[Posted 09/07/2011] ISSUE: FDA notified healthcare professionals that the Boxed Warning for the entire class of Tumor Necrosis Factor-alpha (TNF) blockers has been updated to include the risk of infection from two bacterial pathogens, Legionella and Listeria. In addition, the Boxed Warning and Warnings and Precautions sections of the labels for all of the TNF blockers have been revised so that they contain consistent information about the risk for serious infections and the associated disease-causing pathogens.
Patients treated with TNF blockers are at increased risk for developing serious infections involving multiple organ systems and sites that may lead to hospitalization or death due to bacterial, mycobacterial, fungal, viral, parasitic, and other opportunistic pathogens.
BACKGROUND: The class of TNF blockers are used to treat Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and/or juvenile idiopathic arthritis.
RECOMMENDATION: The risks and the benefits of TNF blockers should be considered prior to initiating therapy in patients with chronic or recurrent infection and patients with underlying conditions that may predispose them to infection. See the Drug Safety Communication for a listing of recommendations for healthcare professionals and patients, as well as a data summary. For more information visit the FDA website at: [Web] and [Web].
[Posted 04/14/2011] ISSUE: FDA continues to receive reports of a rare cancer of white blood cells (known as Hepatosplenic T-Cell Lymphoma or HSTCL, primarily in adolescents and young adults being treated for Crohn’s disease and ulcerative colitis with medicines known as tumor necrosis factors (TNF) blockers, as well as with azathioprine, and/or mercaptopurine. TNF blockers include infliximab (Remicade), etancercept (Enbrel), adalimumab (Humira), certolizumab pegol (Cimzia) and golimumab (Simponi).
BACKGROUND: HSTCL is an aggressive (fast-growing) cancer and is usually fatal. The majority of cases reported were in patients being treated for Crohn’s disease or ulcerative colitis, but also included a patient being treated for psoriasis and two patients being treated for rheumatoid arthritis. FDA is now updating the number of reported cases of HSTCL.
Although most reported cases of HSTCL occurred in patients treated with a combination of medicines known to suppress the immune system, including the TNF blockers, azathioprine, and/or mercaptopurine, there have been cases reported in patients receiving azathioprine or mercaptopurine alone.
Educate patients and caregivers about the signs and symptoms of malignancies such as HSTCL so that they are aware of and can seek evaluation and treatment of any signs or symptoms. These may include splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss.
Monitor for the emergence of malignancies when a patient has been treated with TNF blockers, azathioprine, and/or mercaptopurine.
Know that people with rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis may be more likely to develop lymphoma than the general U.S. population. Therefore, it may be difficult to measure the added risk of TNF blockers, azathioprine, and/or meracaptopurine.
Read the Drug Safety Communications for other specific recommendations for Healthcare Professionals and Patients and the Data Summary for additional information. For more information visit the FDA website at: [Web] and [Web].
REMS:
FDA approved a REMS for etanercept to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page ([Web]) or the ASHP REMS Resource Center ([Web]).
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Rheumatoid Arthritis in Adults
Used to manage the signs and symptoms of rheumatoid arthritis, to induce a major clinical response, to improve physical function, and to inhibit progression of structural damage associated with the disease in adults with moderate to severe active rheumatoid arthritis.
Can be initiated in combination with methotrexate or alone.
Juvenile Arthritis
Management of the signs and symptoms of moderate to severe active polyarticular course juvenile idiopathic arthritis in children.
Psoriatic Arthritis
Used to manage the signs and symptoms of active arthritis, to improve physical function, and to inhibit progression of structural damage associated with the disease in patients with psoriatic arthritis.
Can be used in combination with methotrexate in patients who have not responded adequately to therapy with methotrexate alone.
Management of moderate to severe chronic plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.
Wegener’s Granulomatosis
Under investigation for the management of Wegener’s granulomatosis† (designated an orphan drug by FDA for this use). Clinical benefit is unclear; use with standard immunosuppressive agents has been associated with an increased incidence of solid malignant tumors. Use to induce or maintain remission currently is not justified. Use in patients with Wegener’s granulomatosis† receiving immunosuppressive therapy is not recommended. (See Malignancies and Lymphoproliferative Disorders under Cautions and see Specific Drugs and Laboratory Tests under Interactions.)
Dosage and Administration
General
Methotrexate, glucocorticoids, salicylates, NSAIAs, and analgesics may be continued in adults with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.
Adults and children receiving 50-mg dose: Administer dose as a single injection or as 2 injections given on the same day or 3–4 days apart.
Administer sub-Q injections into the thighs, abdomen, or upper arm. Rotate injection sites. Development of local reactions at the injection site does not preclude continued therapy.
Allow etanercept prefilled syringe and prefilled auto-injector to reach room temperature (about 15–30 minutes) prior to administration. Do not remove the needle cover until the prefilled syringe or prefilled auto-injector has reached room temperature. Solution may contain a small amount of visible, white, proteinaceous particulates; do not administer if discolored or cloudy, or if foreign particulate matter is present.
