Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) cA2
2) CenTNF
3) Infliksimab
4) Infliksimabi
5) Infliximabum
6) CAS 170277-31-3

Available Forms Sources

A)

1) Infliximab is available in the US in individually-boxed single-use vials as lyophilized powder for intravenous infusion (100 mg infliximab in a 20 mL vial) (Prod Info REMICADE(R) IV injection, 2007).

B)

1) CROHN'S DISEASE: Infliximab is approved for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderate-to-severe active Crohn's disease who have had an inadequate response to conventional treatment. It is also used to reduce the number of draining enterocutaneous and rectovaginal fistulas and maintains fistula closure in adult patients with fistulizing Crohn's disease (Prod Info REMICADE(R) IV injection, 2007).
2) SEVERE RHEUMATOID ARTHRITIS: Infliximab is approved for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. Infliximab should be given in combination with methotrexate (Prod Info REMICADE(R) IV injection, 2007).
3) ANKYLOSING SPONDYLITIS: Infliximab is approved for reducing signs and symptoms in patients with active ankylosing spondylitis (Prod Info REMICADE(R) IV injection, 2007).
4) PSORIATIC ARTHRITIS: Infliximab is approved for reducing signs and symptoms of active arthritis in patients with psoriatic arthritis (Prod Info REMICADE(R) IV injection, 2007).
5) PLAQUE PSORIASIS: Infliximab is approved for the treatment of chronic extensive and/or disabling plaque psoriasis in adult patients who are candidates for systemic therapy and when other systemic therapies are medically less appropriate (Prod Info REMICADE(R) IV injection, 2007).
6) ULCERATIVE COLITIS: Infliximab is approved for reducing signs and symptoms, achieving clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who did not adequately respond to conventional therapy (Prod Info REMICADE(R) IV injection, 2007).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Infliximab is used to reduce signs and symptoms of moderate to severe fistulizing Crohn's disease, moderate to severe rheumatoid arthritis (in combination with methotrexate), ankylosing spondylitis, psoriatic arthritis, chronic severe plaque psoriasis, and moderate to severe ulcerative colitis.
B) PHARMACOLOGY: Infliximab is a monoclonal antibody (chimeric IgG1 kappa) with specific activity for human tumor necrosis factor-alpha (TNF-alpha). The specific activity of infliximab is high-affinity binding to TNF-alpha receptors and neutralizing TNF-alpha activity.
C) EPIDEMIOLOGY: Overdose is rare.
D) WITH THERAPEUTIC USE

1) MOST COMMON (greater than 10%): Infections (eg, upper respiratory sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain. OTHER EFFECTS: Nausea, dyspepsia, fatigue, hypertension, chest pain, hypotension, dyspnea, worsening congestive heart failure, prolonged QT interval, rash, flushing, pruritus, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, urinary tract infection, optic neuritis, anemia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, pancytopenia, severe hepatic reactions (eg, acute liver failure, jaundice, hepatitis), hypersensitivity reactions, anaphylaxis, bone fracture, backache, drug-induced lupus erythematosus, polyneuropathy, Pneumocystis, fever, tuberculosis, opportunistic infections (usually present with disseminated infection compared to localized disease), histoplasmosis, mycosis, seizures (rare), and CNS demyelinating disease (rare).

E) WITH POISONING/EXPOSURE

1) Data are limited. Clinical effects are anticipated to be an extension of the adverse effects seen with therapeutic use.

0.2.20)

A) Infliximab is classified as FDA pregnancy category B. There are no adequate and well-controlled studies with infliximab use during pregnancy. Administer to a pregnant woman only if clearly needed. Consider limiting infliximab use to the first 30 weeks of pregnancy. Caution is warranted in live-virus vaccinations, including rotavirus, intranasal influenza vaccine, and BCG, in infliximab-exposed infants up to 6 months of age or with detectable infliximab serum levels.

0.2.21)

A) Cases of aggressive and often fatal hepatosplenic T-cell lymphoma have been reported in postmarketing experience in young adult and adolescent Crohn's disease patients receiving infliximab and azathioprine or 6-mercaptopurine concurrently. During postmarketing use, non-Hodgkin's lymphoma, Hodgkin's disease, and other malignancies, including melanoma and Merkel cell carcinoma, have been reported. In clinical trials, non-lymphoma malignancies (lung or head and neck; most common were breast, colorectal, and melanoma malignancies) have also been reported in patients receiving infliximab.

Laboratory Monitoring

A)

B)

C)

D)

E)

Treatment Overview

0.4.6)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. For severe hypertension, nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. Monitor for signs and symptoms of severe infection (eg, opportunistic infections, tuberculosis). Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Therapeutic doses of infliximab may cause prolongation of the QT interval. In patients with QT prolongation, monitor serum electrolytes including potassium, calcium and magnesium in patients with significant overdose; correct any abnormalities. At the time of this review, torsades de pointes has not been reported with therapy.

C) DECONTAMINATION

1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

D) AIRWAY MANAGEMENT

1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, severe allergic reactions or persistent seizures.

E) ANTIDOTE

1) None.

F) MYELOSUPPRESSION

1) For severe neutropenia, administer colony stimulating factor. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily.

G) ENHANCED ELIMINATION

1) It is unknown if hemodialysis would be effective in overdose.

H) PATIENT DISPOSITION

1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

I) PITFALLS

1) When managing a suspected infliximab overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative.

J) PHARMACOKINETICS

1) Cmax: In multiple sclerosis patients, peak levels of approximately 500 mcg/mL after 10 mg/kg; declined to 200 mcg/mL at 72 hours. Vd (central compartment), adult: 52.7 mL/kg; pediatric: 54.2 mL/kg. Vd (peripheral compartment), adult: 19 mL/kg; pediatric: 29.2 mL/kg. Total body clearance: adult, 5.39 mL/kg/day; pediatric, 5.43 mL/kg/day. Elimination half-life: adult: 12.4 days; pediatric: 13.2 days.

K) DIFFERENTIAL DIAGNOSIS

1) Includes other agents that may cause hypotension, prolonged QT interval, or myelosuppression.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) MOST COMMON (greater than 10%): Infections (eg, upper respiratory sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain. OTHER EFFECTS: Nausea, dyspepsia, fatigue, hypertension, chest pain, hypotension, dyspnea, worsening congestive heart failure, prolonged QT interval, rash, flushing, pruritus, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, urinary tract infection, optic neuritis, anemia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, pancytopenia, severe hepatic reactions (eg, acute liver failure, jaundice, hepatitis), hypersensitivity reactions, anaphylaxis, bone fracture, backache, drug-induced lupus erythematosus, polyneuropathy, Pneumocystis, fever, tuberculosis, opportunistic infections (usually present with disseminated infection compared to localized disease), histoplasmosis, mycosis, seizures (rare), and CNS demyelinating disease (rare).

E)

1) Data are limited. Clinical effects are anticipated to be an extension of the adverse effects seen with therapeutic use.

Vital Signs

3.3.3)

A) WITH THERAPEUTIC USE

1) FEVER: In adult patients with rheumatoid arthritis, fever was reported in 7% of patients treated with 4 or more infliximab infusions (n=1129) compared to 4% of patients in the placebo group (n=350) (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).
2) Of the patients who experienced an infliximab infusion-related reaction, 3% experienced fever and chills (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) OPTIC NEURITIS: Rare cases of optic neuritis have been reported with infliximab therapy (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).
2) In 3 cases, patients experienced toxic optic neuropathy after a third dose of infliximab for rheumatoid arthritis. All patients had capillary dilation and vascular leakage in the optic nerve heads. Central and cecocentral visual field defects suggest a toxic form of anterior optic neuropathy. Vision did not recover with steroid treatment (ten Tusscher et al, 2003).

Cardiovascular

3.5.2)

A) HYPERTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Hypertension was reported in 7% of patients treated with 4 or more infliximab infusions (n=1129) compared with 5% of those treated with placebo (n=350) in clinical trials of adult patients with rheumatoid arthritis (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015; van Oosten et al, 1996a; Targan et al, 1997a).
b) Cardiopulmonary reactions (ie, primarily chest pain, hypotension, hypertension or dyspnea) accompanied infusion reactions (ie, during or within 1 to 2 hours of an infliximab infusion) in 1% of patients in clinical trials (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015; van Oosten et al, 1996a; Targan et al, 1997a).

B) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Cardiopulmonary reactions (ie, primarily chest pain, hypotension, hypertension or dyspnea) accompanied infusion reactions (ie, during or within 1 to 2 hours of an infliximab infusion) in 1% of patients in clinical trials. Serious infusion reactions, including hypotension, occurred in less than 1% of patients in clinical trials (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015; van Oosten et al, 1996a; Targan et al, 1997a).

C) CHEST PAIN

1) WITH THERAPEUTIC USE

a) Cardiopulmonary reactions (ie, primarily chest pain, hypotension, hypertension or dyspnea) accompanied infusion reactions (ie, during or within 1 to 2 hours of an infliximab infusion) in 1% of patients in clinical trials (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015; van Oosten et al, 1996a; Targan et al, 1997a).

D) HEART FAILURE

1) WITH THERAPEUTIC USE

a) In a randomized study (n=150), a higher incidence of mortality, or morbidity requiring hospitalization was reported in patients with moderate-to-severe (NYHA Class III or IV) congestive heart failure (CHF) while receiving treatment with infliximab (10 mg/kg and 5 mg/kg). This phenomenon was especially pronounced in patients receiving infliximab 10 mg/kg/dose. There were increased incidence of dyspnea, hypotension, angina and dizziness in both the 10 mg/kg and 5 mg/kg infliximab groups compared with placebo (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015; Deckelbaum, 2001).
b) In a case series of patients receiving infliximab (reports supplied to the US Food and Drug Administration Medwatch program), 7 cases of new-onset heart failure occurred in patients with no documented risk factors, 5 cases of new-onset heart failure occurred in patients with risk, and 6 cases of heart failure exacerbation were observed (Kwon et al, 2003).

