of patients with infliximab following an extended period without treatment {09}. The risk of potentially serious delayed adverse events should be weighed against the potential benefit of re-treatment if more than 2 years have elapsed since previous infliximab therapy {09}. See Side/Adverse Effects .

For treatment of adverse effects
Recommended treatment of hypersensitivity reactions consists of the following:    • Stopping the infusion if severe reactions occur. {01}
   • Providing symptomatic and supportive treatment. Epinephrine, corticosteroids, antihistamines, and acetaminophen should be available for immediate use. {01}



Parenteral Dosage Forms

INFLIXIMAB FOR INJECTION

Note: Infliximab infusion solutions must be administered via a polyethylene-lined infusion set with an in-line, sterile, nonpyrogenic, low–protein-binding filter with a pore size £ 1.2 micrometers (microns). {01}


Usual adult dose
For moderately to severely active Crohn's disease in patients having an inadequate response to conventional therapy
5 mg per kg of body weight (mg/kg), administered as a single intravenous infusion over at least two hours. {01}

For fistulizing Crohn's disease
Initially, 5 mg/kg administered as an intravenous infusion over at least two hours, followed with additional doses at two and six weeks after the first infusion. {01}

Note: For specific directions for reconstitution, dilution, and administration of the infliximab infusion, see Preparation of dosage form section.


For rheumatoid arthritis
3 mg per kg of body weight (mg/kg), administered as a single intravenous infusion over at least two hours, followed with additional doses at two and six weeks after the first infusion then every 8 weeks thereafter{17}{22}{24}. Infliximab should be administered in combination with methotrexate.{24}

[Ankylosing spondylitis (treatment)]1
Intravenous, 3 to 5 mg per kg of body weight week 0, 2 and 6 and every 8 weeks thereafter, as needed.{27}.{28}{29}{30}{31}{32}{33}{34}{35}


Usual pediatric dose
Safety and efficacy have not been established. {01}

Usual geriatric dose
See Usual adult dose . {01}

Strength(s) usually available
U.S.—


100 mg (Rx) [Remicade (polysorbate 80) (monobasic sodium phosphate) (dibasic sodium phosphate) (sucrose)]

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 8 ºC (36 and 46 ºF). Do not freeze. {01}

Preparation of dosage form:
Calculate the dose and the number of infliximab vials needed; calculate the total volume of reconstituted infliximab solution required {01}.

Reconstitute each infliximab vial with 10 mL of Sterile Water for Injection USP {01}. Using a 21-gauge or smaller needle, direct the stream of diluent to the glass wall of the infliximab vial {01}. To dissolve the lyophilized powder, gently swirl the solution by rotating the vial {01}. Avoid prolonged or vigorous agitation, and do not shake {01}. (Foaming of the solution is not unusual. {01}) Allow the reconstituted solution to stand for 5 minutes {01}. The solution should be colorless to light yellow and opalescent {01}. Because infliximab is a protein, the solution may develop a few translucent particles; however, if opaque particles, discoloration, or other foreign particles are present, do not use the solution {01}.

The total volume of the reconstituted infliximab dose must be diluted to 250 mL with 0.9% Sodium Chloride Injection USP {01}. From a 250-mL glass bottle or polypropylene or polyolefin bag of 0.9% Sodium Chloride Injection USP, withdraw a volume of sodium chloride equal to the volume of reconstituted infliximab and discard {01}. Slowly add the total volume of reconstituted infliximab solution to the infusion bottle or bag and mix gently {01}. The infusion concentration should fall in the range of 0.4 mg/mL to 4 mg/mL {01}.

The infusion solution must be administered over a period of not less than 2 hours and must use a polyethylene-lined infusion set with an in-line, sterile, nonpyrogenic, low–protein-binding filter with a pore size £ 1.2 micrometers (microns) {01}.

Stability:
Infliximab vials do not contain antibacterial preservatives and should be used immediately after reconstitution {01}. Infliximab intravenous infusions should begin within 3 hours of preparation {01}. Any unused portion of infliximab infusion should be discarded.

