Remicade - Side Effects & Drug Interactions

(Page 5)

Antibody development was lower among rheumatoid arthritis and Crohn’s disease patients receiving immunosuppressant therapies such as 6-MP/AZA or MTX. The data reflect the percentage of patients whose test results were positive for antibodies to infliximab in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to infliximab with the incidence of antibodies to other products may be misleading.

Other Adverse Reactions

Safety data are available from 2427 REMICADE-treated patients, including 1304 with rheumatoid arthritis, 1106 with Crohn’s disease, and 17 with conditions other than rheumatoid arthritis or Crohn’s disease. Adverse events reported in =5% of all patients with rheumatoid arthritis receiving 4 or more infusions are in Table 5. The types and frequencies of adverse reactions observed were similar in REMICADE-treated rheumatoid arthritis and Crohn's disease patients except for abdominal pain, which occurred in 26% of REMICADEtreated patients with Crohn’s disease.

In the Crohn's disease studies, there were insufficient numbers and duration of follow-up for patients who never received REMICADE to provide meaningful comparisons. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not predict the rates observed in broader patient populations in clinical practice. The most common serious adverse events observed in clinical trials were infections (see ADVERSE REACTIONS, Infections). Other serious, medically relevant adverse events =0.2% or clinically significant adverse events by body system were as follows:

Body as a whole:

allergic reaction, diaphragmatic hernia, edema, surgical/procedural sequela

Blood:

Pancytopenia

Cardiovascular:

circulatory failure, hypotension, syncope

Gastrointestinal: constipation, gastrointestinal hemorrhage, ileus, intestinal obstruction, intestinal perforation, intestinal stenosis, pancreatitis, peritonitis, proctalgia

Central & Peripheral Nervous:

meningitis, neuritis, peripheral neuropathy, dizziness

Heart Rate and Rhythm:

arrhythmia, bradycardia, cardiac arrest, tachycardia

Liver and Biliary: biliary pain, cholecystitis, cholelithiasis, hepatitis

Metabolic and Nutritional:

Dehydration

Musculoskeletal:

intervertebral disk herniation, tendon disorder

Myo-, Endo-, Pericardial, and Coronary Valve:

myocardial infarction

Platelet, Bleeding, and Clotting:

Thrombocytopenia

Neoplasms:

basal cell, breast, lymphoma

Psychiatric:

confusion, suicide attempt

Red Blood Cell:

anemia, hemolytic anemia

Reproductive:

menstrual irregularity

Resistance Mechanism:

cellulitis, sepsis, serum sickness

Respiratory:

adult respiratory distress syndrome, lower respiratory tract infection (including pneumonia), pleural effusion, pleurisy, pulmonary edema, respiratory insufficiency

Skin and Appendages:

increased sweating, ulceration

Urinary:

renal calculus, renal failure

Vascular (Extracardiac):

brain infarction, pulmonary embolism, thrombophlebitis

White Cell and Reticuloendothelial:

leukopenia, lymphadenopathy

A greater proportion of patients enrolled into the Study RA I who received REMICADE + MTX experienced transient mild (<2 times the

upper limit of normal) or moderate (=2 but <3 times the upper limit of normal) elevations in AST or ALT (49% and 47%, respectively) compared

to patients treated with placebo + MTX (27% and 35%, respectively). Six (1.8%) patients treated with REMICADE + MTX experienced more prolonged elevations in their ALT.

The following adverse events have been reported during post-approval use of REMICADE: neutropenia (see WARNINGS, Hematologic Events), interstitial pneumonitis/fibrosis, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pericardial effusion, systemic and cutaneous vasculitis, Guillain-Barré syndrome, transverse myelitis, and neuropathies (additional neurologic events have also been observed, see WARNINGS, Neurologic Events). 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 REMICADE exposure.

Table 5

ADVERSE EVENTS OCCURRING IN 5% OR MORE OF PATIENTS

RECEIVING 4 OR MORE INFUSIONS FOR RHEUMATOID ARTHRITIS

Average weeks of follow-up

Gastrointestinal

Nausea

Abdominal Pain

Diarrhea

Dyspepsia

Respiratory

Upper respiratory tract infection

Sinusitis

Pharyngitis

Coughing

Bronchitis

Rhinitis

Skin and appendages disorders

Rash

Pruritis

Body as a whole—general disorders

Fatigue

Pain

Resistance mechanism disorders

Fever

Moniliasis

Central and peripheral nervous system

disorders

Headache

Musculoskeletal system disorders

Back pain

Arthralgia

Urinary system disorders

Urinary tract infection

Cardiovascular disorders, general

Hypertension

59

20%

8%

12%

7%

25%

8%

8%

8%

9%

5%

5%

2%

7%

7%

4%

3%

14%

5%

7%

6%

5%

(n=350)

Placebo

66

21%

12%

12%

10%

32%

14%

12%

12%

10%

8%

10%

7%

9%

8%

7%

5%

18%

8%

8%

8%

7%

REMICADE

(n=1129)

10 9

Drug Interactions

Concurrent administration of etanercept (another TNFa-blocking agent) and anakinra (an interleukin-1 antagonist) has been associated with an increased risk of serious infections, and increased risk of neutropenia and no additional benefit compared to these medicinal products alone. Other TNFa-blocking agents (including REMICADE) used in combination with anakinra may also result in similar toxicities (see WARNINGS, RISK OF INFECTIONS).

Specific drug interaction studies, including interactions with MTX, have not been conducted. The majority of patients in rheumatoid arthritis or Crohn’s disease clinical studies received one or more concomitant medications. In rheumatoid arthritis, concomitant medications besides MTX were nonsteroidal anti-inflammatory agents, folic acid, corticosteroids, and/or narcotics. Concomitant Crohn’s disease medications were antibiotics, antivirals, corticosteroids, 6-MP/AZA, and aminosalicylates.

Patients with Crohn’s disease who received immunosuppressants tended to experience fewer infusion reactions compared to patients on no immunosuppressants (see ADVERSE REACTIONS, Immunogenicity and Infusion-related Reactions). Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of Crohn’s disease including corticosteroids, antibiotics (metronidazole or ciprofloxacin), and aminosalicylates.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

A repeat dose toxicity study was conducted with mice given cV1q anti-mouse TNFa to evaluate tumorigenicity. CV1q is an analogous

antibody that inhibits the function of TNFa in mice. Animals were assigned to 1 of 3 dose groups: control, 10 mg/kg, or 40 mg/kg cV1q given weekly for 6 months. The weekly doses of 10 mg/kg and 40 mg/kg are 2 and 8 times, respectively, the human dose of 5 mg/kg for Crohn’s disease. Results indicated that cV1q did not cause tumorigenicity in mice.

No clastogenic or mutagenic effects of infliximab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. Chromosomal aberrations were not observed in an assay performed using human lymphocytes. The significance of these findings for human risk is unknown. It is not known whether infliximab can impair fertility in humans. No impairment of fertility was observed in a fertility and general reproduction toxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study.

Pregnancy Category B

Since infliximab does not cross-react with TNFa in species other than humans and chimpanzees, animal reproduction studies have not been conducted with REMICADE. No evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed in a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFa. Doses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness. Doses up to 40 mg/kg were shown to produce no adverse effects in animal reproduction studies. It is not known whether REMICADE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. REMICADE should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether infliximab is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from REMICADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of REMICADE in patients with juvenile rheumatoid arthritis and in pediatric patients with Crohn’s disease have not been established.

Geriatric Use

In rheumatoid arthritis clinical trials, no overall differences were observed in effectiveness or safety in 181 patients aged 65 or older compared to younger patients although the incidence of serious adverse events in patients aged 65 or older was higher in both infliximab and control groups compared to younger patients. In Crohn’s disease studies, there were insufficient numbers of patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly (see ADVERSE REACTIONS, Infections).