CLASSES

Antipsoriatic Monoclonal Antibodies and Others
Anti-Rheumatic Monoclonal Antibodies
Tumor Necrosis Factor (TNF)-Alpha Inhibitors

BOXED WARNING

Patients who receive adalimumab are at increased risk for developing serious infections that may result in hospitalization and death, and most serious infections during adalimumab treatment have occurred in patients receiving concurrent immunosuppressives such as methotrexate and corticosteroid therapy. These infections involve multiple organ systems and include bacterial infection (Legionella and Listeria), mycobacterial infection (disseminated tuberculosis or extrapulmonary tuberculosis), fungal infection (histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, listeriosis, Pneumocystis jiroveci pneumonia), parasitic infection, viral infection (hepatitis B), and other opportunistic infections. Patients with invasive fungal infections (specifically histoplasmosis) may present with disseminated rather than localized disease. Do not initiate adalimumab in patients with an active infection, including localized infections. Consider the risks and benefits of adalimumab before initiation in patients with chronic or recurrent infection; who have been exposed to tuberculosis (TB); with a history of an opportunistic infection; who have resided or traveled in areas of endemic tuberculosis or endemic mycoses such as histoplasmosis, coccidioidomycosis, or blastomycosis. Also consider infection risk vs. treatment benefit in those with underlying conditions that may predispose them to infection (e.g., elderly and patients with advanced or uncontrolled diabetes mellitus, malignancy, bone marrow suppression, or immunosuppression). Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric antifungal therapy in patients at risk for invasive fungal illness who develop a severe systemic illness. Before initiating adalimumab and periodically during therapy, evaluate patients for active TB, TB risk factors, and test patients with a tuberculin skin test for active or latent infection. The possibility of anergy needs to be considered when interpreting the test result. If tuberculin skin testing is performed for latent TB infection, an induration size of 5 mm or greater should be considered positive even if the patient was vaccinated previously with Bacille Calmette-Guerin. Initiate treatment for latent TB before adalimumab use to reduce the risk of reactivation. Consider antituberculosis therapy before adalimumab initiation in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed and in patients who have several or highly significant risk factors for TB infection (e.g., close contact with infected persons or travel to endemic zones) and have a negative test for latent TB. Educate patients about the symptoms of infection and closely monitor them during and after adalimumab treatment for signs and symptoms of infection including TB among patients who tested negative for a latent disease before adalimumab receipt. Discontinue adalimumab in patients who develop a serious infection or sepsis.[27939] [45593] [62997] [62998] [63793]  

An increased risk of new primary malignancy is associated with the use of TNF-blockers such as adalimumab; lymphoma and other malignancies have been reported in pediatric patients. Postmarketing fatal cases of hepatosplenic T-cell lymphoma have been reported mostly in adolescent and young adult males with inflammatory bowel disease such as Crohn's disease or ulcerative colitis; almost all cases have occurred in patients who had received a TNF-blocker concomitantly with either azathioprine or 6-mercaptopurine (6-MP) at or before diagnosis. However, it is uncertain whether the occurrence of hepatosplenic T-cell lymphoma is related to use of a TNF-blocker or a TNF-blocker in combination with these other immunosuppressants. Consider the risks and benefits of adalimumab before treatment initiation in patients with a known malignancy other than a successfully treated nonmelanoma skin cancer or when considering continued use of adalimumab in patients who have developed a malignancy. Use of adalimumab by patients with malignancy risk factors, a malignancy history, or current malignancy may be inadvisable. Examine all patients, especially those with a medical history of prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment for the presence of nonmelanoma skin cancer before and during adalimumab receipt. Screening for dysplasia (colonoscopy and biopsies) at regular intervals before and during adalimumab receipt may be advisable for patients with inflammatory bowel disease who are at increased risk for dysplasia or colon carcinomas such as those with long-standing ulcerative colitis or primary sclerosing cholangitis and those with a history of dysplasia or colon carcinoma. In controlled trials of other TNF-blockers in adult patients at high risk for malignancy [e.g., patients with chronic obstructive pulmonary disease (COPD) with a significant smoking history and cyclophosphamide-treated patients with Wegener's granulomatosis], a higher incidence of malignancy occurred in the TNF-blocker group as compared with the control group.[27939] [35501] [62997] [62998] [63793]  

DEA CLASS

Rx

DESCRIPTION

TNF-alpha blocker (TNF-blocker); for subcutaneous use
Used for rheumatoid arthritis, psoriatic arthritis, polyarticular juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, plaque psoriasis, ankylosing spondylitis, hidradenitis suppurativa, and uveitis
Boxed warning regarding increased risk for serious infection and malignancy

COMMON BRAND NAMES

AMJEVITA, Humira

HOW SUPPLIED

AMJEVITA/Humira Subcutaneous Inj Sol: 0.1mL, 0.2mL, 0.4mL, 0.8mL, 10mg, 20mg, 40mg, 80mg, 40-80mg

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

40 mg subcutaneously every week or 80 mg subcutaneously every other week for hidradenitis suppurativa and for RA if used without concurrent methotrexate; 40 mg subcutaneously every other week for maintenance dosing for uveitis, psoriatic arthritis, Crohn's disease, plaque psoriasis, ulcerative colitis, ankylosing spondylitis, or for RA if used with methotrexate.

