Infliximab, Infliximab-dyyb

Class: Disease-modifying Antirheumatic Drugs
CAS Number: 170277-31-3
Brands: Inflectra, Remicade

Introduction

In this monograph, unless otherwise stated, the term “infliximab products” refers to infliximab (the reference drug), infliximab-dyyb (the biosimilar), or both drugs.

Biologic response modifiers and disease-modifying antirheumatic drugs (DMARDs); chimeric human-murine monoclonal antibodies that block the biologic activity of tumor necrosis factor (TNF, TNF-α).^{1 7 20 24 167 173 174 175 176 177}

Infliximab-dyyb is biosimilar to infliximab (Remicade).^{167 168 173 174 175 176 177 192} A biosimilar is a biological that is highly similar to an FDA-licensed reference biological with the exception of minor differences in clinically inactive components and for which there are no clinically meaningful differences in safety, purity, or potency.^{168 170 171 172} Biosimilars are approved through an abbreviated licensure pathway that establishes biosimilarity between proposed biological and reference biological but does not independently establish safety and effectiveness of the proposed biological.^{169 170 171 179} Infliximab-dyyb is considered a therapeutic alternative to infliximab; not interchangeable.^{168 170 172 180}

Uses for Infliximab, Infliximab-dyyb

Crohn’s Disease (Infliximab or Infliximab-dyyb)

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 89 136 142 167} (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 94 140 141 142 143 167} 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}

Rheumatoid Arthritis in Adults (Infliximab or Infliximab-dyyb)

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 41 167}

Ankylosing Spondylitis (Infliximab or Infliximab-dyyb)

Management of the signs and symptoms of active ankylosing spondylitis.^{1 72 108 109 117 137 138 167}

Psoriatic Arthritis (Infliximab or Infliximab-dyyb)

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 72 105 106 107 108 131 167}

Plaque Psoriasis (Infliximab or Infliximab-dyyb)

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.^{1 167} Use only in patients who will be closely monitored and who will have regular follow-up visits with a clinician.^{1 167}

Ulcerative Colitis (Infliximab or Infliximab-dyyb)

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 72 112 113 114 147 167}

Infliximab 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 (designated an orphan drug by FDA for treatment of ulcerative colitis in pediatric patients¹⁹¹ ).¹ Although safety and efficacy of infliximab-dyyb for such use also established, labeled indication for infliximab in pediatric patients with ulcerative colitis was still protected by exclusivity provisions of orphan drug designation when FDA approved infliximab-dyyb biosimilar.^{167 168} (See Pediatric Use under Cautions.)

Juvenile Arthritis (Infliximab)

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

Behcet’s Syndrome (Infliximab)

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

Infliximab, Infliximab-dyyb Dosage and Administration

General

Premedication and Patient Monitoring

• Consider administration of premedication prior to each dose to minimize risk of infusion-related reactions.^{1 47 72 167}

• 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.^{1 167}

• When deciding whether to use infliximab products alone or in combination with other immunosuppressive agents (e.g., azathioprine, mercaptopurine), consider both the possibility of an increased risk of hepatosplenic T-cell lymphoma with combination therapy and the observed (in infliximab studies) increase in immunogenicity and hypersensitivity reactions associated with infliximab products given as monotherapy.^{1 167} (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 products without concomitant methotrexate.^{1 17 18 20 21 23 167}

• Corticosteroids and NSAIAs may be continued.^{1 167}

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 products alone or in combination with other immunosuppressive agents (e.g., azathioprine, mercaptopurine), consider both the possibility of an increased risk of hepatosplenic T-cell lymphoma with combination therapy and the observed (in infliximab studies) increase in immunogenicity and hypersensitivity reactions associated with infliximab products given as monotherapy.^{1 167} (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 or infliximab-dyyb 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.^{1 167} (See Acute Sensitivity Reactions and also Delayed Sensitivity Reactions, under Cautions.)

