INFLECTRA (infliximab for Injection) Adverse Reactions

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The adverse drug reaction profiles reported in clinical studies that compared INFLECTRA® to the reference biologic drug were comparable. The description of adverse reactions in this section is based on clinical experience with the reference biologic drug.

Adverse Reaction Overview

The most common adverse drug reactions reported from both clinical trials and post-marketing reports are infections, allergic reactions and infusion-related reactions. Less common adverse drug reactions from these sources, which may be serious and clinically relevant include hepatobiliary events (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic), demyelinating disorders (see WARNINGS AND PRECAUTIONS, Neurological Events), and lymphoma (see WARNINGS AND PRECAUTIONS, Carcinogenesis and Mutagenesis). One of the most common reasons for discontinuation of treatment in clinical trials was infusion-related reactions (dyspnea, flushing, headache and rash) (see WARNINGS AND PRECAUTIONS, Hypersensitivity Reactions). Adverse events have been reported in a higher proportion of rheumatoid arthritis patients receiving the 10 mg/kg dose than the 3 mg/kg dose, however, no differences were observed in the frequency of adverse events between the 5 mg/kg dose and the 10 mg/kg dose in patients with Crohn’s disease or ulcerative colitis and between the 3 mg/kg and 5 mg/kg dose in patients with plaque psoriasis.

Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Description of Data Sources
The data described herein reflect the exposure infliximab for injection in 5561 patients in adequate and well-controlled studies. Infliximab for injection was studied in patients with rheumatoid arthritis (1304 patients exposed), juvenile rheumatoid arthritis (117 patients exposed), Crohn’s disease (1566 patients exposed, including 1427 adult and 139 pediatric patients), ulcerative colitis (544 patients exposed, including 484 adults and 60 children), plaque psoriasis (1373 patients exposed), psoriatic arthritis (293 patients exposed), ankylosing spondylitis (347 patients exposed) and other conditions (17 patients exposed), primarily in double-blind, placebo-controlled trials. In general, integration of data in the following sections is based on clinical trials in rheumatoid arthritis and adult Crohn’s disease. See PART II, CLINICAL TRIALS - REFERENCE BIOLOGIC DRUG for a description of the individual studies conducted in each indication.

Relative Frequency of Adverse Drug Reactions
Adverse events occurring at a frequency of at least 5% in infliximab for injection-treated adult patients with rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis, and ulcerative colitis are shown in Table 1. Adverse events occurring at a frequency of at least 5% in infliximab for injection-treated pediatric patients with Crohn’s disease or ulcerative colitis are shown in Table 2. Adverse events occurring at a frequency of ≥1% to <5% in infliximab for injection-treated adult patients are shown in Table 3. Adverse events occurring at a frequency of ≥1% to <5% in infliximab for injection-treated pediatric patients with Crohn’s disease or ulcerative colitis are shown in Table 4. Adverse events in a juvenile rheumatoid arthritis (JRA) trial are set forth in the section entitled Adverse Reactions in Pediatric Patients, Juvenile Rheumatoid Arthritis. In general, the adverse events in pediatric patients with Crohn’s disease or ulcerative colitis who received Infliximab for injection were similar in frequency and type to those seen in adult patients with Crohn’s disease or ulcerative colitis respectively. Differences from adults and other special considerations are discussed in the section, Adverse Reactions in Pediatric Patients, Crohn’s Disease and Adverse Reactions in Pediatric Patients, Ulcerative Colitis.

Table 1: Number of patients with 1 or more adverse events (with frequency of ≥ 5%) by WHOART system-organ class and preferred term; treated patients ≥ 18 years of age
a
Rheumatoid Arthritis Studies include C0168T07, C0168T09, C0168T14, C0168T15, C0168T18, C0168T22, and C0168T29. Crohn's Disease Studies include C0168T08, C0168T11, C0168T16, C0168T20, C0168T21, C0168T26, and C0168T67. Ankylosing Spondylitis Studies include C0168T51. Ulcerative Colitis Studies include C0168T12, C0168T37 (through Week 54), and C0168T46 (through Week 54 including 24-week study extension). Psoriasis Studies include C0168T31, C0168T38, and C0168T44. Psoriatic Arthritis Studies include C0168T50.
b
The adverse events included in this table are determined by the frequency of events in the combined infliximab for injection group over all indications in this table. Percentages are rounded to an integer value after the adverse event frequency is determined
 

RA Studies

CD studies

AS studies

UC studies

Pso Studies

PsA studies

 

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Treated patients ≥ 18 years of agea,b

427

1304

217

1427

76

275

248

493

334

1373

98

191

Avg duration of follow-up (weeks)

52.0

59.9

29.8

44.8

25.3

87.8

31.9

40.5

18.1

41.9

20.2

42.8

Patient with 1 or more adverse events

353 (82.7%)

1198 (91.9%)

179

(82.5%)

1297 (90.9%)

57

(75.0%)

268 (97.5%)

199 (80.2%)

425 (86.2%)

210 (62.9%)

1209 (88.1%)

66

(67.3%)

162

(84.8%)

System-organ class/preferred term

Respiratory system disorders

Upper respiratory tract infection

22%

29%

15%

23%

14%

49%

17%

18%

16%

25%

13%

24%

Pharyngitis

7%

12%

6%

13%

5%

20%

6%

10%

4%

9%

4%

10%

Sinusitis

7%

13%

6%

9%

1%

11%

5%

9%

3%

8%

4%

11%

Coughing

7%

12%

6%

7%

3%

13%

4%

6%

1%

5%

1%

7%

Rhinitis

4%

8%

5%

6%

5%

21%

2%

4%

1%

6%

2%

4%

Bronchitis

8%

9%

3%

5%

1%

8%

3%

4%

2%

4%

3%

6%

Gastro-intestinal system disorders

Nausea

19%

19%

25%

21%

9%

11%

9%

11%

4%

8%

6%

5%

Abdominal pain

7%

12%

17%

24%

4%

16%

13%

12%

1%

4%

2%

5%

Diarrhea

11%

11%

7%

9%

5%

20%

5%

5%

2%

5%

3%

2%

Vomiting

6%

7%

13%

12%

4%

6%

7%

6%

1%

3%

2%

1%

Dyspepsia

6%

9%

2%

6%

4%

4%

2%

3%

1%

2%

2%

2%

Skin and appendages disorders

Rash

5%

9%

6%

10%

7%

10%

8%

8%

1%

2%

0%

2%

Pruritus

2%

6%

3%

6%

7%

12%

4%

6%

4%

9%

3%

6%

Body as a whole-general disorders

Pain

7%

7%

6%

13%

5%

29%

12%

11%

5%

10%

1%

4%

Fatigue

6%

8%

13%

14%

4%

15%

8%

10%

2%

7%

3%

4%

Musculo skeletal system disorders

Arthralgia

6%

7%

8%

15%

1%

8%

10%

15%

2%

10%

2%

4%

Back pain

4%

7%

6%

8%

3%

12%

8%

4%

3%

5%

6%

9%

Myalgia

3%

3%

4%

6%

3%

4%

5%

6%

1%

6%

0%

2%

Central & peripheral nervous system

disorders

Headache

12%

17%

15%

23%

11%

20%

18%

19%

8%

17%

5%

10%

Dizziness

6%

7%

6%

10%

4%

10%

5%

6%

2%

4%

4%

4%

Resistance mechanism disorders

                       

Fever

4%

7%

11%

11%

0%

8%

9%

10%

1%

4%

1%

2%

Table 2: Number of patients with 1 or more adverse events (with frequency of ≥ 5%) by WHOART system-organ class and preferred term; treated patients < 18 years of age in ulcerative colitis and Crohn’s disease studies
a
CD Studies include C0168T23, C0168T47 (through Week 54), and C0168T55.
b
UC Study include C0168T72.
c
The adverse events included in this table are determined by the frequency of events in the combined infliximab for injection group. Percentages are rounded to an integer value after the adverse event frequency is determined.
 

