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Remicade

Pronunciation

Generic Name: Infliximab
Class: Disease-modifying Antirheumatic Drugs
CAS Number: 170277-31-3

Warning(s)

  • Serious Infections
  • Increased risk of serious infections involving various organ systems and sites that may require hospitalization or result in death; tuberculosis (frequently disseminated or extrapulmonary), invasive fungal infections (may be disseminated), bacterial (e.g., legionellosis, listeriosis) and viral infections, and other opportunistic infections reported.1 72 155 159 (See Infectious Complications under Cautions.)

  • Carefully consider risks and benefits prior to initiating infliximab therapy in patients with chronic or recurring infections.1 159

  • Evaluate patients for latent tuberculosis infection prior to and periodically during infliximab therapy; if indicated, initiate appropriate antimycobacterial regimen prior to initiating infliximab therapy.1 72 118 159

  • Closely monitor patients for infection, including active tuberculosis in those with a negative tuberculin skin test, during and after treatment.1 Discontinue infliximab if serious infection or sepsis occurs.1 34 35 44 118 Consider empiric antifungal therapy if serious systemic illness occurs in a patient at risk for invasive fungal infections.1 155 159

  • Malignancy
  • Lymphoma and other malignancies (some fatal) reported in children and adolescents receiving TNF blocking agents.1 154 160 (See Malignancies and Lymphoproliferative Disorders under Cautions.)

  • Aggressive, usually fatal hepatosplenic T-cell lymphoma reported mainly in adolescents and young adults with Crohn's disease or ulcerative colitis receiving TNF blocking agents, including infliximab.1 154 160 Most of the patients received a combination of immunosuppressive agents, including TNF blocking agents and thiopurine analogs (azathioprine or mercaptopurine).1 154 160

REMS:

FDA approved a REMS for infliximab to ensure that the benefits outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Biologic response modifier and disease-modifying antirheumatic drug (DMARD); chimeric human-murine monoclonal antibody that blocks the biologic activity of tumor necrosis factor (TNF, TNF-α).1 7 20 24

Uses for Remicade

Crohn’s Disease

Used to reduce signs and symptoms of Crohn’s disease and to induce and maintain clinical remission in adults and pediatric patients with moderate to severe active disease who have had an inadequate response to conventional therapies (e.g., corticosteroids, mesalamine or sulfasalazine, azathioprine or mercaptopurine).1 5 6 38 51 72 89 136 142 (See Pediatric Use under Cautions.)

Used to reduce the number of draining enterocutaneous and rectovaginal fistulas and to maintain fistula closure in adults with fistulizing Crohn’s disease (designated an orphan drug by FDA for this use).1 64 94 140 141 142 143 Consider use when fistulas have not responded to appropriate anti-infective regimens (e.g., ciprofloxacin and/or metronidazole) and/or immunosuppressive therapy (e.g., azathioprine or mercaptopurine).47 65 66 70

Slideshow: Drug Treatment for Rheumatoid Arthritis - What Are Your Options?

Rheumatoid Arthritis in Adults

Used in conjunction with methotrexate to manage the signs and symptoms of rheumatoid arthritis, to improve physical function, and to inhibit progression of structural damage associated with the disease in adults with moderate to severe active rheumatoid arthritis.1 14 15 17 18 41

Ankylosing Spondylitis

Management of the signs and symptoms of active ankylosing spondylitis.1 72 108 109 117 137 138

Psoriatic Arthritis

Used to manage the signs and symptoms of active arthritis, inhibit progression of structural damage associated with the disease, and improve physical function in adults with psoriatic arthritis.1 72 105 106 107 108 131

Plaque Psoriasis

Management of chronic, severe (i.e., extensive and/or disabling) plaque psoriasis in adults who are candidates for systemic therapy and in whom other systemic therapies are medically less appropriate.1 Use only in patients who will be closely monitored and who will have regular follow-up visits with a clinician.1

Ulcerative Colitis

Used to manage the signs and symptoms, to induce and maintain clinical remission and mucosal healing, and to eliminate corticosteroid use in adults with moderate to severe active ulcerative colitis who have had an inadequate response to conventional therapies.1 47 72 112 113 114 147

Used to manage the signs and symptoms and to induce and maintain clinical remission in pediatric patients with moderate to severe active ulcerative colitis who have had an inadequate response to conventional therapies.1 (See Pediatric Use under Cautions.)