40 mg subcutaneously every week or 80 mg subcutaneously every other week for hidradenitis suppurativa and for RA if used without concurrent methotrexate; 40 mg subcutaneously every other week for maintenance dosing for uveitis, psoriatic arthritis, Crohn's disease, plaque psoriasis, ulcerative colitis, ankylosing spondylitis, or for RA if used with methotrexate.

Weighing 60 kg or more: 40 mg subcutaneously every other week for JIA, uveitis, and Crohn's disease; 40 mg subcutaneously weekly or 80 mg subcutaneously every other week for hidradenitis suppurativa or ulcerative colitis.
Weighing 40 to 59 kg: 40 mg subcutaneously every other week for JIA, uveitis, Crohn's disease, and hidradenitis suppurativa; 40 mg subcutaneously weekly or 80 mg subcutaneously every other week for ulcerative colitis.
Weighing 30 to 39 kg: 40 mg subcutaneously every other week for JIA, uveitis, and hidradenitis suppurativa; 20 mg subcutaneously every other week for Crohn's disease; 20 mg subcutaneously weekly or 40 mg subcutaneously every other week for ulcerative colitis.
Weighing 20 to 29 kg: 20 mg subcutaneously every other week for JIA, uveitis, and Crohn's disease; 20 mg subcutaneously weekly or 40 mg subcutaneously every other week for ulcerative colitis.
Weighing 17 to 19 kg: 20 mg subcutaneously every other week for JIA, uveitis, and Crohn's disease.
Weighing 15 to 16 kg: 20 mg subcutaneously every other week for JIA and uveitis.

12 years weighing 60 kg or more: 40 mg subcutaneously every other week for JIA, uveitis, and Crohn's disease; 40 mg subcutaneously weekly for hidradenitis suppurativa; 40 mg subcutaneously weekly or 80 mg subcutaneously every other week for ulcerative colitis.
12 years weighing 40 to 59 kg: 40 mg subcutaneously every other week for JIA, uveitis, Crohn's disease, and hidradenitis suppurativa; 40 mg subcutaneously weekly or 80 mg subcutaneously every other week for ulcerative colitis.
12 years weighing 30 to 39 kg: 40 mg subcutaneously every other week for JIA, uveitis, and hidradenitis suppurativa; 20 mg subcutaneously every other week for Crohn's disease; 20 mg subcutaneously weekly or 40 mg subcutaneously every other week for ulcerative colitis.
12 years weighing 20 to 29 kg: 20 mg subcutaneously every other week for JIA, uveitis, and Crohn's disease; 20 mg subcutaneously weekly or 40 mg subcutaneously every other week for ulcerative colitis.
12 years weighing 17 to 19 kg: 20 mg subcutaneously every other week for JIA, uveitis, and Crohn's disease.
12 years weighing 15 to 16 kg: 20 mg subcutaneously every other week for JIA and uveitis.
6 to 11 years weighing 40 kg or more: 40 mg subcutaneously every other week for JIA, uveitis, and Crohn's disease; 40 mg subcutaneously weekly or 80 mg subcutaneously every other week for ulcerative colitis.
6 to 11 years weighing 30 to 39 kg: 40 mg subcutaneously every other week for JIA and uveitis; 20 mg subcutaneously every other week for Crohn's disease; 20 mg subcutaneously weekly or 40 mg subcutaneously every other week for ulcerative colitis.
6 to 11 years weighing 20 to 29 kg: 20 mg subcutaneously every other week for JIA, uveitis, and Crohn's disease; 20 mg subcutaneously weekly or 40 mg subcutaneously every other week for ulcerative colitis.
6 to 11 years weighing 17 to 19 kg: 20 mg subcutaneously every other week for JIA, uveitis, and Crohn's disease.
6 to 11 years weighing 15 to 16 kg: 20 mg subcutaneously every other week for JIA and uveitis.
5 years and weighing 40 kg or more: 40 mg subcutaneously every other week for JIA and uveitis; 40 mg subcutaneously weekly or 80 mg subcutaneously every other week for ulcerative colitis.
5 years and weighing 30 to 39 kg: 40 mg subcutaneously every other week for JIA and uveitis; 20 mg subcutaneously weekly or 40 mg subcutaneously every other week for ulcerative colitis.
5 years and weighing 20 to 29 kg: 20 mg subcutaneously every other week for JIA and uveitis; 20 mg subcutaneously weekly or 40 mg subcutaneously every other week for ulcerative colitis.
5 years and weighing 15 to 19 kg: 20 mg subcutaneously every other week for JIA and uveitis.
5 years and weighing 10 to 14 kg: 10 mg subcutaneously every other week for JIA and uveitis.
2 to 4 years weighing 30 kg or more: 40 mg subcutaneously every other week for JIA and uveitis.
2 to 4 years weighing 15 to 29 kg: 20 mg subcutaneously every other week for JIA and uveitis.
2 to 4 years weighing 10 to 14 kg: 10 mg subcutaneously every other week for JIA and uveitis.
1 year or weighing less than 10 kg: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