E) PROLONGED QT INTERVAL

1) WITH THERAPEUTIC USE

a) During a retrospective, observational study, statistically significant increases in mean QT occurred at month 12 compared with baseline in patients (mean age, 48.6 +/- 10.3 years) with no known heart disease who received infliximab 5 mg/kg every 8 weeks (n=8) or etanercept 25 mg twice weekly (n=26) for the treatment of rheumatoid arthritis or spondyloarthritis. Twelve months after initiation of therapy, significant differences in QT (baseline, 400.88 +/- 25.74 ms vs month 12, 414.41 +/- 27.10 ms; p=0.009), QT dispersion (baseline, 27.94 +/- 8.8 vs month 12, 42.94 +/- 10.01; p less than 0.0001), and rate-corrected QT dispersion (QTd; baseline, 31.38 +/- 11.33 vs month 12, 46.71 +/- 11; p less than 0.0001) were observed in the infliximab and etanercept treatment groups. None of the patients in any group experienced symptoms of cardiovascular disease (DI Franco et al, 2012).

F) MYOCARDITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A case of focal segmental myocarditis was reported in a 21-year-old man within 12 days of first infusion of infliximab 5 mg/kg IV salvage therapy for severe acute ulcerative colitis (UC). The patient presented with a 2-month history of diarrhea and acute severe UC unresponsive to hydrocortisone and mesalazine. UC symptoms improved following infliximab administration, and the patient was discharged days later with a tapering course of corticosteroids. Ten days after discharge, the patient returned with intermittent fever and rash on his neck, shoulders, and legs. UC diarrhea had not recurred. Despite empirical treatment with antibiotics and antivirals, he was readmitted 2 days later with worsening fevers, fatigue, vomiting, and tachycardia (120 bpm). Lab tests revealed elevated C-reactive protein (286 mg/L, range, 0 to 10 mg/L). Imaging tests showed no intraabdominal sepsis. Over the next 48 hours, further imaging tests in response to significant chest pain and sinus tachycardia revealed anteriolateral ST-T changes with cardiomegaly, pulmonary edema, severe left ventricular dysfunction with a 30% ejection fraction, and akinetic anteroseptal walls. Troponin 1 levels were elevated (2.87 mcg/L, range 0 to 0.06 mcg/L). There were no signs of myocardial infarction. The patient was diagnosed with focal segmental myocarditis with secondary dilated cardiomyopathy and was treated with ACE inhibitors and diuretics. Negative viral and immune profiles (with the exception of a weak positive finding for perinuclear antineutrophil cytoplasmic antibodies) pointed to hypersensitivity reaction as the myocarditis impetus. The patient gradually improved and his UC remained controlled with tapering corticosteroids (Slattery et al, 2011).

G) ACUTE CORONARY SYNDROME

1) WITH THERAPEUTIC USE

a) CASE REPORT: A case of acute coronary syndrome was reported in a 40-year-old Caucasian man following infliximab infusion for the treatment of newly-diagnosed, corticoid-resistant, ileocolonic Crohn's disease (CD). The patient had no personal or family history of heart disease, hypertension, hyperlipidemia, diabetes mellitus, smoking or obesity. He had normal ECG and physical examination of the heart prior to infliximab treatment, and was not taking any medications prior to diagnosis of CD. Following an infliximab 375 milligram (mg) infusion that was well tolerated with no acute adverse reactions or laboratory abnormalities (except serum glucose, 146 mg/deciliters), chest X-ray showed a slight elevation in cardiothoracic ratio (enlargement of the heart). On day 3 following the infusion, the patient experienced chest pain. Non-ST segment elevation myocardial infarction (non-STEMI) was confirmed, with an elevated troponin I level of 2.2 nanograms/milliliter. During treatment of non-STEMI with metoprolol, nitrates, low molecular weight heparin, and clopidogrel, the patient experienced an episode of atrial fibrillation that was ameliorated with amiodarone therapy. While the clinical condition of Crohn's disease improved 15 days after infliximab treatment, echocardiography showed hypokinesia of the interventricular septum and overall impaired systolic function of the heart with an ejection fraction of 45%. The patient also had elevated fibrinogen level, low protein S activity, abnormal resistance to activated protein C (APCR), and mild systemic inflammation with C-reactive protein levels of 32.5 mg/liter. Cardiac exercise stress test, protein S activity, and APCR returned to normal one month later (Panteris et al, 2006).
b) CASE REPORT: Acute coronary syndrome was reported during an infliximab infusion in a 49-year-old woman with no prior cardiac history. The patient had been receiving infliximab infusions for 2 years with a total dose of 4,800 mg infused in 14 sessions. On 2 prior visits, the patient had complained of chest pains; however, they were less severe and resolved upon completion of the infusion. During this incident, the patient was 10 minutes into the infusion and had received 20 milligrams (mg) of a scheduled 400 mg dose when she complained of chest pain. The chest pain continued for 2 hours after the infliximab infusion was stopped and was relieved by nitroglycerin, 0.4 mg sublingually. Tests revealed a elevated troponin-I level and ECG changes. The patient was initiated on aspirin, intravenous unfractionated heparin, metoprolol, and simvastatin. On day 4, a cardiac catheterization revealed no significant obstructive coronary artery disease and only a 25% stenosis of the mid-right coronary artery. Coronary vasospasm was considered to be the most probable reason for this occurrence (Abedin et al, 2006).

Respiratory

3.6.2)

A) RESPIRATORY FINDING

1) WITH THERAPEUTIC USE

a) In adult patients with rheumatoid arthritis, the following respiratory effects were reported in patients treated with 4 or more infliximab infusions (n=1129) compared to patients in the placebo group (n=350): Upper respiratory tract infection 32% (infliximab group) vs 25% (placebo group); sinusitis 14% vs 8%; pharyngitis 12% vs 8%; coughing 12% vs 8%; bronchitis 10% vs 9%; rhinitis 8% vs 5% (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

B) TUBERCULOSIS

1) WITH THERAPEUTIC USE

a) SUMMARY: Tuberculosis is a frequently reported adverse effect associated with infliximab use. Tuberculosis occurred in 59% of Spanish patients within 3 months of treatment initiation (Gomez-Reino et al, 2003). The U.S. reported case-rate of tuberculosis among patients treated with infliximab was higher than the background rate of cases in the population (Keane et al, 2001). Onset of tuberculosis usually occurred within 90 days after initial exposure to infliximab treatment (Anon, 2001).
b) Infliximab treatment has been associated with an increased risk of tuberculosis in the Spanish population. As of February 2002, 17 cases of tuberculosis, including two fatalities, were reported in patients exposed to infliximab for the treatment of rheumatoid arthritis (n=15) or psoriatic arthritis (n=2). Tuberculosis was diagnosed within 3 months of treatment initiation in 59% of these patients and the site of active infection was extrapulmonary in 65% of patients. The estimated incidence of tuberculosis associated with infliximab use in patients with rheumatoid arthritis was 1,893 cases per 100,000 patients and 1,113 cases per 100,000 patients in the years 2000 and 2001, respectively. In contrast, the background incidence of tuberculosis in Spain was 21 cases per 100,000 inhabitants in the year 2000. The relative risk of tuberculosis in rheumatoid arthritis patients treated with infliximab as compared with rheumatoid arthritis patients not treated with infliximab was 19.9 (95% CI 16.2 to 24.8) in the year 2000 and 11.7 (95% CI 9.5 to 14.6) in the year 2001 (Gomez-Reino et al, 2003).
c) The European Agency for the Evaluation of Medicinal Products issued a warning regarding an association between infliximab and the development of tuberculosis (TB) and other infections. Postmarketing reports include 28 cases of tuberculosis; the majority occurred after 3 or less infusions of infliximab (Anon, 2001). The MedWatch adverse event spontaneous-reporting system of the U.S. Food and Drug Administration identified 70 cases of tuberculosis in patients treated with infliximab for a median of 12 weeks prior to development of infection; 48 patients developed the disease after 3 or fewer doses, and 40 patients had extrapulmonary disease at the time of diagnosis. The reported case-rate of tuberculosis among patients treated with infliximab was higher than the background rate of cases in the associated population (Keane et al, 2001).
d) Between 1998 and the third quarter of 2002, 35 reported tuberculosis diseases per 100,000 patients treated with etanercept and 144 per 100,000 patients treated with infliximab (p less than 0.001) were reported through the Adverse Event Reporting System of the Food and Drug Administration (FDA). No single infection was reported significantly more often among patients treated with etanercept. The median time to infection was 236 days for etanercept and 40 days for infliximab (p less than 0.001) (Wallis et al, 2004).
e) CASE REPORTS: Despite receiving adequate isoniazid (INH) chemoprophylaxis for latent tuberculosis (TB), 2 patients developed active TB after initiation of infliximab therapy for rheumatoid arthritis. The first patient, a 58-year-old man successfully treated for 14 months with infliximab (6 mg/kg), methotrexate, and sulfasalazine, presented to the hospital with a 3-week history of fever, chills, productive cough, night sweats and altered mental status. Three years prior, he had been treated with a 9-month course of INH for latent TB. Following thorough clinical and laboratory evaluation, the patient was started empirically on INH, rifampin, pyrazinamide, and ethambutol. Nine days after discharge, sputum cultures were positive for mycobacterium tuberculosis. He has since made a full recovery following treatment with ethambutol, INH, rifampin, streptomycin, and pyrazinamide. The second patient, a 77-year-old woman treated with infliximab (4 mg/kg) for 4 months as part of her RA therapy, presented with a 3-week history of worsening weakness and fatigue. She had non-productive cough, fever, and chills for the previous week, and slurred speech as noted by family members. Ten years prior, she had a positive tuberculin skin test (TST) but was not treated at that time. Seven years prior, she had been treated with INH for 7 months after starting prednisone. Her TST was negative 4 years prior. Upon admission and evaluation, she was initially treated with levofloxacin for community acquired pneumonia, but was not improved after 4 days. Miliary tuberculosis was determined by chest CT. On hospital day 9, her sputum culture was positive for mycobacterium TB and rifampin, INH, ethambutol and pyrazinamide were initiated. She was discharged 34 days later (Raychaudhuri et al, 2007).
f) CASE REPORT: Reactivation tuberculosis developed after administration of infliximab for the treatment of fistulizing Crohn's disease, in a 53-year-old man with apparently quiescent disease. Five days after a second infusion of infliximab 5 mg/kg at week 2 of treatment, the patient presented with high fever and malaise. He then developed a pleural effusion, Mycobacterium tuberculosis bacteriuria, and had acid-fast bacilli in bronchoalveolar wash samples obtained by bronchoscopy. The patient became afebrile after the initiation of appropriate treatment (Martinez et al, 2001).
g) CASE REPORT: Reactivation tuberculosis was documented in a 19-year-old man, after receiving three 5-mg doses of infliximab for the treatment of sight-threatening uveitis of unknown cause. The patient presented approximately 60 days after receiving the first dose of infliximab. Twenty months prior to initiating infliximab therapy, the patient was exposed to an individual with smear-positive pulmonary tuberculosis (Lim et al, 2002).