Juvenile Arthritis

Has been used in a limited number of pediatric patients with juvenile arthritis; further study needed.1 72 103 104 153

Behcet’s Syndrome

Has been used in a limited number of patients with Behcet’s syndrome.93 102 115 116

Remicade Dosage and Administration

General

Premedication and Patient Monitoring

  • Consider administration of premedication prior to each dose to minimize risk of infusion-related reactions.47 72

  • Patients receiving initial infusion and patients without a history of acute infusion reactions: Oral diphenhydramine hydrochloride (25–50 mg) and acetaminophen (650 mg) can be given before the infusion.47 72

  • Patients with a history of acute infusion reactions: Oral or IV prednisone (40 mg) or hydrocortisone (100 mg), oral or IV diphenhydramine hydrochloride (25–50 mg), and acetaminophen (650 mg) can be given before the infusion.72 142

  • Monitor patients closely during and after each IV infusion.72 Measure vital signs (pulse and BP) immediately prior to infusion, during the infusion (every 30 minutes in patients without a history of acute infusion reactions and every 15 minutes in those with a history of reactions), and for 30 minutes after completion of the infusion.72

  • If DBP drops 15–20 mm Hg or symptoms of hypersensitivity (e.g., urticaria, shortness of breath) occur, stop the infusion immediately, evaluate manifestations, and initiate appropriate therapy.72

  • If the reaction is not severe and is mitigated with a regimen of oral diphenhydramine hydrochloride (25–50 mg), oral acetaminophen (650 mg), and oral or IV prednisone (40 mg), the infusion may be resumed with caution following the rate titration schedule using an initial rate of 10 mL/hour.72 (See Rate Titration Schedule Table under Dosage and Administration.)

  • The infusion should be discontinued and not completed if the reaction does not resolve with the regimen described above or is more severe and/or requires treatment with epinephrine.72

Concomitant Therapy for Crohn’s Disease

  • Corticosteroids, mesalamine, sulfasalazine, azathioprine, mercaptopurine, methotrexate, and anti-infective agents may be continued.1

  • When deciding whether to use infliximab alone or in combination with other immunosuppressive agents in the management of inflammatory bowel disease (particularly in adolescents and young adults), consider both the possibility of an increased risk of hepatosplenic T-cell lymphoma with combination therapy and the observed increase in immunogenicity and hypersensitivity reactions associated with infliximab given as monotherapy.1 (See Malignancies and Lymphoproliferative Disorders, Acute Sensitivity Reactions, and Delayed Sensitivity Reactions, under Cautions.)

Concomitant Therapy for Rheumatoid Arthritis

  • Intended for use concomitantly with methotrexate; only limited data available regarding the efficacy of infliximab without concomitant methotrexate.1 17 18 20 21 23 1

  • Corticosteroids and NSAIAs may be continued.1

Concomitant Therapy for Psoriatic Arthritis

  • Corticosteroids, NSAIAs, and methotrexate may be continued.1

Concomitant Therapy for Ulcerative Colitis

  • Corticosteroids, azathioprine, mercaptopurine, and 5-aminosalicylates may be continued.1 147

  • When deciding whether to use infliximab alone or in combination with other immunosuppressive agents in the management of inflammatory bowel disease (particularly in adolescents and young adults), consider both the possibility of an increased risk of hepatosplenic T-cell lymphoma with combination therapy and the observed increase in immunogenicity and hypersensitivity reactions associated with infliximab given as monotherapy.1 (See Malignancies and Lymphoproliferative Disorders, Acute Sensitivity Reactions, and Delayed Sensitivity Reactions, under Cautions.)

Reinitiation of Treatment

  • Carefully consider risks and benefits of readministration of infliximab after a period without treatment (especially readministration as a reinduction regimen at 0, 2, and 6 weeks); in patients with psoriasis, reinitiate treatment with a single dose followed by maintenance therapy.1 (See Acute Sensitivity Reactions and also Delayed Sensitivity Reactions, under Cautions.)

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Administer with an in-line, sterile, nonpyrogenic, low-protein-binding filter with a pore diameter of ≤1.2 mcm.1

Consult manufacturer’s labeling for additional information on reconstitution, dilution, and administration of infliximab.1

Reconstitution

Reconstitute vial containing 100 mg of infliximab powder with 10 mL of sterile water for injection to provide a solution containing 10 mg/mL.1 Reconstitute the number of vials needed to provide the indicated dosage of infliximab.1

Direct diluent toward the side of the vial with a sterile syringe and a ≤21-gauge needle; swirl vial gently to ensure dissolution; do not shake or agitate vigorously (to avoid foaming).1

Allow reconstituted solution to stand for 5 minutes before dilution.1

Dilution

Remove the volume of diluent equal to the total required volume of reconstituted infliximab solution from a 250-mL bag or bottle of 0.9% sodium chloride injection.1 Slowly add reconstituted infliximab to the bag to a total volume of 250 mL; mix gently.1 Concentration of the solution for infusion should be 0.4–4 mg/mL.1

Rate of Administration

Infuse over a period of at least 2 hours.1

IV infusions may be given at a rate of 2 mL/minute or, alternatively, a rate titration schedule may be used in an attempt to prevent or ameliorate acute infusion reactions.72

A rate titration schedule can be used in patients receiving an initial infliximab dose, those without a history of acute infusion reactions, and those with a history of such reactions.72

Table 1. Rate Titration Schedule

Rate

Time

10 mL/hour

first 15 minutes72

20 mL/hour

next 15 minutes72

40 mL/hour

next 15 minutes72

80 mL/hour

next 15 minutes72

150 mL/hour

next 30 minutes72

250 mL/hour

next 30 minutes72

Dosage

Pediatric Patients

Crohn’s Disease
Moderate or Severe Active Crohn’s Disease
IV

Children ≥6 years of age: 5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).1 47 86 87