Administration

IV Administration (Infliximab or Infliximab-dyyb)

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

Administer by IV infusion.^{1 167}

Administer with an in-line, sterile, nonpyrogenic, low-protein-binding filter with a pore diameter of ≤1.2 µm.^{1 167}

Consult respective manufacturer’s labeling for additional information on reconstitution, dilution, and administration of infliximab or infliximab-dyyb.^{1 167}

Reconstitution

Reconstitute vial containing 100 mg of infliximab or infliximab-dyyb powder with 10 mL of sterile water for injection to provide a solution containing 10 mg/mL.^{1 167} Reconstitute the number of vials needed to provide the indicated dosage of infliximab or infliximab-dyyb.^{1 167}

Direct diluent toward the side of the vial with a sterile syringe and a 21-gauge or smaller needle; swirl vial gently to ensure dissolution; do not shake or agitate vigorously (to avoid foaming).^{1 167}

Allow reconstituted solution to stand for 5 minutes before dilution.^{1 167}

Dilution

Remove the volume of diluent equal to the total required volume of reconstituted infliximab or infliximab-dyyb solution from a 250-mL bag or bottle of 0.9% sodium chloride injection.^{1 167} Slowly add reconstituted infliximab or infliximab-dyyb to the bag to yield a total volume of 250 mL; mix gently.^{1 167} Concentration of the solution for infusion should be 0.4–4 mg/mL.^{1 167} Begin infliximab or infliximab-dyyb infusion within 3 hours of reconstitution and dilution.^{1 167}

Rate of Administration

Infuse infliximab or infliximab-dyyb over a period of at least 2 hours.^{1 167}

Manufacturer of infliximab states that 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

Dosage

Pediatric Patients

Crohn’s Disease (Infliximab or Infliximab-dyyb)

Moderate or Severe Active Crohn’s Disease

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 87 167}

Ulcerative Colitis (Infliximab)

Moderate to Severe Active Ulcerative Colitis

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 (Infliximab or Infliximab-dyyb)

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

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).^{1 167}

Consider dose of 10 mg/kg for patients who respond initially but subsequently lose response.^{1 167}

Patients who do not respond by week 14 are unlikely to respond with continued administration; consider discontinuing the drug.^{1 167}

Rheumatoid Arthritis (Infliximab or Infliximab-dyyb)

Moderate to Severe Active Rheumatoid Arthritis

3 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).^{1 167}

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 72 167}

Ankylosing Spondylitis (Infliximab or Infliximab-dyyb)

IV

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 6 weeks (maintenance regimen).^{1 167}

Psoriatic Arthritis (Infliximab or Infliximab-dyyb)

IV

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).^{1 167}

Plaque Psoriasis (Infliximab or Infliximab-dyyb)

IV

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).^{1 167}

If treatment is resumed after maintenance therapy is interrupted, reinitiate with a single dose followed by maintenance therapy.^{1 167} (See Acute Sensitivity Reactions and also Delayed Sensitivity Reactions, under Cautions.)

Ulcerative Colitis (Infliximab or Infliximab-dyyb)

Moderate to Severe Active Ulcerative Colitis

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).^{1 167}

Cautions for Infliximab, Infliximab-dyyb

Contraindications

• Doses >5 mg/kg in patients with moderate or severe heart failure.^{1 167} (See Cardiovascular Effects under Cautions.)

• Prior severe hypersensitivity reaction to infliximab products; known hypersensitivity to murine proteins or any ingredient in the formulations.^{1 167}

Warnings/Precautions

Warnings

Based on demonstration of biosimilarity, FDA considers that no clinically meaningful differences in safety exist between infliximab and infliximab-dyyb.¹⁶⁸ No substantial differences in frequencies of adverse effects observed between infliximab and infliximab-dyyb.^{168 173 174 175 176 177 181 182} No new safety concerns identified in patients following a single switch from infliximab to infliximab-dyyb, compared with those receiving continuous infliximab-dyyb therapy.^{168 173 192}

Infectious Complications

Increased risk of serious infections involving various organ systems and sites that may require hospitalization or result in death.^{1 159 167} 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 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.^{1 159 167}

Do not initiate infliximab products in patients with active infections, including clinically important localized infections.^{1 167} 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.^{1 159 167}

Closely monitor patients during and after infliximab product therapy for signs or symptoms of infection (e.g., fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, serious systemic illness including shock).^{1 155 159 167}

If new infection occurs during infliximab product therapy, perform thorough diagnostic evaluation (appropriate for immunocompromised patient), initiate appropriate anti-infective therapy, and closely monitor patient.^{1 155 167} Discontinue infliximab product if serious infection or sepsis develops.^{1 34 35 44 118 155 167}