C) PNEUMOCYSTOSIS PNEUMONIA

1) WITH THERAPEUTIC USE

a) In a review of the Adverse Event Reporting System of the Food and Drug Administration (FDA) for cases of Pneumocystis associated with infliximab therapy from January 1998 through December 2003, 84 cases of Pneumocystis jiroveci (carinii), or PCP were reported. Concomitant immunosuppressive therapy included methotrexate (n=38), prednisone (n=37), azathioprine (n=6), leflunomide (n=6), mercaptopurine (n=5) and cyclosporine (n=4). Six patients had pre-existing chronic lung disease including bronchitis, pulmonary fibrosis, and asthma. When documented, the mean time between infliximab infusion and onset of pneumonia symptoms was 21+/- 18 days (n=40). The number of infusions received before onset of symptoms was 2.1+/ - 1.3 infusions (n=76). Of the 84 cases, 23 resulted in death (27%) (Kaur & Mahl, 2007).
b) Five cases of Pneumocystis carinii pneumonia have also been documented in post-marketing reports (Keenan et al, 2001).

D) INVASIVE PULMONARY ASPERGILLOSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Invasive pulmonary aspergillosis developed in a 25-year-old man, 5 days after receiving a single intravenous infusion of infliximab 5 mg/kg for treatment of fistulizing Crohn's disease. He was not receiving concomitant immunosuppressant agents. The patient initially presented with high fever, productive cough, and dyspnea; chest radiographs revealed the presence of massive, bilateral infiltrates. He subsequently required endotracheal intubation and mechanical ventilatory support within 24 hours of admission. On day 7, tracheal secretions revealed positive growth of Aspergillus fumigatus, later confirmed by repeat cultures of tracheal and bronchoalveolar lavage fluids. Treatment was started with liposomal amphotericin B; however, the patient died on day 24 from multiorgan failure and septic shock. Postmortem histological examination of lung tissue revealed invasive growth of septated hyphae, and tissue cultures confirmed the presence of Aspergillus fumigatus (Warris et al, 2001).

E) BRONCHOCENTRIC GRANULOMATOSIS

1) WITH THERAPEUTIC USE

a) Bronchocentric allergic granulomatosis was reported in a patient receiving infliximab 5 mg/kg for the treatment of ankylosing spondylitis. Following the second dose of infliximab, (given two weeks into treatment), the patient developed a high fever along with enlarged lymph nodes and pulmonary lesions. The infliximab was discontinued, and the symptoms resolved over the next 8 weeks (Braun et al, 2002).

F) PULMONARY SARCOIDOSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A case report describes a 34-year-old man successfully treated for 2 years with infliximab for ankylosing spondylitis (AS), who subsequently developed pulmonary sarcoidosis. Infliximab had been initiated at a dose of 5 mg/kg every 6 weeks; upon diagnosis of Stage II thoracic sarcoidosis, the drug was discontinued. The patient recovered without sequelae, and was asymptomatic at 1 year (Almodovar et al, 2007).

G) LEGIONELLA PNEUMONIA

1) WITH THERAPEUTIC USE

a) According to the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), there have been 80 cases of Legionella pneumonia reported in patients (median age, 56 years; range, 25 to 85 years) treated with tumor necrosis factor (TNF) blockers (infliximab, adalimumab, etanercept, and golimumab) between 1999 and 2010. In the reported cases, the most common indication for TNF blocker therapy was rheumatoid arthritis (65%) with a median treatment duration of 10.4 months (range, less than 1 to 73 months) prior to the onset of infection. Of the 80 cases, 14 were fatal. In the medical literature, 23 cases of Legionella pneumonia were identified in patients (26 to 71 years of age) treated with TNF blockers (infliximab, adalimumab, and etanercept) for rheumatologic disorders, inflammatory bowel disease, and psoriasis. Of the 23 patients, 4 required mechanical ventilation, 5 received treatment in the ICU, and 3 cases were fatal. A second episode of Legionella pneumonia developed in one patient following reintroduction of TNF blocker treatment. The majority of cases, identified by the AERS and medical literature, received concomitant immunosuppressive drugs including methotrexate and/or corticosteroids (U.S. Food and Drug Administration (FDA), 2011).

Neurologic

3.7.2)

A) DEMYELINATING DISEASE OF CENTRAL NERVOUS SYSTEM

1) WITH THERAPEUTIC USE

a) Infliximab has been associated with rare cases of central nervous system demyelinating disease onset or exacerbation, including multiple sclerosis and central nervous system manifestation of systemic vasculitis (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).
b) CASE REPORT: A 50-year-old woman with no previous neurological problems developed diplopia, right foot drop, and left hand weakness and numbness 2 weeks after receiving her fifth dose of intravenous infliximab (3 mg/kg body weight; total exposure 1000 mg) for the treatment of rheumatoid arthritis (RA). The patient's diplopia resolved spontaneously, however, her abnormal neurological symptoms continued to progress. All laboratory measures were within normal limits which included complete blood count, electrolytes, liver enzymes, serum B12, and folate. After 6 months of treatment with intravenous gammaglobulin (IVIG) therapy, the patient continued to have distal limb weakness and loss of ankle reflexes and developed a tremor and mild distal sensory abnormalities in the feet. Electrophysiology studies showed signs of demyelinating polyneuropathy with conduction block. After 35 months of IVIG therapy, most of the patient's symptoms resolved and the conduction block had mostly disappeared, however, the follow-up MRI was unchanged (Jarand et al, 2006).

B) POLYNEUROPATHY

1) WITH THERAPEUTIC USE

a) Two patients who were RA seropositive developed polyneuropathy after infliximab therapy (Jarand et al, 2006).

1) The first patient was an 85-year-old woman that developed peripheral neuropathy (glove and stocking numbness) and ataxia two weeks after her third dose of intravenous infliximab 3 mg/kg body weight. The patient had a history of mild sensory loss in her soles, and neurological examination revealed distal weakness of intrinsic hand muscles, areflexia, and panmodal sensory loss distal to the knees and palms and loss of position sensibility in the toes. The patient was unable to tandem walk. Electrophysiology studies revealed mild declines in motor conduction velocities, distal lower limb denervation and loss of action potentials in the sensory nerves. The patient's sensation improved along with mild electrophysiological improvement nine months after discontinuing infliximab, however the patient remained ataxic. Prior to the infliximab therapy, the patient had failed second-line treatment for rheumatoid arthritis (medications were not provided) (Jarand et al, 2006).
2) The second patient was a 68-year-old woman who was treated with infliximab 3 mg/kg body weight (total exposure 1400 mg) that developed bilateral paresthesia. Pain in her hands and feet developed and progressed as the infliximab infusions continued. Four months after infliximab was discontinued, the neurological examination revealed loss of sensation in the hands and feet including cold sensation, pinprick and light touch, and position sensibility which is consistent with small-fiber sensory neuropathy. Motor testing, deep tendon reflexes, electrophysiologic and laboratory studies were all normal. The patient was also receiving leflunomide and prednisone in addition to infliximab therapy (Jarand et al, 2006).

C) SEIZURE

1) WITH THERAPEUTIC USE

a) Rare cases of seizure have been reported in association with infliximab therapy (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

D) FATIGUE

1) WITH THERAPEUTIC USE

a) In clinical trials, fatigue has been reported in 9% of patients receiving infliximab (n=1129) compared to 7% of the patients receiving placebo (n=350) (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

E) HEADACHE

1) WITH THERAPEUTIC USE

a) In clinical studies, headache has been reported in 18% of patients receiving infliximab (n=1129) compared to 14% of the patients receiving placebo (n=350) (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

F) ASEPTIC MENINGITIS

1) WITH THERAPEUTIC USE

a) Tuberculosis meningitis has been reported in association with infliximab therapy (Kashyap & Kashyap, 2002).
b) CASE REPORT: A 53-year-old man developed aseptic meningitis shortly after receiving a sixth infusion of infliximab 3 mg/kg for the treatment of rheumatoid arthritis. The patient had initially received 4 infusions without incident; however, he developed severe, lower extremity myalgia that was not associated with muscle weakness, within 4 hours of receiving the fifth dose of infliximab. Similar symptoms developed 8 weeks later, within 4 hours of receiving the sixth infliximab dose. Neither the fifth nor sixth infusion was associated with headache, stiff neck, or fever. Clinical neurological examination did not reveal abnormal findings; however, analysis of cerebrospinal fluid (CSF) revealed a leukocytosis (50 cells/cubic millimeter) with 45% lymphocytes accompanied by a mean CSF protein concentration of 0.68 grams/liter (L) and mean immunoglobulin G concentration of 88 mg/L (without oligoclonal bands). In both instances of myalgia, symptoms resolved (within 3 days after symptom onset following the fifth dose), and 1 month later, CSF analysis was normal (Marotte et al, 2001).

G) GUILLAIN-BARRé SYNDROME

1) WITH THERAPEUTIC USE

a) Peripheral demyelinating disorders, including Guillain-Barre syndrome, have been reported during postmarketing use of infliximab (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

Gastrointestinal

3.8.2)

A) RELAPSING PANCREATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 51-year-old woman developed an acute exacerbation of chronic-relapsing, yet quiescent pancreatitis within 1 hour of receiving a single infusion of infliximab 5 mg/kg for treatment of fistulizing ileocolonic Crohn's disease. The pancreatitis had been quiescent for approximately 1 year prior to infliximab exposure. Within an hour of infliximab treatment, the patient developed sharp pain in her left upper abdominal quadrant that radiated into her back. Serum concentrations of amylase and lipase were 616 and 227 International Units, respectively; computerized tomography of the abdomen revealed a diffusely enlarged pancreas with peripancreatic edema. The patient was treated conservatively, and pancreatic enzyme concentrations returned to within normal limits over the following 2 days (Fefferman et al, 2001).

B) CHOLECYSTITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Cholecystitis developed twice in a 15-year-old girl while first receiving etanercept and later while taking infliximab for the treatment of polyarticular juvenile idiopathic arthritis. Following 14 weeks of subcutaneous etanercept therapy (0.4 to 0.5 milligram/kilogram (mg/kg) twice weekly), the girl developed upper abdominal pain, nausea, and weight loss. Abdominal sonography revealed a thickening of the gall bladder wall. Etanercept was discontinued and symptoms resolved. Infliximab was then initiated at a dose of 3 mg/kg and administered at weeks 0, 2, 4, 8, 14, and 20. During week 20, the symptoms of cholecystitis that were observed during etanercept therapy reappeared. Infliximab was stopped and the patient's gall bladder was removed. Four weeks following surgery she was free of abdominal symptoms (Foeldvari et al, 2003).

C) NAUSEA

1) WITH THERAPEUTIC USE

a) In a study of adult patients (n=1129) receiving 4 or more infliximab infusions for rheumatoid arthritis, the incidence of nausea was 21% versus 20% in the placebo arm (n=350) (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

D) ABDOMINAL PAIN

1) WITH THERAPEUTIC USE

a) In a study of adult patients (n=1129) receiving 4 or more infliximab infusions for rheumatoid arthritis, the incidence of abdominal pain was 12% versus 8% in the placebo arm (n=350) (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

E) INDIGESTION

1) WITH THERAPEUTIC USE

a) In a study of adult patients (n=1129) receiving 4 or more infliximab infusions for rheumatoid arthritis, the incidence of dyspepsia was 10% versus 7% in the placebo arm (n=350) (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

Hepatic

3.9.2)

A) CHOLESTATIC JAUNDICE SYNDROME

1) WITH THERAPEUTIC USE

a) Cholestatic jaundice was observed in a 44-year-old woman, 19 days after receiving a single infusion of infliximab 5 mg/kg to treat Crohn's disease . Initial symptoms presented as progressive fatigue with nausea, anorexia, and malaise. These symptoms were followed by development of scleral icterus, dark urine, acholic stools, and pruritus, accompanied by elevations in serum alanine and aspartate aminotransferases, and bilirubin, and an increased international normalized ratio. There was a notable absence of hepatosplenomegaly and abdominal tenderness, and an absence of obstructive biliary disease on ultrasonographic examination. Liver biopsy findings were consistent with "bland" cholestasis without evidence of inflammatory response. Maintenance therapies for her Crohn's disease were continued unchanged throughout the hospital course. Complete resolution of symptoms and laboratory abnormalities occurred one month after symptom onset (Menghini & Arora, 2001).

B) TOXIC LIVER DISEASE

1) WITH THERAPEUTIC USE

a) Severe hepatic reactions, some fatal, which include acute liver failure, jaundice, hepatitis, and cholestasis have been reported rarely in postmarketing data in association with infliximab therapy. Diagnosis of autoimmune hepatitis has also been reported. These reactions have occurred within two weeks to more than 1 year after infliximab initiation; fatal cases and cases requiring liver transplantation have also been reported. Infliximab has also been associated with reactivation of hepatitis B virus infection (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).
b) In a case report, a 28-year-old woman with hepatitis B virus (HBV) and adult onset Still's disease developed fulminant hepatitis 10 days after a second infusion of infliximab (3 mg/kg). The patient had positive hepatitis B surface antigen, but no HBV DNA polymerase activity. Prior to and during infliximab therapy, the patient was on a stable drug regimen of prednisone (10 mg/day), naproxen (1100 mg/day), trimethoprim (80 mg/day), and sulfamethoxazole (400 mg/day). An orthotopic liver transplant was performed 5 days later. There was no evidence of HBV reactivation or other etiological factors. The pathogenesis of the hepatic failure was unclear (Michel et al, 2003).

C) LIVER ENZYMES ABNORMAL

1) WITH THERAPEUTIC USE

a) Mild to moderate elevations in liver enzymes have been reported in patients treated with infliximab, without progression to severe hepatic injury. Transient, mild to moderate elevations in liver enzymes were reported more frequently in patients receiving infliximab and methotrexate than those receiving placebo and methotrexate in rheumatoid arthritis clinical trials (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).
b) Elevations in liver aminotransferases (greater than 1 to less than 3 x the upper limit of normal (ULN): 17% to 51%; 3 x ULN or greater: 2% to 10%; 5 x ULN or greater: less than 1% to up to 4%), particularly ALT, occurred in more patients receiving infliximab compared to controls in placebo-controlled clinical trials, where infliximab was used either as monotherapy or in combination with other immunosuppressive agents. The trials evaluated patients with rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis. Patients developing ALT or AST elevations were asymptomatic and the abnormalities decreased or resolved following either continuation or discontinuation of infliximab, or by modification of concomitant medications (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

D) AUTOIMMUNE HEPATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A case of autoimmune hepatitis was described in a 58-year-old woman treated with infliximab for Crohn's disease (CD). The patient had a 19-year history of predominantly ileal CD when she experienced a flare in CD symptoms. Infliximab 5 mg/kg, which was later increased to 10 mg/kg, was added to current medications, which included mesalamine, azathioprine, and budesonide. Several weeks following infliximab initiation, ALT and AST levels rose to 6 and 8 times the ULN, respectively. Notably, total and direct bilirubin levels remained normal, viral hepatitis was negative, and she experienced new elevations in antinuclear antibody (titer of 1:2560) and IgG levels (1800 mg/dL). Despite discontinuation of several medications, including azathioprine, liver function tests continued to be elevated. A liver biopsy revealed chronic hepatitis with moderate and recent activity, and mild periportal fibrosis consistent with a diagnosis of autoimmune hepatitis. Upon discontinuation of infliximab, AST, ALT, antinuclear antibodies, and IgG levels all returned to normal. Subsequent initiation of adalimumab for CD symptoms did not affect liver function (Goldfeld et al, 2011).
b) CASE REPORT: A 58-year-old woman with a 19-year history of ileal Crohn's disease (CD) developed autoimmune hepatitis after receiving infliximab (5 mg/kg initially and then 10 mg/kg) for several weeks. A liver biopsy revealed chronic hepatitis with moderate and recent activity, and mild periportal fibrosis consistent with a diagnosis of autoimmune hepatitis. Upon discontinuation of infliximab, all laboratory parameters returned to normal. Subsequent initiation of adalimumab for CD symptoms did not affect liver function (Goldfeld et al, 2011).

Genitourinary

3.10.2)

A) URINARY TRACT INFECTIOUS DISEASE

1) WITH THERAPEUTIC USE

a) Urinary tract infection has been reported in studies (Elliott et al, 1994a; Elliott et al, 1997). Concurrent steroid therapy was likely contributory in reported cases.
b) In a study of adult patients (n=1129) receiving 4 or more infliximab infusions for rheumatoid arthritis, the incidence of urinary tract infection was 8% versus 6% in the placebo arm (n=350) (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

Hematologic

3.13.2)

A) ANEMIA

1) WITH THERAPEUTIC USE

a) Anemia was reported in 11% of 103 randomized pediatric Crohn's disease patients receiving 5 mg/kg infliximab through 54 weeks. The incidence of anemia in adult Crohn's disease patients receiving a similar treatment regimen (n=385) was greater than or equal to 0.2% but less than 5% (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

B) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) Cases of leukopenia and other hematological disorders, some fatal, have been reported in patients receiving infliximab. Leukopenia was reported in 9% of 103 randomized pediatric Crohn's disease patients receiving 5 mg/kg infliximab through 54 weeks. The incidence of leukopenia in adult Crohn's disease patients receiving a similar treatment regimen (n=385) was greater than or equal to 0.2% but less than 5% (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).
b) Transient leukopenia was reported in a patient receiving infliximab 5 mg/kg for treatment of ankylosing spondylitis. Following the third dose of infliximab, given 6 weeks into treatment, the patient developed transient leukopenia. There were no further complications (Braun et al, 2002).

C) NEUTROPENIA

1) WITH THERAPEUTIC USE

a) Neutropenia was reported in 7% of 103 randomized pediatric Crohn's disease patients receiving 5 mg/kg infliximab through 54 weeks (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).
b) Cases of neutropenia and other hematological disorders, some fatal, have been reported in patients receiving infliximab (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).
c) Severe neutropenia and thrombocytopenia were reported 1 week after the third infliximab infusion (3 mg/kg) in a 60-year-old woman with refractory rheumatoid arthritis. Examination of bone marrow revealed hypoplasia. Beginning 1 month prior to infliximab therapy, the patient also received methotrexate (7.5 mg/week). Ten days after infliximab and methotrexate discontinuation and initiation of cefepime and granulocyte macrophage colony-stimulating factor, the cytopenias were resolved (Vidal et al, 2003).

D) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) Cases of thrombocytopenia and other hematologic disorders, some fatal, have been reported in patients receiving infliximab (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).
b) Severe thrombocytopenia and neutropenia were reported 1 week after the third infliximab infusion (3 mg/kg) in a 60-year-old woman with refractory rheumatoid arthritis. Examination of bone marrow revealed hypoplasia. Beginning 1 month prior to infliximab therapy, the patient also received methotrexate (7.5 mg/week). Ten days after infliximab and methotrexate discontinuation and initiation of cefepime and granulocyte macrophage colony-stimulating factor, the cytopenias were resolved (Vidal et al, 2003).