Ulcerative Colitis
Moderate to Severe Active Ulcerative Colitis
IV

Children ≥6 years of age: 5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).1

Adults

Crohn’s Disease
Moderate or Severe Active Crohn’s Disease or Fistulizing Crohn’s Disease
IV

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).1

Consider dose of 10 mg/kg for patients who respond initially but subsequently lose response.1

Patients who do not respond by week 14 are unlikely to respond with continued administration; consider discontinuing the drug.1

Rheumatoid Arthritis
Moderate to Severe Active Rheumatoid Arthritis
IV

3 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).1

Increase dosage up to 10 mg/kg and/or administer as often as once every 4 weeks for patients who have an incomplete response to 3 mg/kg; consider that risk of serious infection is increased with higher dosages.1 72

Ankylosing Spondylitis
IV

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 6 weeks (maintenance regimen).1

Psoriatic Arthritis
IV

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).1

Plaque Psoriasis
IV

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).1

If treatment is resumed after maintenance therapy is interrupted, reinitiate with a single dose followed by maintenance therapy.1 (See Acute Sensitivity Reactions and also Delayed Sensitivity Reactions, under Cautions.)

Ulcerative Colitis
Moderate to Severe Active Ulcerative Colitis
IV

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).1

Cautions for Remicade

Contraindications

  • Doses >5 mg/kg in patients with moderate or severe heart failure.1 (See Cardiovascular Effects under Cautions.)

  • Known hypersensitivity to infliximab, murine proteins, or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Infectious Complications

Increased risk of serious infections involving various organ systems and sites that may require hospitalization or result in death.1 159 Opportunistic infections caused by bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms (e.g., aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, tuberculosis) reported, particularly in patients receiving concomitant therapy with immunosuppressive agents (e.g., methotrexate, corticosteroids).1 72 118 144 155 159 Infections frequently are disseminated.1 (See Boxed Warning.)

Increased incidence of serious infections observed with concomitant use of a TNF blocking agent and anakinra or abatacept.1 152 165 (See Specific Drugs under Interactions.)

Patients >65 years of age, with comorbid conditions, and/or receiving concomitant therapy with immunosuppressive agents (e.g., corticosteroids, methotrexate) may be at increased risk of infection.1 159

Do not initiate infliximab in patients with active infections, including clinically important localized infections.1 Consider potential risks and benefits of the drug prior to initiating therapy in patients with a history of chronic, recurring, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who have resided or traveled in regions where tuberculosis or mycoses such as histoplasmosis, coccidioidomycosis, and blastomycosis are endemic.1 159

Closely monitor patients during and after infliximab therapy for signs or symptoms of infection (e.g., fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, serious systemic illness including shock).1 155 159

If new infection occurs during therapy, perform thorough diagnostic evaluation (appropriate for immunocompromised patient), initiate appropriate anti-infective therapy, and closely monitor patient.1 155 Discontinue infliximab if serious infection or sepsis develops.1 34 35 44 118 155

Evaluate all patients for active or latent tuberculosis and for risk factors for tuberculosis prior to and periodically during therapy.1 72 118 159 When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection prior to infliximab therapy.1 14 18 42 59 72 111 118 Also consider antimycobacterial therapy prior to infliximab therapy for individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed and for individuals with a negative tuberculin skin test who have risk factors for tuberculosis.1 Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy.1

Monitor all patients, including those with negative tuberculin skin tests, for active tuberculosis.1 Strongly consider tuberculosis in patients who develop new infections while receiving infliximab, especially if they previously have traveled to countries where tuberculosis is highly prevalent or have been in close contact with an individual with active tuberculosis.1

Failure to recognize invasive fungal infections has led to delays in appropriate treatment.155 Consider empiric antifungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.1 155 159 Whenever feasible, consult specialist in fungal infections when making decisions regarding initiation and duration of antifungal therapy.1 155

When deciding whether to reinitiate TNF blocking agent therapy following resolution of an invasive fungal infection, reevaluate risks and benefits, particularly in patients who reside in regions where mycoses are endemic.155 Whenever feasible, consult specialist in fungal infections.155

Malignancies and Lymphoproliferative Disorders

Lymphoma and other malignancies (some fatal) reported during postmarketing surveillance in children and adolescents receiving TNF blocking agents, particularly in those receiving other immunosuppressive agents (e.g., azathioprine, methotrexate) concomitantly.1 154 Malignancies included lymphomas (about 50% of the cases) (e.g., Hodgkin’s disease, non-Hodgkin’s lymphoma) and various other malignancies (e.g., leukemia, melanoma, solid organ cancers), including rare malignancies usually associated with immunosuppression and malignancies not usually observed in children and adolescents (e.g., leiomyosarcoma, hepatic malignancies, renal cell carcinoma).1 154 Median time to occurrence was 30 months (range: 1–84 months) after the initial TNF blocking agent dose.1 FDA has concluded that there is an increased risk of malignancy with TNF blocking agents in children and adolescents; however, the strength of the association is not fully characterized.154