ADMINISTRATION

Administer by subcutaneous injection only.
Available in a prefilled syringe (Humira, Abrilada, Amjevita, Cyltezo, Hadlima, Hulio, Hyrimoz, Idacio), a prefilled pen (Humira, Abrilada, Amjevita, Hulio, Hyrimoz, Idacio), and an autoinjector (Amjevita, Hadlima) for ease of patient administration. A single-use institutional-use vial (Humira, Abrilada, Hadlima) is available but is ONLY for use and administration within an institutional setting such as a hospital, physician's office, or clinic.
Only an individual trained in subcutaneous drug delivery should administer the injection.
The initial injection should be given by a trained health care professional. A patient or caregiver who is properly trained in the injection technique may self-inject subsequent injections using the prefilled syringe, pen, or autoinjector if the prescriber deems the action appropriate.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear and colorless; Abrilada may appear very light brown, Cyltezo may appear clear to slightly cloudy and colorless to slightly yellow, Hadlima may appear pale brown, Hulio may appear pale brownish-yellow, Hyrimoz may appear slightly yellowish, and Idacio may be pale yellow. Do not use if the solution has visible particles, flakes, color, or is cloudy or milky. Check to ensure that the expiration date has not passed.[27939] [62997] [62998] [63793]

STORAGE

AMJEVITA :
- Avoid extreme temperatures
- Discard if product has been frozen
- Discard product if it contains particulate matter, is cloudy, or discolored
- Discard unused portion. Do not store for later use.
- Do not freeze
- Store in refrigerator at 2 to 8 degrees C (36 to 46 degrees F)
- Store in the original carton to protect from light
- Syringe can be stored at room temperature up to 77 degrees F (25 degrees C) up to 14 days
- Throw away (dispose of) any syringe that has been left at room temperature for longer than 14 days
Humira:
- Discard product if it contains particulate matter, is cloudy, or discolored
- Discard unused portion. Do not store for later use.
- Do not freeze
- Do not use if product has been frozen
- Product must be used within 14 days after removal from refrigeration to room temperature (77 degrees F)
- Protect from light
- Refrigerate (between 36 and 46 degrees F)
- Store away from excessive heat and cold
- Store in carton until time of use

CONTRAINDICATIONS / PRECAUTIONS

Do not administer adalimumab to patients with a history of serious hypersensitivity reactions or anaphylaxis, including a history of angioedema, to the drug. Anaphylaxis and angioneurotic edema (angioedema) have been reported following adalimumab administration. The first dose should always be administered by a health care professional. Immediately discontinue adalimumab and institute appropriate therapy a serious hypersensitivity reaction occurs. Patients with latex hypersensitivity should not handle the needle cover of the prefilled syringes or pens, as some products may contain natural rubber latex.[27939] [62997]  [63793] 

Evaluate patients at risk for hepatitis B exacerbation before initiating TNF-blocker therapy with adalimumab. The use of TNF-blockers, including adalimumab, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. Exercise caution in prescribing adalimumab or other TNF-blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF-blocker therapy to prevent HBV reactivation. For patients who are carriers of HBV and require treatment with TNF-blockers, closely monitor such patients for clinical and laboratory signs of active hepatitis B throughout therapy and for several months following termination of therapy. The majority of HBV reactivations have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. In patients who develop HBV reactivation, stop adalimumab and initiate effective antiviral therapy with appropriate supportive treatment. The safety of resuming TNF-blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of adalimumab and monitor patients closely.[27939] [62997] [62998] [63793]  