Incompatibilities:
Reconstituted infliximab and diluted infliximab infusion solutions are incompatible with plasticized PVC (polyvinylchloride) equipment or devices {01}. Diluted infliximab solutions should be prepared only in glass infusion bottles or polypropylene or polyolefin infusion bags and administered through polyethylene-lined administration sets {01}.

No physical biochemical compatibility studies have been conducted to evaluate the coadministration of infliximab with other agents {01}. Infliximab should not be infused concomitantly in the same intravenous line with other agents {01}.

Auxiliary labeling:
   • Do not shake.



Developed: 05/05/1999
Revised: 01/30/2003



References
  1. Remicade package insert (Centocor—US), New 8/12/98, Rec 9/24/98.
  1. Personal communication, Dr. R. Shaw, Medical Information Specialist, Centocor, 10/13/98.
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  1. Scallon, BJ, Moore MA, Trinh H, et al. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995 April; 7(3): 251-9.
  1. Plevy SE, Landers CJ, Prehn J, et al. A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn's disease. J Immunol 1997; 159: 6276-82.
  1. Van Dullemen HM, Van Deventer SJH, Hommes DW, et al. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995 Jul; 109(1): 129-35.
  1. Targan SR, Hanauer SB, Van Deventer, SJH, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor-alpha for Crohn's disease. N Engl J Med 1997 Oct; 337(15): 1029-35.
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  1. Present D, Mayer L, VanDeventer SJH, et al. Anti-TNF-alpha chimeric antibody (cA2) is effective in the treatment of fistulae of Crohn"s disease: a multicenter, randomized, double-blind, placebo-controlled study [abstract]. Am J Gastro 1997; A648.
  1. Hanauer SB, Cohen RD, Becker RV III, et al. Advances in the management of Crohn"s disease: economic and clinical potential of infliximab. Clin Ther 1998; 20(5): 1009-28.
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  1. Elliott MJ, Maini RN, Feldmann M, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor-alpha. Arthritis Rheum 1993 Dec; 36(12): 1681-90.
  1. Elliott MJ, Maini RN, Feldmann M, et al. Repeated therapy with monoclonal antibody to tumour necrosis factor-alpha (cA2) in patients with rheumatoid arthritis. Lancet 1994 Oct 22; 344: 1125-7.
  1. Elliott MJ, Maini RN, Feldmann M, et al. Randomized double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor-alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994 Oct 22; 344: 1105-10.
  1. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor-alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998 Sep; 41(9): 1552-63.
  1. Kavanaugh AF, Cush JJ, St Clair EW, et al. Anti-TNF-alpha monoclonal antibody (mAb) treatment of rheumatoid arthritis (RA) patients with active disease on methotrexate (MTX): results of a double-blind, placebo controlled multicenter trial [abstract]. Arthritis Rheum 1996 Sep; 39(9 Suppl): 575.
  1. Kavanaugh AF, Cush, JJ, St Clair EW, et al. Anti-TNF-alpha monoclonal antibody (mAb) treatment of rheumatoid arthritis (RA) patients with active disease on methotrexate (MTX): results of open label, repeated dose administration following a single dose double-blind, placebo controlled trial [abstract]. Arthritis Rheum 1996 Sep; 39(9 Suppl): 1296.
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  1. Reviewers' consensus on monograph draft of 3/99.
  1. Manufacturer comment, 4/99.
  1. Personal communication, Centocor, 4/20/99.
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  1. Consensus on review of evidence table. 1/06/2003.
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  1. Brandt J et al. Successful short-term treatment of severe undifferentiated spondyloarthropathy with the anti-tumor necrosis factor-alpha monoclonal antibody infliximab. J Rheumatol 2002;29(1): 118-22.
  1. Stone M et al. Clinical and imaging correlates of response to treatment with infliximab in patients with ankylosing spondylitis. J Rheumatol 2001; 28(7): 1605-14.
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  1. Van Den Bosch F et al. Crohn's disease associated with spondyloarthropathy: effect of TNF-alpha blockade with infliximab on articular symptoms. Lancet 2000; 356 (9244):1821-2.
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