CD studiesa

UC studiesb

Placebo

Infliximab for injection

5 mg/kg

Placebo

Infliximab for injection

5 mg/kg

Treated patients < 18 years of age in ulcerative colitis and Crohn’s disease studiesc

0

139

0

60

Avg duration of follow-up (weeks)

N/A

44.1

N/A

38.0

Patients with 1 or more adverse events

0 (N/A)

125 (89.9%)

0 (N/A)

57 (95.0%)

System-organ class/preferred term

Gastro-intestinal system disorders

Colitis ulcerative

NA

0%

NA

47%

Abdominal pain

NA

22%

NA

13%

Vomiting

NA

22%

NA

8%

Nausea

NA

19%

NA

5%

Blood in stool

NA

7%

NA

3%

Diarrhea

NA

13%

NA

3%

Crohn's disease

NA

27%

NA

0%

Respiratory system disorders

Upper respiratory tract infection

N/A

29%

N/A

23%

Pharyngitis

N/A

19%

N/A

18%

Coughing

N/A

11%

N/A

10%

Sinusitis

N/A

8%

N/A

5%

Rhinitis

N/A

8%

N/A

2%

Resistance mechanism disorders

Fever

N/A

17%

N/A

13%

Skin and appendages disorders

Rash

N/A

10%

N/A

5%

Pruritus

N/A

9%

N/A

2%

Body as a whole-general disorders

Pain

N/A

9%

N/A

8%

Central & peripheral nervous system disorders

Headache

N/A

31%

N/A

13%

Musculo-skeletal system disorders

Arthralgia

N/A

9%

N/A

2%

Red blood cell disorders

Anemia

N/A

9%

N/A

10%

White cell and res disorders

Neutropenia

N/A

6%

N/A

3%

Leukopenia

N/A

8%

N/A

2%

Vascular (extracardiac) disorders

Flushing

N/A

8%

N/A

3%

Table 3: Number of patients with 1 or more adverse events (with frequency of ≥ 1% to < 5%) by WHOART system-organ class and preferred term; treated patients ≥ 18 years of age
a
Rheumatoid Arthritis Studies include C0168T07, C0168T09, C0168T14, C0168T15, C0168T18, C0168T22, and C0168T29. Crohn's Disease Studies include C0168T08, C0168T11, C0168T16, C0168T20, C0168T21, C0168T26, and C0168T67. Ankylosing Spondylitis Studies include C0168T51. Ulcerative Colitis Studies include C0168T12, C0168T37 (through Week 54), and C0168T46 (through Week 54 including 24-week study extension). Psoriasis Studies include C0168T31, C0168T38, and C0168T44. Psoriatic Arthritis Studies include C0168T50.
b
The adverse events included in this table are determined by the frequency of events in the combined infliximab for injection group over all indications in this table. Percentages are rounded to an integer value after the adverse event frequency is determined.
 

RA Studies

CD studies

AS studies

UC studies

Pso Studies

PsA studies

 

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Placebo

Infliximab for injection

Treated patients ≥ 18 years of agea,b

427

1304

217

1427

76

275

248

493

334

1373

98

191

Avg duration of follow-up (weeks)

52.0

59.9

29.8

44.8

25.3

87.8

31.9

40.5

18.1

41.9

20.2

42.8

Patient with 1 or more adverse events

353 (82.7%)

1198 (91.9%)

179

(82.5%)

1297 (90.9%)

57

(75.0%)

268 (97.5%)

199 (80.2%)

425 (86.2%)

210 (62.9%)

1209 (88.1%)

66

(67.3%)

162

(84.8%)