Intended for use under the guidance and supervision of a clinician, but may be self-administered if the clinician determines that the patient and/or their caregiver is competent to prepare and safely administer the drug. The initial self-administered dose should be made under the supervision of a healthcare professional.
Reconstitution
Multiple-dose vial: Reconstitute lyophilized powder by adding 1 mL of bacteriostatic water for injection (containing 0.9% benzyl alcohol) provided by the manufacturer to a 25-mg vial to provide a solution containing 25 mg/mL.
During reconstitution, very slowly add the diluent to the vial and gently swirl the contents to minimize foaming during dissolution; some foaming will occur.
Avoid shaking and excessive or vigorous agitation of the vial to avoid excessive foaming.
The final volume in the vial will be about 1 mL.
Dissolution usually takes less than 10 minutes. Do not filter solutions during preparation or administration.
Preparation Considerations
50-mg dose given as a single injection: Preferred preparations are the 50-mg prefilled syringe or prefilled auto-injector.
50-mg dose given as 2 injections: Appropriate preparation is the multiple-dose vial or 25-mg prefilled syringe.
Dose <50 mg: Appropriate preparation is the multiple-dose vial.
Dosage
Pediatric Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Juvenile Arthritis
Sub-Q
Children 2–17 years of age: 0.8 mg/kg per week (up to a dosage of 50 mg per week).
Children <31 kg: 25-mg prefilled syringe should not be used.
Adults
Rheumatoid Arthritis
Sub-Q
50 mg weekly.
Psoriatic Arthritis
Sub-Q
50 mg weekly.
Ankylosing Spondylitis
Sub-Q
50 mg weekly.
Psoriasis
Sub-Q
Initially, 50 mg twice weekly for 3 months. Initial dosages of 25 mg once or twice weekly also have been effective; proportion of responders related to etanercept dosage.
Maintenance dosage: 50 mg weekly.
Prescribing Limits
Pediatric Patients
Juvenile Arthritis
Sub-Q
Maximum 50 mg weekly.
Adults
Rheumatoid Arthritis
Sub-Q
Maximum 50 mg weekly.
Psoriatic Arthritis
Sub-Q
Maximum 50 mg weekly.
Ankylosing Spondylitis
Sub-Q
Maximum 50 mg weekly.
Special Populations
Renal Impairment
Limited data indicate that dosage adjustment is not necessary in patients with renal failure.
Serious, sometimes fatal infections (including sepsis, tuberculosis, and opportunistic infections) reported, particularly in patients receiving concomitant therapy with immunosuppressive agents that, in addition to their underlying disease, could have predisposed them to infections.
Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation), invasive opportunistic fungal infections, and other infections reported in patients receiving etanercept or other TNF blocking agents.
Do not initiate etanercept in patients with active infections, including chronic or localized infections. Exercise caution when considering etanercept therapy in patients with a history of recurring infections or with underlying conditions that may predispose to infections.
Discontinue etanercept if serious infection develops. Closely monitor any patient who develops a new infection.
Evaluate all patients for active or latent tuberculosis prior to initiation of therapy. When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection prior to etanercept therapy. Monitor all patients, including those with negative tuberculin skin tests, for active tuberculosis.
Invasive fungal infections often not recognized in patients receiving TNF blocking agents; this has led to delays in appropriate treatment.
Increased incidence of serious infection observed with concomitant use of etanercept and anakinra (a human interleukin-1 receptor antagonist). (See Specific Drugs and Laboratory Tests under Interactions.)
Increased incidence of infection and serious infection reported with concomitant use of a TNF blocking agent and abatacept. (See Specific Drugs and Laboratory Tests under Interactions.)
Hepatitis B Virus (HBV) Reactivation
Reactivation of HBV infection reported in patients who are chronic carriers of the virus (i.e., hepatitis B surface antigen-positive [HBsAg-positive]). Death reported in a few individuals. Use of multiple immunosuppressive agents may contribute to HBV reactivation.
Screen patients at risk prior to initiation of therapy. Evaluate and monitor HBV carriers before, during, and for up to several months after therapy. Safety and efficacy of antiviral therapy for prevention of HBV reactivation not established. Discontinue etanercept and initiate appropriate treatment (e.g., antiviral therapy) if HBV reactivation occurs. Not known whether etanercept can be readministered once control of a reactivated HBV infection is achieved; caution advised in this situation.
Nervous System Effects
Exacerbation of clinical manifestations and/or radiographic evidence of demyelinating disorders reported rarely in patients receiving etanercept or other TNF blocking agents. Transverse myelitis, optic neuritis, multiple sclerosis, and new onset or exacerbation of seizure disorders reported in patients receiving etanercept; increased disease activity observed in patients with multiple sclerosis receiving other TNF blocking agents.