Patients who receive adalimumab are at increased risk for developing serious infections that may result in hospitalization and death, and most serious infections during adalimumab treatment have occurred in patients receiving concurrent immunosuppressives such as methotrexate and corticosteroid therapy. These infections involve multiple organ systems and include bacterial infection (Legionella and Listeria), mycobacterial infection (disseminated tuberculosis or extrapulmonary tuberculosis), fungal infection (histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, listeriosis, Pneumocystis jiroveci pneumonia), parasitic infection, viral infection (hepatitis B), and other opportunistic infections. Patients with invasive fungal infections (specifically histoplasmosis) may present with disseminated rather than localized disease. Do not initiate adalimumab in patients with an active infection, including localized infections. Consider the risks and benefits of adalimumab before initiation in patients with chronic or recurrent infection; who have been exposed to tuberculosis (TB); with a history of an opportunistic infection; who have resided or traveled in areas of endemic tuberculosis or endemic mycoses such as histoplasmosis, coccidioidomycosis, or blastomycosis. Also consider infection risk vs. treatment benefit in those with underlying conditions that may predispose them to infection (e.g., elderly and patients with advanced or uncontrolled diabetes mellitus, malignancy, bone marrow suppression, or immunosuppression). Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric antifungal therapy in patients at risk for invasive fungal illness who develop a severe systemic illness. Before initiating adalimumab and periodically during therapy, evaluate patients for active TB, TB risk factors, and test patients with a tuberculin skin test for active or latent infection. The possibility of anergy needs to be considered when interpreting the test result. If tuberculin skin testing is performed for latent TB infection, an induration size of 5 mm or greater should be considered positive even if the patient was vaccinated previously with Bacille Calmette-Guerin. Initiate treatment for latent TB before adalimumab use to reduce the risk of reactivation. Consider antituberculosis therapy before adalimumab initiation in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed and in patients who have several or highly significant risk factors for TB infection (e.g., close contact with infected persons or travel to endemic zones) and have a negative test for latent TB. Educate patients about the symptoms of infection and closely monitor them during and after adalimumab treatment for signs and symptoms of infection including TB among patients who tested negative for a latent disease before adalimumab receipt. Discontinue adalimumab in patients who develop a serious infection or sepsis.[27939] [45593] [62997] [62998] [63793]  

Use adalimumab with caution in patients with congestive heart failure (CHF). Cases of worsening and new onset CHF have been reported with TNF-blockers, including adalimumab. Adalimumab has not been formally studied in patients with CHF; however, in clinical trials of another TNF-blocker, a higher rate of CHF-related adverse reactions was observed. Carefully monitor patients with heart failure who receive adalimumab.[27939]   

An increased risk of new primary malignancy is associated with the use of TNF-blockers such as adalimumab; lymphoma and other malignancies have been reported in pediatric patients. Postmarketing fatal cases of hepatosplenic T-cell lymphoma have been reported mostly in adolescent and young adult males with inflammatory bowel disease such as Crohn's disease or ulcerative colitis; almost all cases have occurred in patients who had received a TNF-blocker concomitantly with either azathioprine or 6-mercaptopurine (6-MP) at or before diagnosis. However, it is uncertain whether the occurrence of hepatosplenic T-cell lymphoma is related to use of a TNF-blocker or a TNF-blocker in combination with these other immunosuppressants. Consider the risks and benefits of adalimumab before treatment initiation in patients with a known malignancy other than a successfully treated nonmelanoma skin cancer or when considering continued use of adalimumab in patients who have developed a malignancy. Use of adalimumab by patients with malignancy risk factors, a malignancy history, or current malignancy may be inadvisable. Examine all patients, especially those with a medical history of prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment for the presence of nonmelanoma skin cancer before and during adalimumab receipt. Screening for dysplasia (colonoscopy and biopsies) at regular intervals before and during adalimumab receipt may be advisable for patients with inflammatory bowel disease who are at increased risk for dysplasia or colon carcinomas such as those with long-standing ulcerative colitis or primary sclerosing cholangitis and those with a history of dysplasia or colon carcinoma. In controlled trials of other TNF-blockers in adult patients at high risk for malignancy [e.g., patients with chronic obstructive pulmonary disease (COPD) with a significant smoking history and cyclophosphamide-treated patients with Wegener's granulomatosis], a higher incidence of malignancy occurred in the TNF-blocker group as compared with the control group.[27939] [35501] [62997] [62998] [63793]  

Exercise caution in considering the use of adalimumab in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders. Discontinue adalimumab if such neurological disease develops. Use of TNF blocking agents, including adalimumab, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis and optic neuritis, and peripheral demyelinating disease, including Guillain-Barre syndrome. There is a known association between intermediate uveitis and central demyelinating disorders.[27939] [62997] [62998] [63793]   Systemic administration of TNF-blockers has not provided clinical benefit for those who have multiple sclerosis; evidence suggests that these therapies exacerbate disease activity.

Treatment with adalimumab may result in the formation of autoantibodies (e.g., positive antinuclear antibodies) and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with adalimumab, discontinue treatment.[27939] [62997] [62998] [63793]  

Avoid vaccination of adalimumab recipients with live virus vaccines because of the possibility of secondary transmission of infection by the vaccine. Limited data examining the responses to vaccination in patients receiving adalimumab are available. If possible, bring children and adolescents with juvenile idiopathic arthritis who will receive adalimumab up to date with all immunizations in agreement with current immunization guidelines before adalimumab initiation.   

