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REMICADE has been approved for the treatment of pediatric patients with moderate to severe Crohn's disease.

REACH Trial

The FDA approval for REMICADE therapy in pediatric Crohn's disease was based on the results of the REACH clinical trial. REACH stands for "A Randomized, Multicenter, Open-Label Study to Evaluate the Safety and Efficacy of Anti-TNF alpha Chimeric Monoclonal Antibody in Pediatric Subjects with Moderate to Severe Crohn's Disease."

REACH trial background

REACH was a multicenter, randomized, open-label, controlled trial, which evaluated the safety and efficacy of REMICADE in 112 pediatric patients (ages 6-17 years) with active CD. The primary objective of this trial was to evaluate the efficacy of a 3-dose induction regimen of REMICADE in reducing signs and symptoms in pediatric patients with moderately to severely active CD. Additionally, the safety profile of REMICADE in these patients was also evaluated. The secondary objective was to compare maintenance of clinical response and remission with REMICADE 5 mg/kg administered every 8 weeks or every 12 weeks.

Patients included in the trial had moderate-severe CD (Pediatric Crohn's Disease Activity Index [PCDAI] >30) and failed to respond to an immunomodulator. Induction of clinical response, the primary endpoint, was evaluated 10 weeks after the initial infusion. At Week 54, clinical response, clinical remission and change from baseline in average daily corticosteroid use were evaluated as secondary efficacy endpoints. Clinical response was defined as a decrease of ≥15 in the PCDAI and a total PCDAI value ≤30. Clinical remission was defined as a PCDAI score of ≤10.

Of the 112 patients enrolled in this study, 103 patients achieved clinical response to induction therapy (REMICADE 5 mg/kg 0, 2 and 6) and were subsequently randomized to REMICADE 5 mg/kg every 8 weeks (n=52) or every 12 weeks (n=51) through Week 46.

REACH study findings

Clinical response at Week 10, the primary endpoint, was achieved in 88% of the patients. Additional response and remission rates are summarized in Table 1.

Table 1. RESPONSE AND REMISSION IN STUDY PEDS CROHN'S

	5 mg/kg REMICADE
	Every 8 Week	Every 12 Week
	Treatment Group	Treatment Group
Patients randomized	52	51
Clinical Response¹
Week 30	73%**	47%
Week 54	64%**	33%
Clinical Remission²
Week 30	60%*	35%
Week 54	56%**	24%

¹Defined as a decrease from baseline in the PCDAI score of ≥15 points and total score of ≤30 points.
²Defined as a PCDAI score of ≤10 points.
*p-value < 0.05
**p-value < 0.01

REMICADE every 8 weeks allowed 75% of kids with Crohn's to eliminate steroid use through Week 54 (P<0.001).

Indications

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.

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.

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.

Adult Crohn's Disease
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult 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.

Pediatric Crohn’s Disease
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy.

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.

Ankylosing Spondylitis
REMICADE is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

IMPORTANT SAFETY INFORMATION

RISK OF INFECTIONS
Tuberculosis (TB) (frequently disseminated or extrapulmonary at clinical presentation), bacterial infections including sepsis, invasive fungal infections, and other opportunistic infections have been observed in patients receiving REMICADE. Some of these infections have led to hospitalizations and death. Patients should be evaluated for TB risk factors and tested for latent TB.^1,2 Treatment of latent TB infection should be initiated prior to therapy with REMICADE. Some patients who received treatment for latent or active TB or who tested negative for latent TB prior to receiving REMICADE have developed active TB. In consultation with a physician with expertise in the treatment of TB, consider anti-TB treatment prior to REMICADE therapy in patients with a history of latent or active TB, when adequate treatment cannot be confirmed, or in patients who have a negative test for latent TB, but have several or highly significant risk factors.³ Monitor all patients receiving REMICADE for signs and symptoms of active TB.

Serious infections have occurred in patients on REMICADE alone or on concomitant immunosuppressive therapy that, in addition to their disease, could predispose them to infections. Cases of pneumonia, histoplasmosis, coccidioidomycosis, listeriosis, and pneumocystosis have been reported. For patients who have resided in regions where histoplasmosis or coccidioidomycosis is endemic, the benefits and risks of REMICADE should be considered before initiation of therapy. REMICADE should not be given to patients with a clinically important, active infection. Use with caution in patients with a history of infection. Monitor and educate patients for infection during or after treatment. Discontinue REMICADE if a patient develops a serious infection.

MALIGNANCIES
HEPATOSPLENIC T-CELL LYMPHOMAS
Rare postmarketing cases of hepatosplenic T-cell lymphoma have been reported in adolescent and young adult patients with Crohn’s disease treated with REMICADE. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. All of these hepatosplenic T-cell lymphomas with REMICADE have occurred in patients on concomitant treatment with azathioprine or 6-mercaptopurine.

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 REMICADE-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected. 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 REMICADE infusions. 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.

Please see Full Prescribing Information and Medication Guide for REMICADE.

References

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.
See Centers for Disease Control for latest guidelines and recommendations for latent tuberculosis testing in immunocompromised patients.
Gardam MA, et al. Anti-tumor necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148-155

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Last Updated: December 18, 2008