E) BONE MARROW DEPRESSION

1) WITH THERAPEUTIC USE

a) CASE REPORT: Acute bone marrow depression was diagnosed 10 days following first exposure to infliximab being used to treat refractory rheumatoid arthritis in a 66-year-old man. Hematology revealed pancytopenia (white cells to 1 x 10(9)/L, hemoglobin 7.5 g/dL, and platelets 15 x 10(9)/L). Bone marrow biopsy was consistent with hypoplasia. Aggressive supportive treatment including transfusion led to complete recovery within 2 weeks. Infliximab could not be exclusively implicated because of other risks, which included recent drug treatment with leflunomide, methotrexate and allopurinol, and concomitant medical problems including nephropathy. Prior to infliximab, existing bone marrow toxicity was reflected in a depressed platelet count (125 x 10(9)) (Marchesoni et al, 2003).

F) HEMOPHAGOCYTIC SYNDROME

1) WITH THERAPEUTIC USE

a) Hemophagocytic syndrome (HPS) developed in a 46-year-old woman who received infliximab (3 mg/kg) for refractory rheumatoid arthritis. Six weeks after the seventh infliximab infusion, the patient presented with fever, dehydration, weight loss, lethargy, hepatosplenomegaly and right flank pain; Escherichia coli was found in urine and blood cultures, HPS was diagnosed and confirmed by bone marrow aspiration. The authors suggest that infliximab weakened the immune system, which may have been responsible for the bacterial infection that led to HPS (Aouba et al, 2003).

G) PANCYTOPENIA

1) WITH THERAPEUTIC USE

a) Cases of pancytopenia and other hematologic disorders, some fatal, have been reported in patients receiving infliximab (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

H) AGRANULOCYTOSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Agranulocytosis developed after infliximab administration in a 28-year-old man with a suspected small intestine inflammatory flare of Crohn's disease. The patient, who had been maintained on azathioprine 150 mg daily and occasional oral budesonide, was initially admitted to the hospital with nausea, vomiting, abdominal pain, constipation, and fever. Mild leukocytosis, neutrophilia, an elevated C-reactive protein level, and a mesenteric fluid collection and mesenteric inflammatory changes were found upon investigation. Despite treatment with antibiotics (ie, ciprofloxacin and metronidazole, and later, piperacillin/tazobactam), IV corticosteroids, and parenteral nutrition for 3 weeks, abdominal pain and vomiting persisted with oral intake attempts. Infliximab 5 mg/kg was administered, with relief of abdominal symptoms; however, absolute neutropenia and fever developed postinfusion. Bone marrow biopsy revealed a myeloid series expression of 23% made up of promyelocytes, with no mature-stage cells; blood cultures were negative. Cefepime, amikacin, fluconazole, and colony stimulating factor were administered, and the neutropenia resolved and the patient was discharged. Normal leukocyte counts were noted at later outpatient visits (Rosales-Zabal et al, 2011).

Dermatologic

3.14.2)

A) SKIN FINDING

1) WITH THERAPEUTIC USE

a) Serious skin reactions, including erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome, have been reported rarely with the use of tumor necrosis factor-alpha antagonists, including infliximab (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015; United States Food and Drug Administration, 2008). In general, presenting symptoms of the serious skin reactions were mainly rash and skin lesions on the trunk, legs, arms, shoulder, back, hands, and face. Additionally, oral mucositis or ulceration, genital ulceration, and/or fever were present in some SJS cases (United States Food and Drug Administration, 2008).
b) The United States Food and Drug Administration has received reports of 21 cases (16 postmarketing and 5 study/registry) of serious skin reactions following infliximab administration, including 15 cases of erythema multiforme (EM), one case of toxic epidermal necrolysis (TEN), and 5 cases of Stevens-Johnson syndrome (SJS). The majority of patients affected were women (76%) and were being treated for rheumatoid arthritis (62%). Fifteen patients (71%) were receiving concomitant medications associated with EM, TEN, and/or SJS; additionally, 5 of these cases reported one or more other suspected medications including sulfasalazine, mercaptopurine, and leflunomide. The median time to skin reaction onset was 28 days, with a median of 2 infusions (range, 1-6 infusions) administered before the reaction occurred. Twelve patients with skin reactions required hospitalization and one patient died of multi-organ system failure 20 days following first infusion. One negative rechallenge, 2 positive rechallenges, and 15 positive dechallenges were reported (United States Food and Drug Administration, 2008).
c) CASE REPORT: A 36-year-old woman receiving concomitant clomipramine and amitriptyline experienced eczema-like cutaneous lesions over her trunk and all limbs one day after receiving a second infusion of infliximab (2 weeks after the first) for the treatment of rheumatoid arthritis. The lesions resolved with administration of an antihistamine. One month later, a third infusion resulted in severe generalized erythroderma associated with Stevens-Johnson syndrome (SJS), including mucositis and fissures on her hands and feet. Infliximab-induced erythroderma with SJS was diagnosed upon skin biopsy and a negative immunofluorescence test. Infliximab was discontinued and the skin reaction improved over several weeks, after receiving systemic corticosteroids, antihistamines, and cutaneous care (United States Food and Drug Administration, 2008).

B) FLUSHING

1) WITH THERAPEUTIC USE

a) Skin flushing was reported in 9% of pediatric patients (n=103) with Crohn's disease who received infliximab (5 mg/kg) for 54 weeks (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

C) ERUPTION

1) WITH THERAPEUTIC USE

a) In adult patients with rheumatoid arthritis, rash was reported in 10% of patients treated with 4 or more infliximab infusions (n=1129) compared to 5% of patients in the placebo group (n=350) (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).
b) CASE REPORT: Bullous skin lesions were reported in a 72-year-old man 1 day after the fourth dose of infliximab for the treatment of rheumatoid arthritis. A definitive causal relationship could not be established (Kent et al, 2002).
c) CASE REPORT: A cutaneous psoriasiform eruption was reported in a 46-year-old woman receiving infliximab for the treatment of Crohn's disease. The patient had pruriginous, erythematous, desquamative plaques on her knees, elbows, hands and buttocks after the second and third infliximab doses. Histology revealed a lichenoid pattern. No additional cutaneous lesions developed after the discontinuation of infliximab (Verea et al, 2004).

D) ITCHING OF SKIN

1) WITH THERAPEUTIC USE

a) In adult patients with rheumatoid arthritis, pruritus was reported in 7% of patients treated with 4 or more infliximab infusions (n=1129) compared to 2% of patients in the placebo group (n=350) (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

E) DRUG-INDUCED ERYTHEMA

1) WITH THERAPEUTIC USE

a) Three cases of red-man syndrome from too-rapid infusion rates of infliximab point out the importance of distinguishing between true allergic reaction and the red-man syndrome. Each patient was being treated for severe Crohn's disease. In one 50-year-old man, exposed to infliximab for the second time, infusion (300 mg/250 mL saline) at 100 mL/hour for less than 1 minute resulted in widespread flushing, tachycardia, and shortness of breath. Administration of IV antihistamine was immediately successful in reversing symptoms. Restarting the infusion at 40 mL/hour was well-tolerated. Despite premedication with antihistamine, however, two other patients experienced red man syndrome (at first and second exposures) during upward titration of infusion rates to 150 mL/hour, though both tolerated rates up to 80 mL/hour (Lobel et al, 2003).

F) NECROTIZING FASCIITIS

1) WITH THERAPEUTIC USE

a) Necrotizing fasciitis, resulting in severe sepsis and death, developed in a 54-year-old man after receiving a minimum of 4 treatments with intravenous infliximab 3 mg/kg and concomitant methotrexate therapy over an 8-week interval for management of treatment-refractory rheumatoid arthritis. The patient had previously required a left total hip arthroplasty with 2 subsequent revisions. He initially presented with an acute pustular dermatitis, accompanied by a general feeling of lethargy and of being unwell, and loss of appetite; however, he was afebrile. White blood cell count on admission was 14.82 x 10(9) cells/liter (L), with 13.99 x 10(9) neutrophils/L. Five hours after initial presentation, the patient experienced syncope and collapsed. His left leg was noted to be painful, with tense edema. Surgical exploration of the extremity revealed marked necrosis of the adductor muscle group and associated fascia; subsequent biopsy sample and blood cultures grew isolates of hemolytic group A streptococcus. The patient remained afebrile, yet he subsequently died after developing disseminated intravascular coagulopathy and multi-organ failure that did not respond to aggressive treatment (Chan et al, 2002).

G) LICHEN PLANOPILARIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 37-year-old man who was taking methotrexate, developed lichen planopilaris after 11 months of treatment with infliximab for recalcitrant plaque psoriasis. He presented with follicular hyperkeratosis, papulo-pustules, perifollicular erythema, and scaling, as well as progressive hair loss of the frontal and parietal regions of the scalp and eyebrows. A skin biopsy revealed hyperkeratosis, and lymphoid inflammatory infiltrate in the dermis. He was given a diagnosis of lichen planopilaris, and treatment with oral deflazacort 35 mg/day was initiated and tapered with a mild response of his scalp and eyebrows. Due to the lack of progression of lichenoid lesions and satisfactory control of his psoriasis, infliximab therapy was continued (Fernandez-Torres et al, 2010).

Musculoskeletal

3.15.2)

A) FRACTURE OF BONE

1) WITH THERAPEUTIC USE

a) Bone fracture was reported in 7% of 103 randomized pediatric Crohn's disease patients receiving 5 mg/kg infliximab through 54 weeks (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

B) BACKACHE

1) WITH THERAPEUTIC USE

a) In a study of adult patients (n=1129) receiving 4 or more infliximab infusions for rheumatoid arthritis, the incidence of back pain was 8% versus 5% for the placebo arm (n=350) (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

Immunologic

3.19.2)

A) ANAPHYLAXIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 37-year-old man with ankylosing spondylitis developed an anaphylactic reaction leading to cardiopulmonary arrest after a second infusion of infliximab (Miki et al, 2011).
b) CASE REPORT: Severe anaphylaxis developed in a 33-year-old man with Crohn's disease during administration of the second of 3 scheduled infliximab infusions. Hypotension, chest pain, dyspnea, flushing, nausea and vomiting, tachycardia, and urticaria were observed 5 minutes after the second infusion. Symptoms gradually regressed after discontinuation of the infliximab infusion. The authors relate the anaphylactic reaction to the development of a human chimeric antibody response to infliximab (Soykan et al, 2000).
c) CASE REPORTS: Severe infusion-related reactions were reported in 2 adolescent girls receiving infliximab for the treatment of Crohn's disease, approximately 2 minutes after the start of the third and second infusion, respectively. Flushing, tachycardia, dyspnea, hypotension, chest pain, dysphagia, and urticaria were associated with these reactions. Both patients responded to volume expansion, steroids, and antihistamines with symptom resolution in 4 to 5 hours. The authors reported a preference for premedicating (antihistamine and steroid) all patients prior to infliximab infusions to avoid severe reactions (Diamanti et al, 2002).
d) CASE REPORT: A 35-year-old woman had a fatal anaphylactic reaction after receiving the third dose of infliximab 5 mg/kg for treatment of fistulous Crohn's disease. Shortly after receiving an infusion of 5 milliliters diluted solution, the patient developed chest pain and dyspnea, followed thereafter by cyanosis, cough with frothy sputum, generalized skin rash, respiratory failure and refractory hypotension. The author reports that the patient had shown previous hypersensitivity reactions to mesalamine compounds (Lankarani, 2001).