System-organ class/preferred term

Respiratory system disorders

Dyspnea

2%

5%

1%

4%

3%

5%

2%

3%

1%

3%

1%

3%

Pneumonia

1%

4%

1%

1%

0%

1%

0%

2%

0%

1%

0%

3%

Respiratory tract allergic reaction

1%

2%

0%

1%

0%

1%

0%

1%

0%

2%

1%

2%

Epistaxis

1%

1%

0%

1%

0%

2%

0%

1%

0%

1%

0%

1%

Gastro-intestinal system disorders

Gastroenteritis

3%

4%

6%

4%

4%

7%

2%

3%

1%

3%

3%

1%

Crohn`s disease

0%

0%

12%

13%

0%

0%

0%

0%

0%

0%

0%

0%

Stomatis ulcerative

5%

6%

1%

3%

1%

1%

1%

1%

0%

1%

1%

1%

Flatulence

1%

2%

3%

6%

0%

1%

2%

4%

0%

0%

0%

0%

Constipation

3%

2%

2%

4%

1%

3%

1%

2%

0%

1%

2%

0%

Gastro-esophageal reflux

1%

2%

0%

2%

0%

3%

2%

1%

0%

1%

1%

2%

Colitis ulcerative

0%

0%

0%

0%

0%

0%

25%

16%

0%

0%

0%

0%

Tooth ache

0%

1%

1%

2%

0%

1%

0%

1%

1%

2%

0%

1%

Anorexia

1%

1%

2%

2%

0%

0%

1%

1%

0%

0%

0%

1%

Blood in stool

1%

1%

1%

2%

0%

1%

1%

1%

0%

0%

0%

0%

Intestinal obstruction

0%

0%

2%

4%

0%

0%

0%

0%

0%

0%

0%

0%

Skin and appendages disorders

Urticaria

1%

4%

0%

2%

0%

2%

0%

1%

1%

4%

0%

4%

Sweating increased

0%

2%

3%

3%

5%

4%

3%

3%

0%

2%

0%

2%

Alopecia

2%

3%

2%

3%

0%

1%

1%

3%

1%

1%

2%

3%

Dermatitis

1%

2%

0%

2%

1%

7%

2%

1%

0%

2%

0%

1%

Dermatitis fungal

1%

3%

1%

1%

0%

5%

3%

1%

0%

2%

1%

2%

Psoriasis

0%

0%

1%

1%

1%

5%

1%

0%

7%

5%

2%

4%

Eczema

1%

2%

0%

3%

0%

3%

3%

1%

1%

1%

0%

1%

Acne

0%

1%

1%

3%

0%

3%

1%

2%

1%

1%

0%

0%

Skin dry

0%

1%

1%

2%

0%

7%

1%

3%

1%

1%

0%

0%

Skin wound

2%

2%

1%

1%

0%

2%

0%

1%

0%

2%

0%

1%

Erythema

0%

2%

1%

1%

0%

3%

1%

1%

0%

1%

1%

0%

Rash erythematous

1%

1%

0%

1%

1%

5%

0%

1%

0%

0%

0%

1%

Folliculitis

0%

1%

1%

1%

0%

1%

0%

1%

1%

1%

0%

0%

Body as a whole-general disorders

Chest pain

3%

4%

4%

5%

1%

6%

2%

3%

0%

4%

2%

4%

Edema peripheral

4%

4%

2%

5%

1%

4%

4%

4%

2%

3%

0%

3%

Chills

2%

3%

1%

2%

3%

3%

2%

4%

1%

3%

0%

1%

Infusion syndrome

0%

2%

0%

2%

1%

3%

0%

2%

0%

3%

0%

2%

Wound

1%

1%

0%

1%

1%

3%

0%

1%

0%

3%

1%

3%

Hot flushes

0%

2%

1%

2%

1%

3%

2%

1%

0%

1%

0%

2%

Allergic reaction

0%

1%

1%

2%

0%

5%

0%

2%

1%

1%

1%

1%

Asthenia

1%

1%

0%

3%

0%

2%

0%

1%

0%

1%

1%

1%

Reaction

unevaluable

0%

1%

2%

2%

0%

2%

1%

1%

1%

1%

0%

0%

Musculo skeletal system disorders

Arthritis

1%

1%

2%

4%

5%

14%

1%

1%

3%

7%

5%

5%

Bone fracture

3%

4%

0%

1%

0%

4%

0%

1%

1%

1%

0%

4%

Skeletal muscle

strain

2%

2%

0%

1%

0%

1%

1%

0%

1%

3%

1%

2%

Tendinitis

2%

0%

0%

1%

1%

5%

1%

1%

0%

1%

2%

1%

Central & peripheral nervous system disorders

Paresthesia

2%

3%

2%

3%

0%

7%

3%

3%

1%

3%

0%

0%

Muscle contractions involuntary

2%

4%

2%

2%

1%

3%

3%

2%

0%

2%

1%

1%

Hypesthesia

1%

2%

1%

2%

4%

3%

1%

1%

0%

2%

1%

1%

Migraine

1%

1%

1%

2%

0%

1%

0%

1%

0%

1%

0%

1%

Vertigo

2%

2%

0%

1%

3%

1%

1%

1%

0%

1%

1%

2%

Resistance mechanism disorders

Abscess

3%

4%

4%

9%

3%

6%

3%

3%

1%

3%

2%

2%

Flu syndrome

3%

4%

1%

6%

1%

8%

2%

4%

1%

3%

0%

3%

Moniliasis

3%

5%

0%

5%

0%

5%

2%

3%

0%

1%

0%

1%

Influenza-like

symptoms

0%

2%

2%

3%

1%

2%

2%

3%

1%

2%

0%

2%

Herpes simplex

1%

2%

2%

2%

0%

9%

2%

1%

1%

2%

1%

4%

Infection

2%

3%

0%

2%

3%

4%

1%

1%

1%

2%

0%

1%

Influenza

1%

2%

2%

3%

1%

1%

2%

2%

1%

2%

0%

1%

Cellulitis

1%

2%

0%

1%

0%

2%

0%

1%

1%

1%

1%

3%

Herpes zoster

1%

1%

0%

1%

0%

0%

0%

1%

1%

1%

0%

2%

Infection bacterial

1%

1%

2%

1%

0%

1%

0%

0%

0%

1%

0%

2%

Psychiatric disorders

Insomnia

4%

4%

3%

6%

1%

4%

2%

4%

1%

2%

1%

0%

Depression

5%

5%

2%

4%

0%

4%

2%

3%

1%

3%

2%

3%

Anxiety

1%

3%

1%

3%

1%

2%

3%

2%

0%

2%

1%

0%

Liver and biliary system disorders

Sgpt increased

4%

5%

1%

3%

5%

12%

1%

1%

1%

4%

1%

8%

Sgot increased

2%

3%

1%

2%

3%

9%

0%

1%

1%

3%

2%

5%

Hepatic enzymes

increased

3%

4%

1%

1%

0%

2%

0%

1%

0%

4%

0%

2%

Hepatic function

abnormal

1%

2%

2%

1%

0%

2%

0%

0%

0%

1%

1%

2%

Vascular (extracardiac) disorders

Flushing

0%

3%

1%

2%

3%

4%

1%

2%

0%

5%

0%

3%

Ecchymosis

2%

4%

0%

2%

0%

2%

1%

1%

0%

2%

0%

1%

Hemorrhoids

1%

1%

0%

2%

1%

3%

3%

1%

0%

0%

0%

1%

Urinary system disorders

Urinary tract

infection

5%

7%

3%

4%

0%

2%

2%

2%

1%

2%

4%

3%

Metabolic and nutritional disorders

Hypokalemia

0%

2%

1%

4%

0%

0%

0%

1%

0%

0%

0%

1%

Weight increase

2%

2%

0%

0%

1%

3%

0%

0%

0%

1%

0%

0%

Cardiovascular disorders, general

Hypertension

5%

6%

2%

3%

5%

8%

2%

2%

3%

4%

2%

3%

Hypotension

1%

2%

0%

2%

1%

3%

0%

2%

0%

1%

0%

2%

Eye and vision disorders

Conjunctivitis

2%

4%

2%

4%

1%

4%

3%

1%

0%

1%

1%

1%

Vision abnormal

1%

2%

1%

2%

0%

4%

2%

1%

0%

1%

0%

2%

Ear and hearing disorders

Otitis

0%

2%

1%

1%

0%

2%

1%

1%

0%

1%

0%

0%

White cell and res disorders

Leukopenia

1%

2%

3%

2%

0%

2%

0%

2%

0%

1%

0%

1%

Lympha-denopathy

0%

1%

1%

2%

0%

2%

1%

1%

0%

1%

0%

1%

Neutropenia

0%

1%

0%

1%

0%

3%

0%

0%

0%

1%

0%

3%

Red blood cell disorders

                       

Anemia

4%

4%

4%

4%

1%

4%

10%

5%

0%

1%

0%

0%

Heart rate and rhythm disorders

Tachycardia

2%

2%

0%

1%

1%

1%

2%

1%

1%

1%

1%

1%

Palpitation

1%

2%

0%

1%

0%

3%

1%

1%

0%

1%

0%

1%

Administration / application site disorders

Injection site infiltration

3%

2%

0%

1%

0%

0%

1%

0%

0%

2%

0%

0%

Collagen disorders

Arthritis rheumatoid

6%

7%

0%

0%

0%

0%

0%

0%

0%

0%

0%

0%

Table 4: Number of patients with 1 or more adverse events (with frequency of ≥ 1% to < 5%)) by WHOART system-organ class and preferred term; treated patients < 18 years of age in ulcerative colitis and Crohn’s disease studies
a
CD Studies include C0168T23, C0168T47 (through Week 54), and C0168T55.
b
UC Study include C0168T72.
c
The adverse events included in this table are determined by the frequency of events in the combined infliximab for injection group. Percentages are rounded to an integer value after the adverse event frequency is determined.
 

CD studiesa

UC studiesb

Placebo

Infliximab for injection

5 mg/kg

Placebo

Infliximab for injection

5 mg/kg

Treated patients < 18 years of age in ulcerative colitis and Crohn’s disease studiesc

0

139

0

60

Avg duration of follow-up (weeks)

N/A

44.1

N/A

38.0

Patients with 1 or more adverse events

0 (N/A)

125 (89.9%)

0 (N/A)

57 (95.0%)

System-organ class/preferred term

Gastro-intestinal system disorders

Stomatitis ulcerative

NA

2%

NA

5%

Diarrhea bloody

NA

1%

NA

2%

Pancreatitis

NA

2%

NA

2%

Anal fistula

NA

3%

NA

0%

Anorexia

NA

3%

NA

0%

Constipation

NA

6%

NA

0%

Dyspepsia

NA

6%

NA

0%

Dysphagia

NA

1%

NA

0%

Enterocolitis

NA

3%

NA

0%

Flatulence

NA

4%

NA

0%

Gastroenteritis

NA

5%

NA

0%

Hemorrhage rectum

NA

1%

NA

0%

Intestinal obstruction

NA

1%

NA

0%

Intestinal stenosis

NA

2%

NA

0%

Oral pain

NA

1%

NA

0%

Proctalgia

NA

2%

NA

0%

Tooth ache

NA

2%

NA

0%

Respiratory system disorders

Dyspnea

NA

4%

NA

5%

Bronchitis

NA

5%

NA

3%

Asthma

NA

1%

NA

2%

Respiratory tract allergic reaction

NA

4%

NA

2%

Bronchospasm

NA

1%

NA

0%

Epistaxis

NA

3%

NA

0%

Pneumonia

NA

2%

NA

0%

Resistance mechanism disorders

Influenza

NA

3%

NA

5%

Cellulitis

NA

1%

NA

3%

Infection

NA

3%

NA

3%

Influenza-like symptoms

NA

1%

NA

3%

Moniliasis

NA

4%

NA

3%

Herpes simplex

NA

1%

NA

2%

Herpes zoster

NA

1%

NA

2%

Infection bacterial

NA

5%

NA

2%

Infection viral

NA

6%

NA

2%

Abscess

NA

4%

NA

0%

Flu syndrome

NA

5%

NA

0%

Infectious mononucleosis

NA

1%

NA

0%

Skin and appendages disorders

Alopecia

NA

1%

NA

3%

Eczema

NA

4%

NA

3%

Acne

NA

2%

NA

2%

Dermatitis

NA

1%

NA

2%

Onychocryptosis

NA

1%

NA

2%

Skin lesion

NA

3%

NA

2%

Sweating increased

NA

1%

NA

2%

Urticaria

NA

1%

NA

2%

Verruca

NA

2%

NA

2%

Cracking of skin

NA

4%

NA

0%

Dermatitis contact

NA

2%

NA

0%

Dermatitis fungal

NA

2%

NA

0%

Rash erythematous

NA

2%

NA

0%

Skin dry

NA

2%

NA

0%

Skin hypertrophy

NA

1%

NA

0%

Body as a whole-general disorders

Chest pain

NA

3%

NA

3%

Fatigue

NA

5%

NA

3%

Chills

NA

1%

NA

2%

Cyst (type unknown)