There are limited data about adalimumab use during pregnancy from a prospective cohort pregnancy registry. Data from the registry report a 10% rate of major birth defects for first-trimester use of adalimumab in pregnant women compared to a rate of 7.5% in untreated controls. These data cannot definitively establish the absence of any risk with adalimumab use during pregnancy; however, the data and the data of the OTIS pregnancy registry suggest that relative risk of major birth defects and spontaneous abortions in adalimumab-exposed women are similar between that of unexposed women with underlying disease and also healthy women.[27939] [62179] [62997] [62998] [63793] [64760] [64761] [65708] Monoclonal antibodies, like adalimumab, are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. In a study of pregnant women with inflammatory bowel disease who received their last adalimumab dose 1 to 56 days prior to delivery, cord blood adalimumab concentrations on the day of birth were higher than maternal concentrations in 9 of 10 women. Adalimumab concentrations were 0.16 to 19.7 mcg/mL in cord blood, 4.28 to 17.7 mcg/mL in infant blood, and 0 to 16.1 mcg/mL in maternal blood.[27939] Some experts for inflammatory bowel disease suggest that adalimumab not be administered in the last 3 to 4 weeks of pregnancy due to the increased placental transfer, while rheumatic expert groups suggest ideally halting adalimumab therapy at 20 weeks gestation (prior to the 3rd trimester), and continuing later in pregnancy only if necessary/indicated.[61808] [62180] In dermatologic conditions, adalimumab use during pregnancy is only advisable for severe, recalcitrant disease.[62792] The pregnancy registry (OTIS AutoImmune Diseases in Pregnancy Study) collects data regarding use of adalimumab for various indications during human pregnancy. Practitioners are encouraged to register women who become pregnant while taking adalimumab by calling the Organization of Teratology Information Specialists (OTIS) in the U.S. at (877) 311-8972 or visiting the website at mothertobaby.org/pregnancy-studies. Neonates and infants exposed in utero to adalimumab should be monitored carefully after birth, as data suggest adalimumab can be detected in the serum of the exposed infants for at least 3 months after birth. Immune response in the in utero exposed infant may be affected. Consider risks and benefits prior to administering live or live-attenuated vaccines to neonates or infants exposed to adalimumab in utero.[27939] [62997] [62998] [61808] [62180] [63793] [64760] [64761] [65708] Infants exposed to biologics should not receive live vaccines for at least the first several months of life or until drug levels are undetectable, with consideration given to manufacturer and consensus recommendations, if available.[61808] [27939] [62997] [62998] In animal studies, no fetal harm or malformations were observed in cynomolgus monkeys exposed to up to 373 times the maximum recommended human dose (MRHD) of adalimumab during organogenesis and later during gestation.[27939]

Consider the benefits of breast-feeding along with the mother's clinical need for adalimumab and any potential adverse effects on the breast-fed infant from adalimumab or the underlying maternal condition before use during lactation. Limited data from published case reports describe the presence of adalimumab in human breast milk at infant doses of 0.1% to 1% of the maternal serum concentration. Published data suggests systemic exposure to the infant following breast-feeding should be low because adalimumab is a large molecule and it is degraded in the gastrointestinal tract; however, the effects of local exposure in the gastrointestinal tract are unknown. There are no reports of adverse effects of adalimumab on the breast-fed infant and no effects on milk production.[27939] [62997] [62998] [63793]   In a case report, the adalimumab peak milk concentration of 31 mcg/L was obtained 6 days after injection of a single adalimumab 40 mg dose and was 1/100th of the mother's peak serum concentration (4,300 mcg/L). The low level of adalimumab found in the breast milk in this case report would be unlikely to be significant for the infant following degradation in the gastrointestinal tract before any absorption.[48843] Experts usually consider adalimumab compatible with breast-feeding based on the low levels detected in milk and the peak milk concentration that occurs 1 to 6 days following a dose.[61808] [48842] [62180] [62791] Etanercept and infliximab may be potential alternatives to consider during breast-feeding. However, indication and patient-specific factors should be assessed before considering an alternative agent.[27939] [48842]

An increased risk of lymphoma and other cancers is associated with the use of TNF-blockers in children and adolescents, and adalimumab may affect host defenses against infection. Prior to treatment initiation, pediatric patients who will receive adalimumab should be brought up to date with all immunizations in agreement with current immunization guidelines.[27939]  

Use adalimumab with caution in geriatric patients. Although no overall difference in efficacy was observed in clinical trials, the frequency of serious infection and malignancy among adalimumab-treated patients was higher in patients older than 65 years compared to their younger counterparts.[27939]  

Before starting adalimumab test potential drug recipients for hepatitis C (IgG) and HIV serum status (HIV-1 and HIV-2 antibodies and HIV-1 antigen). Consider ongoing screening (e.g., annually) in people who are at increased risk for HIV or hepatitis C infection. Retest for HIV infection in any person who displays symptoms or other conditions that may suggest HIV seroconversion or infection. In patients found to be infected with HIV, consider involving relevant specialists to ensure HIV viral load is suppressed on antiretroviral therapy. Similarily, retest for viral hepatitis in any person who develops unexplained elevations in hepatic enzymes. It is recommended to consult a hepatologist when using a biological therapy in patients who are infected with hepatitis C, whether newly diagnosed or chronically infected.