Evaluate all patients for active or latent tuberculosis and for risk factors for tuberculosis prior to and periodically during therapy with infliximab products.^{1 72 118 159 167} When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection prior to infliximab product therapy.^{1 14 18 42 59 72 111 118 167} Also consider antimycobacterial therapy prior to use of infliximab products in 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.^{1 167} Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy.^{1 167}

Monitor all patients, including those with negative tuberculin skin tests, for active tuberculosis.^{1 167} Strongly consider tuberculosis in patients who develop new infections while receiving infliximab products, 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.^{1 167} Active tuberculosis reported in some patients receiving infliximab products while receiving therapy for latent tuberculosis.^{1 167}

Failure to recognize invasive fungal infections has led to delays in appropriate treatment.¹⁵⁵ Serologic tests for histoplasmosis may be negative in some patients with active infection.^{1 167} Consider empiric antifungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.^{1 155 159 167} Whenever feasible, consult specialist in fungal infections when making decisions regarding initiation and duration of antifungal therapy.^{1 155 167}

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.^{1 154 167} 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).^{1 154 167} Median time to occurrence was 30 months (range: 1–84 months) after the initial TNF blocking agent dose.^{1 167} 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 adolescent and young adult males with Crohn’s disease or ulcerative colitis receiving TNF blocking agents and/or thiopurine analogs (mercaptopurine or azathioprine).^{1 154 160 167} Most of the patients received a combination of immunosuppressive agents, including TNF blocking agents and thiopurine analogs.^{1 160 167} Unclear whether occurrence is related to TNF blocking agents or combination of TNF blocking agents and other immunosuppressive agents.^{1 167}

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 42 160 167} 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.^{1 154 167} 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.^{1 154 167}

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 product therapy in patients with moderate to severe COPD.^{1 167}

In infliximab-treated psoriasis patients, nonmelanoma skin cancer reported more commonly in those who had received prior phototherapy; monitor psoriasis patients receiving infliximab products, especially those who have received prolonged prior phototherapy, for nonmelanoma skin cancer.^{1 167}

Melanoma and Merkel cell carcinoma reported in patients receiving infliximab products.^{1 167} Periodic skin examination recommended for all patients, particularly those with risk factors for skin cancer.^{1 167}

Other malignancies (basal cell carcinoma, breast cancer, colorectal cancer, rectal adenocarcinoma, squamous cell carcinoma) also reported during clinical studies 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 product 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 64 167} Carefully consider risks and benefits of TNF blocking agents, especially in adolescent and young adult males and in those with Crohn’s disease or ulcerative colitis.^{1 160 167}

When deciding whether to use infliximab product alone or in combination with other immunosuppressive agents, consider both the possibility of an increased risk of hepatosplenic T-cell lymphoma with combination therapy and the observed (in infliximab studies) increase in immunogenicity and hypersensitivity reactions associated with infliximab products given as monotherapy.^{1 167}

Other Warnings and Precautions

Based on demonstration of biosimilarity, FDA considers that no clinically meaningful differences in safety exist between infliximab and infliximab-dyyb.¹⁶⁸ No substantial differences in frequencies of adverse effects observed between infliximab and infliximab-dyyb.^{168 173 174 175 176 177 181 182} No new safety concerns identified in patients following a single switch from infliximab to infliximab-dyyb, compared with those receiving continuous infliximab-dyyb therapy.^{168 173 192}

HBV Reactivation

Infliximab products associated with reactivation of HBV infection in patients who are chronic carriers of the virus (i.e., hepatitis B surface antigen-positive [HBsAg-positive]).^{1 144 167} Use of multiple immunosuppressive agents may contribute to HBV reactivation.^{1 167}

Screen all patients prior to initiation of infliximab product therapy.^{1 167} Consultation with expert in treatment of hepatitis B is recommended for HBsAg-positive patients.^{1 167} Evaluate and monitor HBV carriers before, during, and for up to several months after therapy.^{1 167} Safety and efficacy of antiviral therapy for prevention of HBV reactivation not established.^{1 167} Discontinue infliximab product and initiate appropriate treatment (e.g., antiviral therapy) if HBV reactivation occurs.^{1 167}