NA

1%

NA

2%

Edema

NA

1%

NA

2%

Edema peripheral

NA

1%

NA

2%

Reaction unevaluable

NA

1%

NA

2%

Allergic reaction

NA

4%

NA

0%

Asthenia

NA

1%

NA

0%

Central &peripheral nervous system disorders

Hyperkinesia

NA

0%

NA

3%

Dizziness

NA

6%

NA

2%

Muscle contractions involuntary

NA

1%

NA

2%

Migraine

NA

1%

NA

0%

Paresthesia

NA

2%

NA

0%

Musculo-skeletal system disorders

Back pain

NA

2%

NA

3%

Bone development abnormal

NA

1%

NA

2%

Joint swelling

NA

1%

NA

2%

Sprain

NA

1%

NA

2%

Bone fracture

NA

6%

NA

0%

Myalgia

NA

4%

NA

0%

Red blood cell disorders

Anemia iron deficiency

NA

1%

NA

2%

Psychiatric disorders

Anxiety

NA

2%

NA

2%

Depression

NA

2%

NA

2%

Insomnia

NA

4%

NA

2%

Thinking abnormal

NA

1%

NA

2%

Irritability

NA

1%

NA

0%

Somnolence

NA

3%

NA

0%

Suicide attempt

NA

1%

NA

0%

Urinary system disorders

Urinary tract infection

NA

1%

NA

8%

Dysuria

NA

1%

NA

0%

Liver and biliary system disorders

Hepatic enzymes increased

NA

2%

NA

3%

Hepatic function abnormal

NA

2%

NA

2%

Sgot increased

NA

1%

NA

2%

Sgpt increased

NA

1%

NA

2%

White cell and res disorders

Neutrophilia

NA

1%

NA

2%

Eosinophilia

NA

3%

NA

0%

Lymphadenopathy

NA

1%

NA

0%

Monocytosis

NA

1%

NA

0%

Eye and vision disorders

       

Conjunctivitis

NA

4%

NA

3%

Eye pain

NA

3%

NA

0%

Metabolic and nutritional disorders

Dehydration

NA

2%

NA

0%

Weight decrease

NA

3%

NA

0%

Vascular (extracardiac) disorders

Ecchymosis

NA

4%

NA

0%

Cardiovascular disorders, general

Hypotension

NA

1%

NA

0%

Syncope

NA

2%

NA

0%

Collagen disorders

Antinuclear factor test positive

NA

3%

NA

2%

Ear and hearing disorders

Otitis

NA

1%

NA

2%

Otitis media

NA

2%

NA

2%

Earache

NA

2%

NA

0%

Platelet, bleeding & clotting disorders

Thrombocythemia

NA

1%

NA

3%

Thrombocytopenia

NA

1%

NA

0%

Heart rate and rhythm disorders

Palpitation

NA

1%

NA

2%

Administration/application site disorders

Injection site infiltration

NA

4%

NA

0%

Reproductive disorders

Dysmenorrhea

NA

2%

NA

0%

Ovarian cyst

NA

1%

NA

0%

Infusion-related Reactions

Acute infusion reactions
An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In Phase 3 clinical studies, 18% of infliximab for injection-treated patients experienced an infusion reaction compared with 5% of placebo-treated patients. Of infliximab for injection-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period. Approximately 3% of patients discontinued infliximab for injection because of infusion reactions, and all patients recovered with treatment and/or discontinuation of infusion.

In clinical trials, approximately 3% of infliximab for injection infusions were accompanied by nonspecific symptoms such as fever or chills, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension or dyspnea), <1% were accompanied by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions occurred in less than 1% of patients and included anaphylaxis, convulsions, erythematous rash and hypotension.

Infliximab for injection infusions beyond the initial infusion were not associated with a higher incidence of reactions. In psoriatic arthritis (IMPACT 2), infusion reactions were reported in 12% of infliximab for injection-treated patients compared with 7% of placebo-treated patients. Among the 1376 infliximab for injection infusions, 2% of these led to an infusion reaction. In plaque psoriasis, infusion reactions were reported in 22% of infliximab for injection-treated patients compared with 5% of placebo-treated patients. Among the 8366 infliximab for injection infusions, 5% of these led to an infusion reaction. In the ankylosing spondylitis study ASSERT, infusion reactions were reported in 19% of infliximab for injection-treated patients compared with 9% of placebo-treated patients. Among the 4257 infliximab for injection infusions, 2% of these led to an infusion reaction.

In a clinical study of patients with early rheumatoid arthritis (ASPIRE), 66% of all treated patients (686 out of 1040) received at least one shortened infusion of 90 minutes or less and 44% of the patients (454 out of 1040) received at least one shortened infusion of 60 minutes or less. Of the infliximab for injection-treated patients who received at least one shortened infusion of 90 minutes or less at the dose of 3 mg/kg, infusion-related reactions occurred in 19% (48/248) of patients and serious infusion reactions occurred in 0.4% (1/248) of patients. Of the infliximab for injection-treated patients who received at least one shortened infusion of 90 minutes or less at the dose of 6 mg/kg, infusion-related reactions occurred in 11% (26/246) of patients and serious infusion reactions occurred in 0.4% (1/246) of patients. Shortened infusions at doses >6 mg/kg have not been studied (see PART II, CLINICAL TRIALS - REFERENCE BIOLOGIC DRUG, Rheumatoid Arthritis).

In the UC studies ACT 1 and ACT 2 through Week 30, the proportion of subjects with infusion reactions was comparable in the placebo and combined infliximab for injection treatment groups. Through Week 54, the proportion of subjects with infusion reactions rose and was greater in the combined infliximab for injection treatment group than in the placebo treatment group (13.4% versus 9.4%, respectively). A greater proportion of subjects in the 10 mg/kg than in the 5 mg/kg infliximab for injection treatment group (16.1% versus 10.7%) experienced an infusion reaction.

In a clinical study of patients with Crohn’s disease (SONIC), infusion-related reactions occurred in 17% of patients receiving infliximab for injection monotherapy, 5% of patients receiving infliximab for injection in combination with azathioprine (AZA) and 6% of patients receiving AZA monotherapy. One patient experienced a serious infusion reaction with infliximab for injection monotherapy.

Patients who became positive for antibodies to infliximab were more likely to develop infusion reactions than were those who were negative (approximately 3-fold). Use of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to infliximab and infusion reactions (see WARNINGS AND PRECAUTIONS, Immunogenicity and DRUG INTERACTIONS).

In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngeal edema, severe bronchospasm, and seizure have been associated with infliximab for injection administration (see WARNINGS AND PRECAUTIONS, Neurological Events). Cases of transient visual loss occurring during or within 2 hours of infliximab for injection infusion have been reported. Cerebrovascular accidents, myocardial ischemia/infarction (some fatal), and arrhythmia occurring within 24 hours of initiation of infusion have also been reported.