Hepatosplenic T-cell lymphoma (a rare, aggressive, usually fatal T-cell lymphoma) reported mainly in adolescents and young adults with Crohn’s disease or ulcerative colitis receiving TNF blocking agents and/or thiopurine analogs (mercaptopurine or azathioprine).1 154 160 Most of the patients received a combination of immunosuppressive agents, including TNF blocking agents and thiopurine analogs.1 160 Unclear whether occurrence is related to infliximab or combination of infliximab and other immunosuppressive agents.1

In controlled studies, lymphoma was reported more frequently in patients receiving infliximab or other TNF blocking agents than in control patients.1 Patients with Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, or plaque psoriasis, especially those with highly active disease and/or chronic exposure to immunosuppressive therapies, may be at increased risk of lymphoma;1 28 30 38 42 160 may be difficult to measure added risk of TNF-blocking agents, azathioprine, and/or mercaptopurine.160

Acute and chronic leukemias (some fatal) reported during postmarketing surveillance of TNF blocking agents in adults and pediatric patients, particularly in those receiving other immunosuppressive agents concomitantly.1 154 Leukemia (most commonly acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) generally occurred during first 2 years of therapy.154 FDA has concluded that there is a possible association between TNF blocking agents and development of leukemia; interpretation of findings is complicated because patients with rheumatoid arthritis may be at increased risk for leukemia independent of any treatment with TNF blocking agents.1 154

Malignancies (mainly lung cancer or head and neck malignancies) reported in more infliximab-treated than placebo-treated patients with moderate to severe COPD; all had been heavy smokers.1 157 Exercise caution when considering infliximab therapy in patients with moderate to severe COPD.1

In infliximab-treated psoriasis patients, nonmelanoma skin cancer reported more commonly in those who had received prior phototherapy; monitor psoriasis patients, especially those who have received prolonged prior phototherapy, for nonmelanoma skin cancer.1

Other malignancies (basal cell carcinoma, breast cancer, melanoma, colorectal cancer, rectal adenocarcinoma, squamous cell carcinoma) reported in patients receiving infliximab.1 14 17 141

In controlled clinical studies of infliximab, the rate of malignancies other than lymphoma and nonmelanoma skin cancer was increased in infliximab-treated patients compared with control patients, but the rate was similar to the expected rate in the general population.1

In controlled studies of other TNF blocking agents in adults at increased risk for malignancies (e.g., patients with Wegener’s granulomatosis receiving concomitant cyclophosphamide), a greater proportion of malignancies occurred in patients receiving the TNF blocking agent compared with control patients.164

Some immune related diseases (e.g., Crohn’s disease) have been shown to increase risk of cancer independent of treatment with TNF blocking agents, while for others (e.g., juvenile idiopathic arthritis) it is unknown whether there is an increased risk of cancer.154

Consider possibility of and monitor for occurrence of malignancies during and following treatment with TNF blocking agents.154 160

Exercise caution when considering infliximab therapy in patients with a history of malignancy or when deciding whether to continue therapy in patients who develop a malignancy.1 33 34 35 44 59 64 Carefully consider risks and benefits of TNF blocking agents, especially in adolescents and young adults and especially in the treatment of Crohn’s disease or ulcerative colitis.160

When deciding whether to use infliximab alone or in combination with other immunosuppressive agents in the management of inflammatory bowel disease (particularly in adolescents and young adults), consider both the possibility of an increased risk of hepatosplenic T-cell lymphoma with combination therapy and the observed increase in immunogenicity and hypersensitivity reactions associated with infliximab given as monotherapy.1

Other Warnings and Precautions

HBV Reactivation

Increased risk of reactivation of HBV infection in patients who are chronic carriers of the virus (i.e., hepatitis B surface antigen-positive [HBsAg-positive]).1 144 Use of multiple immunosuppressive agents may contribute to HBV reactivation.1

Screen at-risk patients prior to initiation of therapy.1 Evaluate and monitor HBV carriers before, during, and for up to several months after therapy.1 Safety and efficacy of antiviral therapy for prevention of HBV reactivation not established.1 Discontinue infliximab and initiate appropriate treatment (e.g., antiviral therapy) if HBV reactivation occurs.1 Not known whether infliximab can be readministered once control of a reactivated HBV infection is achieved; caution advised in this situation.1

Hepatic Effects

Severe hepatic reactions (e.g., acute liver failure, jaundice, hepatitis, cholestasis, autoimmune hepatitis) reported; some cases were fatal or needed liver transplantation.1 144 Hepatic reactions occurred between 2 weeks and >1 year following initiation of therapy; elevations of hepatic transaminase enzymes not observed prior to discovery of liver injury in many cases.1 144

Evaluate patients with signs of liver dysfunction.1 144 If jaundice and/or marked hepatic aminotransferase elevations (≥5 times the ULN) develop, discontinue infliximab and investigate hepatic abnormality.1

Cardiovascular Effects

Associated with adverse outcomes in patients with heart failure (increased mortality and hospitalization due to worsening heart failure).1 139

Use in patients with heart failure only after consideration of other treatment options.1 If used in patients with moderate or severe heart failure, do not exceed doses of 5 mg/kg and monitor cardiac status closely.1 (See Contraindications under Cautions.)

