Important Safety Information For

• Infliximab

  INDICATIONS

  Crohn’s Disease

  Infliximab is indicated for:

  • reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease (CD) who have had an inadequate response to conventional therapy.
  • reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing CD.

  Pediatric Crohn’s Disease

  Infliximab is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active CD who have had an inadequate response to conventional therapy.

  Ulcerative Colitis

  Infliximab is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy.

  Pediatric Ulcerative Colitis

  Infliximab is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active UC who have had an inadequate response to conventional therapy.

  Rheumatoid Arthritis

  Infliximab, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis (RA).

  Ankylosing Spondylitis

  Infliximab is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis (AS).

  Psoriatic Arthritis

  Infliximab is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in adult patients with psoriatic arthritis (PsA).

  Plaque Psoriasis

  Infliximab is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis (Ps) who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. Infliximab should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.

  IMPORTANT SAFETY INFORMATION FOR Infliximab

  SERIOUS INFECTIONS

  Patients treated with Infliximab are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue Infliximab if a patient develops a serious infection or sepsis.

  Reported infections include:

  • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with Infliximab.^1,2 Treatment for latent infection should be initiated prior to treatment with Infliximab.
  • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, pneumocystosis, and cryptococcosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
  • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella, Listeria, and Salmonella.

  The risks and benefits of treatment with Infliximab should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Infliximab, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy, who are on treatment for latent TB, or who were previously treated for TB infection.

  Risk of infection may be higher in patients greater than 65 years of age, pediatric patients, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. In clinical trials, other serious infections observed in patients treated with Infliximab included pneumonia, cellulitis, abscess, and skin ulceration.

  MALIGNANCIES

  Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including Infliximab. Approximately half of these cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

  Post-marketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including Infliximab. These cases have had a very aggressive disease course and have been fatal. The majority of reported Infliximab cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with Infliximab at or prior to diagnosis. Carefully assess the risks and benefits of treatment with Infliximab, especially in these patient types.

  In clinical trials of all TNF blockers, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF blockers, including Infliximab, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with Infliximab was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with post-marketing TNF-blocker use. As the potential role of TNF blockers in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).

  Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocker therapy, including Infliximab. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

  A population-based retrospective cohort study found a 2- to 3-fold increase in the incidence of invasive cervical cancer in women with rheumatoid arthritis treated with Infliximab compared to biologics-naïve patients or the general population, particularly those over 60 years of age. A causal relationship between Infliximab and cervical cancer cannot be excluded. Periodic screening should continue in women treated with Infliximab.

  CONTRAINDICATIONS

  The use of Infliximab at doses >5 mg/kg is contraindicated in patients with moderate or severe heart failure. Infliximab is contraindicated in patients with a previous severe hypersensitivity reaction to Infliximab or any of the inactive ingredients of Infliximab or any murine proteins (severe hypersensitivity reactions have included anaphylaxis, hypotension, and serum sickness).

  HEPATITIS B REACTIVATION

  TNF blockers, including Infliximab, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients should be tested for HBV infection before initiating Infliximab. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. Exercise caution when prescribing Infliximab for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with Infliximab. Discontinue Infliximab in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of Infliximab and monitor patients closely.

  HEPATOTOXICITY

  Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported in patients receiving Infliximab post-marketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of normal) develop, Infliximab should be discontinued, and a thorough investigation of the abnormality should be undertaken.

  HEART FAILURE

  In a randomized, placebo-controlled study in patients with moderate or severe heart failure (NYHA Functional Class III/IV), higher mortality rates and a higher risk of hospitalization were observed at Week 28 at a dose of 10 mg/kg and higher rates of cardiovascular events were observed at both 5 mg/kg and 10 mg/kg. There have been post-marketing reports of new onset and worsening heart failure, with and without identifiable precipitating factors. Patients with moderate or severe heart failure taking Infliximab (≤5 mg/kg) or patients with mild heart failure should be closely monitored and treatment should be discontinued if new or worsening symptoms appear.

  HEMATOLOGIC EVENTS

  Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to Infliximab therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of Infliximab in patients who develop significant hematologic abnormalities.

  HYPERSENSITIVITY

  Infliximab has been associated with hypersensitivity reactions that differ in their time of onset. Anaphylaxis, acute urticaria, dyspnea, and hypotension have occurred in association with infusions of Infliximab. Medications for the treatment of hypersensitivity reactions should be available.

  CARDIOVASCULAR AND CEREBROVASCULAR REACTIONS DURING AND AFTER INFUSION

  Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of Infliximab infusion. Cases of transient visual loss have been reported during or within 2 hours of Infliximab infusion. Monitor patients during infusion and if a serious reaction occurs, discontinue infusion. Manage reactions according to signs and symptoms.

  NEUROLOGIC EVENTS

  TNF blockers, including Infliximab, have been associated with CNS manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering Infliximab in patients with these disorders and consider discontinuation if these disorders develop.

  CONCURRENT ADMINISTRATION WITH OTHER BIOLOGICS

  Concurrent use of Infliximab with anakinra, abatacept, tocilizumab, or other biologics used to treat the same conditions as Infliximab is not recommended because of the possibility of an increased risk of infection. Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

  AUTOIMMUNITY

  Treatment with Infliximab may result in the formation of autoantibodies and in the development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.

  VACCINATIONS AND USE OF LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS

  Prior to initiating Infliximab, update vaccinations in accordance with current vaccination guidelines. Live vaccines or therapeutic infectious agents should not be given with Infliximab due to the possibility of clinical infections, including disseminated infections.

  At least a 6-month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to Infliximab.

  ADVERSE REACTIONS

  In clinical trials, the most common adverse reactions occurring in >10% of Infliximab-treated patients included infections (eg, upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.

  For more information, please see the full Prescribing Information, including Boxed Warning, and Medication Guide for Infliximab. Provide the Medication Guide to your patients and encourage discussion.

  References: 1. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221-S247. 2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.

  cp-253862v1

  INDICATIONS