[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 adalimumab to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of adalimumab and consists of the following: medication guide and communication plan. 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. Use alone or in combination with methotrexate or other DMARDs.
Juvenile Arthritis
Management of the signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in children. Use with or without methotrexate.
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 adults with psoriatic arthritis. Use alone or in combination with other DMARDs.
Used to reduce signs and symptoms of Crohn’s disease and to induce and maintain clinical remission in adults with moderately to severely active disease who have had inadequate response to conventional therapy. Also used to reduce signs and symptoms of the disease and to induce clinical remission in adults with moderately to severely active Crohn’s disease who have lost response to or are intolerant to infliximab.
Plaque Psoriasis
Management of moderate to severe chronic plaque psoriasis in adults who are candidates for systemic therapy or phototherapy and in whom other systemic therapies are medically less appropriate. Use only in patients who will be closely monitored and who will have regular follow-up visits with a clinician.
Dosage and Administration
General
Methotrexate, other DMARDs, corticosteroids, salicylates, NSAIAs, and analgesics may be continued in adults with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.
Aminosalicylates, corticosteroids, and/or immunomodulatory agents (e.g., mercaptopurine, azathioprine) may be continued in adults with Crohn’s disease.
Administration
Sub-Q Injection
Administer by sub-Q injection every other week or every week.
Administer sub-Q injections into thighs or abdomen; do not make abdominal injections within 5.18 cm (2 inches) of the umbilicus. Rotate injection sites. Give new injections ≥2.54 cm (1 inch) from an old site; do not make injections into areas where the skin is tender, bruised, red, or hard, or into scars or stretch marks.
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 safely administer the drug after appropriate training and with medical follow-up as necessary. The initial self-administered dose should be made under the supervision of a health-care professional.
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 4–17 years of age weighing 15 to <30 kg: 20 mg once every other week.
Children 4–17 years of age weighing ≥30 kg: 40 mg once every other week.
Adults
Rheumatoid Arthritis
Sub-Q
40 mg once every other week.
Patients not receiving methotrexate may obtain additional benefit from once weekly doses of 40 mg.
Psoriatic Arthritis
Sub-Q
40 mg once every other week.
Ankylosing Spondylitis
Sub-Q
40 mg once every other week.
Crohn’s Disease
Sub-Q
160 mg once on day 1 (as four 40-mg injections in one day or as two 40-mg injections per day for two consecutive days), followed by 80 mg once 2 weeks later (on day 15). Start maintenance dosage of 40 mg once every other week on day 29 (2 weeks after the 80-mg dose).
Plaque Psoriasis
Sub-Q
Initially, 80 mg followed by 40 mg once every other week (maintenance dosage) starting 1 week after the initial dose.
Prescribing Limits
Adults
Crohn’s Disease
Manufacturer states safety and efficacy of continuing adalimumab beyond 1 year have not been evaluated in clinical studies.
Plaque Psoriasis
Manufacturer states safety and efficacy of continuing adalimumab beyond 1 year have not been evaluated in clinical studies.
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 adalimumab or other TNF blocking agents.
Do not initiate adalimumab in patients with active infections, including chronic or localized infections. Exercise caution when considering adalimumab therapy in patients with a history of recurring infections or with underlying conditions that may predispose to infections.
Discontinue adalimumab if serious infection develops. Closely monitor any patient who develops a new infection.
Caution advised if adalimumab therapy is considered in patients who reside in regions where tuberculosis or histoplasmosis is endemic.
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 adalimumab 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.
Consider empiric antifungal therapy in patients at risk of histoplasmosis or other invasive fungal infections.
Increased incidence of serious infection observed with concomitant use of etanercept (another agent that blocks TNF) and anakinra (a human interleukin-1 receptor antagonist). Similar toxicities expected with use of anakinra and other agents that block TNF, including adalimumab. (See Specific Drugs under Interactions.)
Increased incidence of infection and serious infection reported with concomitant use of a TNF blocking agent and abatacept. (See Specific Drugs under Interactions.)
Hepatitis B Virus (HBV) Reactivation
Increased risk of reactivation of HBV infection in patients who are chronic carriers of the virus (i.e., hepatitis B surface antigen-positive [HBsAg-positive]). 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 adalimumab and initiate appropriate treatment (e.g., antiviral therapy) if HBV reactivation occurs. Not known whether adalimumab 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, including multiple sclerosis, reported rarely in patients receiving adalimumab or other TNF blocking agents.
Exercise caution when considering adalimumab therapy in patients with preexisting or recent-onset CNS demyelinating disorders.
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 adalimumab or other TNF blocking agents than in control patients. Patients with rheumatoid arthritis, 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.
Possible pancytopenia (including aplastic anemia), leukopenia, or thrombocytopenia. Consider discontinuance in patients with confirmed hematologic abnormalities.
Sensitivity Reactions
Hypersensitivity Reactions
Anaphylaxis reported rarely. Other allergic reactions (e.g., allergic rash, anaphylactoid reactions, fixed drug eruption, nonspecified drug reaction, urticaria) also observed.
If serious allergic reaction or anaphylaxis occurs, immediately discontinue adalimumab and initiate appropriate therapy.
Latex Sensitivity
The needle cover of prefilled syringes of adalimumab contains dry natural rubber (latex) and should not be handled by individuals sensitive to latex.
General Precautions
Cardiovascular Effects
Worsening CHF and new-onset CHF reported in patients receiving adalimumab or other TNF blocking agents. Use with caution and carefully monitor 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 adalimumab.
No evidence of depression of delayed-type hypersensitivity, decrease in immunoglobulin concentrations, or change in the enumeration of effector cell populations, monocytes/macrophages, or neutrophils observed.
Safety and efficacy in patients with immunosuppression not evaluated.
Immunization
Antibody response to inactivated vaccines (i.e., pneumococcal polysaccharide vaccine, influenza virus vaccine inactivated) has been investigated. No difference in antibody response to pneumococcal polysaccharide vaccine detected between patients with rheumatoid arthritis receiving adalimumab and those receiving placebo. Adalimumab-treated rheumatoid arthritis patients receiving influenza vaccine virus inactivated have developed protective antibody titers; however, titers to influenza antigens were lower in patients receiving adalimumab than in placebo-treated patients.
Avoid live virus vaccines. (See Vaccines under Interactions.)
Specific Populations
Pregnancy
Category B.
Pregnancy registry at 877-311-8972.
Lactation
Not known whether adalimumab is distributed into milk or is absorbed systemically following ingestion. Discontinue nursing or the drug.
Pediatric Use
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.
Safety and efficacy for the management of juvenile idiopathic arthritis established in pediatric patients 4–17 years of age. Not studied in children <4 years of age; data in patients weighing <15 kg limited.
Review vaccination status of the child and administer all age-appropriate vaccines, if possible, prior to initiation of adalimumab.
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 agent was initiated for the treatment of juvenile arthritis, Crohn’s disease, or other diseases. (See Malignancies and Lymphoproliferative Disorders under Cautions.)
Geriatric Use
No substantial differences in efficacy relative to younger adults.
The incidence of serious infection and malignancy in adalimumab-treated patients >65 years of age is higher than the incidence in younger adults. The overall incidence of infection and malignancy is higher in the geriatric population in general than in younger adults; use with caution.
Pediatric patients 4–17 years of age: Infection, injection site pain, injection site reaction, hypersensitivity reaction (e.g., localized allergic sensitivity reaction, rash), increased CPK concentration.
Interactions
Administered concomitantly with aminosalicylates, methotrexate, other DMARDs, corticosteroids, other immunomodulatory agents, and/or NSAIAs in clinical studies.
Increased incidence of serious infections and increased risk of neutropenia reported with anakinra and etanercept (another agent that blocks TNF); similar toxicities expected with adalimumab and anakinra
Concomitant use not recommended
Methotrexate
Decreased adalimumab clearance
Dosage adjustment not needed
Pharmacokinetics
Absorption
Bioavailability
Bioavailability is approximately 64%. Peak serum concentrations achieved in 131 hours.
Distribution
Extent
Distributed into synovial fluid.
Not known whether adalimumab is distributed into milk.
Elimination
Metabolism
Metabolic fate undetermined.
Elimination Route
Unknown.
Half-life
2 weeks (range: 10–20 days).
Special Populations
In patients with adalimumab antibodies, clearance of adalimumab is higher.
Clearance of adalimumab is lower with increasing age in patients 40–>75 years of age.
Stability
Storage
Parenteral
Injection
2–8°C. Do not freeze. Protect from light; store in original carton until time of administration.
Actions
Potent antagonist of TNF biologic activity.
Has high specificity and affinity for TNF (TNF-α); does not bind to or inactivate lymphotoxin α (TNF-β). Prevents the binding of TNF to cell surface TNF receptors, thereby blocking the biologic activity of TNF.
An immunoglobulin G1 (IgG1) made by phage display technology with amino acid sequences from the human germline; does not contain nonhuman components or artificially fused human peptide sequences. Indistinguishable in structure and function from naturally occurring human IgG.
Produced by recombinant DNA technology in a mammalian cell expression system; purified by a process that includes specific viral inactivation and removal steps.
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 adalimumab, provide careful instructions regarding proper dosage and administration of adalimumab, 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, and 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.
Humira® (preservative-free; available as disposable prefilled syringes)
Abbott
40 mg/0.8 mL
Humira® (preservative-free; available as disposable prefilled syringes and as prefilled injection pen)
Abbott
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.
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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