Discontinue therapy if new or worsening symptoms of heart failure occur.1

Use in patients with heart failure (NYHA class III or IV) associated with increased mortality in patients who received infliximab 10 mg/kg and an increase in adverse cardiovascular effects (dyspnea, hypotension, angina, dizziness) in patients who received 5 or 10 mg/kg.1 Worsening heart failure (with and without identifiable precipitating factors) and new-onset heart failure (including in patients with no known pre-existing cardiovascular disease and/or who were < 50 years of age) reported.1 Not evaluated in patients with mild (NYHA class I or II) heart failure.1

Hematologic Effects

Possible leukopenia, neutropenia, thrombocytopenia, and pancytopenia, sometimes with fatal outcome.1 Use with caution in patients with a history of substantial hematologic abnormalities.1 Consider discontinuance of the drug in patients with confirmed hematologic abnormalities.1

Acute Sensitivity Reactions

Acute infusion reactions consistent with hypersensitivity reactions reported within 1–2 hours after IV infusion.1 10 14 18 21 36 38 41 64 72 92 128

Signs/symptoms include urticaria, dyspnea, hypotension, fever, chills, headache, pruritus, chest pain, and/or hypertension.1 5 10 14 15 18 21 36 38 41 64 72 92 128 136 Anaphylactic reactions (e.g., laryngeal/pharyngeal edema, severe bronchospasm), seizures, erythematous rash, myocardial ischemia/infarction, and transient vision loss reported.1 36 128

Drugs for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids, and/or epinephrine) should be immediately available.1 72

Monitor patients; consider premedication; initiate infusion slowly; adjust rate or discontinue based on patient tolerance.47 72 47 72 (See Premedication and Patient Monitoring and also see Rate Titration Schedule Table under Dosage and Administration.)

Mild acute infusion reactions often controlled by slowing or discontinuing the infusion or appropriate treatment (antihistamines).1 5 10 14 18 23 28 38 42 47 72 92 Discontinue immediately for severe hypersensitivity reaction; initiate appropriate therapy.1

Patients with antibodies to infliximab appear to be 2–3 times more likely to have an infusion reaction than patients who do not have antibodies to the drug.1

Incidence of acute infusion reactions may be lower in patients receiving concomitant therapy with immunosuppressive agents (e.g., azathioprine, mercaptopurine, methotrexate) than in those not receiving such therapy.1 47

Readministration after a period without treatment associated with a higher incidence of infusion reactions compared with regular maintenance treatment.1 In general, carefully consider risks and benefits of readministration after a period without treatment (especially readministration as a reinduction regimen at 0, 2, and 6 weeks); in patients with psoriasis, reinitiate treatment with a single dose followed by maintenance therapy.1

Delayed Sensitivity Reactions

Delayed infusion reactions occur 3–12 days after an infusion; first reported in patients retreated after a period of 2–4 years.1 5 10 40 42

Reactions appear to be delayed hypersensitivity or serum sickness-like reactions; signs/symptoms include fever, rash, pruritus, urticaria, headache, sore throat, myalgia, polyarthralgia, hand and facial edema, and/or dysphagia.1 10 38 40 42 136

Discontinue for severe hypersensitivity reaction; initiate appropriate therapy.1

Delayed infusion reactions generally resolve within 1–3 days following treatment with corticosteroids, antihistamines, acetaminophen, and/or epinephrine.1 5 40

Caution when retreatment follows an extended period of time (e.g., after ≥1 year).1 10 40 42 In general, carefully consider risks and benefits of readministration after a period without treatment (especially readministration as a reinduction regimen at 0, 2, and 6 weeks); in patients with psoriasis, reinitiate treatment with a single dose followed by maintenance therapy.1

These reactions reported most frequently in patients who have developed infliximab-specific antibodies (human antichimeric antibodies [HACA]); reactions are associated with loss of detectable infliximab serum concentrations and possible loss of efficacy.1 (See Immunologic Reactions and Antibody Formation under Cautions.)

