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InFLIXimab

Pronunciation

Pronunciation

(in FLIKS e mab)

Index Terms

  • Avakine
  • Inflectra
  • Infliximab, Recombinant

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Remicade: 100 mg (1 ea) [contains polysorbate 80]

Brand Names: U.S.

  • Remicade

Pharmacologic Category

  • Antirheumatic, Disease Modifying
  • Gastrointestinal Agent, Miscellaneous
  • Immunosuppressant Agent
  • Monoclonal Antibody
  • Tumor Necrosis Factor (TNF) Blocking Agent

Pharmacology

Infliximab is a chimeric monoclonal antibody that binds to human tumor necrosis factor alpha (TNFα), thereby interfering with endogenous TNFα activity. Elevated TNFα levels have been found in involved tissues/fluids of patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn disease and ulcerative colitis. Biological activities of TNFα include the induction of proinflammatory cytokines (interleukins), enhancement of leukocyte migration, activation of neutrophils and eosinophils, and the induction of acute phase reactants and tissue degrading enzymes. Animal models have shown TNFα expression causes polyarthritis, and infliximab can prevent disease as well as allow diseased joints to heal.

Distribution

Within the vascular compartment; Vd: 3-6 L (Klotz 2007)

Onset of Action

Crohn disease: 1-2 weeks; Rheumatoid arthritis: 3-7 days

Duration of Action

Crohn disease: 8-48 weeks; Rheumatoid arthritis: 6-12 weeks

Half-Life Elimination

7-12 days (Klotz 2007)

Use: Labeled Indications

Ankylosing spondylitis: Treatment of adults with active ankylosing spondylitis (to reduce signs/symptoms)

Crohn disease: Treatment adults and children ≥6 years (US labeling) or ≥9 years (Canadian labeling) with moderately- to severely-active Crohn disease with inadequate response to conventional therapy (to reduce signs/symptoms and induce and maintain clinical remission) or to reduce the number of draining enterocutaneous and rectovaginal fistulas and maintain fistula closure

Plaque psoriasis: Treatment of adults with chronic severe (extensive and/or disabling) plaque psoriasis as an alternative to other systemic therapy

Psoriatic arthritis: Treatment of adults with psoriatic arthritis (to reduce signs/symptoms of active arthritis and inhibit progression of structural damage and improve physical function)

Rheumatoid arthritis: Treatment of adults with moderately- to severely-active rheumatoid arthritis (with methotrexate) (to reduce signs/symptoms of active arthritis and inhibit progression of structural damage and improve physical function)

Ulcerative colitis: Treatment of adults and children ≥6 years with moderately- to severely-active ulcerative colitis with inadequate response to conventional therapy (to reduce signs/symptoms and induce and maintain clinical remission, mucosal healing and eliminate corticosteroid use)

Note: Remsima and Inflectra [Canadian products] are biosimilar agents and are not approved for use in pediatric patients or in patients with Crohn disease or ulcerative colitis.

Contraindications

Hypersensitivity to infliximab, murine proteins, or any component of the formulation; doses >5 mg/kg in patients with moderate or severe heart failure (NYHA Class III/IV)

Canadian labeling: Additional contraindications (not in US labeling): Severe infections (eg, sepsis, abscesses, tuberculosis, and opportunistic infections); use in patients with moderate or severe heart failure (NYHA Class III/IV)

Dosing: Adult

Note: Premedication with antihistamines (H1-antagonist +/- H2-antagonist), acetaminophen, and/or corticosteroids may be considered to prevent and/or manage infusion-related reactions. Remsima and Inflectra [Canadian products] are biosimilar agents and are not approved for use in Crohn disease or ulcerative colitis.

Ankylosing spondylitis: IV: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 6 weeks thereafter (Canadian labeling recommends every 6 to 8 weeks thereafter)

Crohn disease: IV: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter; dose may be increased to 10 mg/kg in patients who respond but then lose their response. If no response by week 14, consider discontinuing therapy.

Plaque psoriasis: IV: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter. Note: The Canadian labeling recommends discontinuing therapy at 14 weeks if response to therapy is inadequate.

Psoriatic arthritis (with or without methotrexate): IV: 5 mg/kg at 0,2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter. Note: The Canadian labeling recommends discontinuing therapy at 24 weeks in patients unresponsive to therapy.