Patients who undergo surgery while taking a biologic therapy, such as adalimumab, may be at greater risk for postoperative infections. In patients undergoing elective surgery, balance the risk of postoperative infection against the risk of developing a severe or unstable disease by stopping the biologic therapy. When possible, it is advised to stop the biologic therapy 3- to 5-times the half-live or the length of the treatment cycle (whichever is longer) between the last dose and the planned surgery. Restart the biologic therapy postoperatively if there is no evidence of infection and wound healing is satisfactory.

ADVERSE REACTIONS

pericardial effusion / Delayed / 0-5.0
myocardial infarction / Delayed / 0-5.0
arrhythmia exacerbation / Early / 0-5.0
atrial fibrillation / Early / 0-5.0
cardiac arrest / Early / 0-5.0
pericarditis / Delayed / 0-5.0
bronchospasm / Rapid / 0-5.0
pleural effusion / Delayed / 0-5.0
agranulocytosis / Delayed / 0-5.0
GI bleeding / Delayed / 0-5.0
thrombosis / Delayed / 0-5.0
GI perforation / Delayed / 0-5.0
hepatic necrosis / Delayed / 0-5.0
cholecystitis / Delayed / 0-5.0
osteonecrosis / Delayed / 0-5.0
bone fractures / Delayed / 0-5.0
anaphylactoid reactions / Rapid / 0-1.0
lupus-like symptoms / Delayed / 0-0.1
heart failure / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
anaphylactic shock / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
pulmonary fibrosis / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
lymphoma / Delayed / Incidence not known
nephrotic syndrome / Delayed / Incidence not known
proteinuria / Delayed / Incidence not known
Guillain-Barre syndrome / Delayed / Incidence not known
stroke / Early / Incidence not known
hepatitis B exacerbation / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known

antibody formation / Delayed / 1.0-61.0
hyperlipidemia / Delayed / 7.0-7.0
hypercholesterolemia / Delayed / 6.0-6.0
peripheral edema / Delayed / 0-5.0
encephalopathy / Delayed / 0-5.0
chest pain (unspecified) / Early / 0-5.0
hypertension / Early / 5.0-5.0
sinus tachycardia / Rapid / 0-5.0
palpitations / Early / 0-5.0
impaired wound healing / Delayed / 0-5.0
dyspnea / Early / 0-5.0
subdural hematoma / Early / 0-5.0
polycythemia / Delayed / 0-5.0
cystitis / Delayed / 0-5.0
hematuria / Delayed / 5.0-5.0
dehydration / Delayed / 0-5.0
confusion / Early / 0-5.0
cholelithiasis / Delayed / 0-5.0
esophagitis / Delayed / 0-5.0
synovitis / Delayed / 0-5.0
cataracts / Delayed / 0-5.0
myasthenia / Delayed / 0-5.0
elevated hepatic enzymes / Delayed / 0.9-4.4
psoriasis / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
psoriaform rash / Delayed / Incidence not known

infection / Delayed / 0-78.0
rash / Early / 1.0-12.0
headache / Early / 12.0-12.0
sinusitis / Delayed / 11.0-11.0
nausea / Early / 9.0-9.0
influenza / Delayed / 7.0-7.0
abdominal pain / Early / 7.0-7.0
back pain / Delayed / 6.0-6.0
syncope / Early / 0-5.0
menstrual irregularity / Delayed / 0-5.0
paresthesias / Delayed / 0-5.0
tremor / Early / 0-5.0
vomiting / Early / 0-5.0
muscle cramps / Delayed / 0-5.0
pelvic pain / Delayed / 0-5.0
arthralgia / Delayed / 3.0-3.0
urticaria / Rapid / 1.0-1.0
alopecia / Delayed / Incidence not known
lichen planus-like eruption / Delayed / Incidence not known
fever / Early / Incidence not known
dental caries / Delayed / Incidence not known
pharyngitis / Delayed / Incidence not known

