Sivelestat

434.5 g/mol

434.46

DWI62G0P59

DTXSID9048304

147 Ų

213-217 °C

Humira must be refrigerated at 2 to 8 °C (36 to 46 °F). DO NOT FREEZE. Protect the prefilled syringe from exposure to light. Store in original carton until time of administration.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Adalimumab has been associated with a low rate of serum aminotransferase elevations during therapy, but these have been transient, mild and asymptomatic, and have rarely required dose modification. ALT levels above 3 times ULN have been reported in 1 to 3.5% of adalimumab recipients compared to 0.9 to 1.8% of controls. Rare instances of clinically apparent liver injury have been reported with adalimumab, resembling the hepatic injury that has been described with infliximab therapy. In at least one instance, liver injury arising during adalimumab therapy did not recur on switching to etanercept. The onset of injury was within 3 months and the pattern of serum enzyme elevations was hepatocellular. The injury promptly resolved on stopping adalimumab.

When abatacept and a tumor necrosis facto blocking agent were used concomitantly in patients with rheumatoid arthritis, an increased incidence of infection and serious infection was observed, with no substantial improvement in efficacy over that observed with a tumor necrosis facto blocking agent alone. Concomitant use of adalimumab and abatacept is not recommended.|An increased incidence of serious infection and an increased risk of neutropenia were observed when anakinra (a human interleukin-1 receptor antagonist) and etanercept (another agent that blocks tumor necrosis factor (TNF; TNF-a)) were used concomitantly in patients with rheumatoid arthritis.Similar toxicities would be expected with concomitant use of anakinra and other agents that block tumor necrosis factor, including adalimumab. Concomitant use of adalimumab and anakinra is not recommended.|Potential pharmacokinetic interaction (decreased clearance of adalimumab); dosage adjustment not recommended.

Adalimumab is a monoclonal antibody to human tumor necrosis factor (TNF) alpha which has potent antiinflammatory activity and is used in the therapy of severe rheumatoid arthritis and inflammatory bowel disease. Adalimumab has been linked to rare instances of idiosyncratic acute liver injury and is a potential cause of reactivation of hepatitis B.

Antirheumatic Agents; Dermatologic Agents; Gastrointestinal Agents

Adalimumab is used for the management of 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.1 Adalimumab can be used alone or in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDs). /Included in US product label/|Adalimumab is used for the management of the signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (formerly known as juvenile rheumatoid arthritis) in patients 4 years of age or older. Adalimumab can be used with or without methotrexate. /Included in US product label/|Adalimumab is used for the management of the signs and symptoms of active arthritis, to improve physical function, and to inhibit structural damage associated with the disease in adults with psoriatic arthritis. Adalimumab can be used alone or in combination with disease-modifying antirheumatic drugs. Clinical evaluations of adalimumab have shown that the drug is more effective than placebo in the management of psoriatic arthritis. /Included in US product label/|For more Therapeutic Uses (Complete) data for Adalimumab (7 total), please visit the HSDB record page.

/BOXED WARNING/ WARNINGS: SERIOUS INFECTIONS Patients treated with Humira are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Humira should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before Humira use and during therapy. Treatment for latent infection should be initiated prior to Humira use. Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. Bacterial, viral and other infections due to opportunistic pathogens. The risks and benefits of treatment with Humira should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Humira, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. MALIGNANCY: Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which Humira is a member.|In August 2009, the US Food and Drug Administration (FDA) reported the results of a review of 147 cases of leukemia in adult and pediatric patients who received TNF blocking agents; these cases had been identified during postmarketing surveillance. Of the 147 cases, acute myeloid leukemia (44 cases), chronic lymphocytic leukemia (31 cases), and chronic myeloid leukemia (23 cases) were the most frequent types of leukemia reported. Four cases of leukemia also were reported in children. Most patients (61%) also were receiving other immunosuppressive drugs. There were a total of 30 deaths reported; leukemia was reported as the cause of 26 of the 30 deaths, and the event was associated with the use of TNF blocking agents. Leukemia generally occurred during the first 2 years of therapy. The interpretation of these findings was complicated by the fact that published epidemiologic studies suggest that patients with rheumatoid arthritis may be at increased risk of leukemia, independent of any treatment with TNF blocking agents. However, based on the available data, FDA has concluded that there is a possible association between treatment with TNF blocking agents and the development of leukemia in patients receiving these drugs. /Tumor necrosis factor blocking agents/|The possibility exists for agents that block tumor necrosis factor (TNF; TNF-a), including adalimumab, to affect host defenses against infections since TNF mediates inflammation and modulates cellular immune responses. Serious and sometimes fatal infections, including sepsis, tuberculosis, and opportunistic infections (e.g., pulmonary or disseminated histoplasmosis, coccidioidomycosis, blastomycosis), have been reported in patients receiving TNF blocking agents. Patients should be closely monitored during and after treatment with TNF blocking agents for the development of signs or symptoms of infection (e.g., fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, serious systemic illness including shock). Many serious infections reported in patients receiving TNF blocking agents occurred in those receiving concomitant therapy with immunosuppressive agents that, in addition to their underlying condition, could have predisposed them to infections. In placebo-controlled trials in patients with rheumatoid arthritis, the rate of infection was 1 or 0.9 per patient-year in those receiving adalimumab or placebo, respectively; the rate of serious infection was 0.04 or 0.02 per patient-year, respectively. Serious infections have included pneumonia, septic arthritis, prosthetic infection, postsurgical infection, erysipelas, cellulitis, diverticulitis, and pyelonephritis. Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation), invasive fungal infections, and other opportunistic infections also have occurred in patients receiving adalimumab or other TNF blocking agents. Most of the cases of tuberculosis occurred within the first 8 months following initiation of adalimumab therapy; these cases may reflect recrudescence of latent tuberculosis infection.|Exacerbation of clinical manifestations and/or radiographic evidence of demyelinating disorders, including multiple sclerosis, has been reported rarely in patients receiving adalimumab or other tumor necrosis factor blocking agents. Clinicians should exercise caution when considering adalimumab therapy in patients with preexisting or recent-onset CNS demyelinating disorders|For more Drug Warnings (Complete) data for Adalimumab (28 total), please visit the HSDB record page.