Exercise caution when considering etanercept therapy in patients with preexisting or recent-onset CNS demyelinating disorders.
Hematologic Effects
Possible pancytopenia including aplastic anemia, sometimes with fatal outcome. Use with caution in patients with a history of substantial hematologic abnormalities. Consider discontinuance in patients with confirmed hematologic abnormalities.
Malignancies and Lymphoproliferative Disorders
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Lymphoma reported more frequently in patients receiving etanercept or other TNF blocking agents than in control patients. Patients with rheumatoid arthritis or psoriasis, especially those with highly active disease, may be at increased risk of lymphoma.
FDA is investigating possible increased risk of Hodgkin’s disease, non-Hodgkin’s lymphoma, and other cancers in children and young adults receiving TNF blocking agents. (See Pediatric Use under Cautions.)
Role of TNF blocking agents in development of malignancies not fully determined.
Other malignancies (e.g., colon, breast, lung, and prostate cancer) have occurred.
Solid malignant tumors reported in patients with Wegener’s granulomatosis receiving etanercept and cyclophosphamide; malignancies not reported in control patients receiving standard immunosuppressive therapy (corticosteroids plus cyclophosphamide or methotrexate) for Wegener’s granulomatosis. (See Specific Drugs and Laboratory Tests under Interactions.)
Sensitivity Reactions
Hypersensitivity Reactions
Possible allergic reactions. If serious allergic reaction or anaphylaxis occurs, immediately discontinue etanercept and initiate appropriate therapy.
Latex Sensitivity
The needle covers of prefilled syringes and prefilled auto-injectors contain dry natural rubber (latex); individuals sensitive to latex should not handle the needle covers.
General Precautions
Cardiovascular Effects
Worsening CHF (with and without identifiable precipitating factors) and new-onset CHF (including in patients without known cardiovascular disease) reported rarely. Use with caution and monitor carefully in patients with heart failure.
Immunologic Reactions and Antibody Formation
Possible formation of autoimmune antibodies. Lupus-like syndrome reported. If manifestations suggestive of lupus-like syndrome develop, discontinue etanercept.
Not known whether etanercept is distributed into milk or is absorbed systemically following ingestion. Discontinue nursing or the drug.
Pediatric Use
Used for treatment of polyarticular course juvenile idiopathic arthritis in children ≥2 years of age. Not studied in children <2 years of age. Safety and efficacy not established in children with plaque psoriasis.
Review vaccination status of the child and administer all age-appropriate vaccines, if possible, prior to initiation of therapy.
Varicella infection associated with septic meningitis reported. If a varicella-susceptible child has a clinically important exposure to varicella while receiving etanercept, discontinue the drug temporarily and consider use of varicella-zoster immune globulin.
Headache, abdominal pain, nausea, and vomiting reported more frequently in children than in adults. Adverse effects reported in children 2–4 years of age similar to those reported in older children.
Hodgkin’s disease, non-Hodgkin’s lymphoma, and other cancers reported in children and young adults who were ≤18 years of age when therapy with a TNF blocking agents was initiated for the treatment of juevnile idiopathetic arthritis, Crohn’s disease, or other diseases. (See Malignancies and Lymphoproliferative Disorders under Cautions.)
Geriatric Use
No substantial differences in safety or efficacy relative to younger adults.
Possible increased incidence of infections in geriatric patients; use with caution.
Common Adverse Effects
Injection site reactions, respiratory tract infections, headache.
Store reconstituted solutions at 2–8°C; do not freeze. Discard reconstituted solutions after 14 days.
Prefilled Syringe and Prefilled Auto-injector
2–8°C. Do not freeze. Store in original carton until time of administration. Do not shake.
Actions
Potent antagonist of TNF biologic activity.
High binding affinity for TNF and lymphotoxin-α (TNF-β); each molecule can bind to 2 TNF molecules. Prevents the binding of TNF to cell surface TNF receptors, thereby blocking the biologic activity of TNF.
Produced by recombinant DNA technology in a mammalian cell expression system.
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
If the patient or caregiver is to administer etanercept, provide careful instructions regarding proper dosage and administration of etanercept, including proper aseptic technique, and proper disposal of needles and syringes.
Provide copy of manufacturer’s patient information.
Importance of advising patients to seek immediate medical attention if signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) develop.
Importance of alerting clinician if allergy to latex exists.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any other illnesses (e.g., concomitant or recurrent infections, history of tuberculosis, history of HBV infection).
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Enbrel® (with mannitol, sucrose, and tromethamine and prefilled syringe containing 1 mL bacteriostatic water for injection [with benzyl alcohol 0.9%] diluent, plunger, vial adapter, and alcohol swabs; also available as disposable prefilled syringes [preservative free])
Amgen, (also promoted by Wyeth)
50 mg/mL
Enbrel® (preservative free; available as disposable prefilled syringes and prefilled auto-injector [SureClick®])
Amgen, (also promoted by Wyeth)
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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