DRUG INTERACTIONS

Abatacept: (Major) Concomitant use of abatacept with other biologic agents, such as tumor necrosis factor (TNF) inhibitors, is not recommended because of the possibility of additive immunosuppression and increased risk of infection. In controlled clinical trials, patients receiving concomitant abatacept and TNF inhibitor therapy experienced more infections (63%) and serious infections (4.4%) as compared with patients treated with only TNF inhibitors (43% and 0.8%, respectively). These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of abatacept with a TNF inhibitor. Monitor patients for signs of infection during the transition from TNF antagonist therapy to abatacept therapy.
Anakinra: (Major) Avoid the concomitant use of anakinra with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection with no additional clinical benefit. Data suggest a higher rate of serious infections when anakinra and a TNF inhibitor is used in combination with anakinra compared with either drug given alone. Neutropenia (1,000/mcL or less) was observed in 2% of patients receiving the combination. The use of anakinra with a TNF inhibitor in combination did not yield any additional clinical benefit as compared to the use of the TNF inhibitor alone.
Anifrolumab: (Major) Coadministration is not recommended. Anifrolumab has not been studied in combination with other biologic therapies including tumor necrosis factor modifiers (TNF blockers). Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
Antithymocyte Globulin: (Moderate) The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with adalimumab may be at a greater risk of developing an infection. Many of the serious infections occurred in patients on immunosuppressive therapy that received adalimumab.
Azathioprine: (Moderate) The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated. Patients receiving azathioprine along with adalimumab may be at a greater risk of developing an infection.
Baricitinib: (Major) Concomitant use of baricitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Belimumab: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including tumor necrosis factor modifiers (TNF blockers). Therefore, belimumab use is not recommended in combination with TNF blockers. Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
Canakinumab: (Major) Avoid concomitant administration of canakinumab with tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection. An increased incidence of serious infections and an increased risk of neutropenia have been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Based upon the potential for similar interactions, concomitant administration of canakinumab and TNF inhibitors is not recommended.
Certolizumab pegol: (Contraindicated) Do not use certolizumab in combination with other tumor necrosis factor (TNF) modifier therapy, including adalimumab, due to the potential for additive effects and drug toxicity. It is unknown if any adverse effects would occur if certolizumab is used concomitantly with adalimumab. A potential exists for increased risk of infection or an impact on the development of malignancies from increased activity toward TNF.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cyclophosphamide: (Moderate) The safety and efficacy of adalimumab in patients taking concomitant immunosuppressants have not been evaluated. Patients receiving cyclophosphamide along with adalimumab may be at a greater risk of developing an infection.
Cyclosporine: (Moderate) The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated. Patients receiving cyclosporine along with adalimumab may be at a greater risk of developing an infection.
Etanercept: (Contraindicated) Do not use etanercept in combination with other tumor necrosis factor (TNF) modifier therapy, including adalimumab, due to the potential for additive effects and drug toxicity. It is unknown if any adverse effects would occur if etanercept is used concomitantly with adalimumab. A potential exists for increased risk of infection or an impact on the development of malignancies from increased activity toward TNF.
Golimumab: (Contraindicated) Do not use golimumab in combination with other tumor necrosis factor (TNF) modifier therapy, including adalimumab, due to the potential for additive effects and drug toxicity. It is unknown if any adverse effects would occur if golimumab is used concomitantly with adalimumab. A potential exists for increased risk of infection or an impact on the development of malignancies from increased activity toward TNF.
Infliximab: (Contraindicated) Do not use infliximab in combination with other tumor necrosis factor (TNF) modifier therapy, including adalimumab, due to the potential for additive effects and drug toxicity. It is unknown if any adverse effects would occur if infliximab is used concomitantly with adalimumab. A potential exists for increased risk of infection or an impact on the development of malignancies from increased activity toward TNF.
Live Vaccines: (Contraindicated) Do not administer live vaccines to adalimumab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving adalimumab. Before initiation of adalimumab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Adalimumab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
Methotrexate: (Minor) Methotrexate reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively; however, data do not suggest the need for dose adjustment for either drug.
Natalizumab: (Major) Natalizumab for Crohn's disease should not be used in combination with tumor necrosis factor (TNF) modifiers. Coadministration may further increase the risk of serious infections, including progressive multifocal leukoencephalopathy and other opportunistic infections. Ordinarily, patients with mulitple sclerosis who are receiving chronic TNF-modifier therapy should not be treated with natalizumab.
Rabies Vaccine: (Major) If administered concurrently, adalimumab can impair the immunologic response to the rabies vaccine, thereby, decreasing its protective effect. If possible, administration of immunosuppressive mediations, such as adalimumab, should be avoided during use of the rabies vaccine for postexposure prophylaxis. When immunosuppressive therapies must be administered to persons also receiving the rabies vaccine for postexposure prophylaxis, a serum rabies antibody titer should be obtained on day 14 (day of the 4th vaccination) to ensure an acceptable antibody response has been induced.
Rilonacept: (Contraindicated) Concurrent use of rilonacept and tumor necrosis factor (TNF) modifiers is not advised, as the risk of serious infections may be increased. Although concurrent use has not been evaluated in clinical trials, an increased incidence of serious infections and neutropenia has been associated with administration of another drug that blocks IL-1 in combination with TNF inhibitors.
Rituximab: (Major) Avoid the concomitant use of rituximab with adalimumab, a tumor necrosis factor (TNF) inhibitor; coadministration may result in additive immunosuppression and an increased risk of infection. Higher rates of serious infection were observed in patients with rheumatoid arthritis treated with rituximab who received subsequent treatment with a TNF inhibitor.
Rituximab; Hyaluronidase: (Major) Avoid the concomitant use of rituximab with adalimumab, a tumor necrosis factor (TNF) inhibitor; coadministration may result in additive immunosuppression and an increased risk of infection. Higher rates of serious infection were observed in patients with rheumatoid arthritis treated with rituximab who received subsequent treatment with a TNF inhibitor.
Sarilumab: (Major) Avoid the concomitant use of sarilumab with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tetanus Toxoid: (Major) No data are available on the response to tetanus toxid in patients receiving adalimumab. Use of these drugs together may reduce the effectiveness of tetanus toxoid.
Tocilizumab: (Major) Avoid the concomitant use of tocilizumab with biological DMARDs, such as tumor necrosis factor (TNF) modifiers; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
Tofacitinib: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Adalimumab may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of adalimumab therapy.
Upadacitinib: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
Vedolizumab: (Major) Vedolizumab should not be used in combination with tumor necrosis factor (TNF) modifiers because of the potential for increased risk of progressive multifocal leukoencephalopathy and other infections. Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with vedolizumab.