B) HYPERSENSITIVITY REACTION

1) WITH THERAPEUTIC USE

a) Hypersensitivity reactions have occurred during or within 2 hours of infusion with symptoms including dyspnea, urticaria, and/or hypotension. Serum-sickness like reactions have occurred in patients with Crohn's disease following an extended period without infliximab therapy. These reactions were observed 3 to 12 days after infusion with symptoms including rash, fever, headache, sore throat, polyarthralgias, myalgias, hand and facial edema and/or dysphagia (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015). Respiratory tract allergic reactions were reported in 6% of 103 randomized pediatric Crohn's disease patients receiving 5 mg/kg infliximab through 54 weeks (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015). Crohn's disease patients that developed Human antichimeric antibodies (HACA) to infliximab were more likely to experience an infusion reaction than those not developing antibodies (36% versus 11%, respectively). It is not clear whether pre-medicating patients who have had previous exposure to infliximab will decrease the frequency of immediate or delayed hypersensitivity reactions. It is also unknown whether HACA concentrations are predictive for delayed hypersensitivity reactions (Riegert-Johnson et al, 2002).
b) Crohn's disease patients who developed antibodies against infliximab were at an increased risk of immediate infusion reactions and had a shorter response duration compared to patients who did not develop antibodies. Antibody concentrations greater than 8 mcg/mL predicted a higher risk of infusion reaction (p less than 0.001). The use of concomitant immunosuppressive therapy seemed to reduce serum antibody levels, which decreased the frequency of infusion reactions and increased the duration of response (Baert et al, 2003).
c) CASE REPORT: A 33-year-old man developed a delayed hypersensitivity reaction complicated by adult respiratory distress syndrome (ARDS), within 7 days of receiving a second dose of infliximab for treatment of an exacerbation of Crohn's colitis. The patient had received an initial dose of infliximab 15 months earlier, without adverse sequelae. Seven days after receiving a second infusion of infliximab 5 mg/kg, the patient presented with complaints of arthralgias, myalgias, nausea and vomiting. Symptoms progressed over the next 3 days to include dyspnea, fever, and chills. Computed tomography of the chest revealed the presence of interstitial infiltrates in the right middle and left lower lobes, with coalescence of infiltrates in small nodules. Open-lung biopsy confirmed the presence of a patchy fibrinous exudates with marked eosinophilia, consistent with eosinophilic pneumonia. Human antichimeric antibody titer showed a high concentration (22.52 mcg/mL) at time of admission. The man's pulmonary function worsened after biopsy, eventually requiring intubation and mechanical ventilatory support. Follow-up chest radiography revealed diffuse, ground-glass infiltrates, consistent with ARDS. All microbiological cultures were negative for pathogens. The patient was treated with intravenous methylprednisolone, his pulmonary function consistently improved, and he was successfully extubated 29 days after receiving the second infliximab dose, with hospital discharge occurring 9 days thereafter (Riegert-Johnson et al, 2002).

C) IMMUNE SYSTEM FINDING

1) WITH THERAPEUTIC USE

a) Human anti-infliximab (cA2) antibodies, double-stranded DNA antibodies, cardiolipin antibodies reported up to 3 months after infusion in some patients (Targan et al, 1997a; Elliott et al, 1994a; Higgins, 1997). Persistence of serum infliximab levels may have interfered with human anti-infliximab assay (Targan et al, 1997a).
b) Patients who develop human anti-chimeric antibodies (HACA) to infliximab may be predisposed to experiencing infusion-related reactions. In addition, development of HACA may be associated with diminishing response to infliximab given alone. It has been postulated that combining infliximab with methotrexate may result in decreased formation of HACA, resulting in a longer duration of response to infliximab (Luong et al, 2000).

D) DRUG-INDUCED LUPUS ERYTHEMATOSUS

1) WITH THERAPEUTIC USE

a) Approximately half of infliximab-treated patients in clinical trials who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately one-fifth of the placebo-treated patients. Reports of lupus-like syndromes, however, remain uncommon (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).

E) DISSEMINATED CYTOMEGALOVIRUS INFECTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: In a case report, a 9-year-old boy with comorbid sickle-cell anemia and Crohn's disease developed fatal disseminated cytomegalovirus (CMV) infection following treatment with infliximab (last treatment 5 weeks earlier) and 6-mercaptopurine. The patient presented with fever, extremity pain, and bloody diarrhea, and upon evaluation had icteric sclera and abnormal hemoglobin and leukocyte counts. CMV was isolated from the urine, and CMV IgM and IgG serologies were positive. Peripheral blood leukocytes were negative for CMV antigen when tested after 2 weeks of antiviral therapy. The 6-mercaptopurine was discontinued, and despite treatment with IV hydration, vancomycin, ticarcillin/clavulanate, ganciclovir, foscarnet, immune globulin, and antifungal therapy, the patient continued to deteriorate and died 4 weeks after hospitalization. Postmortem examination revealed bronchopneumonia, giant cells in the lungs with a single focus positive for CMV antigen, and acute and chronic inflammatory cells in the esophagus, stomach, pancreas, liver, and spleen. The bowel was ulcerated with cryptitis and crypt abscess formation (Pickering et al, 2009).

F) HERPES ZOSTER

1) WITH THERAPEUTIC USE

a) During clinical trials of infliximab for pediatric use, 3 cases of herpes zoster were reported. In a study of children with Crohn's disease, 2 patients receiving infliximab every 8 weeks developed herpes zoster infection (no such infections were observed in patients receiving every 12-week infusions). In a study of children receiving concomitant infliximab and methotrexate for juvenile rheumatoid arthritis, one patient developed herpes zoster infection (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015).
b) CASE REPORT: Severe herpes zoster rash developed in a 72-year-old rheumatoid arthritis patient following his second infliximab infusion (Kinder et al, 2004).

Reproductive

3.20.1)

A) Infliximab is classified as FDA pregnancy category B. There are no adequate and well-controlled studies with infliximab use during pregnancy. Administer to a pregnant woman only if clearly needed. Consider limiting infliximab use to the first 30 weeks of pregnancy. Caution is warranted in live-virus vaccinations, including rotavirus, intranasal influenza vaccine, and BCG, in infliximab-exposed infants up to 6 months of age or with detectable infliximab serum levels.

3.20.2)

A) LACK OF INFORMATION

1) It is not known if congenital malformations may be caused by fetal exposure (Prod Info INFLECTRA intravenous injection, 2016; Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015a).

B) LACK OF EFFECT

1) In 3 registry studies of 300 pregnancy outcomes, exposure to infliximab during pregnancy did not show a significantly increased risk of fetal anomalies when compared with women without infliximab exposure or exposed to other immunosuppressive therapies during pregnancy (Djokanovic et al, 2011)
2) During an observational study of 212 pregnancy outcomes, exposure to infliximab (IFX) or adalimumb (ADA) did not lead to an increased risk of fetal anomalies compared with untreated women; however, premature deliveries were observed more frequently in women with direct exposure to IFX or ADA compared with the control group. There were a total of 42 pregnancies with direct exposure to IFX or ADA, 23 pregnancies prior to IBD diagnosis, 78 pregnancies after diagnosis of IBD and before IFX implementation, 53 pregnancies with indirect IFX exposure, and 56 pregnancies in healthy women. Thirty-two of the 42 direct IFX exposure pregnancies resulted in live births, although one child died after 13 days due to necrotizing enterocolitis. Seven premature deliveries, 6 children with low birth weight, and one stillbirth were observed. Of the 42 pregnancies, one was terminated due to trisomy 18. There were a total of 44 live births from 53 pregnancies with indirect exposure to IFX and one elective abortion due to trisomy 21. Additionally, there were a total of 65 live births from 78 pregnancies after diagnosis of IBD but prior to IFX implementation and a total of one elective abortion due to karyotype45/XO. There were a total of 48 live births from 56 pregnancies in the control group and no reports of neonatal malformations resulting in an elective abortion (Schnitzler et al, 2011).
3) High levels of infliximab were found in a breast-fed infant following infliximab therapy for Crohn's disease (CD) in the 35-year-old mother prior to and during pregnancy. Throughout pregnancy, the mother received 5 infliximab 10 mg/kg infusions at 6 to 8 week intervals, with the last infusion 2 weeks prior to delivery. The infant was born at 41 weeks gestation without complications. Two weeks following delivery, the mother's CD required another 10 mg/kg of infliximab. Due to the mother's concerns regarding tumor necrosis factor (TNF) inhibitors increasing the chance of developing lymphoma, she requested serum infliximab levels be measured. Both mother and infant serum levels were measured 6 weeks following delivery (4 weeks following the last maternal infliximab infusion) and found to be 40 mcg/mL and 39.5 mcg/mL, respectively. However, infliximab was not detected in the breast milk. Consecutive serum measurements showed a continual decrease in the infant's infliximab levels during the next 6 months, despite breast feeding and subsequent maternal infliximab treatment. The authors suggest that infliximab be avoided after 30-weeks' gestation and the mother bridged with steroids if necessary to control CD until after delivery (Vasiliauskas et al, 2006).
4) A retrospective analysis suggests maternal treatment with infliximab during pregnancy is not associated with adverse outcome to the pregnancy or the infant. Ten women were intentionally treated with infliximab 5 mg/kg for induction and maintenance therapy of Crohn's disease during pregnancy. Upon delivery and at a mean follow-up at age 6 months, none of the 10 infants had congenital malformations, intrauterine growth retardation, or was small for gestational age. Of the 10 pregnancies, 3 were born premature and 1 with low-birth weight (Mahadevan et al, 2005).