Administration of an immunosuppressive agent (e.g., azathioprine, mercaptopurine, methotrexate) for ≥3 months prior to infliximab associated with a lower rate of development of HACA and a lower rate of infusion reactions.1 18 47 72

Nervous System Effects

CNS manifestations of systemic vasculitis, seizures, and new onset or exacerbation of central or peripheral nervous system demyelinating disorders (e.g., multiple sclerosis, optic neuritis, Guillain-Barré syndrome) reported rarely in patients receiving infliximab or other TNF blocking agents.1

Exercise caution when considering infliximab in patients with these neurologic disorders.1 Consider discontinuance of the drug if these disorders develop.1

Immunologic Reactions and Antibody Formation

Possible formation of autoimmune antibodies.1 14 17 18 19 20 23 28 34 35 38 41 44 64 90 136 Lupus-like syndrome reported.1 If manifestations suggestive of lupus-like syndrome develop, discontinue infliximab.1

Antibodies to infliximab may develop.1 22 42 28 38 64 70 84 85 Antibody-positive patients more likely to experience an infusion reaction.1 10 23 70 85 (See Acute Sensitivity Reactions and also Delayed Sensitivity Reactions, under Cautions.)

Immunization

Avoid live vaccines (e.g., measles virus vaccine live, mumps virus vaccine live, rubella virus vaccine live, smallpox vaccine, typhoid vaccine live oral, varicella virus vaccine live, yellow fever vaccine).1 (See Vaccines under Interactions.)

GI Effects

Safety and efficacy data in Crohn’s disease patients with intestinal strictures is limited.4 5 38 72 88 Development or worsening of intestinal strictures and/or intestinal obstruction reported rarely in these patients.4 47 70

Use with caution in Crohn’s disease patients with intestinal strictures.47 70 72

Psoriasis

New-onset psoriasis, including pustular and palmoplantar psoriasis, and exacerbation of existing psoriasis reported with TNF blocking agents, including infliximab.1 154 Most patients experienced improvement following discontinuance of the TNF blocking agent.154

Consider possibility of and monitor for manifestations (e.g., new rash) of new or worsening psoriasis, particularly pustular and palmoplantar psoriasis.154

Specific Populations

Pregnancy

Category B.1

Some clinicians suggest that pregnancy be ruled out (negative pregnancy test) before initiating therapy and that an effective contraceptive be used.110

Lactation

Not known whether infliximab is distributed into milk.1 Due to potential risk in nursing infant, discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy established in children ≥6 years of age with Crohn’s disease; studied in this age group only in conjunction with conventional immunosuppressive agents.1 Safety and efficacy of long-term (>1 year) therapy not established.1

Adverse effects reported more frequently in children than in adults with Crohn’s disease include anemia, leukopenia, flushing, viral infection, neutropenia, bone fracture, infection, bacterial infection, and respiratory tract allergy.1

Safety and efficacy in children ≥6 years of age with ulcerative colitis supported by clinical studies in adults and an uncontrolled study in pediatric patients 6–17 years of age; about half of these pediatric patients received immunosuppressive agents (azathioprine, mercaptopurine, or methotrexate) concomitantly at the start of the study.1 Safety and efficacy of long-term (>1 year) therapy not established.1

Adverse effects in pediatric patients with ulcerative colitis similar to those in adults with this disease.1 Proportion of patients with infections similar to that in pediatric patients with Crohn’s disease but greater than that in adults with ulcerative colitis.1

Younger children (6–11 years of age) and adolescents (12–17 years of age) with ulcerative colitis had similar overall rates of adverse effects, including infusion reactions, but a greater proportion of the younger children had serious adverse effects or discontinued therapy because of adverse effects.1 Proportion of patients with infections was higher in the younger age group, but similar proportions of patients in both age groups had serious infections.1

Malignancies, some fatal, reported in children and adolescents who received TNF blocking agents.1 154 160 (See Malignancies and Lymphoproliferative Disorders under Cautions.)

Carefully assess risks and benefits when deciding whether to use infliximab alone or in combination with other immunosuppressive agents in the treatment of inflammatory bowel disease.1 Use in the absence of other immunosuppressive agents may increase the likelihood of infliximab-specific antibody formation and increase the risk of hypersensitivity reactions.1 (See Acute Sensitivity Reactions, Delayed Sensitivity Reactions, and Immunologic Reactions and Antibody Formation, under Cautions.) Unclear whether reported cases of hepatosplenic T-cell lymphoma related to infliximab or use of the drug in conjunction with other immunosuppressive agents.1 (See Malignancies and Lymphoproliferative Disorders under Cautions.)

Safety and efficacy not established in children with plaque psoriasis.1

Has been evaluated in children 4–17 years of age with juvenile arthritis who had not responded adequately to methotrexate.1 153 Further study needed to evaluate safety and efficacy.1 72 104 153

Bring all vaccinations up to date prior to initiation of therapy in all pediatric patients.1

Geriatric Use

Rheumatoid arthritis, plaque psoriasis: No substantial difference in safety or efficacy relative to younger adults.1

Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, ulcerative colitis: Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Possible increased incidence of infections in geriatric patients; use with caution.1 (See Infectious Complications under Cautions.)

