Pharmaceutical Name

Trade (marketing or proprietary) name: HUMIRA®

Generic (nonproprietary or active ingredient) name: Adalimumab injection for subcutaneous use.

Indication and Usage

Reason the product has been approved for sale on the market.

HUMIRA is a tumor necrosis factor (TNF) blocker indicated for:

• Rheumatoid Arthritis (RA) (1.1): reducing signs and symptoms, inducing
  major clinical response, inhibiting the progression of structural damage, and
  improving physical function in adult patients with moderately to severely
  active RA.
• Juvenile Idiopathic Arthritis (JIA) (1.2): reducing signs and symptoms of
  moderately to severely active polyarticular JIA in patients 2 years of age
  and older.
• Psoriatic Arthritis (PsA) (1.3): reducing signs and symptoms, inhibiting
  the progression of structural damage, and improving physical function in
  adult patients with active PsA.
• Ankylosing Spondylitis (AS) (1.4): reducing signs and symptoms in adult
  patients with active AS.
• Crohn’s Disease (CD) (1.5): treatment of moderately to severely active
  Crohn’s disease in adults and pediatric patients 6 years of age and older.
• Ulcerative Colitis (UC) (1.6): treatment of moderately to severely active
  ulcerative colitis in adults and pediatric patients 5 years of age and older.
  Limitations of Use: Effectiveness has not been established in patients who
  have lost response to or were intolerant to TNF blockers.
• Plaque Psoriasis (Ps) (1.7): treatment of adult patients with moderate to
  severe chronic plaque psoriasis who are candidates for systemic therapy or
  phototherapy, and when other systemic therapies are medically less
  appropriate.
• Hidradenitis Suppurativa (HS) (1.8): treatment of moderate to severe
  hidradenitis suppurativa in patients 12 years of age and older.
• Uveitis (UV) (1.9): treatment of non-infectious intermediate, posterior.

Manufacturer Insert

Ingredients

Adalimumab is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary (CHO)) expression system and is purified by a process that includes specific viral inactivation and removal steps.

• Each 80 mg/0.8 mL prefilled syringe or prefilled pen delivers 0.8 mL (80 mg) of drug product. Each 0.8 mL of HUMIRA contains adalimumab (80 mg), mannitol (33.6 mg), polysorbate 80 (0.8 mg), and Water for Injection, USP.
• Each 40 mg/0.4 mL prefilled syringe or prefilled pen delivers 0.4 mL (40 mg) of drug product. Each 0.4 mL of HUMIRA contains adalimumab (40 mg), mannitol (16.8 mg), polysorbate 80 (0.4 mg), and Water for Injection, USP.
• Each 40 mg/0.8 mL prefilled syringe, prefilled pen, or single-dose institutional use vial delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of HUMIRA contains adalimumab (40 mg), citric acid monohydrate (1.04 mg), dibasic sodium phosphate dihydrate (1.22 mg), mannitol (9.6 mg), monobasic sodium phosphate dihydrate (0.69 mg), polysorbate 80 (0.8 mg), sodium chloride (4.93 mg), sodium citrate (0.24 mg) and Water for Injection, USP. Sodium hydroxide is added as necessary to adjust pH.
• Each 20 mg/0.2 mL prefilled syringe delivers 0.2 mL (20 mg) of drug product. Each 0.2 mL of HUMIRA contains adalimumab (20 mg), mannitol (8.4 mg), polysorbate 80 (0.2 mg), and Water for Injection, USP.
• Each 20 mg/0.4 mL prefilled syringe delivers 0.4 mL (20 mg) of drug product. Each 0.4 mL of HUMIRA contains adalimumab (20 mg), citric acid monohydrate (0.52 mg), dibasic sodium phosphate dihydrate (0.61 mg), mannitol (4.8 mg), monobasic sodium phosphate dihydrate (0.34 mg), polysorbate 80 (0.4 mg), sodium chloride (2.47 mg), sodium citrate (0.12 mg) and Water for Injection, USP. Sodium hydroxide is added as necessary to adjust pH.
• Each 10 mg/0.1 mL prefilled syringe delivers 0.1 mL (10 mg) of drug product. Each 0.1 mL of HUMIRA contains adalimumab (10 mg), mannitol (4.2 mg), polysorbate 80 (0.1 mg), and Water for Injection, USP.
• Each 10 mg/0.2 mL prefilled syringe delivers 0.2 mL (10 mg) of drug product. Each 0.2 mL of HUMIRA contains adalimumab (10 mg), citric acid monohydrate (0.26 mg), dibasic sodium phosphate dihydrate (0.31 mg), mannitol (2.4 mg), monobasic sodium phosphate dihydrate (0.17 mg), polysorbate 80 (0.2 mg), sodium chloride (1.23 mg), sodium citrate (0.06 mg) and Water for Injection, USP. Sodium hydroxide is added as necessary to adjust pH.