Rheumatoid arthritis (in combination with methotrexate therapy): IV 3 mg/kg at 0, 2, and 6 weeks, followed by 3 mg/kg every 8 weeks thereafter; Remicade doses have ranged from 3 to 10 mg/kg repeated at 4- to 8-week intervals

Ulcerative colitis: IV: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter. The Canadian labeling suggests that after assessment of infliximab trough levels and antibody titers, dose adjustment to 10 mg/kg may be considered in some patients to sustain response/remission.

Pustular psoriasis (off-label use): IV: 5 mg/kg at week 0, 2, and 6, followed by 5 mg/kg every 8 weeks for up to 46 weeks (Suguira 2014; Torii 2011)

Dosage adjustment with heart failure (HF): Weigh risk versus benefits for individual patient:

Mild HF (NYHA Class I/II):

US labeling: No dosage adjustment necessary; use with caution and monitor closely for worsening of HF

Canadian labeling: ≤5 mg/kg

Moderate to severe (NYHA Class III or IV):

US labeling: ≤5 mg/kg

Canadian labeling: Use is contraindicated.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Premedication with antihistamines (H1-antagonist +/- H2-antagonist), acetaminophen, and/or corticosteroids may be considered to prevent and/or manage infusion-related reactions. Remsima and Inflectra [Canadian products] are biosimilar agents and are not approved for use in pediatric patients.

Crohn disease: Children and Adolescents: US labeling ≥6 years, Canadian labeling ≥9 years: IV: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter; if no response by week 14, consider discontinuing therapy

Ulcerative colitis: Children ≥6 years and Adolescents: IV: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter

Juvenile idiopathic arthritis (off-label use): Children ≥4 years and Adolescents: IV: Initial: 3 mg/kg at 0, 2, and 6 weeks; then 3 to 6 mg/kg/dose every 8 weeks thereafter, in combination with methotrexate during induction and maintenance (Ruperto, 2010). Alternatively, some studies used 6 mg/kg starting at week 14 of a methotrexate induction regimen (weeks 0 to 13); repeat dose (6 mg/kg) at week 16 and 20, then every 8 weeks thereafter (Ruperto, 2007; Visvanathan, 2012).

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Reconstitution

Reconstitute vials with 10 mL sterile water for injection (SWFI) with a 21-guage or smaller needle, directing the SWFI towards the wall of the vial. Swirl vial gently to dissolve powder; do not shake. Allow solution to stand for 5 minutes. Total dose of reconstituted product should be further diluted to 250 mL of 0.9% sodium chloride injection (add reconstituted infliximab slowly) to a final concentration of 0.4 to 4 mg/mL. Do not dilute reconstituted infliximab solution with any other diluent. Infusion should begin within 3 hours of preparation (see Storage/Stability for additional information).

Administration

The infusion should begin within 3 hours of reconstitution and dilution. Infuse over at least 2 hours; do not infuse with other agents; use in-line low protein binding filter (≤1.2 micron). Temporarily discontinue or decrease infusion rate with infusion-related reactions. Antihistamines (H1-antagonist +/- H2-antagonist), acetaminophen and/or corticosteroids may be used to manage reactions. Infusion may be reinitiated at a lower rate upon resolution of mild to moderate symptoms.

Note: The Canadian labeling suggests that patients with rheumatoid arthritis who have tolerated 3 infusions over 2 hours (doses ≤6 mg/kg) may receive subsequent infusions at the same dose over not less than 1 hour. Safety of shortened infusion has not been studied with doses >6 mg/kg.

Guidelines for the treatment and prophylaxis of infusion reactions: (Note: Limited to adult patients and dosages used in Crohn disease; prospective data for other populations [pediatrics, other indications/dosing] are not available).

A protocol for the treatment of infusion reactions, as well as prophylactic therapy for repeat infusions, has been published (Mayer, 2006).