PREGNANCY AND LACTATION

Consider the benefits of breast-feeding along with the mother's clinical need for adalimumab and any potential adverse effects on the breast-fed infant from adalimumab or the underlying maternal condition before use during lactation. Limited data from published case reports describe the presence of adalimumab in human breast milk at infant doses of 0.1% to 1% of the maternal serum concentration. Published data suggests systemic exposure to the infant following breast-feeding should be low because adalimumab is a large molecule and it is degraded in the gastrointestinal tract; however, the effects of local exposure in the gastrointestinal tract are unknown. There are no reports of adverse effects of adalimumab on the breast-fed infant and no effects on milk production.[27939] [62997] [62998] [63793]   In a case report, the adalimumab peak milk concentration of 31 mcg/L was obtained 6 days after injection of a single adalimumab 40 mg dose and was 1/100th of the mother's peak serum concentration (4,300 mcg/L). The low level of adalimumab found in the breast milk in this case report would be unlikely to be significant for the infant following degradation in the gastrointestinal tract before any absorption.[48843] Experts usually consider adalimumab compatible with breast-feeding based on the low levels detected in milk and the peak milk concentration that occurs 1 to 6 days following a dose.[61808] [48842] [62180] [62791] Etanercept and infliximab may be potential alternatives to consider during breast-feeding. However, indication and patient-specific factors should be assessed before considering an alternative agent.[27939] [48842]

MECHANISM OF ACTION

Adalimumab neutralizes the biological activity of tumor necrosis factor (TNF)-alpha by binding to it and blocking its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). Tumor necrosis factor-alpha (TNF-alpha) is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Biological activities attributed to TNF-alpha include induction of pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6; enhancement of leukocyte migration by increasing endothelial layer permeability; expression of adhesion molecules by endothelial cells and leukocytes; activation of neutrophil and eosinophil functional activity; fibroblast proliferation; inhibition of osteoblast differentiation; upregulation of Fas-mediated apoptosis of osteoblasts; synthesis of prostaglandins; indirect induction of osteoclast differentiation and bone resorption; and induction of acute-phase and other liver proteins. Activated macrophages release TNF-alpha, which acts on chondrocytes, fibroblasts, and osteoclasts to release metalloproteinases (MMP) and other effector molecules that induce the migration of polymorphonuclear cells.
 
Elevated levels of TNF are found in the synovial fluid of patients with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques. In psoriasis, treatment with adalimumab may reduce the epidermal thickness and infiltration of inflammatory cells. After treatment with adalimumab, a decrease in levels of acute-phase reactants of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. A decrease in CRP levels was also observed in patients with Crohn's disease, ulcerative colitis, and hidradenitis suppurativa. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.[27939]

PHARMACOKINETICS

Adalimumab is given by subcutaneous injection. The volume of distribution (Vd) ranged from 4.7 to 6 L following intravenous dosing in pharmacokinetic studies. The systemic clearance of adalimumab is approximately 12 mL/hour. Clearance of adalimumab does not appear to change over at least 2 years of use. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Adalimumab concentrations in the synovial fluid from rheumatoid arthritis patients (n = 5) ranged from 31% to 96% of those in serum.[27939] [62997] [62998] [63793] [64760] [64761] [65708]