Warnings and Precautions

Per the FDA, warnings are clinically significant adverse reactions or risks. According to the CDC, a precaution is a condition in a recipient that might increase the risk for a serious adverse reaction, might cause diagnostic confusion, or might compromise the effectiveness of the product. In general, a product should be deferred when a precaution is present.

Serious Infections: Patients treated with HUMIRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.

Tuberculosis: Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients receiving HUMIRA, including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating HUMIRA and periodically during therapy.

Monitoring: Closely monitor patients for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with HUMIRA.
Discontinue HUMIRA if a patient develops a serious infection or sepsis. For a patient who
develops a new infection during treatment with HUMIRA, closely monitor them, perform a
prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy.

Invasive Fungal Infections: If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider appropriate empiric antifungal therapy, taking into account both the risk for severe fungal infection and the risks of antifungal therapy, while a diagnostic workup is being performed. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections.

Malignancies: Consider the risks and benefits of TNF-blocker treatment including HUMIRA prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy.

Hypersensitivity Reactions: Anaphylaxis and angioneurotic edema have been reported following HUMIRA administration. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue administration of HUMIRA and institute appropriate therapy. In clinical trials of HUMIRA, hypersensitivity reactions (e.g., rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed.

Hepatitis B Virus Reactivation: Use of TNF blockers, including HUMIRA, 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. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. Exercise caution in prescribing 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 HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, stop HUMIRA and initiate effective anti-viral 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 HUMIRA therapy in this situation and monitor patients closely.

Neurologic Reactions: Use of TNF blocking agents, including HUMIRA, 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 (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of HUMIRA in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of HUMIRA should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders.

Hematological Reactions: Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with HUMIRA. The causal relationship of these reports to HUMIRA remains unclear. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on HUMIRA. Consider discontinuation of HUMIRA therapy in patients with confirmed significant hematologic abnormalities.

Increased Risk of Infection when Used with Anakinra: Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of HUMIRA and anakinra is not recommended.

Heart Failure: Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with HUMIRA. HUMIRA has not been formally studied in patients with CHF; however, in clinical trials of another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed. Exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully.

Autoimmunity: Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, discontinue treatment.

Immunizations: In a placebo-controlled clinical trial of patients with RA, no difference was detected in antipneumococcal antibody response between HUMIRA and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with HUMIRA. Similar proportions of patients developed protective levels of anti-influenza antibodies between HUMIRA and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving HUMIRA. The clinical significance of this is unknown. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving HUMIRA.

The safety of administering live or live-attenuated vaccines in infants exposed to HUMIRA in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live attenuated) exposed infants.

Increased Risk of Infection When Used with Abatacept: In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including HUMIRA is not recommended.

Manufacturer-Listed Adverse Reactions

Per the CDC, adverse reactions are an undesirable medical condition that has been demonstrated to be caused by a vaccine. Evidence for the causal relation is usually obtained through randomized clinical trials, controlled epidemiologic studies, isolation of the vaccine strain from the pathogenic site, or recurrence of the condition with repeated vaccination (i.e., rechallenge); synonyms include side effect and adverse effect.