Treatment of infusion reactions: Medications for the treatment of hypersensitivity reactions should be available for immediate use. For mild reactions, the rate of infusion should be decreased to 10 mL/hour. Initiate a normal saline infusion (500 to 1,000 mL/hour) and appropriate symptomatic treatment (eg, acetaminophen and diphenhydramine); monitor vital signs every 10 minutes until normal. After 20 minutes, the infusion may be increased at 15-minute intervals, as tolerated, to completion (initial increase to 20 mL/hour, then 40 mL/hour, then 80 mL/hour, etc [maximum of 125 mL/hour]). For moderate reactions, the infusion should be stopped or slowed. Initiate a normal saline infusion (500 to 1,000 mL/hour) and appropriate symptomatic treatment. Monitor vital signs every 5 minutes until normal. After 20 minutes, the infusion may be reinstituted at 10 mL/hour; then increased at 15-minute intervals, as tolerated, to completion (initial increase 20 mL/hour, then 40 mL/hour, then 80 mL/hour, etc [maximum of 125 mL/hour]). For severe reactions, the infusion should be stopped with administration of appropriate symptomatic treatment (eg, hydrocortisone/methylprednisolone, diphenhydramine and epinephrine) and frequent monitoring of vitals (consult institutional policies, if available). Re-treatment after a severe reaction should only be done if the benefits outweigh the risks and with appropriate prophylaxis. Delayed infusion reactions typically occur 1 to 7 days after an infusion. Treatment should consist of appropriate symptomatic treatment (eg, acetaminophen, antihistamine, methylprednisolone).

Prophylaxis of infusion reactions: Premedication with acetaminophen and diphenhydramine 90 minutes prior to infusion may be considered in all patients with prior infusion reactions, and in patients with severe reactions corticosteroid administration is recommended. Steroid dosing may be oral (prednisone 50 mg orally every 12 hours for 3 doses prior to infusion) or intravenous (a single dose of hydrocortisone 100 mg or methylprednisolone 20 to 40 mg administered 20 minutes prior to the infusion). On initiation of the infusion, begin with a test dose at 10 mL/hour for 15 minutes. Thereafter, the infusion may be increased at 15-minute intervals, as tolerated, to completion (initial increase 20 mL/hour, then 40 mL/hour, then 80 mL/hour, etc). A maximum rate of 125 mL/hour is recommended in patients who experienced prior mild to moderate reactions and 100 mL/hour is recommended in patients who experienced prior severe reactions. In patients with cutaneous flushing, aspirin may be considered (Becker, 2004). For delayed infusion reactions, premedicate with acetaminophen and diphenhydramine 90 minutes prior to infusion. On initiation of the infusion, begin with a test dose at 10 mL/hour for 15 minutes. Thereafter, the infusion may be increased to infuse over 3 hours. Postinfusion therapy with acetaminophen for 3 days and an antihistamine for 7 days is recommended.

Compatibility

Stable in NS; do not infuse with other agents.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). The manufacturer recommends that diluted solutions for infusion should be used within 3 hours of preparation. However, a stability study of infliximab 0.4 mg/mL prepared in 0.9% sodium chloride in polyvinyl chloride (PVC) bags found no loss of biological activity when stored refrigerated at 4°C for up to 14 days (Ikeda 2012).

Drug Interactions

Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Avoid combination

Adalimumab: May enhance the immunosuppressive effect of InFLIXimab. Avoid combination

Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Avoid combination

Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Etanercept: May enhance the immunosuppressive effect of InFLIXimab. Avoid combination

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Golimumab: May enhance the immunosuppressive effect of InFLIXimab. Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Avoid combination

Tofacitinib: Anti-TNF Agents may enhance the adverse/toxic effect of Tofacitinib. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Ustekinumab: May enhance the immunosuppressive effect of InFLIXimab. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Vedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Headache (18%)

Gastrointestinal: Abdominal pain (Crohn disease: 26%; other indications: 12%), nausea (21%)

Hepatic: Increased serum ALT (<3x ULN: 17% to 51%; ≥3x ULN: 2% to 10%; ≥5x ULN: 1% to 4%)

Immunologic: Increased ANA titer (~50%), antibody development (double-stranded DNA, 20%), antibody development (anti-infliximab; variable; ~10% to 15% [range: 6% to 61%]; Mayer 2006)

Infection: Infection (Crohn disease: 50% to 59%; other indications: 27% to 36%), abscess (Crohn disease patients with fistulizing disease: 6% to 15%)

Respiratory: Upper respiratory tract infection (32%), sinusitis (14%), cough (12%), pharyngitis (12%)

Miscellaneous: Infusion related reaction (18%; severe: <1%)

1% to 10%:

Cardiovascular: Flushing (Crohn disease: 9%), hypertension (7%), chest pain (≤1%), bradycardia (≥0.2%), edema (≥0.2%), hypotension (≥0.2%), thrombophlebitis (deep) (≥0.2%)

Central nervous system: Fatigue (9%), pain (8%), chills (≤3%), dizziness (≥0.2%)

Dermatologic: Skin rash (1% to 10%), pruritus (≤7%), cellulitis (≥0.2%), diaphoresis (≥0.2%)

Endocrine & metabolic: Dehydration (≥0.2%)

Gastrointestinal: Dyspepsia (10%), GI moniliasis (5%), constipation (≥0.2%), intestinal obstruction (≥0.2%)

Genitourinary: Urinary tract infection (8%)

Hematologic & oncologic: Anemia (children with Crohn disease: 11%; adults: ≥0.2%), hemolytic anemia (≥0.2%), leukopenia (Crohn disease: 9%; other indications: ≥0.2%), lymphadenopathy (≥0.2%), malignant lymphoma (≥0.2%), neutropenia (Crohn disease: 7%), pancytopenia (≥0.2%), sarcoidosis (≥0.2%), thrombocytopenia (≥0.2%)

Hepatic: Hepatitis (≥0.2%)

Hypersensitivity: Hypersensitivity reaction (Crohn disease: 6%; other indications: ≥0.2%), delayed hypersensitivity (plaque psoriasis: 1%), serum sickness (≥0.2%)

Infection: Viral infection (Crohn disease: 8%), bacterial infection (Crohn disease: 6%), serious infection (1% to 5%), sepsis (≥0.2%)

Neuromuscular & skeletal: Arthralgia (1% to 8%), bone fracture (Crohn disease: 7%), myalgia (1%)

Respiratory: Bronchitis (10%), dyspnea (≤1%), lower respiratory tract infection (≥0.2%), pleurisy (≥0.2%), pulmonary edema (≥0.2%)

Miscellaneous: Fever (≤3% to 7%)

<1% (Limited to important or life-threatening): Acute hepatic failure, agranulocytosis, anaphylactic shock, anaphylaxis, angina pectoris, autoimmune hepatitis, cardiac failure (worsening), cholecystitis, cholestasis, confusion, convulsions, demyelinating disease of the central nervous system (eg, multiple sclerosis, optic neuritis), demyelinating disease (peripheral; eg, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy), dysgeusia, erythema multiforme, erythematous rash, exacerbation of psoriasis, gastrointestinal hemorrhage, hepatic carcinoma, hepatic failure, hepatic injury, hepatitis B (reactivation), hepatotoxicity (idiosyncratic) (Chalasani 2014), hepatosplenic T-cell lymphomas (mainly young adult or adolescent males), Hodgkin lymphoma, immune thrombocytopenia, increased liver function tests (transient), interstitial fibrosis, interstitial pneumonitis, intestinal stenosis, leukemia, lupus-like syndrome (drug-induced), malignant melanoma, malignant neoplasm (leiomyosarcoma), meningitis, Merkel cell carcinoma, myocardial infarction, nephrolithiasis, neuritis, neuropathy, opportunistic infection, pancreatitis, pericardial effusion, peripheral neuropathy, pleural effusion, pneumonia, psoriasis (including new onset, palmoplantar, pustular, or exacerbation), pulmonary disease, pulmonary fibrosis, reactivated tuberculosis, renal cell carcinoma, renal failure, seizure, Stevens-Johnson syndrome, syncope, tachycardia, tendon disease, thrombotic thrombocytopenia purpura, toxic epidermal necrolysis, transverse myelitis, tuberculosis, ulcer, vasculitis (systemic and cutaneous), vision loss (transient)

ALERT: U.S. Boxed Warning

Serious infections:

Patients treated with infliximab are at an increased risk of developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

Discontinue infliximab if a patient develops a serious infection or sepsis.

Reported infections include the following:

Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before infliximab use and during therapy. Initiate treatment for latent infection prior to infliximab use.

Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric antifungal therapy in patients at risk of invasive fungal infections who develop severe systemic illness.

Bacterial, viral, and other infections caused by opportunistic pathogens, including Legionella and Listeria.

Carefully consider the risks and benefits of treatment with infliximab prior to initiating therapy in patients with long-term or recurrent infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with infliximab, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

Malignancy:

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including infliximab.

Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including infliximab. These cases had a very aggressive disease course and have been fatal. Almost all patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of reported infliximab cases have occurred in patients with Crohn disease or ulcerative colitis, and most were in adolescent and young adult males.

Warnings/Precautions

Concerns related to adverse effects:

• Autoimmune disorder: Positive antinuclear antibody titers have been detected in patients (with negative baselines). Rare cases of autoimmune disorder, including lupus-like syndrome, have been reported; monitor and discontinue if symptoms develop.

• Hematologic disorders: Hematologic toxicities (eg, leukopenia, neutropenia, thrombocytopenia, pancytopenia) have been reported (may be fatal). Patients must be advised to seek medical attention if they develop signs and symptoms suggestive of blood dyscrasias (eg, persistent fevers); discontinue if significant hematologic abnormalities are confirmed. Use with caution in patients with history of hematologic abnormalities.

• Hepatic reactions: Severe hepatic reactions (including hepatitis, jaundice, acute hepatic failure, and cholestasis) have been reported during treatment; reactions occurred between 2 weeks to >1 year after initiation of therapy and some cases were fatal or necessitated liver transplantation; discontinue with jaundice and/or marked increase in liver enzymes (≥5 times ULN).

• Hepatitis B: Reactivation of hepatitis B virus (HBV) has occurred in chronic carriers of the virus, usually in patients receiving concomitant immunosuppressants (may be fatal); evaluate for HBV prior to initiation in all patients. Monitor during and for several months following discontinuation of treatment in HBV carriers; interrupt therapy if reactivation occurs and treat appropriately with antiviral therapy; if resumption of therapy is deemed necessary, exercise caution and monitor patient closely.

• Hypersensitivity or infusion reactions: Acute infusion reactions may occur. Hypersensitivity reaction may occur within 2 hours of infusion. Medication and equipment for management of hypersensitivity reaction should be available for immediate use. Interruptions and/or reinstitution at a slower rate may be required (consult protocols). Pretreatment may be considered, and may be warranted in all patients with prior infusion reactions. Serum sickness-like reactions have occurred; may be associated with a decreased response to treatment. The development of antibodies to infliximab may increase the risk of hypersensitivity and/or infusion reactions; concomitant use of immunosuppressants may lessen the development of anti-infliximab antibodies. The risk of infusion reactions may be increased with re-treatment after an interruption or discontinuation of prior maintenance therapy. Re-treatment in psoriasis patients should be resumed as a scheduled maintenance regimen without any induction doses; use of an induction regimen should be used cautiously for re-treatment of all other patients.

• Infections: [US Boxed Warning]: Patients receiving infliximab are at increased risk for serious infections which may result in hospitalization and/or fatality; infections usually developed in patients receiving concomitant immunosuppressive agents (eg, methotrexate or corticosteroids) and may present as disseminated (rather than local) disease. Active tuberculosis (or reactivation of latent tuberculosis), invasive fungal (including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and pneumocystosis) and bacterial, viral or other opportunistic infections (including legionellosis and listeriosis) have been reported. Monitor closely for signs/symptoms of infection. Discontinue for serious infection or sepsis. Consider risks versus benefits prior to use in patients with a history of chronic or recurrent infection. Consider empiric antifungal therapy in patients who are at risk for invasive fungal infection and develop severe systemic illness. Caution should be exercised when considering use in the elderly or in patients with conditions that predispose them to infections (eg, diabetes) or residence/travel from areas of endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), or with latent or localized infections. Do not initiate infliximab therapy in patients with an active infection, including clinically important localized infection. Patients who develop a new infection while undergoing treatment should be monitored closely.

• Malignancy: [US Boxed Warning]: Lymphoma and other malignancies (may be fatal) have been reported in children and adolescent patients receiving TNF-blocking agents including infliximab. Half the cases are lymphomas (Hodgkin’s and non-Hodgkin’s) and the other cases are varied but include malignancies not typically observed in this population. [US Boxed Warning]: Postmarketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with infliximab. Almost all patients had received concurrent or prior treatment with azathioprine or mercaptopurine at or prior to diagnosis and the majority of reported cases occurred in adolescent and young adult males with Crohn disease or ulcerative colitis. Malignancies occurred after a median of 30 months (range: 1 to 84 months) after the first dose of TNF blocker therapy; most patients were receiving concomitant immunosuppressants. The impact of infliximab on the development and course of malignancies is not fully defined. As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis alone has been previously associated with an increased rate of lymphoma. Use caution in patients with a history of COPD, higher rates of malignancy were reported in COPD patients treated with infliximab. Psoriasis patients with a history of phototherapy had a higher incidence of nonmelanoma skin cancers. Melanoma and Merkel cell carcinoma have been reported in patients receiving TNF-blocking agents including infliximab. Perform periodic skin examinations in all patients during therapy, particularly those at increased risk for skin cancer.

• Tuberculosis: [US Boxed Warning]: Infliximab treatment has been associated with active tuberculosis (may be disseminated or extrapulmonary) or reactivation of latent infections. Evaluate patients for tuberculosis risk factors and latent tuberculosis infection (with a tuberculin skin test) prior to and during therapy. Treatment of latent tuberculosis should be initiated before use. Patients with initial negative tuberculin skin tests should receive continued monitoring for tuberculosis throughout treatment. Most cases of reactivation have been reported within the first couple months of treatment. Caution should be exercised when considering the use in patients who have been exposed to tuberculosis.

Disease-related concerns:

• Demyelinating CNS disease: Use with caution in patients with pre-existing or recent onset CNS demyelinating disorders; rare cases of optic neuritis and demyelinating disease (including multiple sclerosis, systemic vasculitis, and Guillain-Barré syndrome) have been reported; consider discontinuation of therapy if patient develops significant CNS reactions.

• Heart failure (HF): Use with caution in patients with mild HF (NYHA Class I, II) or decreased left ventricular function; worsening and new-onset HF has been reported; doses >5 mg/kg should not be administered in patients with moderate to severe HF (NYHA Class III/IV); discontinue therapy with onset of new or worsening symptoms. The Canadian labeling contraindicates use in moderate or severe HF.

• Seizure disorders: Use with caution in patients with a history of seizures; discontinue if significant CNS adverse reactions develop.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: Malignancies have been reported among children and adolescents receiving TNF-blocking agents. Efficacy was not established in a study to evaluate infliximab use in juvenile idiopathic arthritis (JIA).

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

Other warnings/precautions:

• Immunizations: Patients should be brought up to date with all immunizations before initiating therapy. Live vaccines should not be given concurrently; there is no data available concerning secondary transmission of live vaccines in patients receiving therapy. A fatal outcome has been reported in an infant who received a live vaccine (BCG) after in utero exposure to infliximab; infliximab crosses the placenta and has been detected in infants’ serum for up to 6 months. It is recommended to wait ≥6 months following birth before administering any live vaccine to infants exposed to infliximab in utero.

Monitoring Parameters

Monitor improvement of symptoms and physical function assessments. During infusion, if reaction is noted, monitor vital signs every 2-10 minutes, depending on reaction severity, until normal. Latent TB screening prior to initiating and during therapy; signs/symptoms of infection (prior to, during, and following therapy); CBC with differential; signs/symptoms/worsening of heart failure; HBV screening prior to initiating (all patients), HBV carriers (during and for several months following therapy); signs and symptoms of hypersensitivity reaction; symptoms of lupus-like syndrome; LFTs (discontinue if >5 times ULN); signs and symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss).

Psoriasis patients with history of phototherapy should be monitored for nonmelanoma skin cancer.

Pregnancy Risk Factor

B

Pregnancy Considerations

Animal reproduction studies have not been conducted. Infliximab crosses the placenta and can be detected in the serum of infants for up to 6 months following in utero exposure. A fatal outcome has been reported in an infant who received a live vaccine (BCG) after in utero exposure to infliximab; it is recommended to wait ≥6 months following birth before administering any live vaccine to infants exposed to infliximab in utero. If a biologic agent such as infliximab is needed to treat inflammatory bowel disease during pregnancy, it is recommended to hold therapy after 30 weeks gestation (Habal, 2012). The Canadian labeling recommends that women of childbearing potential use effective contraception during therapy and for at least 6 months after discontinuation.

Healthcare providers are also encouraged to enroll women exposed to infliximab during pregnancy in the MotherToBaby Autoimmune Diseases Study by contacting the Organization of Teratology Information Specialists (OTIS) (877-311-8972).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, flushing, or injection site irritation. Have patient report immediately to prescriber signs of infection, loss of strength and energy, bruising, bleeding, signs of lupus (rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs); signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes); shortness of breath; excessive weight gain or loss; swelling of arms or legs; burning or numbness feeling; severe back pain; severe headache; dysphagia; pale skin; enlarged lymph nodes; night sweats; vision changes; blindness; black, tarry, or bloody stools; mole changes; skin growths; severe dizziness; passing out; bradycardia; or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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