Infusion reactions following readministration of infliximab for injection
In rheumatoid arthritis, Crohn’s disease and psoriasis clinical trials, readministration of infliximab for injection after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment.

In a clinical trial of patients with moderate to severe psoriasis designed to assess the efficacy of long-term maintenance therapy versus re-treatment with an induction cycle of infliximab for injection, 4% (8/219) of patients in the intermittent therapy arm experienced serious infusion reactions versus < 1% (1/222) in the maintenance therapy arm. Patients enrolled in this trial did not receive any concomitant immunosuppressant therapy. Intermittent therapy in this trial was defined as the readministration of an induction cycle (maximum of four infusions at 0, 2, 6, and 14 weeks) of infliximab for injection upon disease flare after a period of no treatment. In this study, the majority of serious infusion reactions occurred during the second infusion at Week 2. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension. In all cases, infliximab for injection treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms (see WARNINGS AND PRECAUTIONS, Immune, Infusion reactions following readministration of infliximab for injection).

Delayed hypersensitivity/Reactions following readministration of infliximab for injection
In a clinical study where 37 of 41 patients with Crohn’s disease were retreated with infliximab for injection following a 2 to 4 year period without infliximab for injection treatment, 10 patients experienced adverse events manifesting 3 to 12 days following infusion of which 6 were considered serious. Signs and symptoms included myalgia and/or arthralgia with fever and/or rash, with some patients also experiencing pruritus, facial, hand or lip edema, dysphagia, urticaria, sore throat, and headache. Patients experiencing these adverse events had not experienced infusion-related adverse events associated with their initial infliximab for injection therapy. Of these patients, adverse events occurred in 9 of 23 (39%) who had received liquid formulation which is no longer in use and 1 of 14 (7%) who received lyophilized formulation. The clinical data are not adequate to determine if occurrence of these reactions is due to differences in formulation. Patients’ signs and symptoms improved substantially or resolved with treatment in all cases. There are insufficient data on the incidence of these events after drug-free intervals of 1 to 2 years. These events have been observed only infrequently in clinical studies and post-marketing surveillance with retreatment intervals up to 1 year.

In 3 other psoriasis studies, 1% (15/1373) of patients experienced a possible delayed hypersensitivity reaction with symptoms of arthralgia, myalgia, fever, and rash, often early in the treatment course following infliximab for injection infusions. There were no possible delayed hypersensitivity reactions identified in the psoriatic arthritis study (IMPACT 2) (see WARNINGS AND PRECAUTIONS, Immune, Hypersensitivity Reactions).

Infections

In infliximab for injection clinical studies, primarily of RA and CD, treated infections were reported in 36% of infliximab for injection-treated patients (average of 53 weeks of follow-up) and in 28% of placebo treated patients (average of 47 weeks of follow-up). In the ATTRACT1, study, 60% of infliximab for injection-treated RA patients (average of 97 weeks of follow-up) had treated infections reported vs. 43% of placebo-treated patients (average of 75 weeks of follow-up); treated infections were more common with higher doses of infliximab for injection. In the ASPIRE2 study, 37% of infliximab for injection-treated RA patients (average of 54 weeks of follow-up) had treated infections reported vs. 30% of placebo-treated patients (average of 52 weeks of follow-up). The infections most frequently reported in the RA studies were respiratory tract infections (including URI, sinusitis, pharyngitis, and bronchitis) and urinary tract infections. No increased risk of serious infections or sepsis was observed with infliximab for injection compared with placebo in the ATTRACT or ACCENT I3 and II4 studies. However, in the ATTRACT study, the incidence of serious events of pneumonia and lobar pneumonia combined was higher in patients receiving infliximab for injection plus MTX vs. MTX alone (2.6% vs. 1.2%, respectively). In the ASPIRE study, the incidence of serious pneumonia was also higher in patients receiving infliximab for injection plus MTX vs. MTX alone (2.5% vs. 0%, respectively). In other RA trials, the incidence of serious infections including pneumonia was higher in infliximab for injection plus MTX treated patients compared with methotrexate alone, especially at higher than recommended induction regimen of infliximab for injection 6 mg/kg or greater. Among infliximab for injection-treated patients, serious infections included pneumonia, cellulitis, abscess and sepsis. In ATTRACT, one patient died with miliary tuberculosis, one died with disseminated coccidioidomycosis and one died due to sepsis. In the ASPIRE study, four patients were diagnosed with tuberculosis. In the ACCENT I study, one patient was diagnosed with tuberculosis. In EXPRESS II5, two patients with psoriasis were diagnosed with tuberculosis. Other cases of tuberculosis, including disseminated tuberculosis, also have been reported post-marketing. Most of the cases of tuberculosis occurred within the first two months after initiation of therapy with infliximab for injection and may reflect recrudescence of latent disease (see WARNINGS AND PRECAUTIONS, Risk of Infections). In the ACCENT II study, serious infections of nocardiosis (one patient) and cytomegalovirus (one patient) were reported. Twelve percent of patients with fistulising Crohn’s disease developed a new abscess 8 to 16 weeks after the last infusion of infliximab for injection in the T20 study. In the ACCENT II study, there was no difference between the infliximab for injection and placebo maintenance arms for proportions of patients with newly diagnosed fistula-related abscesses (see CLINICAL TRIALS TRIALS - REFERENCE BIOLOGIC DRUG, Fistulising Crohn’s Disease). In the psoriasis studies, 1.5% of patients (average of 41.9 weeks of follow up) receiving infliximab for injection and 0.6% of patients (average of 18.1 weeks of follow up) receiving placebo developed serious infections. In EXPRESS6, one patient died due to sepsis. In the IMPACT 27 study of psoriatic arthritis, 1.6% of patients (average 42.8 weeks of follow-up) receiving infliximab for injection and 2.0% of patients (average 20.2 weeks of follow-up) receiving placebo developed serious infections.

In the infliximab for injection clinical studies in patients with ulcerative colitis (ACT 1 and ACT 28), the most frequently reported infections were upper respiratory infection (URI), sinusitis, pharyngitis, bronchitis and moniliasis. In the UC studies, infections were reported in 30.6% and 40.1% of infliximab for injection-treated patients at Week 30 (average 26.9 weeks of follow-up) and at Week 54 (average 41.1 weeks of follow-up) and in 29.5% and 32.8% of placebo-treated patients at Week 30 (average 22.2 weeks of follow up) and at Week 54 (average 32.2 weeks of follow-up). The types of infections, including serious infections, reported in patients with ulcerative colitis were similar to those reported in other clinical studies, and included one case of tuberculosis and a fatal case of histoplasmosis.

In post-marketing experience, infections have been observed with various pathogens including viral, bacterial, fungal, and protozoal organisms. Infections have been noted in all organ systems and have been reported in patients receiving infliximab for injectionalone or in combination with immunosuppressive agents.


1
ATTRACT (the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy)
2
ASPIRE (the Active-controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset
3
ACCENT I (the Anti-TNF Trial in Long-term Treatment of Moderately to Severely Active Crohn’s Disease)
4
ACCENT II (the Anti-TNF Trial in Long-term Treatment of Fistulising Crohn’s Disease)
5
EXPRESS II Evaluation of Infliximab for Psoriasis in a REMICADE Efficacy and Safety Study
6
EXPRESS European infliximab for Psoriasis (REMICADE) Efficacy and Safety Study
7
IMPACT 2 Induction and Maintenance Psoriatic Arthritis Clinical Trial
8
ACT 1 and ACT 2 (the Anti-TNF Trials in moderately to severely active ulcerative colitis)

Autoantibodies/Lupus-like Syndrome

Approximately 55% of 1598 infliximab for injection-treated patients in clinical trials (primarily RA and CD) who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately 20% of 265 placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately 19% of 2116 infliximab for injection-treated patients compared with 0% of 422 placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.