Exogenous or endogenous compounds which inhibit SERINE ENDOPEPTIDASES. (See all compounds classified as Serine Proteinase Inhibitors.)

The single dose pharmacokinetics of adalimumab in rheumatoid arthritis (RA) patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The distribution volume (Vss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/hr. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum.|The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 + or - 1.6 ug/mL and 131 + or - 56 hours respectively, following a single 40 mg subcutaneous administration of Humira to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose.|After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab was slow, with peak serum concentrations being reached about 5 days after administration. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. After single intravenous doses ranging from 0.25 to 10 mg/kg, concentrations were dose proportional. After doses of 0.5 mg/kg (approximately 40 mg), clearances ranged from 11 to 15 mL/hour, the distribution volume (Vss) ranged from 5 to 6 litres and the mean terminal phase half life was approximately two weeks. Adalimumab concentrations in the synovial fluid from several rheumatoid arthritis patients ranged from 31-96% of those in serum.

The single dose pharmacokinetics of adalimumab in rheumatoid arthritis (RA) patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. ... The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies.

IAdalimumab is a fully human monoclonal antibody to tumor necrosis factor (TNF), which was recently introduced as a therapy for Crohn's disease and rheumatoid arthritis. Besides neutralization, induction of apoptosis of monocytes/macrophages and T cells is thought to be an important mechanism of action of the anti-tumor necrosis factor monoclonal antibody infliximab, at least in Crohn's disease therapy. AIM: To study caspase activation and the induction of apoptosis by adalimumab and the effect of a caspase inhibitor in vivo. For in vitro studies, THP-1 cells (human monocytic cell line) were incubated with adalimumab, infliximab, or human immunoglobulin G, and annexin V + propidium iodide, Apo2.7, and 7-amino actinomycin-D were used to study apoptosis on the cell membrane, mitochodrial, and DNA level, respectively. Active caspase-3 was detected by intracellular staining. For in vivo studies, a chimeric human-mouse model was used, in which THP-1 cells were injected intraperitoneally in SCID-Beige mice followed by treatment with adalimumab, infliximab, or human immunoglobulin G. Effects of a pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyketone on apoptosis induction were evaluated. In vitro analysis revealed that apoptosis could be induced in THP-1 cells by both adalimumab and infliximab. Activation of caspase-3 after incubation with adalimumab was demonstrated by intracellular staining. In addition, in the chimeric mouse model, a higher percentage of residual THP-1 cells were apoptotic, and lower cell numbers were recovered in the adalimumab- or infliximab-treated mouse. Apoptosis induction by adalimumab could be abrogated through in vivo pretreatment of mice with the pan-caspase inhibitor. Adalimumab, besides neutralizing tumor necrosis factor, also induces apoptosis of transmembrane tumor necrosis factor-positive THP-1 cells by activating intracellular caspases. This activity is likely to be important for the clinical effect of this biodrug.|Adalimumab has high specificity and affinity for TNF (TNF-a); adalimumab does not bind to or inactivate lymphotoxin a (TNF-beta). Adalimumab binds to TNF before TNF can interact with the p55 and p75 cell surface tumor necrosis factor receptors (TNFRs).By preventing the binding of TNF to cell surface TNFRs, adalimumab blocks the biologic activity of TNF.In vitro, adalimumab lyses surface TNF-expressing cells in the presence of complement.|Adalimumab binds specifically to tumor necrosis factor (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 levels of TNF are found in the synovial fluid of rheumatoid arthritis, including juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis patients 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 (Ps) plaques. In plaque psoriasis, 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. Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M).

