HYRIMOZ (adalimumab-adaz) injection

Adalimumab-adaz is a tumor necrosis factor blocker. Adalimumab-adaz is a recombinant human IgG1 monoclonal antibody with human derived heavy and light chain variable regions and human IgG1:k constant regions. Adalimumab-adaz is produced by recombinant DNA technology in a Chinese hamster ovary cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.

HYRIMOZ (adalimumab-adaz) injection is supplied as a sterile, preservative-free solution for subcutaneous administration. The drug product is supplied as either a single-dose, prefilled pen (Sensoready Pen) or as a single-dose, prefilled 1 mL glass syringe. Enclosed within the Pen is a single-dose, 1 mL prefilled glass syringe. The solution of HYRIMOZ is clear, colorless to slightly yellowish, with a pH of about 5.2.

Each 40mg/0.8mL HYRIMOZ single-dose prefilled Sensoready Pen or HYRIMOZ single-dose prefilled syringe delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of HYRIMOZ contains adalimumab-adaz40 mg, adipic acid (2.69 mg), citric acid monohydrate (0.206 mg), mannitol (9.6 mg), polysorbate 80 (0.8 mg), sodium chloride (4.93 mg), and Water for Injection, USP. Hydrochloric acid and sodium hydroxide are added as necessary to adjust pH.

Each 10mg/0.2 mL HYRIMOZ single-dose prefilled syringe delivers 0.2mL (10mg) of drug product. Each 0.2 mL of HYRIMOZ contains adalimumab-adaz 10 mg, adipic acid (0.67 mg), citric acid monohydrate (0.051mg), mannitol (2.4 mg), polysorbate 80 (0.2 mg), sodium chloride (1.23 mg), and Water for Injection, USP. Hydrochloric acid and sodium hydroxide are added as necessary to adjust pH.

INDICATIONS AND USAGE

Rheumatoid Arthritis: HYRIMOZ is indicated for 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 rheumatoid arthritis. HYRIMOZ can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).

Juvenile Idiopathic Arthritis: HYRIMOZ is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. HYRIMOZ can be used alone or in combination with methotrexate.

Psoriatic Arthritis: HYRIMOZ is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. HYRIMOZ can be used alone or in combination with non-biologic DMARDs.

Ankylosing Spondylitis: HYRIMOZ is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

Crohn’s Disease: HYRIMOZ is indicated for the treatment of moderately to severely active Crohn’s disease in adults and pediatric patients 6 years of age and older.

Ulcerative Colitis: HYRIMOZ is indicated for the treatment of moderately to severely active ulcerative colitis in adult patients.

Limitations of Use:

The effectiveness of adalimumab products has not been established in patients who have lost response to or were intolerant to TNF blockers.

Plaque Psoriasis: HYRIMOZ is indicated for the 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. HYRIMOZ should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.

Mechanism of Action

Adalimumab products bind specifically to TNF alpha and block its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab products also lyse surface TNF expressing cells in vitro in the presence of complement. Adalimumab products do 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 HYRIMOZ may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab products exert their clinical effects is unknown.

Adalimumab products also modulate biological responses that are induced or regulated by TNF, including changes in the concentrations of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10^-10M).

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

Serious Infections: Patients treated with adalimumab products, including HYRIMOZ, 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.

The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of HYRIMOZ and these biologic products is not recommended in the treatment of patients with RA.

Treatment with HYRIMOZ should not be initiated in patients with an active infection, including localized infections. Patients 65 years of age and older, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating therapy in patients:

with chronic or recurrent infection;
who have been exposed to tuberculosis;
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; or
with underlying conditions that may predispose them to infection.

Malignancies: Consider the risks and benefits of TNF blocker-treatment including HYRIMOZ 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 administration of adalimumab products. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue administration of HYRIMOZ and institute appropriate therapy. In clinical trials of adalimumab, 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 HYRIMOZ, 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 HYRIMOZ 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 HYRIMOZ therapy in this situation and monitor patients closely.

Neurologic Reactions: Use of TNF blocking agents, including adalimumab products, 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 HYRIMOZ in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of HYRIMOZ should be considered if any of these disorders develop.

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 adalimumab products. The causal relationship of these reports to adalimumab products 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 HYRIMOZ. Consider discontinuation of HYRIMOZ 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 TNFblocker, 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 HYRIMOZ and anakinra is not recommended.

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

Autoimmunity: Treatment with adalimumab products 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 HYRIMOZ, discontinue treatment.

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

DRUG INTERACTIONS

Methotrexate: Adalimumab has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX).Although MTX reduced the apparent clearance of adalimumab, the data do not suggest the need for dose adjustment of either HYRIMOZ or MTX.

Biological Products: In clinical studies in patients with RA, an increased risk of serious infections has been observed with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of HYRIMOZ with abatacept or anakinra is not recommended in patients with RA. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNFblocker. There is insufficient information regarding the concomitant use of HYRIMOZ and other biologic products for the treatment of RA, PsA, AS, CD, UC and Ps. Concomitant administration of HYRIMOZ with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions.

Live Vaccines: Avoid the use of live vaccines with HYRIMOZ.

Cytochrome P450 Substrates: The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for products that antagonize cytokine activity, such as adalimumab products, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of HYRIMOZ in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

USE IN SPECIFIC POPULATIONS

Pregnancy: Available studies with use of adalimumab during pregnancy do not reliably establish an association between adalimumab and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS)/Mother To Baby Pregnancy Registry in pregnant women with rheumatoid arthritis (RA) or Crohn’s disease (CD) treated with adalimumab.

Registry results showed a rate of 10% for major birth defects with first trimester use of adalimumab in pregnant women with RA or CD and a rate of7.5% for major birth defects in the disease-matched comparison cohort. The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects.

Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in-utero exposed infant. In an embryo-fetal perinatal development study conducted in cynomolgus monkeys, no fetal harm or malformations were observed with intravenous administration of adalimumab during organogenesis and later in gestation, at doses that produced exposures up to approximately 373 times the maximum recommended human dose (MRHD) of 40 mg subcutaneous without methotrexate.

Published data suggest that the risk of adverse pregnancy outcomes in women with RA or inflammatory bowel disease (IBD) is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

OVERDOSAGE

Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

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HYRIMOZ (adalimumab-adaz) injection

HYRIMOZ (adalimumab-adaz) injection