In the ATTRACT rheumatoid arthritis study through Week 102, 62% of infliximab for injection-treated patients developed antinuclear antibodies (ANA) between screening and last evaluation, compared with 27% of placebo-treated patients. In the ASPIRE study through Week 58, 66% of Infliximab for injection-treated patients developed antinuclear antibodies (ANA) between screening and last evaluation, compared with 21% of placebo-treated patients. In both RA studies, anti-dsDNA antibodies developed in approximately 15% of infliximab for injection-treated patients, compared to none of the placebo-treated patients. No association was seen between infliximab for injection dose/schedule and development of ANA or anti-dsDNA antibodies.

Of Crohn’s disease patients treated with infliximab for injection who were evaluated for antinuclear antibodies (ANA), 40% developed ANA between screening and last evaluation. Anti-dsDNA antibodies developed in approximately 20% of Crohn’s disease patients treated with infliximab for injection. The development of anti-dsDNA antibodies was not related to either the dose or duration of infliximab for injection treatment. However, baseline therapy with an immunosuppressant in Crohn’s disease patients was associated with reduced development of anti-dsDNA antibodies (3% compared to 21% in patients not receiving any immunosuppressant). Crohn’s disease patients were approximately 2 times more likely to develop anti-dsDNA antibodies if they were ANA-positive at study entry.

In the EXPRESS plaque psoriasis study through Week 50, 59% of infliximab for injection-treated patients developed antinuclear antibodies following infliximab for injection treatment compared to 2% of placebo-treated patients. Anti-dsDNA antibodies developed in 16% of infliximab for injection-treated patients, compared to none of the placebo-treated patients. In the EXPRESS II plaque psoriasis study through Week 50, 65% of infliximab for injection-treated patients developed antinuclear antibodies following infliximab for injection treatment compared to 8% of placebo-treated patients. Anti-dsDNA antibodies developed in 27% of infliximab for injection-treated patients, compared to none of the placebo-treated patients. No association was seen between infliximab for injection dose/schedule and development of ANA or anti-dsDNA antibodies.

In the IMPACT 2 psoriatic arthritis study through Week 66, 59% of infliximab for injection-treated patients developed antinuclear antibodies following infliximab for injectiontreatment compared to 11% of placebo-treated patients. Anti-dsDNA antibodies developed in 12% of infliximab for injection-treated patients, compared to none of the placebo-treated patients.

In the ASSERT ankylosing spondylitis study through week 102, 35% of infliximab for injection-treated patients developed antinuclear antibodies following infliximab for injection treatment compared to 1% of placebo-treated patients. Anti-dsDNA antibodies developed in 30% of infliximab for injection-treated patients, compared to none of the placebo-treated patients.

In clinical studies, 22 patients were diagnosed with a possible lupus-like syndrome, four with Crohn’s disease, eight patientswith plaque psoriasis [seven (0.5%) patients treated with infliximab for injection and one (0.3%) patient treated with placebo], 8 patients with ankylosing spondylitis, and two with rheumatoid arthritis. Twenty-one patients improved following discontinuation of therapy and/or appropriate medical treatment. One psoriasis patient on concomitant hydralazine had central nervous system involvement. No patients had renal involvement. No cases of lupus-like syndromes were reported in the psoriatic arthritis studies. The lupus-like syndrome in one patient with rheumatoid arthritis and one patient with ankylosing spondylitis remained ongoing at the end of the study. One case of a lupus-like reaction has been observed in a Crohn’s disease patient in up to three years of long-term follow-up (see WARNINGS AND PRECAUTIONS, Autoimmunity).

Hepatobiliary Events

In post-marketing surveillance, cases of jaundice and hepatitis, some with features of autoimmune hepatitis, have been reported in patients receiving infliximabfor injection (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving infliximabfor injection without progression to severe hepatic injury. Elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving infliximab for injectionthan in controls, both when infliximab for injectionwas given as monotherapy and when it was used in combination with other immunosuppressive agents. Most aminotransferase abnormalities were transient; however, a small number of patients experienced more prolonged elevations. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of infliximab for injection, or modification of concomitant medications.

Malignancies/Lymphoproliferative Disease

The potential role of TNF-blocking therapy in the development of malignancies is not known. Rates in clinical trials for infliximab for injection cannot be compared to rates in clinical trials of other TNF-blockers and may not predict rates observed in a broader patient population. Caution should be exercised in considering infliximab for injection treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving infliximab for injection.

In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF-blocker compared with control patients. In the controlled and open-label portions of infliximab for injection clinical trials, 5 patients developed lymphomas among 5780 patients treated with infliximab for injection (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In rheumatoid arthritis patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately 3-fold higher than expected in the general population. In the combined clinical trial population for rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, psoriasis, ankylosing spondylitis, and ulcerative colitis, 5 lymphomas were observed for a rate of 0.09 cases per 100 patient-years of follow-up, which is approximately 4-fold higher than expected in the general population. Patients with Crohn’s disease or rheumatoid arthritis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several-fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy.

In the controlled portions of clinical trials of some TNF-blocking agents including infliximab for injection, more cases of non-lymphoma malignancies have been observed in patients receiving those TNF-blockers compared with control patients. During the controlled portions of infliximab for injection trials in patients with moderately to severely active rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, psoriasis, ankylosing spondylitis, and ulcerative colitis, 14 patients were diagnosed with non-lymphoma malignancies among 4019 infliximab for injection-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 patient-years among infliximab for injection-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for infliximab for injection-treated patients and 0.4 years for control patients. Of these, the most common malignancies were breast, colorectal, and melanoma. The rate of non-lymphoma malignancies among infliximab for injection-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected.

Among the 345 patients who received infliximab for injection in ankylosing spondylitis trials, 3 patients developed malignancies (1 patient had a squamous cell and a basal cell carcinoma, 1 patient had a pulmonary carcinoma, and 1 patient had breast cancer). Additionally, 1 patient in ASSERT developed a nonseminoma testicular carcinoma after leaving the trial, approximately 1 year after his last dose of infliximab for injection.

In the IMPACT 2 study of psoriatic arthritis, 2 malignancies were reported through Week 54 (Stage I Hodgkin’s lymphoma in an infliximab for injection-treated patient and basal cell carcinoma in a placebo-treated patient). No malignancies were reported through Week 50 of IMPACT. An adenocarcinoma of the pancreas was reported 2 months after completing the year 2 extension of IMPACT.

During the infliximab for injection plaque psoriasis trials, no patients developed lymphoma. In the placebo-controlled portions of the psoriasis studies, 7 of 1123 patients who received infliximab for injection at any dose (443 patient-years) were diagnosed with a nonmelanoma skin cancer (NMSC) compared to 0 of 334 patients who received placebo (113 patient-years). Among the 1373 patients with psoriasis who received infliximab for injection at any dose in the controlled and uncontrolled portions of the psoriasis studies (1101 patient-years), a total of 17 were diagnosed with NMSC (12 basal cell cancers, 5 squamous cell cancers). The size of the placebo group and limited duration of the controlled portions of studies precludes the ability to draw firm conclusions. Patients on infliximab for injection should be monitored for the development of NMSC. Two noncutaneous malignancies (breast cancer and adenocarcinoma) were reported during the psoriasis clinical trials.

A population-based retrospective cohort study found an increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab for injection compared to biologics-naïve patients or the general population, including those over 60 years of age.

Congestive Heart Failure

In a phase II study evaluating infliximab for injection in NYHA Class III/IV CHF patients (left ventricular ejection fraction ≤35%), higher incidences of mortality and hospitalization due to worsening heart failure were seen in infliximab for injection-treated patients, especially those treated with 10 mg/kg. One hundred and fifty patients were treated with 3 infusions of infliximab for injection 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At 28 weeks, 4 of 101 patients treated with infliximab for injection (1 at 5 mg/kg and 3 at 10 mg/kg) died compared with no deaths among the 49 placebo-treated patients. In follow-up, at 38 weeks, 9 patients treated with infliximab for injection (2 at 5 mg/kg and 7 at 10 mg/kg) died compared with one death among the placebo-treated patients. At 28 weeks, 14 of 101 patients treated with infliximab for injection (3 at 5 mg/kg and 11 at 10 mg/kg) were hospitalized for worsening CHF compared with 5 of the 49 placebo-treated patients (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Cardiovascular).