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ WARNINGS: SERIOUS INFECTIONS Patients treated with Humira are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Humira should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before Humira use and during therapy. Treatment for latent infection should be initiated prior to Humira use. Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. Bacterial, viral and other infections due to opportunistic pathogens. The risks and benefits of treatment with Humira should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Humira, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. MALIGNANCY: Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which Humira is a member.|/SIGNS AND SYMPTOMS/ In August 2009, the US Food and Drug Administration (FDA) reported the results of a review of 147 cases of leukemia in adult and pediatric patients who received TNF blocking agents; these cases had been identified during postmarketing surveillance. Of the 147 cases, acute myeloid leukemia (44 cases), chronic lymphocytic leukemia (31 cases), and chronic myeloid leukemia (23 cases) were the most frequent types of leukemia reported. Four cases of leukemia also were reported in children. Most patients (61%) also were receiving other immunosuppressive drugs. There were a total of 30 deaths reported; leukemia was reported as the cause of 26 of the 30 deaths, and the event was associated with the use of TNF blocking agents. Leukemia generally occurred during the first 2 years of therapy. The interpretation of these findings was complicated by the fact that published epidemiologic studies suggest that patients with rheumatoid arthritis may be at increased risk of leukemia, independent of any treatment with TNF blocking agents. However, based on the available data, FDA has concluded that there is a possible association between treatment with TNF blocking agents and the development of leukemia in patients receiving these drugs. /Tumor necrosis factor blocking agents/|/SIGNS AND SYMPTOMS/ The possibility exists for agents that block tumor necrosis factor (TNF; TNF-a), including adalimumab, to affect host defenses against infections since TNF mediates inflammation and modulates cellular immune responses. Serious and sometimes fatal infections, including sepsis, tuberculosis, and opportunistic infections (e.g., pulmonary or disseminated histoplasmosis, coccidioidomycosis, blastomycosis), have been reported in patients receiving TNF blocking agents. Patients should be closely monitored during and after treatment with TNF blocking agents for the development of signs or symptoms of infection (e.g., fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, serious systemic illness including shock). Many serious infections reported in patients receiving TNF blocking agents occurred in those receiving concomitant therapy with immunosuppressive agents that, in addition to their underlying condition, could have predisposed them to infections. In placebo-controlled trials in patients with rheumatoid arthritis, the rate of infection was 1 or 0.9 per patient-year in those receiving adalimumab or placebo, respectively; the rate of serious infection was 0.04 or 0.02 per patient-year, respectively. Serious infections have included pneumonia, septic arthritis, prosthetic infection, postsurgical infection, erysipelas, cellulitis, diverticulitis, and pyelonephritis. Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation), invasive fungal infections, and other opportunistic infections also have occurred in patients receiving adalimumab or other TNF blocking agents. Most of the cases of tuberculosis occurred within the first 8 months following initiation of adalimumab therapy; these cases may reflect recrudescence of latent tuberculosis infection.|/CASE REPORTS/The introduction of targeted immunotherapies has greatly improved the therapeutic options of several inflammatory diseases such as psoriatic arthritis. However treatment-related opportunistic infections and viral reactivations may still occur. We describe a case of varicella zoster virus encephalitis due to the reactivation of latent varicella zoster virus infection during a long therapy with the anti-tumor necrosis factor-alpha (TNF-alpha) drug Adalimumab. The low incidence of varicella zoster virus encephalitis in patients treated with biological agents does not justify varicella zoster virus serological screening in these subjects, but careful monitoring of the patients is recommended to recognize early signs and symptoms of herpes zoster to start prompt antiviral therapy to prevent associated complications.|For more Human Toxicity Excerpts (Complete) data for Adalimumab (15 total), please visit the HSDB record page.

N-(2-(4-(2,2-dimethylpropionyloxy)phenylsulfonylamino)benzoyl)aminoacetic acid

Parenteral: Injection, for subcutaneous use: 20 mg/0.4 mL Humira (available as disposable prefilled syringes), (Abbott); 40 mg/0.8 mL Humira (available as disposable prefilled syringes and as prefilled injection pen), (Abbott).|Humira|Trudexa

Anti-immunoglobulin G1