Not known whether infliximab products can be readministered once control of a reactivated HBV infection is achieved; caution advised in this situation.^{1 167}

Hepatic Effects

Severe hepatic reactions (e.g., acute liver failure, jaundice, hepatitis, cholestasis, autoimmune hepatitis) reported in patients receiving infliximab products; some cases were fatal or needed liver transplantation.^{1 144 167} 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.^{1 144 167} If jaundice and/or marked hepatic aminotransferase elevations (≥5 times the ULN) develop, discontinue drug and investigate hepatic abnormality.^{1 167}

Cardiovascular Effects

Infliximab products associated with adverse outcomes in patients with heart failure (increased mortality and hospitalization due to worsening heart failure).^{1 139 167}

Use of infliximab in patients with heart failure (NYHA class III or IV) associated with increased mortality in patients who received infliximab 10 mg/kg and with 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 preexisting 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

Use infliximab products in patients with heart failure only after consideration of other treatment options.^{1 167} If used in patients with moderate or severe heart failure, do not exceed doses of 5 mg/kg and monitor cardiac status closely.^{1 167} (See Contraindications under Cautions.)

Discontinue infliximab product therapy if new or worsening symptoms of heart failure occur.^{1 167}

Hematologic Effects

Possible leukopenia, neutropenia, thrombocytopenia, and pancytopenia, sometimes with fatal outcome.^{1 167} Use infliximab products with caution in patients with a history of substantial hematologic abnormalities.^{1 167} Consider discontinuance of the drug in patients with confirmed hematologic abnormalities.^{1 167}

Acute Sensitivity Reactions

Acute infusion reactions consistent with hypersensitivity reactions reported within 1–2 hours after IV infusion of infliximab products.^{1 10 14 18 21 36 38 41 64 72 92 128 167}

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 92 128 136 167} Anaphylactic reactions (e.g., laryngeal/pharyngeal edema, severe bronchospasm), seizures, erythematous rash, myocardial ischemia/infarction, and transient vision loss reported.^{1 36 128 167}

Drugs for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids, and/or epinephrine) should be immediately available.^{1 72 167}

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 92 167} Discontinue infliximab product immediately for severe hypersensitivity reaction; initiate appropriate therapy.^{1 167}

In clinical studies of infliximab, patients with antibodies to the drug were 2–3 times more likely to have an infusion reaction than patients who did not have antibodies to the drug.¹

Incidence of acute infusion reactions in infliximab product-treated patients may be lower in those receiving concomitant therapy with immunosuppressive agents (e.g., azathioprine, mercaptopurine, methotrexate) than in those not receiving such therapy.^{1 47 167}

Readministration of infliximab 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 infliximab product readministration after a period without treatment (especially readministration as a reinduction regimen at 0, 2, and 6 weeks); in patients with psoriasis, reinitiate infliximab product treatment with a single dose followed by maintenance therapy.^{1 167}

Delayed Sensitivity Reactions

Delayed infusion reactions first reported in patients retreated with infliximab after a period of 2–4 years.^{5 10 42} Reactions appear to be delayed hypersensitivity or serum sickness-like reactions.^{10 42 136}

Discontinue infliximab product therapy for severe hypersensitivity reaction; initiate appropriate therapy.^{1 167}

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 infliximab product readministration after a period without treatment (especially readministration as a reinduction regimen at 0, 2, and 6 weeks); in patients with psoriasis, reinitiate infliximab product treatment with a single dose followed by maintenance therapy.^{1 167}

Administration of an immunosuppressive agent (e.g., azathioprine, mercaptopurine, methotrexate) for ≥3 months prior to infliximab associated with a lower rate of development of human antichimeric antibodies (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 products or other TNF blocking agents.¹

Exercise caution when considering infliximab products in patients with these neurologic disorders.^{1 167} Consider discontinuance of the drug if these disorders develop.^{1 167}

Immunologic Reactions and Antibody Formation

Possible formation of autoimmune antibodies.^{1 14 17 18 19 20 23 28 34 35 38 41 44 64 90 136 167} Lupus-like syndrome reported.¹ If manifestations suggestive of lupus-like syndrome develop, discontinue infliximab product therapy.^{1 167}

In patients receiving infliximab products, antibodies to the drug may develop.^{1 22 42 28 38 64 70 84 85 167} 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, rotavirus vaccine live oral, rubella virus vaccine live, smallpox vaccine [no longer commercially available in US], typhoid vaccine live oral, varicella virus vaccine live, yellow fever vaccine).^{1 167} (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 products.^{1 154 167} 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

No adequate and well controlled studies to date.^{1 167} Infliximab detected for up to 6 months in serum of infants whose mothers received infliximab products during pregnancy.¹ (See Pediatric Use under Cautions.)

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 products are distributed into milk.^{1 167} Due to potential risk in nursing infant, discontinue nursing or the drug.^{1 167}

Pediatric Use

Safety and efficacy of infliximab products established in children ≥6 years of age with Crohn’s disease; infliximab studied in this age group only in conjunction with conventional immunosuppressive agents.^{1 167} Safety and efficacy of long-term (>1 year) infliximab product therapy not established.^{1 167}

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

Safety and efficacy of infliximab 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 Although safety and efficacy of infliximab-dyyb for such use also established, labeled indication for infliximab in pediatric patients with ulcerative colitis was still protected by exclusivity provisions of orphan drug designation when FDA approved infliximab-dyyb biosimilar.^{167 168} Safety and efficacy of long-term (>1 year) therapy with infliximab not established.¹

Adverse effects in infliximab-treated pediatric patients with ulcerative colitis similar to those in infliximab-treated 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 while receiving infliximab, including infusion reactions, but a greater proportion of the younger children had serious adverse effects or discontinued infliximab 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.^{1 154 160 167} (See Malignancies and Lymphoproliferative Disorders under Cautions.)

Carefully assess risks and benefits when deciding whether to use infliximab products alone or in combination with other immunosuppressive agents.^{1 167} Use of infliximab products in the absence of other immunosuppressive agents may increase the likelihood of infliximab-specific antibody formation and increase the risk of hypersensitivity reactions.^{1 167} (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 TNF blocking agents or use of TNF blocking agents in conjunction with other immunosuppressive agents.^{1 167} (See Malignancies and Lymphoproliferative Disorders under Cautions.)

Safety and efficacy of infliximab products not established in children with plaque psoriasis.^{1 167}

Infliximab 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 infliximab product therapy in all pediatric patients.^{1 167}

Infliximab detected for up to 6 months in the serum of infants whose mothers received infliximab products during pregnancy.^{1 167} Infants exposed to infliximab products in utero may be at increased risk of infection; fatal disseminated BCG infection reported in an infant who received BCG vaccine after having been exposed to infliximab in utero.^{1 167} Infants exposed to infliximab products in utero should not receive live vaccines (e.g., BCG vaccine, rotavirus vaccine live oral) for ≥6 months after birth.^{1 167}

Geriatric Use

Rheumatoid arthritis, plaque psoriasis: No substantial difference in safety or efficacy relative to younger adults in clinical studies of infliximab.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 infliximab products with caution.^{1 167} (See Infectious Complications under Cautions.)

Hepatic Impairment

Possible reactivation of HBV in patients receiving infliximab products who are chronic carriers of this virus.^{1 144 167}

Renal Impairment

Infliximab or infliximab-dyyb not studied in patients with renal impairment.^{1 167}

Common Adverse Effects

Infliximab: 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}

No substantial differences in frequencies of adverse effects observed between infliximab and infliximab-dyyb.^{168 173 174 175 176 177 181 182}

Interactions for Infliximab, Infliximab-dyyb

No formal drug interaction studies to date.^{1 167}

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 69 167} (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 41 167}

Administered concomitantly with corticosteroids, azathioprine or mercaptopurine, and/or 5-aminosalicylates in patients with ulcerative colitis.^{1 147 167} (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 products may normalize formation of CYP enzymes.^{1 167}

Drugs metabolized by CYP isoenzymes that have a low therapeutic index: Monitor therapeutic effect and serum concentrations following initiation or discontinuance of infliximab products; adjust dosage as needed.^{1 167}

Biologic Agents

Use caution when switching from one biologic DMARD to another, since overlapping biologic activity may further increase the risk of infection.^{1 167}

Insufficient data regarding concomitant use of infliximab products with other biologic agents used to treat the same conditions.^{1 167} Concomitant use not recommended because of an increased risk of infection.^{1 167}

Immunosuppressive Agents

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

When deciding whether to use infliximab products alone or in combination with other immunosuppressive agents, 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 (in infliximab studies) increase in immunogenicity and hypersensitivity reactions associated with infliximab products given as monotherapy.^{1 167}

Vaccines and Therapeutic Infectious Agents

Consult current vaccination guidelines regarding interval between vaccination and initiation of infliximab product therapy.^{1 167}

Live vaccines: Avoid concomitant use.^{1 167} Risk of infections, including disseminated infections.^{1 167} Limited data regarding response to live vaccines or secondary transmission of infection by live vaccines.^{1 167} Infants exposed to infliximab products in utero should not receive live vaccines for ≥6 months after birth.^{1 167} (See Pediatric Use under Cautions.)

Live therapeutic infectious agents: Avoid concomitant use.^{1 167} Risk of infections, including disseminated infections.^{1 167}

Specific Drugs

Infliximab, Infliximab-dyyb Pharmacokinetics

Pharmacokinetic similarity between infliximab and infliximab-dyyb demonstrated; FDA considers that the pharmacokinetic data provide support for a totality-of-evidence determination of biosimilarity between the 2 drugs.^{168 174 176 177 188 193}

Absorption

Infliximab: 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}

Infliximab: 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 infliximab 5 mg/kg.¹

Special Populations

Infliximab: 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

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

Infliximab products cross the placenta.^{1 167}

Not known whether infliximab products distribute into milk.^{1 167}

Elimination

Metabolism

Infliximab: Metabolic fate not fully characterized; the drug may be eliminated by the reticuloendothelial system.^{1 47}

Infliximab: Not metabolized by CYP isoenzymes.³⁹

Half-life

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

Infliximab: 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

Infliximab: 2–8°C.¹ May store unopened vial at temperatures up to 30°C for single period of up to 6 months; following removal from refrigerated storage, do not return to refrigerated storage.¹

Infliximab-dyyb: 2–8°C.¹⁶⁷

Infliximab or infliximab-dyyb: Prepare diluted solutions of the drug immediately prior to use.^{1 167}

Compatibility

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

Parenteral

Solution Compatibility (Infliximab)^{1 HID}

Solution Compatibility (Infliximab-dyyb)¹⁶⁷

Drug Compatibility (Infliximab or Infliximab-dyyb)

The manufacturers recommend that infliximab or infliximab-dyyb not be admixed with other drugs or infused in the same IV line with other drugs.^{1 167}

Information on the physical and/or chemical compatibility with other drugs is not available.^{1 167}

Actions

• Potent antagonist of TNF biologic activity.^{1 7 20 24 167}

• Has high specificity and affinity for TNF (TNF-α); does not bind to or inactivate lymphotoxin α (TNF-β).^{1 7 20 24 167} Prevents the binding of TNF to cell surface TNF receptors, thereby blocking the biologic activity of TNF.^{1 7 20 24 167}

• A chimeric human-murine immunoglobulin G₁ kappa (IgG₁ kappa) monoclonal antibody.^{1 7 20 24 167}

• 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 the chimeric antibody; 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 or infliximab-dyyb should be provided to all patients prior to each infusion session.^{1 154 167} Importance of advising patients about potential benefits and risks of infliximab products.^{1 154 159 160 167} Importance of patients reading the medication guide prior to initiation of therapy and each time they receive an infusion of the drug.^{1 159 160 167}

• Increased susceptibility to infection.^{1 167} 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.^{1 167}

• Risk of lymphoma, including hepatosplenic T-cell lymphoma, leukemia, or other malignancies with use of TNF blocking agents.^{1 154 160 167} 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.^{1 167}

• 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).^{1 154 167}

• 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.^{1 167}

• Importance of informing clinician if they have recently received or are scheduled to receive a vaccine.^{1 167}

• For postpartum women who received infliximab or infliximab-dyyb during pregnancy, importance of informing the infant's clinician of this use since alteration of the infant's vaccination schedule may be indicated.^{1 167}

• Risk of acute or delayed sensitivity reactions.^{1 167} 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.^{1 155 159 167}

• Importance of informing patients of other important precautionary information.^{1 167} (See Cautions.)

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.