There have also been post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age.

Less Common Clinical Trial Adverse Drug Reactions

Other medically relevant adverse events occurring at a frequency <1% were as follows, presented by body system:

Administration / application site: injection site inflammation, injection site ecchymosis, injection site swelling, injection site infection
Autonomic Nervous System: fecal incontinence
Body as a whole: anaphylactoid reaction, diaphragmatic hernia, generalized edema, surgical/procedural sequela, substernal chest pain, rigors
Blood: pancytopenia, splenomegaly
Cardiovascular: circulatory failure, hypotension postural, pallor
Collagen: LE syndrome, anti-DNA antibodies, positive antinuclear factor test, anticardiolipin antibodies
Ear and Hearing: otitis externa
Endocrine: adrenal insufficiency, hypothyroidism
Eye and Vision: lacrimation abnormal, iritis, scleritis, eye pain, glaucoma
Gastrointestinal: ileus, intestinal stenosis, pancreatitis, peritonitis, rectal hemorrhage, appetite increased, anal fistula, diarrhea bloody, gastritis, intestinal obstruction, intestinal perforation
Central & Peripheral Nervous: meningitis, neuritis, optic neuritis, peripheral neuropathy, neuralgia, ataxia, dysesthesia, tremor, hyperkinesia
Heart Rate and Rhythm: arrhythmia, bradycardia, cardiac arrest, palpitations
Liver and Biliary: cholelithiasis, hepatitis, bilirubinemia, cholecystitis, hepatocellular damage, elevated GGT, fatty liver, hepatomegaly
Metabolic and Nutritional: hypercholesterolemia
Musculoskeletal: intervertebral disk herniation, tendon disorder, joint stiffness
Myo-, Endo-, Pericardial and Coronary Valve: myocardial infarction, mitral insufficiency, heart murmur, cardiac failure
Platelet, Bleeding and Clotting: thrombocytopenia
Neoplasms: adenocarcinoma, basal cell carcinoma, breast cancer, lymphoma, malignant melanoma, squamous cell carcinoma, bladder carcinoma, rectal carcinoma, uterine cancer, pulmonary carcinoma
Psychiatric: confusion, suicide attempt, irritability, nervousness, amnesia
Red Blood Cell: iron deficiency anemia, hemolytic anemia
Reproductive: menstrual irregularity, dysmenorrhea, menorrhagia, breast fibroadenosis, amenorrhea, female breast pain
Resistance Mechanism: sepsis, serum sickness, tuberculosis, fungal infection, viral infection, sarcoid-like reaction
Respiratory: Adult respiratory distress syndrome, respiratory tract infection, pleural effusion, lobar pneumonia, pulmonary edema, respiratory insufficiency, bronchospasm, asthma, hemoptysis, epistaxis, laryngitis
Skin and Appendages: erythema nodosum, rash maculopapular, rash pustular, photosensitivity reaction, edema periorbital, fascitis
Special Senses, Other: taste perversion, taste loss
Urinary: renal failure, dysuria, renal calculus, pyelonephritis
Vascular (Extracardiac): brain infarction, thrombophlebitis, vasculitis, brain ischemia, pulmonary embolism
White Cell and Reticuloendothelial: neutropenia, neutrophilia, lymphocytosis

Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Serious, medically relevant hematologic adverse events ≥0.2%, or clinically relevant hematologic adverse reactions observed in clinical trials include: pancytopenia, thrombocytopenia, anemia, hemolytic anemia, neutropenia and leukopenia.

The proportion of patients with abnormal ALT levels in response to infliximab for injection is presented in Table 5.

Table 5: Proportion of patients with elevated ALT in infliximab for injection Clinical Trials
1
Note that placebo patients received methotrexate while infliximab for injection patients received both infliximab for injection and methotrexate. Median follow-up was 58 weeks for placebo patients and infliximab for injection-treated patients. RA trials include ATTRACT (T22) and ASPIRE (T29).
2
Note that placebo patients in 2 of the 3 Phase III trials in Crohn’s disease, ACCENT I and ACCENT II, received an initial dose of 5 mg/kg infliximab for injection at study start and were on placebo in the maintenance phase. Patients who were randomized to the placebo maintenance group and then later crossed over to infliximab for injection are included in the infliximab for injection group in this table. Median follow-up time was 54 weeks. In SONIC, placebo patients received AZA 2.5 mg/kg/day.
3
Ulcerative colitis trials include ACT I (C0168T37) through Week 54 and ACT II (C0168T46) through Week 30; median duration of follow up was 30.8 weeks for the infliximab for injection group and 30.1 weeks for placebo group.
4
IMPACT 2 median duration of follow up was 39.1 weeks for the infliximab for injection group and 18.1 weeks for placebo group.
5
EXPRESS and EXPRESS II median duration of follow up was 16.1 weeks for placebo and 50.1 weeks for infliximab for injection groups.
6
Patients from pediatric Crohn’s disease trials T23, T55 and T47 (REACH). Median follow-up was 53.0 weeks.
7
Patients from the ASSERT trial (T51); median duration of follow-up was 24.1 weeks for placebo and 101.9 weeks for the infliximab for injection group.
8
Data from the pediatric ulcerative colitis study T72.
 

Proportion of patients with elevated ALT

 

>1 to <3 X ULN

≥3 X ULN

≥5 X ULN

 

Placebo

Infliximab for

injection

Placebo

Infliximab for

injection

Placebo

Infliximab for

injection

Rheumatoid arthritis1

24.0%

34.4%

3.2%

3.9%

0.8%

0.9%

Crohn’s disease2

24.1%

34.9%

2.2%

4.9%

0.0%

1.5%

Ulcerative colitis3

12.4%

17.4%

1.2%

2.5%

0.4%

0.6%

Psoriatic arthritis4

16.3%

49.5%

0.0%

6.8%

0.0%

2.1%

Plaque psoriasis5

23.8%

49.4%

0.4%

7.7%

0.0%

3.4%

Pediatric Crohn’s disease6

N/A

18.2%

N/A

4.4%

N/A

1.5%

Ankylosing spondylitis7

14.5%

51.1%

0.0%

9.5%

0.0%

3.6%

Pediatric ulcerative colitis8

N/A

16.7%

N/A

6.7%

N/A

1.7%

The difference in rates of ALT elevations ≥3 X ULN between infliximab for injection and placebo treatment groups tended to be greater in ankylosing spondylitis, psoriasis and psoriatic arthritis clinical trials than in rheumatoid arthritis, Crohn’s disease and ulcerative colitis clinical trials. See Hepatobiliary Events.

Clinical Trial Adverse Reactions (Pediatrics)

Crohn’s Disease

Adverse events occurring at a frequency of ≥5% or from ≥1% to <5% in infliximab for injection-treated pediatric patients with Crohn’s disease are shown in Tables 2 and 4, respectively. In general, the adverse events in pediatric patients who received infliximab for injection were similar in frequency and type to those seen in adult patients with Crohn’s disease. Differences from adults and other special considerations are discussed in the following paragraphs.

The following adverse events were reported more commonly in the 103 randomised pediatric patients with Crohn’s disease (Phase 3 Trial, REACH) who received 5 mg/kg infliximab for Injection through 54 weeks than in the 385 adult patients with Crohn’s disease (ACCENT I) where 193/385 patients received 5 mg/kg and 192/385 received 10 mg/kg infliximab for injection through 54 weeks: anemia (10.7%), blood in stool (9.7%), leukopenia (8.7%), flushing (8.7%), viral infection (7.8%), neutropenia (6.8%), bone fracture (6.8%), bacterial infection (5.8%), and respiratory tract allergic reaction (5.8%). The Phase 3 study (REACH) enrolled 112 pediatric patients 6 to 17 years old (median age 13.0 years) with moderately to severely active Crohn’s disease and an inadequate response to conventional therapies.

Infections were reported in 56.3% of randomised pediatric patients in the REACH trial, and in 50.3% of patients in the ACCENT I Study. In the pediatric Phase 3 trial, infections were reported more frequently for subjects who received q8 week as opposed to q12 week infusions (73.6% and 38.0%, respectively), while serious infections were reported for 3 patients in the q8 week and 4 patients in the q12 week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Pneumonia was reported for 3 patients, 2 in the q8 week and 1 in the q12 week maintenance treatment groups. Herpes zoster was reported for 2 patients in the q8 week maintenance treatment group.

In REACH, 17.5% of randomised patients experienced 1 or more infusion reactions, with no notable difference between treatment groups (17.0% and 18.0% of patients in the q8 week and q12 week maintenance treatment groups, respectively). There were no serious infusion reactions, and 2 patients had non-serious anaphylactic reactions.

Antibodies to infliximab developed in 3 (2.9%) pediatric patients in the REACH trial and in the patients in the Phase 2 trial (T23).

Juvenile Rheumatoid Arthritis

The efficacy of infliximab for injection in the treatment of children with juvenile rheumatoid arthritis, JRA, has not been established. In a clinical trial where children were treated with either 3 mg/kg or 6 mg/kg of infliximab for injection, the proportion of children with infusion reactions, most commonly vomiting, fever, headache and hypotension, was 35% at a dosage of 3 mg/kg. Four of these reactions were serious, and three were considered to be possible anaphylactic reactions. Two of the 4 patients who experienced serious infusion reactions at a dose of 3 mg/kg received infliximab for injection by rapid infusion (duration time less than 2 hours). Antibodies to infliximab developed in 37.7% of children receiving that dosage, but only in 12.2% receiving a higher dosage (6 mg/kg).

Ulcerative Colitis

Overall, the adverse reactions reported in the pediatric ulcerative colitis (Study Peds UC) and adult ulcerative colitis (ACT 1 and ACT 2) studies were generally consistent. In Study Peds UC, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache. In Study Peds UC, there were a total of 20 serious adverse events: 10 were serious adverse events of ulcerative colitis, 7 were infections (which included cellulitis, urinary tract infection, pneumonia, pharyngitis, ulcerative colitis, viral infection, and infection not otherwise specified) and one event each of anemia, neutropenia and pancreatitis. An additional 12 adverse events were considered to be severe (4 events of ulcerative colitis, 3 of abdominal pain and 1 event each of pharyngitis, sinusitis, malnutrition, inflammation and headache). None of these serious or severe adverse events were opportunistic infections.

Infections were reported in 31 (51.7%) of 60 treated patients in Study Peds UC and 22 (36.7%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in Study Peds UC was similar to that in the pediatric Crohn’s disease study (REACH) but higher than the proportion in the adult ulcerative colitis studies (ACT 1 and ACT 2). Unlike REACH, in which infections were reported more frequently for patients who received q8 week as opposed to q12 week infusions; in Study Peds UC, the overall incidence of infections was similar in the q8 week (13/22 [59.1%]) and q12 week (14/23 [60.9%]) maintenance treatment groups. In Study Peds UC, serious infections were reported for 3 of 22 (13.6%) patients in the q8 week and 3 of 23 (13.0%) patients in the q12 week maintenance treatment group. Upper respiratory tract infection (7/60 [11.7%]) and pharyngitis (5/60 [8.3%]) were the most frequently reported respiratory system infections among all treated patients. The infections occurring in more than one patient in a treatment group that required antimicrobial treatment were pharyngitis (4/60 [6.7%]), urinary tract infection (4/60 [6.7%]), and bronchitis (2/60 [3.3%]).

Overall, 8 (13.3%) of 60 treated patients experienced one or more infusion reactions, with 4 of 22 (18.2%) in the q8 week and 3 of 23 (13.0%) in the q12 week treatment maintenance group. No serious infusion reactions were reported. All infusion reactions were mild or moderate in intensity.

Antibodies to infliximab were detected in 4 of 52 (7.7%) patients through week 54.

In Study Peds UC, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group (45/60 [75.0%]) vs.15/60 [25.0%]). While the numbers of patients in each subgroup are too small to make any definitive conclusions about the effect of age on safety events, there were higher proportions of patients with serious adverse events and discontinuation due to adverse events in the younger age group than in the older age group. While the proportion of patients with infections was also higher in the younger age group, the proportions of patients with serious infections were similar in the two age groups. Overall proportions of adverse events and infusion reactions were similar between the 6 to 11 and 12 to 17 year age groups.

Post-Market Adverse Reactions

Additional adverse events, some with fatal outcome, reported from worldwide post-marketing experience with infliximab for injection are included in Table 6 (see ADVERSE REACTIONS, Infections and Infusion-related Reactions). Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to infliximab for injection exposure.

The most common serious adverse events reported in the post-marketing experience in children were infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, and hypersensitivity reactions. Spontaneous serious adverse events in the postmarketing experience with infliximab for injection in the pediatric population have also included malignancies, transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.

Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with infliximab for injection with the vast majority of cases occurring in Crohn’s disease and ulcerative colitis, most of whom were adolescent or young adult males (see WARNINGS AND PRECAUTIONS, Carcinogenesis and Mutagenesis, Hepatosplenic T-cell Lymphoma).

Hemophagocytic lymphohistiocytosis (HLH) has been very rarely reported in patients treated with infliximab for Injection.

Table 6: POST-MARKETING REPORTS
 
* including bovine tuberculosis (disseminated BCG infection), see WARNINGS AND PRECAUTIONS, Live Vaccines/Therapeutic Infectious Agents.

Blood and Lymphatic System Disorders

agranulocytosis (including infants exposed in utero to infliximab for injection), idiopathic thrombocytopenic purpura, hemolytic anemia, pancytopenia, thrombotic thrombocytopenic purpura

General Disorders and Administration Site Conditions

anaphylactic reactions, anaphylactic shock, infusion-related reactions, serum sickness

Cardiac Disorders

pericardial effusion, myocardial ischemia/myocardial (within 24 hours of initiation of infusion), arrhythmia (within 24 hours of initiation of infusion)

Eye Disorders

Transient visual loss occurring during or within 2 hours of infusion

Immune System Disorders

vasculitis, sarcoidosis

Neoplasm Benign and Malignant

hepatosplenic T-cell lymphoma (the vast majority in Crohn’s disease and ulcerative colitis: primarily adolescents and young adults), pediatric malignancy, leukemia, melanoma, Merkel cell carcinoma, cervical cancer

Hepatobiliary System Disorders

hepatocellular damage, hepatitis, jaundice, autoimmune hepatitis, liver failure

Nervous System Disorders

central nervous system demyelinating disorders (such as multiple sclerosis and optic neuritis), peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy), neuropathies, numbness, seizure, tingling, transverse myelitis, cerebrovascular accidents occurring within approximately 24 hours of initiation of infusion

Infections and Infestations

opportunistic infections (such as aspergillosis, atypical mycobacteria, coccidioidomycosis, cryptococcosis, candidiasis, histoplasmosis, legionellosis, listeriosis, pneumocystosis), salmonellosis, sepsis tuberculosis, protozoal infections, hepatitis B reactivation and vaccine breakthrough infection (after in utero exposure to infliximab for injection)*

Respiratory, Thoracic and Mediastinal Disorders

interstitial lung disease, including pulmonary fibrosis/interstitial pneumonitis, and rapidly progressive disease

Skin and Subcutaneous Tissue Disorders

vasculitis (primarily cutaneous) , psoriasis including new onset and pustular (primarily palmar/plantar), erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, linear IgA bullous dermatosis (LABD), acute generalized exanthematous pustulosis (AGEP), lichenoid reactions