Patients treated with HUMIRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Cases of reactivation of tuberculosis and new onset tuberculosis infections including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Anaphylaxis/angioneurotic (blood vessels and nerves) edema, Rash, Fixed drug reaction/non-specified drug reaction, Urticaria (hives), and Risk of reactivation of hepatitis B virus (HBV). New onset/exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Pancytopenia including aplastic anemia, Worsening congestive heart failure (CHF) and new onset CHF, Formation of autoantibodies and, rarely, in the development of a lupus-like syndrome, Diverticulitis, Large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, Pancreatitis, Pyrexia (fever), Liver failure, Hepatitis, Sarcoidosis (abnormal collections of inflammatory cells that form lumps known as granulomata), Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin), Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), Cerebrovascular (blood vessels of the brain) accident, Interstitial lung disease, including pulmonary fibrosis, Pulmonary embolism, Stevens Johnson Syndrome, Cutaneous vasculitis, Erythema multiforme, New or worsening psoriasis (all sub-types including pustular and palmoplantar), Alopecia (baldness), Lichenoid skin reaction, Systemic vasculitis, Deep vein thrombosis, Upper respiratory infection, Sinusitis, Flu syndrome, Nausea, Abdominal pain, Headache, Back pain, Urinary tract infection, Hypertension, Pelvic pain, Thorax (chest) pain, Arrhythmia, Atrial fibrillation, Coronary artery disorder, Heart arrest, Hypertensive encephalopathy, Myocardial infarct, Palpitation, Pericardial effusion, Pericarditis, Syncope (fainting), Tachycardia (increased heart rate), Cholecystitis, Cholelithiasis, Esophagitis, Gastroenteritis, Gastrointestinal hemorrhage, Hepatic necrosis, Vomiting, Parathyroid disorder, Agranulocytosis, Polycythemia, Dehydration, Healing abnormal, Ketosis, Paraproteinemia, Peripheral edema, Arthritis, Bone disorder, Bone necrosis, Joint disorder, Muscle cramps, Myasthenia, Pyogenic arthritis, Synovitis, Tendon disorder, Confusion, Paresthesia, Subdural hematoma, Tremor, Asthma, Bronchospasm, Dyspnea, Adenoma (benign tumor of epithelial tissue with glandular origin), Bone fracture (not spontaneous), Lung function decreased, Pleural effusion, Cataract, Thrombosis leg, Cystitis, Kidney calculus, and Menstrual disorder.

Specific Populations

Pregnancy

Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in-utero exposed infant.

Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester (see Data). Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to HUMIRA in utero.

Breastfeeding

Limited data from case reports in the published literature describe the presence of adalimumab in human milk at infant doses of 0.1% to 1% of the maternal serum concentration. Published data suggest that the systemic exposure to a breastfed infant is expected to be low because adalimumab is a large molecule and 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 breastfed infant and no effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HUMIRA and any potential adverse effects on the breastfed child from HUMIRA or from the underlying maternal condition.

Fertility

Long-term animal studies of HUMIRA have not been conducted to evaluate the carcinogenic
potential or its effect on fertility.

Pediatric

Due to its inhibition of TNFα, HUMIRA administered during pregnancy could affect immune
response in the in utero-exposed newborn and infant. Data from eight infants exposed to
HUMIRA in utero suggest adalimumab crosses the placenta [see Use in Specific Populations
(8.1)]. The clinical significance of elevated adalimumab concentrations in infants is unknown.
The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants. Post-marketing cases of lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including HUMIRA

Mechanism of Action

This is the specific biochemical interaction through which a drug or vaccine substance produces its pharmacological effect. This section also includes the minimum protective level designated for a certain disease.

Adalimumab binds specifically to TNF-alpha and blocks 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). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated concentrations of TNF are found in the synovial fluid of patients with RA, JIA, PsA, and AS and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased concentrations of TNF are also found in psoriasis plaques. In Ps, treatment with HUMIRA may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which HUMIRA exerts its clinical effects is unknown.

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