Hepatic Impairment

Possible reactivation of HBV in patients who are chronic carriers of this virus.1 144

Renal Impairment

Not studied in patients with renal impairment.1

Common Adverse Effects

Infections (upper respiratory infection, fistula-related abscess), acute infusion reactions, delayed infusion reactions, development of autoantibodies (ANA, Anti-dsDNA), development of antibodies to infliximab, abdominal pain, increases in serum AST or ALT concentrations.1 4 5 6 10 14 15 17 18 19 20 21 23 28 38 51 64 65 67 70 136

Interactions for Remicade

No formal drug interaction studies to date.1

Administered concomitantly with corticosteroids, mesalamine or sulfasalazine, azathioprine or mercaptopurine, and/or anti-infective agents in patients with Crohn’s disease; serum concentrations of infliximab not affected by corticosteroids, mesalamine or sulfasalazine, or anti-infectives (ciprofloxacin, metronidazole).1 5 6 38 64 69 (See Immunosuppressive Agents under Interactions.)

Administered concomitantly with methotrexate, corticosteroids, NSAIAs, folic acid, and narcotics in patients with rheumatoid arthritis or psoriatic arthritis.1 14 15 17 18 41

Administered concomitantly with corticosteroids, azathioprine or mercaptopurine, and/or 5-aminosalicylates in patients with ulcerative colitis.1 147 (See Immunosuppressive Agents under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Because increased levels of cytokines (e.g., TNF-α) during chronic inflammation may suppress formation of CYP isoenzymes, antagonism of cytokine activity by infliximab may normalize formation of CYP enzymes.1

Drugs metabolized by CYP isoenzymes that have a low therapeutic index: Monitor therapeutic effect and serum concentrations following initiation or discontinuance of infliximab; adjust dosage as needed.1

Biologic Antirheumatic Agents

Use caution when switching from one biologic DMARD to another, since overlapping biologic activity may further increase the risk of infection.1

Immunosuppressive Agents

Incidence of some adverse immunologic reactions (e.g., infusion reactions, formation of antibodies to infliximab) decreased in patients receiving immunosuppressive agents.1 18 (See Acute Sensitivity Reactions, Delayed Sensitivity Reactions, and Immunologic Reactions and Antibody Formation, under Cautions.)

When deciding whether to use infliximab alone or in combination with other immunosuppressive agents in the management of inflammatory bowel disease (particularly in adolescents and young adults), consider both the possibility of an increased risk of hepatosplenic T-cell lymphoma with combination therapy (see Malignancies and Lymphoproliferative Disorders under Cautions) and the observed increase in immunogenicity and hypersensitivity reactions associated with infliximab given as monotherapy.1

Vaccines

Data not available on the effects of immunization in patients receiving infliximab.1

Avoid live vaccines.1 No data available on secondary transmission of infection by live vaccines in infliximab-treated patients.1 (See Immunization under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Abatacept

Increased incidence of infection and serious infection, without additional clinical benefit, reported with abatacept and TNF blocking agents in rheumatoid arthritis;1 152 158 similar toxicities expected with infliximab and abatacept1

Concomitant use not recommended1 152 158

Use caution when switching from one biologic DMARD to another, since overlapping biologic activity may further increase risk of infection1

Anakinra

Increased incidence of serious infections and neutropenia, without additional clinical benefit, reported with anakinra and etanercept (another TNF blocking agent) in rheumatoid arthritis;1 165 similar toxicities expected with infliximab and anakinra1

Concomitant use not recommended1 165

Use caution when switching from one biologic DMARD to another, since overlapping biologic activity may further increase risk of infection1

Cyclosporine

Possible effect on cyclosporine metabolism; because increased levels of cytokines (e.g., TNF-α) during chronic inflammation may suppress formation of CYP isoenzymes, antagonism of cytokine activity by infliximab may normalize formation of CYP enzymes1

Monitor therapeutic effect and serum concentrations of cyclosporine following initiation or discontinuance of infliximab; adjust dosage as needed1

Methotrexate

Possible decreased clearance18 39 and increased concentrations of infliximab1

Possible decrease in rate of development of antibodies to infliximab1

Interaction not studied specifically;13 17 18 23 25 84 85 used concomitantly in clinical studies 13 17 18 23 25 39 84 85

Natalizumab

Increased risk of progressive multifocal leukoencephalopathy (PML) or other serious infections162

Avoid concomitant use in the management of Crohn’s disease162

Rituximab

Increased risk of serious infection reported in patients who received rituximab and subsequently received a TNF blocking agent164

Use caution when switching from one biologic DMARD to another, since overlapping biologic activity may further increase risk of infection1

Theophylline

Possible effect on theophylline metabolism; because increased levels of cytokines (e.g., TNF-α) during chronic inflammation may suppress formation of CYP isoenzymes, antagonism of cytokine activity by infliximab may normalize formation of CYP enzymes1

Monitor therapeutic effect and serum concentrations of theophylline following initiation or discontinuance of infliximab; adjust dosage as needed1

Tocilizumab

Concomitant use not studied; possibility of increased immunosuppression and increased risk of infection1 161

Avoid concomitant use1 161

Use caution when switching from one biologic DMARD to another, since overlapping biologic activity may further increase risk of infection1

Warfarin

Possible effect on warfarin metabolism; because increased levels of cytokines (e.g., TNF-α) during chronic inflammation may suppress formation of CYP isoenzymes, antagonism of cytokine activity by infliximab may normalize formation of CYP enzymes1

Monitor therapeutic effect of warfarin following initiation or discontinuance of infliximab; adjust dosage as needed1

Remicade Pharmacokinetics

Absorption

Systemic accumulation does not appear to occur in adults receiving multiple IV infusions once every 4 or 8 weeks following an initial 3-dose induction regimen.1 38 39 41

Peak and trough concentrations in pediatric patients 6–17 years of age with Crohn’s disease or ulcerative colitis similar to those in adults with these diseases following administration of the recommended dosage regimen.1

Special Populations

No differences observed in pharmacokinetics based on age or weight in adults with rheumatoid arthritis or Crohn’s disease.1 14 17 18 38 39 41

Distribution

Extent

Distribution into body tissues and fluids, including joints, has not been fully characterized.39

Not known whether infliximab crosses the placenta or is distributed into milk.1

Elimination

Metabolism

Metabolic fate not fully characterized; the drug may be eliminated by the reticuloendothelial system.1 47

Not metabolized by CYP isoenzymes.39

Half-life

8–12 days in adults with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis.1 14 41

Terminal elimination half-life in pediatric patients 6–17 years of age with Crohn’s disease or ulcerative colitis similar to that reported in adults with these diseases.1

Stability

Storage

Parenteral

Powder for Injection

2–8°C; do not freeze.1

Diluted solutions of the drug should be prepared immediately prior to use.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1

Compatible

Sodium chloride 0.9%

Information on the physical and/or chemical compatibility with other IV infusion fluids is not available.1

Drug Compatibility

The manufacturer recommends that infliximab not be admixed with other drugs or infused in the same IV line with other drugs.1

Information on the physical and/or chemical compatibility with other drugs is not available.1

Actions

  • Potent antagonist of TNF biologic activity.1 7 20 24

  • Has high specificity and affinity for TNF (TNF-α); does not bind to or inactivate lymphotoxin α (TNF-β).1 7 20 24 Prevents the binding of TNF to cell surface TNF receptors, thereby blocking the biologic activity of TNF.1 7 20 24

  • A chimeric human-murine immunoglobulin G1 kappa (IgG1 kappa) monoclonal antibody (75% human and 25% murine).1 7 20 24

  • The exact mechanism of the anti-inflammatory effects in Crohn’s disease or rheumatoid arthritis remain to be more fully determined; binding and neutralization of TNF appears to be a principal mechanism.1 3 5 7 8 9 25 33 37 38 39 42 43 50 57 59

  • Produced by continuous fermentation of a mouse myeloma cell line that has been transinfected with cloned DNA coding for cA2; purified by measures to inactivate and removes viruses.1 7 20

Advice to Patients

  • A copy of the manufacturer’s patient information (medication guide) for infliximab should be provided to all patients prior to each infusion session.1 154 Importance of advising patients about potential benefits and risks of infliximab.1 154 159 160 Importance of patients reading the medication guide prior to initiation of therapy and each time they receive an infusion of the drug.1 159 160

  • Increased susceptibility to infection.1 Importance of seeking immediate medical attention if signs and symptoms suggestive of infection (e.g., fever; fatigue; cough; warm, red, or painful skin; sores on the body) develop.1

  • Risk of lymphoma, including hepatosplenic T-cell lymphoma, leukemia, or other malignancies with use of TNF blocking agents.1 154 160 Importance of informing patients and caregivers about the increased risk of cancer development in children, adolescents, and young adults, taking into account the clinical utility of TNF blocking agents, the relative risks and benefits of these and other immunosuppressive drugs, and the risks associated with untreated disease.154 160 Importance of promptly informing clinicians if signs and symptoms of malignancies (e.g., unexplained weight loss; fatigue; abdominal pain; persistent fever; night sweats; easy bruising or bleeding; swollen lymph nodes in the neck, underarm, or groin; hepatomegaly or splenomegaly) occur.154 160

  • Importance of immediately notifying clinician if manifestations of liver dysfunction (e.g., jaundice, dark brown urine, right-sided abdominal pain, fever, fatigue) occur.1

  • Importance of informing clinician of any new or worsening medical conditions (e.g., neurologic conditions [e.g., demyelinating disorders], heart failure, autoimmune disorders [e.g., lupus-like syndrome], psoriasis, cytopenias).1 154

  • Importance of taking the drug as prescribed and of not altering or discontinuing therapy without first consulting with a clinician.154 160

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinician if they have recently received or are scheduled to receive a vaccine.1

  • Risk of acute or delayed sensitivity reactions.1 Importance of advising patient to seek medical advice and treatment if they develop manifestations consistent with a delayed infusion reaction.40

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses or any history of cancer, tuberculosis, HBV infection, or other chronic or recurring infections.1 155 159

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Infliximab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

100 mg

Remicade

Janssen, (formerly Centocor Ortho Biotech)

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Remicade 100MG Solution (JANSSEN BIOTECH): 1/$790.96 or 3/$2,320.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions March 28, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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