3.20.3)

A) PREGNANCY CATEGORY

1) The manufacturer has classified infliximab and infliximab-dyyb as FDA pregnancy category B (Prod Info INFLECTRA intravenous injection, 2016; Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015a).
2) Administer to a pregnant woman only if clearly needed (Prod Info INFLECTRA intravenous injection, 2016; Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015a). Consider limiting infliximab use to the first 30 weeks of pregnancy. Caution is warranted in live-virus vaccinations, including rotavirus, intranasal influenza vaccine, and BCG, in infliximab-exposed infants up to 6 months of age or with detectable infliximab serum levels (Djokanovic et al, 2011).

B) PLACENTAL BARRIER

1) As infliximab is known to cross the placental barrier and serum levels have been detected in infants exposed to infliximab in-utero for up to 6 months, caution is advised when administering live vaccines, such as rotavirus, intranasal influenza vaccine, and bacilli Calmette-Guerin (BCG), to infants exposed to infliximab (Prod Info INFLECTRA intravenous injection, 2016; Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015a; Djokanovic et al, 2011) and a 6-month waiting period is recommended prior to administration of live vaccines (Prod Info INFLECTRA intravenous injection, 2016). Infliximab is not expected to cross the placenta until late second and third trimesters and therefore may spare the fetus from infliximab exposure during the critical organogenesis period. Consider limiting infliximab use to the first 30 weeks of pregnancy to minimize fetal exposure (Djokanovic et al, 2011).
2) In 3 registry studies of 300 pregnancy outcomes, infliximab exposure did not lead to a significantly increased risk of fetal anomalies compared with untreated women or women exposed to other immunosuppressives; however, the impact and duration of immune suppression remains unclear, as illustrated by a case of fatal disseminated mycobacterial infection that occurred after bacilli Calmette-Guerin (BCG) vaccination in a healthy infliximab-exposed infant (Djokanovic et al, 2011).

C) SMALL FOR GESTATIONAL AGE

1) A 36-year-old pregnant woman treated during the second trimester with infliximab 5 mg/kg salvage therapy for recurrent severe ulcerative colitis (UC) gave birth prematurely (week 37) to a small-for-gestational-age infant. There were no delivery complications or neonatal morbidity, and the infant's weight increased to normal ranges within 4 weeks of birth (Aratari et al, 2011).

D) PREMATURE DELIVERY

1) A 36-year-old pregnant woman treated during the second trimester with infliximab 5 mg/kg salvage therapy for recurrent severe ulcerative colitis (UC) gave birth prematurely (week 37) to a small-for-gestational-age infant. There were no delivery complications or neonatal morbidity, and the infant's weight increased to normal ranges within 4 weeks of birth (Aratari et al, 2011).
2) In a single case report, a 26-year-old woman with active Crohn's disease received 2 infusions of infliximab at approximately week 1 and week 3 after conception. The baby was born prematurely (at 24 weeks postconception; birth weight 681 grams) and died of complications on day 3 of life. The patient was also receiving azathioprine, metronidazole, and mesalamine at the time of conception. It is unclear what role infliximab may have played in the outcome of this pregnancy, as active Crohn's disease is a risk factor for low birth weight and premature delivery (Srinivasan, 2001).

E) LACK OF EFFECT

1) During an observational study of 212 pregnancy outcomes in women with inflammatory bowel disease (IBD) aged 18 to 40 years, exposure to infliximab (IFX) or adalimumb (ADA) did not lead to an increased risk of fetal anomalies compared with untreated women; however, premature deliveries were observed more frequently in women with direct exposure to IFX or ADA (27 out of 161 live births) compared with the control group (3 out of 48 live births). There were a total of 42 pregnancies with direct exposure to IFX (n=35) or ADA (n=7), 23 pregnancies prior to IBD diagnosis, 78 pregnancies after diagnosis of IBD and before IFX implementation, 53 pregnancies with indirect IFX exposure, and 56 pregnancies in healthy women. Thirty-two of the 42 direct IFX exposure pregnancies resulted in live births, although one child died after 13 days due to necrotizing enterocolitis. Seven premature deliveries, 6 children with low birth weight, and one stillbirth were observed. Of the 42 pregnancies, one was terminated due to trisomy 18. There were a total of 44 live births from 53 pregnancies with indirect exposure to IFX and one elective abortion due to trisomy 21. Additionally, there were a total of 65 live births from 78 pregnancies after diagnosis of IBD but prior to IFX implementation and a total of one elective abortion due to karyotype45/XO. There were a total of 48 live births from 56 pregnancies in the control group and no reports of neonatal malformations resulting in an elective abortion (Schnitzler et al, 2011).

F) ANIMAL STUDIES

1) Infliximab does not cross-react with TNF-alpha in species other than humans and chimpanzees. Therefore, no animal reproduction studies have been performed with infliximab. When an analogous antibody that selectively inhibits the functional activity of mouse TNF-alpha was used in an animal study, no embryotoxic or teratogenic effects were observed (Prod Info INFLECTRA intravenous injection, 2016; Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015a).

3.20.4)

A) BREAST MILK

1) Discontinue infliximab or discontinue nursing taking into account the importance of the drug to the mother (Prod Info INFLECTRA intravenous injection, 2016; Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015a).
2) Within 12 hours of the first infusion of infliximab, levels in breast milk rose rapidly and peaked at 90 to 105 ng/mL on days 2 to 3 in mothers (n=3) treated with infliximab for Crohn's disease. Breast milk samples were collected for up to 8 days following the first infusion of infliximab 5 mg/kg, which was not initiated during the first 5 days following delivery to avoid expression in colostrum milk. Testing was accurate to detect infliximab levels as low as 10 nanograms/mL in breast milk. Following peak levels on days 2 to 3, the levels plateaued thereafter. Corresponding blood levels during this period ranged from 18 to 64 mcg/mL. In all 3 infliximab-treated women, breastfeeding was discontinued following infliximab initiation (Ben-Horin et al, 2011).
3) Data suggests infliximab is undetectable in the breast milk of mothers receiving infliximab. Three case studies of women (ages 29, 32, and 24 years) with Crohn's disease began receiving infliximab 5 mg/kg either prior to or during pregnancy and while breast feeding. Each mother and child had serum and breast milk samples collected postpartum (no serum samples available from 1 child). Levels of infliximab detected in the mothers' serum samples were 74.27 mcg/mL, 62.62 mcg/mL, and 59.97 mcg/mL, respectively. However, infliximab serum levels (less than 0.1 mcg/mL) were undetectable in all 3 mother's breast milk, as well as in all 3 children (Kane et al, 2009).
4) No clinically significant amounts of infliximab were detected in a 22-year-old woman with Crohn's disease who received infliximab treatment during pregnancy and breast feeding. The mother received a total of 6 infliximab 10 mg/kg doses during her pregnancy with the last infusion administered 2 weeks prior to delivery. The child was born healthy at 39 weeks gestation. At this time, the mother decided to continue treatment with infliximab while breast feeding. Serum and breast milk infliximab levels were monitored throughout a period of 30 days. During analysis, breast milk samples were spiked with infliximab 40 ng/mL to match the mother's serum concentration. On day 30, infliximab was identified in all the spiked samples but none in the mother's regular breast milk. At 27 months of age, no developmental issues were noted in the child (Stengel & Arnold, 2008).

3.20.5)

A) ANIMAL STUDIES

1) In a fertility and general reproduction toxicity study (with the analogous mouse antibody used in the 6-month chronic toxicity study), there was no impairment of fertility (Prod Info INFLECTRA intravenous injection, 2016; Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2015a).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS170277-31-3 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) Cases of aggressive and often fatal hepatosplenic T-cell lymphoma have been reported in postmarketing experience in young adult and adolescent Crohn's disease patients receiving infliximab and azathioprine or 6-mercaptopurine concurrently. During postmarketing use, non-Hodgkin's lymphoma, Hodgkin's disease, and other malignancies, including melanoma and Merkel cell carcinoma, have been reported. In clinical trials, non-lymphoma malignancies (lung or head and neck; most common were breast, colorectal, and melanoma malignancies) have also been reported in patients receiving infliximab.

3.21.3)

A) LYMPHOMA

1) Cases of aggressive and often fatal hepatosplenic T-cell lymphoma have been reported in post marketing experience in young adult and adolescent Crohn's disease patients receiving infliximab and azathioprine or 6-mercaptopurine concurrently (Prod Info REMICADE(R) IV injection, 2007).
2) An increased risk of lymphoma and other malignancies was reported in children and adolescents receiving tumor necrosis factor (TNF) blockers. An 8-year review identified 48 cases, not limited to the United States, of malignancies in children and adolescents receiving TNF blockers, with approximately half of the cases reported as lymphomas, including hepatosplenic T-cell (10 cases), Hodgkin (6 cases), and non-Hodgkin (7 cases) lymphoma. Leukemia (6 cases), malignant melanoma (3 cases), and solid organ cancers were also reported. Most of the cases (88%) were also receiving concurrent immunosuppressive therapy with agents such as azathioprine and methotrexate. Rare malignancies included leiomyosarcoma (1 case), hepatic malignancy (1 case), and renal cell carcinoma (1 case). Of the cases reported, 31 cases were associated with infliximab (5 cases with rheumatic conditions), 15 cases were associated with etanercept (14 cases with rheumatic conditions), and 2 cases were associated with adalimumab (1 case with rheumatic conditions). Overall, 11 cases of malignancy were fatal, and causes of death included hepatosplenic T-cell lymphoma (9 cases), T-cell lymphoma (1 case), and sepsis following remission of the lymphoma (1 case). No specific dose was identified as being associated with the development of the malignancies (US Food and Drug Administration, 2009; US Food and Drug Administration, 2009). As of December 31, 2010, the US Food and Drug Administration has documented 20 cases worldwide of hepatosplenic T-cell lymphoma in patients who received infliximab and 5 cases in patients who received infliximab/adalimumab since the initiation of TNF blockers to the market. Most cases were fatal (n=21) and most occurred in patients receiving concomitant therapy with azathioprine or mercaptopurine. The patients were primarily adolescents and young adults who were being treated for Crohn disease or ulcerative colitis. No specific dose or duration of use was identified as being associated with the development of hepatosplenic T-cell lymphoma (US Food and Drug Administration, 2011).
3) In an "Early Communication", the FDA warns about a possible association between tumor necrosis factor (TNF) blockers and the development of lymphoma and other cancers in children and young adults. Over a 10-year period, there were 30 reports of cancer in children and young adults who received TNF blockers and other immunosuppressive agents (eg, methotrexate, azathioprine or 6-mercaptopurine) for Juvenile Idiopathic Arthritis, Crohn's disease or other diseases. Approximately 50% of the cancers were lymphomas (both Hodgkin's and non-Hodgkin's lymphoma), and other cancers included leukemia, melanoma, and solid organ cancers. Causality has not been established and the potential association between TNF blockers and malignancies is being assessed. The FDA recommends the potential benefit should outweigh the potential risk when using TNF blockers in children or young adults (US Food and Drug Administration, 2008).
4) CASE REPORT - A case of fatal hepatosplenic T-cell lymphoma occurred in a 17-year-old girl 27 months after starting infliximab therapy for ileocolonic Crohn's disease complicated by perianal fistulae and growth failure. The patient's therapy consisted of 5 mg/kg infliximab infusions at weeks 0, 2, and 6 with succeeding treatments performed at 5 to 8 week intervals as needed. Her concurrent medications included 6-mercaptopurine (50 mg/day) and mesalamine (3 g/day). After 27 months of infliximab treatment, the patient developed fever, malaise, and right upper quadrant abdominal pain; clinical examination and diagnostic tests revealed splenomegaly with enlargement of the portal vein. Upon the presumptive diagnosis of autoimmune hepatitis, she was started on prednisone and her 6-mercaptopurine and mesalamine were both discontinued. Despite the changes in her drug regimen, her hepatic transaminases remained elevated and the patient was reevaluated for a second opinion. A review of her earlier liver biopsy with additional testing supported the diagnosis of a malignant alpha-beta type T-cell lymphoma. A subsequent liver biopsy and an unremarkable bone marrow aspiration confirmed the lymphoma diagnosis. At this point in time, the patient had already received a total of twenty 5 mg/kg infliximab doses during the previous 29 months and 4.5 years of daily 6-mercaptopurine (50 to 75 mg ) doses. She was treated with neoadjuvant chemotherapy in advance of a bone marrow transplant and died of complications related to pancytopenia and sepsis 3 months after her diagnosis (Thayu et al, 2005).
5) There were 8 cases of hepatosplenic T-cell lymphoma (HSTCL) in young patients (age range 12 to 31 years; 7 males) receiving infliximab for the treatment of Crohn's disease (n=7) and ulcerative colitis (n=1) reported to the US Food and Drug Administration's Adverse Event Reporting System up until October 5, 2006. Six out of these 8 cases were fatal. All patients were receiving concomitant immunosuppressant therapy, including azathioprine, mercaptopurine, prednisone and mesalamine, in which at least 7 of these patients started infliximab treatment after concomitant medications were initiated. Therefore, a causal relationship has not been established. However, in the 100 or more reported HSTCL cases, 8 of these patients were receiving infliximab treatment. Additionally, although there have been 15 cases reported as T-cell lymphoma in patients receiving infliximab for a variety of indications, the subtype was not reported (Mackey et al, 2007).
6) Non-Hodgkin's lymphoma and Hodgkin's disease have been reported during postmarketing use (Prod Info REMICADE(R) IV injection, 2007).

B) LEUKEMIA

1) A review of 147 postmarketing reports of leukemia in all patients using tumor necrosis factor (TNF) blockers included 44 cases of acute myeloid leukemia, 31 cases of chronic lymphocytic leukemia, and 23 cases of chronic myeloid leukemia. Four cases of leukemia were reported in pediatric patients. Concomitant immunosuppressive therapies were used in 61% of the cases. In 26 of the 30 deaths reported, the cause was attributed to leukemia and was associated with the use of TNF blockers. Leukemia occurred within the first 1 to 2 years of therapy (US Food and Drug Administration, 2009).

C) MERKEL CELL CARCINOMA

1) Merkel cell carcinoma has been reported in patients receiving tumor necrosis factor blockers, including infliximab, during postmarketing surveillance (Prod Info REMICADE(R) intravenous lyophilized concentrate injection, 2013).

D) SKIN CANCERS

1) Melanoma has been reported in patients receiving tumor necrosis factor blockers, including infliximab, during postmarketing surveillance (Prod Info REMICADE(R) intravenous lyophilized concentrate injection, 2013).
2) Results from meta- and exposure-adjusted pooled analyses involving 8808 patients with rheumatoid arthritis found no increase in the odds of non-melanoma skin cancers associated with recommended doses of adalimumab, etanercept, or infliximab. Results of 18 randomized controlled trials with over 7846 years of follow-up were included in the analyses. The odds ratio for non-melanoma skin cancer using the unadjusted meta-analytic method was 1.27 (95% CI, 0.67 to 2.42). In the studies that reported incidence of malignancies, 34 of 4099 patients who were randomized to recommended doses over 3805 patient-years developed malignancies (0.8%). Of these malignancies, 12 occurred after crossover while 10 were unable to be allocated to the controlled or uncontrolled portion of the trial. Of the 2672 control patients, 15 (0.6%) developed a malignancy over 2124 patient-years. Overall, there was no increased risk for lymphomas, non-melanoma skin cancers, or the composite endpoint of non-cutaneous cancer and melanoma at recommended doses (Leombruno et al, 2008).

E) OTHER MALIGNANCIES

1) In clinical trials, non-lymphoma malignancies (lung or head and neck; most common were breast, colorectal, and melanoma malignancies) have been reported in patients receiving infliximab (Prod Info REMICADE(R) IV injection, 2007).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
B) Monitor vital signs, mental status, and liver enzymes in symptomatic patients.
C) Obtain an ECG, and institute continuous cardiac monitoring.
D) Monitor serial CBC with differential and platelet count.
E) Monitor patient for clinical signs of infection.

Treatment

Life Support

A)

Patient Disposition

6.3.2)

6.3.2.1) ADMISSION CRITERIA/PARENTERAL

A) Patients with severe symptoms despite treatment should be admitted.

6.3.2.2) HOME CRITERIA/PARENTERAL

A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.

6.3.2.3) CONSULT CRITERIA/PARENTERAL

A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

6.3.2.5) OBSERVATION CRITERIA/PARENTERAL

A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

A)

B)

C)

D)

E)

Oral Exposure

6.5.1)

A) Gastrointestinal decontamination is not necessary; administered via the parenteral route.

Abstracts

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) INFLIXIMAB

1) Varies by indication. Range of 3 mg/kg to 5 mg/kg IV over 2 hours at 0, 2, and 6 weeks followed by a maintenance dose of 3 mg/kg or 5 mg/kg IV every 6 to 8 weeks. Doses up to 10 mg/kg or as frequent as every 4 weeks may be considered in some patients (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2013).

B) INFLIXIMAB-DYYB

1) Varies by indication. Range of 3 mg/kg to 5 mg/kg IV over 2 hours at 0, 2, and 6 weeks followed by a maintenance dose of 3 mg/kg or 5 mg/kg IV every 6 to 8 weeks. Doses up to 10 mg/kg or as frequent as every 4 weeks may be considered in some patients (Prod Info INFLECTRA intravenous injection, 2016).

7.2.2)

A) INFLIXIMAB

1) AGED 6 YEARS AND OLDER: Varies by indication; 5 mg/kg IV as an induction regimen at 0, 2, and 6 weeks followed by a maintenance dose of 5 mg/kg IV every 8 weeks (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2013).
2) Safety and efficacy of infliximab have not been established in children younger than 6 years of age (Prod Info REMICADE(R) intravenous injection lyophilized concentrate, 2013).

B) INFLIXIMAB-DYYB

1) AGED 6 YEARS AND OLDER WITH CROHN'S DISEASE: 5 mg/kg IV as an induction regimen at 0, 2, and 6 weeks followed by a maintenance dose of 5 mg/kg IV every 8 weeks (Prod Info INFLECTRA intravenous injection, 2016).
2) Safety and effectiveness have not been established in pediatric patients less than 6 years of age (Prod Info INFLECTRA intravenous injection, 2016).

Maximum Tolerated Exposure

A)

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) In patients with juvenile rheumatoid arthritis, intravenous administration of infliximab at doses of 6 mg/kg in patients weighing up to 35 kg and at doses of 3 mg/kg in patients weighing greater than 35 kg up to adult body weight resulted in steady state AUC values that were similar to those seen in adults receiving the 3 mg/kg dose (Prod Info REMICADE(R) IV injection, 2007).

Workplace Standards

A)

1) Not Listed

B)

1) Not Listed

C)

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D)

1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

A)

B)

C)

D)

Physicochemical

Physical Characteristics

A)

Ph

A)

Molecular Weight

A)

Animal Toxicology

References

General Bibliography

1)

2)

3)

4)

5)

6)

7)

8)

9)

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

174)

175)

176)

177)

178)

179)

180)

181)

182)

183)

184)

185)

186)

187)

188)

189)

190)

191)

192)

193)

194)

195)

196)

197)

198)

199)

200)

201)

202)

203)

204)

205)

206)

207)

208)

209)

210)

211)

212)

213)

214)

215)

216)

217)

218)

219)

220)

221)

222)

223)

224)

225)

226)

227)

228)

229)

230)

231)

232)

233)

234)

235)

236)

237)

238)

239)

240)

241)

242)

243)

244)

245)

246)

247)

248)

249)

250)

FeedBack

INFLIXIMAB

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Hematologic

Dermatologic

Musculoskeletal

Immunologic

Reproductive

Carcinogenicity

Monitoring Parameters Levels

Life Support

Patient Disposition

Monitoring

Oral Exposure

Summary

Therapeutic Dose

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Pharmacologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography