These Highlights Do Not Include All The Information Needed To Use Adalimumab-adbm Safely And Effectively. See Full Prescribing Information For Adalimumab-adbm.

SERIOUS INFECTIONS

Patients treated with adalimumab products, including Adalimumab-adbm, are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Discontinue Adalimumab-adbm if a patient develops a serious infection or sepsis.

Reported infections include:

• Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before Adalimumab-adbm use and during therapy. Initiate treatment for latent TB prior to Adalimumab-adbm 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. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
• Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria.

Carefully consider the risks and benefits of treatment with Adalimumab-adbm prior to initiating therapy in patients with chronic or recurrent infection.

Monitor patients closely for the development of signs and symptoms of infection during and after treatment with Adalimumab-adbm, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Storage and Stability

Do not use beyond the expiration date on the container. Adalimumab-adbm must be refrigerated at 36°F to 46°F (2°C to 8°C). DO NOT FREEZE. Do not use if frozen even if it has been thawed.

Store in original carton until time of administration to protect from light.

If needed, for example when traveling, Adalimumab-adbm may be stored at room temperature up to a maximum of 77°F (25°C) for a period of up to 14 days, with protection from light. Adalimumab-adbm should be discarded if not used within the 14-day period. Record the date when Adalimumab-adbm is first removed from the refrigerator in the spaces provided on the carton and dose tray.

Do not store Adalimumab-adbm in extreme heat or cold.

INSTRUCTIONS FOR USE

Adalimumab-adbm (ada-LIM-u-mab adbm)

injection, for subcutaneous use

Single-Dose Adalimumab-adbm Prefilled Syringe

This product is CYLTEZO^® (adalimumab-adbm).

Adalimumab-adbm is a single-dose prefilled syringe that delivers a fixed dose of medicine. The prefilled syringe cannot be reused.

Important: Read these instructions before using a Adalimumab-adbm prefilled syringe.

• Do not use a Adalimumab-adbm prefilled syringe until you have been shown the right way to give the injections and have read and understood this Instructions for Use. If your doctor decides that you or a caregiver may be able to give your injections at home, you should receive training on the right way to prepare and give the injection. To help you remember when to inject Adalimumab-adbm, you can mark your calendar ahead of time.
• Do not remove the cap until you are ready to inject.

How should I store Adalimumab-adbm?

• Store Adalimumab-adbm in the refrigerator at 36°F to 46°F (2°C to 8°C). Store Adalimumab-adbm in the original carton until use to protect it from light.
• Do not freeze Adalimumab-adbm. Do not use Adalimumab-adbm if frozen, even if it has been thawed.
• Refrigerated Adalimumab-adbm may be used until the expiration date printed on the Adalimumab-adbm carton, dose tray, or prefilled syringe. Do not use Adalimumab-adbm after the expiration date.
• If needed, for example, when you are traveling, you may also store Adalimumab-adbm at room temperature up to 77°F (25°C) for up to 14 days. Store Adalimumab-adbm in the original carton until use to protect it from light.
• Throw away Adalimumab-adbm if it has been kept at room temperature and not been used within 14 days.
• Record the date you first remove Adalimumab-adbm from the refrigerator in the spaces provided on the carton and dose tray.
• Do not store Adalimumab-adbm in extreme heat or cold.
• Do not use a prefilled syringe if the liquid is milky, discolored, or has flakes or particles in it.
• Do not drop or crush Adalimumab-adbm. The prefilled syringe is glass.

Keep Adalimumab-adbm, injection supplies, and all other medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 USA

US License Number 2006

Manufactured for: Quallent Pharmaceuticals Health LLC, Grand Cayman, Cayman Islands

CYLTEZO ^® is a registered trademark of and is used under license from Boehringer Ingelheim International GmbH.

Other trademarks referenced are owned by third parties not affiliated with Boehringer Ingelheim Pharmaceuticals, Inc.

For more information about Adalimumab-adbm, go to www.quallentpharmaceuticals.com or call 1-877-605-7243.

Copyright © 2024 Boehringer Ingelheim International GmbH

ALL RIGHTS RESERVED

COL13735BD052024

Revised: 04/2024

Adalimumab-adbm is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients 2 years of age and older.

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.

Consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdose management recommendations.

• National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Incidence Crude Rates, 17 Registries, 2000-2007.

Adalimumab-adbm is a tumor necrosis factor blocker. Adalimumab-adbm is a recombinant human IgG1 monoclonal antibody 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. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.

Adalimumab-adbm injection is supplied as a sterile, preservative-free solution of adalimumab-adbm for subcutaneous administration. The drug product is supplied as either a single-dose, prefilled pen (Adalimumab-adbm Pen) or as a single-dose, 1 mL prefilled glass syringe. Enclosed within the pen is a single-dose, 1 mL prefilled glass syringe. The solution of Adalimumab-adbm is clear to slightly opalescent and colorless to slightly yellow, with a pH of about 5.5.

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 Adalimumab-adbm contains adalimumab-adbm (40 mg), glacial acetic acid (0.03 mg), polysorbate 80 (0.2 mg), sodium acetate trihydrate (0.47 mg), trehalose dihydrate (30.3 mg), and Water for Injection, USP.

Each 40 mg/0.8 mL prefilled syringe or prefilled pen delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of Adalimumab-adbm contains adalimumab-adbm (40 mg), glacial acetic acid (0.13 mg), polysorbate 80 (0.8 mg), sodium acetate trihydrate (2.4 mg), trehalose dihydrate (65.0 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 Adalimumab-adbm contains adalimumab-adbm (20 mg), glacial acetic acid (0.06 mg), polysorbate 80 (0.4 mg), sodium acetate trihydrate (1.21 mg), trehalose dihydrate (32.5 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 Adalimumab-adbm contains adalimumab-adbm (10 mg), glacial acetic acid (0.03 mg), polysorbate 80 (0.2 mg), sodium acetate trihydrate (0.61 mg), trehalose dihydrate (16.3 mg), and Water for Injection, USP.

Consider the risks and benefits of TNF-blocker treatment including Adalimumab-adbm 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.

Treatment with adalimumab products may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome or autoimmune hepatitis [see Adverse Reactions (6.1, 6.3)]. If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with Adalimumab-adbm, discontinue treatment and evaluate the patient.

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 Adalimumab-adbm or MTX [see Clinical Pharmacology (12.3)].

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 adalimumab products. Adalimumab products have 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 Adalimumab-adbm in patients who have heart failure and monitor them carefully.

Avoid the use of live vaccines with Adalimumab-adbm [see Warnings and Precautions (5.10)].

The safety and effectiveness of Adalimumab-adbm have not been established in pediatric patients with psoriatic arthritis, ankylosing spondylitis, or plaque psoriasis.

The safety and effectiveness of Adalimumab-adbm have been established for:

• reducing signs and symptoms of moderately to severely active polyarticular JIA in pediatric patients 2 years of age and older.
• the treatment of moderately to severely active Crohn's disease in pediatric patients 6 years of age and older.
• the treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older.
• the treatment of non-infectious intermediate, posterior, and panuveitis in pediatric patients 2 years of age and older.

A pediatric assessment for Adalimumab-adbm demonstrates that Adalimumab-adbm is safe and effective for pediatric patients in an indication for which Humira (adalimumab) is approved. However, Adalimumab-adbm is not approved for such indication due to marketing exclusivity for Humira (adalimumab).

Due to their inhibition of TNFα, adalimumab products administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to adalimumab 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 adalimumab products [see Warnings and Precautions (5.2)].

In clinical studies of RA (Studies RA-I, RA-II, RA-III, and RA-IV), a total of 519 subjects 65 years of age and older, including 107 subjects 75 years of age and older, received adalimumab. No overall difference in effectiveness was observed between these subjects and younger adult subjects.

The frequency of serious infection and malignancy among adalimumab-treated subjects 65 years of age and older was higher than for those less than 65 years of age. Consider the benefits and risks of Adalimumab-adbm in patients 65 years of age and older. In patients treated with Adalimumab-adbm, closely monitor for the development of infection or malignancy [see Warnings and Precautions (5.1, 5.2)].

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 subjects 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 Adalimumab-adbm 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.

It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Adalimumab-adbm therapy. Patients on Adalimumab-adbm may receive concurrent vaccinations, except for live vaccines.

The safety of administering live or live-attenuated vaccines in infants exposed to adalimumab products in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants [see Use in Specific Populations (8.1, 8.4)].

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of adalimumab or of other adalimumab products.

There are two assays that have been used to measure anti-adalimumab antibodies. With the ELISA, antibodies to adalimumab could be detected only when serum adalimumab concentrations were <2 mcg/mL. The ECL assay can detect anti-adalimumab antibody titers independent of adalimumab concentrations in the serum samples. The incidence of anti-adalimumab antibody (AAA) development in patients treated with adalimumab are presented in Table 2.

Adalimumab-adbm is indicated for the treatment of moderately to severely active Crohn's disease in adults and pediatric patients 6 years of age and older.

None.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Serious Infections [see Warnings and Precautions (5.1)]
• Malignancies [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Hepatitis B Virus Reactivation [see Warnings and Precautions (5.4)]
• Neurologic Reactions [see Warnings and Precautions (5.5)]
• Hematological Reactions [see Warnings and Precautions (5.6)]
• Heart Failure [see Warnings and Precautions (5.8)]
• Autoimmunity [see Warnings and Precautions (5.9)]

• Abatacept: Increased risk of serious infection. (5.1, 5.11, 7.2)
• Anakinra: Increased risk of serious infection. (5.1, 5.7, 7.2)
• Live vaccines: Avoid use with Adalimumab-adbm. (5.10, 7.3)

Adalimumab-adbm 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. Adalimumab-adbm should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Warnings and Precautions (5)].

The Adalimumab-adbm Pen is a single-dose prefilled pen that delivers a fixed dose of medicine. The Adalimumab-adbm Pen cannot be reused.

Important: Read these instructions before using a Adalimumab-adbm Pen.

• Do not use a Adalimumab-adbm Pen until you have been shown the right way to give the injections and have read and understood this Instructions for Use. If your doctor decides that you or a caregiver may be able to give your injections of Adalimumab-adbm at home, you should receive training on the right way to prepare and inject Adalimumab-adbm. To help you remember when to inject Adalimumab-adbm, you can mark your calendar ahead of time.
• Do not remove the cap until you are ready to inject.

How should I store Adalimumab-adbm?

• Store Adalimumab-adbm in the refrigerator at 36°F to 46°F (2°C to 8°C). Store Adalimumab-adbm in the original carton until use to protect it from light.
• Do not freeze Adalimumab-adbm. Do not use Adalimumab-adbm if frozen, even if it has been thawed.
• Refrigerated Adalimumab-adbm may be used until the expiration date printed on the Adalimumab-adbm carton, dose tray, or pen. Do not use Adalimumab-adbm after the expiration date.
• If needed, for example, when you are traveling, you may also store Adalimumab-adbm at room temperature up to 77°F (25°C) for up to 14 days. Store Adalimumab-adbm in the original carton until use to protect it from light.
• Throw away Adalimumab-adbm if it has been kept at room temperature and not been used within 14 days.
• Record the date you first remove Adalimumab-adbm from the refrigerator in the spaces provided on the carton and dose tray.
• Do not store Adalimumab-adbm in extreme heat or cold.
• Do not use a Adalimumab-adbm Pen if the liquid is milky, discolored, or has flakes or particles in it.
• Do not drop or crush Adalimumab-adbm. The prefilled syringe inside the pen is glass.

Keep Adalimumab-adbm, injection supplies, and all other medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 USA

US License Number 2006

Manufactured for: Quallent Pharmaceuticals Health LLC, Grand Cayman, Cayman Islands

CYLTEZO^® is a registered trademark of and is used under license from Boehringer Ingelheim International GmbH.

Other trademarks referenced are owned by third parties not affiliated with Boehringer Ingelheim Pharmaceuticals, Inc.

For more information about Adalimumab-adbm, go to www.quallentpharmaceuticals.com or call 1-877-605-7243.

Copyright © 2024 Boehringer Ingelheim International GmbH

ALL RIGHTS RESERVED

COL13736BD052024

Revised: 04/2024

After treatment with adalimumab, a decrease in concentrations 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 concentrations was also observed in patients with Crohn's disease, ulcerative colitis and hidradenitis suppurativa. Serum concentrations of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.

The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10 mg/kg following administration of a single intravenous dose (adalimumab products are not approved for intravenous use). Following 20, 40, and 80 mg every other week and every week subcutaneous administration, adalimumab mean serum trough concentrations at steady state increased approximately proportionally with dose in RA patients. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Healthy subjects and patients with RA displayed similar adalimumab pharmacokinetics.

Adalimumab exposure in patients treated with 80 mg every other week is estimated to be comparable with that in patients treated with 40 mg every week.

Adalimumab-adbm is indicated for the treatment of moderately to severely active ulcerative colitis in adult patients.

Patients treated with adalimumab products, including Adalimumab-adbm, 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 Adalimumab-adbm and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions (5.7, 5.11) and Drug Interactions (7.2)].

Treatment with Adalimumab-adbm 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.

Adalimumab-adbm is a tumor necrosis factor (TNF) blocker 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. (1.1)
• Reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. (1.2)
• Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. (1.3)
• Reducing signs and symptoms in adult patients with active ankylosing spondylitis. (1.4)
• Treatment of moderately to severely active Crohn's disease in adults and pediatric patients 6 years of age and older. (1.5)
• Treatment of moderately to severely active ulcerative colitis in adult patients. (1.6)
  
  Limitations of Use: Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers.
• 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. (1.7)
• Treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older. (1.8)
• Treatment of non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients 2 years of age and older. (1.9)

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

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 Adalimumab-adbm with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions (5.7, 5.11)]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker. There is insufficient information regarding the concomitant use of Adalimumab-adbm and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of Adalimumab-adbm 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.

Adalimumab-adbm 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. Adalimumab-adbm can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).

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 Adalimumab-adbm 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 × 10^-10M).

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 Adalimumab-adbm in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of Adalimumab-adbm should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders.

Adalimumab-adbm is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

• Serious infections: Do not start Adalimumab-adbm during an active infection. If an infection develops, monitor carefully, and stop Adalimumab-adbm if infection becomes serious. (5.1)
• Invasive fungal infections: For patients who develop a systemic illness on Adalimumab-adbm, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic. (5.1)
• Malignancies: Incidence of malignancies was greater in adalimumab-treated patients than in controls (5.2)
• Anaphylaxis or serious hypersensitivity reactions may occur (5.3)
• Hepatitis B virus reactivation: Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop Adalimumab-adbm and begin anti-viral therapy. (5.4)
• Demyelinating disease: Exacerbation or new onset, may occur. (5.5)
• Cytopenias, pancytopenia: Advise patients to seek immediate medical attention if symptoms develop, and consider stopping Adalimumab-adbm. (5.6)
• Heart failure: Worsening or new onset, may occur. (5.8)
• Autoimmunity: Stop Adalimumab-adbm if lupus-like syndrome or autoimmune hepatitis develop. (5.9)

• Administer by subcutaneous injection (2)

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis (2.2):

• Adults: 40 mg every other week.

Some patients with RA not receiving methotrexate may benefit from increasing the dosage to 40 mg every week or 80 mg every other week.

Juvenile Idiopathic Arthritis or Pediatric Uveitis (2.3):

Crohn's Disease (2.4):

• Adults: 160 mg on Day 1 (given in one day or split over two consecutive days); 80 mg on Day 15; and 40 mg every other week starting on Day 29.
• Pediatric Patients 6 Years of Age and Older:

Ulcerative Colitis (2.5):

• Adults: 160 mg on Day 1 (given in one day or split over two consecutive days), 80 mg on Day 15 and 40 mg every other week starting on Day 29. Discontinue in patients without evidence of clinical remission by eight weeks (Day 57).

Plaque Psoriasis or Adult Uveitis (2.6):

• Adults: 80 mg initial dose, followed by 40 mg every other week starting one week after initial dose.

Hidradenitis Suppurativa (2.7):

• Adults:
  • Day 1: 160 mg (given in one day or split over two consecutive days)
  • Day 15: 80 mg
  • Day 29 and subsequent doses: 40 mg every week or 80 mg every other week
• Adolescents 12 years of age and older:

  Adolescent Weight	Recommended Dosage
  30 kg (66 lbs) to less than 60 kg (132 lbs)	Day 1: 80 mg Day 8 and subsequent doses: 40 mg every other week
  60 kg (132 lbs) and greater	Day 1: 160 mg (given in one day or split over two consecutive days) Day 15: 80 mg Day 29 and subsequent doses: 40 mg every week or 80 mg every other week

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 Adalimumab-adbm. Consider discontinuation of Adalimumab-adbm therapy in patients with confirmed significant hematologic abnormalities.

Adalimumab-adbm is indicated for the treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older.

Adalimumab-adbm is a clear to slightly opalescent and colorless to slightly yellow solution available as:

The following adverse reactions have been identified during post-approval use of adalimumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to adalimumab products exposure.

Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis

General disorders and administration site conditions: Pyrexia

Hepato-biliary disorders: Liver failure, hepatitis, autoimmune hepatitis

Immune system disorders: Sarcoidosis

Neoplasms benign, malignant and unspecified (including cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin)

Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident

Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism

Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia, lichenoid skin reaction

Vascular disorders: Systemic vasculitis, deep vein thrombosis

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 Adalimumab-adbm 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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reaction with adalimumab was injection site reactions. In placebo-controlled trials, 20% of subjects treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of subjects receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.

The proportion of subjects who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in subjects with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for subjects taking adalimumab and 4% for placebo-treated subjects. The most common adverse reactions leading to discontinuation of adalimumab in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).

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 Adalimumab-adbm 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.

Adalimumab-adbm is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. Adalimumab-adbm can be used alone or in combination with methotrexate.

Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Use of TNF blockers, including Adalimumab-adbm, 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 Adalimumab-adbm 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 Adalimumab-adbm therapy in this situation and monitor patients closely.

Adalimumab-adbm injection is supplied as a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution for subcutaneous administration. The following packaging configurations are available.

Prior to initiating Adalimumab-adbm and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions (5.1)].

The safety and efficacy of adalimumab were assessed in randomized, double-blind, placebo-controlled studies in 1696 adult subjects with moderate to severe chronic plaque psoriasis (Ps) who were candidates for systemic therapy or phototherapy.

Study Ps-I evaluated 1212 subjects with chronic Ps with ≥10% body surface area (BSA) involvement, Physician's Global Assessment (PGA) of at least moderate disease severity, and Psoriasis Area and Severity Index (PASI) ≥12 within three treatment periods. In period A, subjects received placebo or adalimumab at an initial dose of 80 mg at Week 0 followed by a dose of 40 mg every other week starting at Week 1. After 16 weeks of therapy, subjects who achieved at least a PASI 75 response at Week 16, defined as a PASI score improvement of at least 75% relative to baseline, entered period B and received open-label 40 mg adalimumab every other week. After 17 weeks of open label therapy, subjects who maintained at least a PASI 75 response at Week 33 and were originally randomized to active therapy in period A were re-randomized in period C to receive 40 mg adalimumab every other week or placebo for an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 19 and the baseline Physician's Global Assessment score ranged from "moderate" (53%) to "severe" (41%) to "very severe" (6%).

Study Ps-II evaluated 99 subjects randomized to adalimumab and 48 subjects randomized to placebo with chronic plaque psoriasis with ≥10% BSA involvement and PASI ≥12. Subjects received placebo, or an initial dose of 80 mg adalimumab at Week 0 followed by 40 mg every other week starting at Week 1 for 16 weeks. Across all treatment groups the mean baseline PASI score was 21 and the baseline PGA score ranged from "moderate" (41%) to "severe" (51%) to "very severe" (8%).

Studies Ps-I and II evaluated the proportion of subjects who achieved "clear" or "minimal" disease on the 6-point PGA scale and the proportion of subjects who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at Week 16 (see Table 16 and 17).

Additionally, Study Ps-I evaluated the proportion of subjects who maintained a PGA of "clear" or "minimal" disease or a PASI 75 response after Week 33 and on or before Week 52.

Additionally, in Study Ps-I, subjects on adalimumab who maintained a PASI 75 were re-randomized to adalimumab (N=250) or placebo (N=240) at Week 33. After 52 weeks of treatment with adalimumab, more subjects on adalimumab maintained efficacy when compared to subjects who were re-randomized to placebo based on maintenance of PGA of "clear" or "minimal" disease (68% vs. 28%) or a PASI 75 (79% vs. 43%).

A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. Median time to relapse (decline to PGA "moderate" or worse) was approximately 5 months. During the withdrawal period, no subject experienced transformation to either pustular or erythrodermic psoriasis. A total of 178 subjects who relapsed re-initiated treatment with 80 mg of adalimumab, then 40 mg every other week beginning at week 1. At week 16, 69% (123/178) of subjects had a response of PGA "clear" or "minimal".

A randomized, double-blind study (Study Ps-III) compared the efficacy and safety of adalimumab versus placebo in 217 adult subjects. Subjects in the study had to have chronic plaque psoriasis of at least moderate severity on the PGA scale, fingernail involvement of at least moderate severity on a 5-point Physician's Global Assessment of Fingernail Psoriasis (PGA-F) scale, a Modified Nail Psoriasis Severity Index (mNAPSI) score for the target-fingernail of ≥8, and either a BSA involvement of at least 10% or a BSA involvement of at least 5% with a total mNAPSI score for all fingernails of ≥20. Subjects received an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeks followed by open-label adalimumab treatment for an additional 26 weeks. This study evaluated the proportion of subjects who achieved "clear" or "minimal" assessment with at least a 2-grade improvement on the PGA-F scale and the proportion of subjects who achieved at least a 75% improvement from baseline in the mNAPSI score (mNAPSI 75) at Week 26.

At Week 26, a higher proportion of subjects in the adalimumab group than in the placebo group achieved the PGA-F endpoint. Furthermore, a higher proportion of subjects in the adalimumab group than in the placebo group achieved mNAPSI 75 at Week 26 (see Table 18).

Nail pain was also evaluated and improvement in nail pain was observed in Study Ps-III.

WARNING: SERIOUS INFECTIONS AND MALIGNANCY

See full prescribing information for complete boxed warning.

SERIOUS INFECTIONS (5.1, 6.1):

• Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens.
• Discontinue Adalimumab-adbm if a patient develops a serious infection or sepsis during treatment.
• Perform test for latent TB; if positive, start treatment for TB prior to starting Adalimumab-adbm.
• Monitor all patients for active TB during treatment, even if initial latent TB test is negative.

MALIGNANCY (5.2):

• Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including adalimumab products.
• Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have occurred in adolescent and young adults with inflammatory bowel disease treated with TNF blockers including adalimumab products.

The safety and efficacy of adalimumab was assessed in two randomized, double-blind, placebo-controlled studies in 413 subjects with psoriatic arthritis (PsA). Upon completion of both studies, 383 subjects enrolled in an open-label extension study, in which 40 mg adalimumab was administered every other week.

Study PsA-I enrolled 313 adult subjects with moderately to severely active PsA (>3 swollen and >3 tender joints) who had an inadequate response to NSAID therapy in one of the following forms: (1) distal interphalangeal (DIP) involvement (N=23); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of plaque psoriasis) (N=210); (3) arthritis mutilans (N=1); (4) asymmetric PsA (N=77); or (5) AS-like (N=2). Subjects on MTX therapy (158 of 313 subjects) at enrollment (stable dose of ≤30 mg/week for >1 month) could continue MTX at the same dose. Doses of adalimumab 40 mg or placebo every other week were administered during the 24-week double-blind period of the study.

Compared to placebo, treatment with adalimumab resulted in improvements in the measures of disease activity (see Tables 8 and 9). Among subjects with PsA who received adalimumab, the clinical responses were apparent in some subjects at the time of the first visit (two weeks) and were maintained up to 88 weeks in the ongoing open-label study. Similar responses were seen in subjects with each of the subtypes of psoriatic arthritis, although few subjects were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. Responses were similar in subjects who were or were not receiving concomitant MTX therapy at baseline.

Subjects with psoriatic involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses. At 24 weeks, the proportions of subjects achieving a 75% or 90% improvement in the PASI were 59% and 42% respectively, in the adalimumab group (N=69), compared to 1% and 0% respectively, in the placebo group (N=69) (p<0.001). PASI responses were apparent in some subjects at the time of the first visit (two weeks). Responses were similar in subjects who were or were not receiving concomitant MTX therapy at baseline.

Similar results were seen in an additional, 12-week study in 100 subjects with moderate to severe psoriatic arthritis who had suboptimal response to DMARD therapy as manifested by ≥3 tender joints and ≥3 swollen joints at enrollment.

The efficacy and safety of adalimumab were assessed in five randomized, double-blind studies in subjects ≥18 years of age with active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Subjects had at least 6 swollen and 9 tender joints. Adalimumab was administered subcutaneously in combination with methotrexate (MTX) (12.5 to 25 mg, Studies RA-I, RA-III and RA-V) or as monotherapy (Studies RA-II and RA-V) or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study RA-IV).

Study RA-I evaluated 271 subjects who had failed therapy with at least one but no more than four DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks.

Study RA-II evaluated 544 subjects who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of adalimumab were given as monotherapy every other week or weekly for 26 weeks.

Study RA-III evaluated 619 subjects who had an inadequate response to MTX. Subjects received placebo, 40 mg of adalimumab every other week with placebo injections on alternate weeks, or 20 mg of adalimumab weekly for up to 52 weeks. Study RA-III had an additional primary endpoint at 52 weeks of inhibition of disease progression (as detected by X-ray results). Upon completion of the first 52 weeks, 457 subjects enrolled in an open-label extension phase in which 40 mg of adalimumab was administered every other week for up to 5 years.

Study RA-IV assessed safety in 636 subjects who were either DMARD-naïve or were permitted to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Subjects were randomized to 40 mg of adalimumab or placebo every other week for 24 weeks.

Study RA-V evaluated 799 subjects with moderately to severely active RA of less than 3 years duration who were ≥18 years old and MTX naïve. Subjects were randomized to receive either MTX (optimized to 20 mg/week by week 8), adalimumab 40 mg every other week or adalimumab/MTX combination therapy for 104 weeks. Subjects were evaluated for signs and symptoms, and for radiographic progression of joint damage. The median disease duration among subjects enrolled in the study was 5 months. The median MTX dose achieved was 20 mg.

The safety and efficacy of adalimumab were assessed in adult subjects with non-infectious intermediate, posterior and panuveitis excluding subjects with isolated anterior uveitis, in two randomized, double-masked, placebo-controlled studies (UV I and II). Subjects received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week after the initial dose. The primary efficacy endpoint in both studies was ‘time to treatment failure’.

Treatment failure was a multi-component outcome defined as the development of new inflammatory chorioretinal and/or inflammatory retinal vascular lesions, an increase in anterior chamber (AC) cell grade or vitreous haze (VH) grade or a decrease in best corrected visual acuity (BCVA).

Study UV I evaluated 217 subjects with active uveitis while being treated with corticosteroids (oral prednisone at a dose of 10 to 60 mg/day). All subjects received a standardized dose of prednisone 60 mg/day at study entry followed by a mandatory taper schedule, with complete corticosteroid discontinuation by Week 15.

Study UV II evaluated 226 subjects with inactive uveitis while being treated with corticosteroids (oral prednisone 10 to 35 mg/day) at baseline to control their disease. Subjects subsequently underwent a mandatory taper schedule, with complete corticosteroid discontinuation by Week 19.

Adalimumab-adbm is intended for use under the guidance and supervision of a physician. A patient may self-inject Adalimumab-adbm or a caregiver may inject Adalimumab-adbm using either the Adalimumab-adbm Pen or prefilled syringe if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique.

Adalimumab-adbm can be taken out of the refrigerator for 15 to 30 minutes before injecting to allow the liquid to come to room temperature. Do not remove the cap while allowing it to reach room temperature. Carefully inspect the solution in the Adalimumab-adbm Pen or prefilled syringe for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. Adalimumab-adbm does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe. NOTE: Instruct patients sensitive to latex not to handle the needle cap of the Adalimumab-adbm 40 mg/0.8 mL and 40 mg/0.4 mL Pen or 40 mg/0.8 mL, 40 mg/0.4 mL, 20 mg/0.4 mL, and 10 mg/0.2 mL prefilled syringe because they contain natural rubber latex [see How Supplied/Storage and Handling (16)].

Instruct patients using the Adalimumab-adbm Pen or prefilled syringe to inject the full amount in the syringe, according to the directions provided in the Instructions for Use [see Instructions for Use].

Injections should occur at separate sites in the thigh or abdomen. Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red or hard.

If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.

The safety and efficacy of adalimumab 40 mg every other week was assessed in 315 adult subjects in a randomized, 24 week double-blind, placebo-controlled study in subjects with active ankylosing spondylitis (AS) who had an inadequate response to glucocorticoids, NSAIDs, analgesics, methotrexate or sulfasalazine. Active AS was defined as subjects who fulfilled at least two of the following three criteria: (1) a Bath AS disease activity index (BASDAI) score ≥4 cm, (2) a visual analog score (VAS) for total back pain ≥40 mm, and (3) morning stiffness ≥1 hour. The blinded period was followed by an open-label period during which subjects received adalimumab 40 mg every other week subcutaneously for up to an additional 28 weeks.

Improvement in measures of disease activity was first observed at Week 2 and maintained through 24 weeks as shown in Figure 2 and Table 11.

Responses of subjects with total spinal ankylosis (n=11) were similar to those without total ankylosis.

Figure 2. ASAS 20 Response By Visit, Study AS-I

At 12 weeks, the ASAS 20/50/70 responses were achieved by 58%, 38%, and 23%, respectively, of subjects receiving adalimumab, compared to 21%, 10%, and 5% respectively, of subjects receiving placebo (p <0.001). Similar responses were seen at Week 24 and were sustained in subjects receiving open-label adalimumab for up to 52 weeks.

A greater proportion of subjects treated with adalimumab (22%) achieved a low level of disease activity at 24 weeks (defined as a value <20 [on a scale of 0 to 100 mm] in each of the four ASAS response parameters) compared to subjects treated with placebo (6%).

A second randomized, multicenter, double-blind, placebo-controlled study of 82 subjects with ankylosing spondylitis showed similar results.

Subjects treated with adalimumab achieved improvement from baseline in the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score (-3.6 vs. -1.1) and in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) score (7.4 vs. 1.9) compared to placebo-treated subjects at Week 24.

Two randomized, double-blind, placebo-controlled studies (Studies HS-I and II) evaluated the safety and efficacy of adalimumab in a total of 633 adult subjects with moderate to severe hidradenitis suppurativa (HS) with Hurley Stage II or III disease and with at least 3 abscesses or inflammatory nodules. In both studies, subjects received placebo or adalimumab at an initial dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every week starting at Week 4 and continued through Week 11. Subjects used topical antiseptic wash daily. Concomitant oral antibiotic use was allowed in Study HS-II.

Both studies evaluated Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12. HiSCR was defined as at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count relative to baseline (see Table 19). Reduction in HS-related skin pain was assessed using a Numeric Rating Scale in subjects who entered the study with an initial baseline score of 3 or greater on a 11-point scale.

In both studies, a higher proportion of adalimumab- than placebo-treated subjects achieved HiSCR (see Table 19).

In both studies, from Week 12 to Week 35 (Period B), subjects who had received adalimumab were re-randomized to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 40 mg every other week, or placebo). Subjects who had been randomized to placebo were assigned to receive adalimumab 40 mg every week (Study HS-I) or placebo (Study HS-II).

During Period B, flare of HS, defined as ≥25% increase from baseline in abscesses and inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects who were withdrawn from adalimumab treatment following the primary efficacy timepoint in two studies.

The safety and efficacy of multiple doses of adalimumab were assessed in adult subjects with moderately to severely active Crohn's disease, CD, (Crohn's Disease Activity Index (CDAI) ≥220 and ≤450) in randomized, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted, and 79% of subjects continued to receive at least one of these medications.

Induction of clinical remission (defined as CDAI <150) was evaluated in two studies. In Study CD-I, 299 TNF-blocker naïve subjects were randomized to one of four treatment groups: the placebo group received placebo at Weeks 0 and 2, the 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, the 80/40 group received 80 mg at Week 0 and 40 mg at Week 2, and the 40/20 group received 40 mg at Week 0 and 20 mg at Week 2. Clinical results were assessed at Week 4.

In the second induction study, Study CD-II, 325 subjects who had lost response to, or were intolerant to, previous infliximab therapy were randomized to receive either 160 mg adalimumab at Week 0 and 80 mg at Week 2, or placebo at Weeks 0 and 2. Clinical results were assessed at Week 4.

Maintenance of clinical remission was evaluated in Study CD-III. In this study, 854 subjects with active disease received open-label adalimumab, 80 mg at week 0 and 40 mg at Week 2. Subjects were then randomized at Week 4 to 40 mg adalimumab every other week, 40 mg adalimumab every week, or placebo. The total study duration was 56 weeks. Subjects in clinical response (decrease in CDAI ≥70) at Week 4 were stratified and analyzed separately from those not in clinical response at Week 4.

The safety and efficacy of adalimumab was assessed in two studies (Studies JIA-I and JIA-II) in subjects with active polyarticular juvenile idiopathic arthritis (JIA).

The safety and efficacy of adalimumab were assessed in adult subjects with moderately to severely active ulcerative colitis (Mayo score 6 to 12 on a 12 point scale, with an endoscopy subscore of 2 to 3 on a scale of 0 to 3) despite concurrent or prior treatment with immunosuppressants such as corticosteroids, azathioprine, or 6-MP in two randomized, double-blind, placebo-controlled clinical studies (Studies UC-I and UC-II). Both studies enrolled TNF-blocker naïve subjects, but Study UC-II also allowed entry of subjects who lost response to or were intolerant to TNF-blockers. Forty percent (40%) of subjects enrolled in Study UC-II had previously used another TNF-blocker.

Concomitant stable doses of aminosalicylates and immunosuppressants were permitted. In Studies UC-I and II, subjects were receiving aminosalicylates (69%), corticosteroids (59%) and/or azathioprine or 6-MP (37%) at baseline. In both studies, 92% of subjects received at least one of these medications.

Induction of clinical remission (defined as Mayo score ≤2 with no individual subscores >1) at Week 8 was evaluated in both studies. Clinical remission at Week 52 and sustained clinical remission (defined as clinical remission at both Weeks 8 and 52) were evaluated in Study UC-II.

In Study UC-I, 390 TNF-blocker naïve subjects were randomized to one of three treatment groups for the primary efficacy analysis. The placebo group received placebo at Weeks 0, 2, 4 and 6. The 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, and the 80/40 group received 80 mg adalimumab at Week 0 and 40 mg at Week 2. After Week 2, subjects in both adalimumab treatment groups received 40 mg every other week.

In Study UC-II, 518 subjects were randomized to receive either adalimumab 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week starting at Week 4 through Week 50, or placebo starting at Week 0 and every other week through Week 50. Corticosteroid taper was permitted starting at Week 8.

In both Studies UC-I and UC-II, a greater percentage of the subjects treated with 160/80 mg of adalimumab compared to subjects treated with placebo achieved induction of clinical remission. In Study UC-II, a greater percentage of the subjects treated with 160/80 mg of adalimumab compared to subjects treated with placebo achieved sustained clinical remission (clinical remission at both Weeks 8 and 52) (Table 15).

In Study UC-I, there was no statistically significant difference in clinical remission observed between the adalimumab 80/40 mg group and the placebo group at Week 8.

In Study UC-II, 17.3% (43/248) in the adalimumab group were in clinical remission at Week 52 compared to 8.5% (21/246) in the placebo group (treatment difference: 8.8%; 95% confidence interval (CI): [2.8%, 14.5%]; p<0.05).

In the subgroup of subjects in Study UC-II with prior TNF-blocker use, the treatment difference for induction of clinical remission appeared to be lower than that seen in the whole study population, and the treatment differences for sustained clinical remission and clinical remission at Week 52 appeared to be similar to those seen in the whole study population. The subgroup of subjects with prior TNF-blocker use achieved induction of clinical remission at 9% (9/98) in the adalimumab group versus 7% (7/101) in the placebo group, and sustained clinical remission at 5% (5/98) in the adalimumab group versus 1% (1/101) in the placebo group. In the subgroup of subjects with prior TNF-blocker use, 10% (10/98) were in clinical remission at Week 52 in the adalimumab group versus 3% (3/101) in the placebo group.

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 Adalimumab-adbm and anakinra is not recommended [see Drug Interactions (7.2)].

NDC 82009-144-22

ATTENTION PHARMACIST:

Each Patient is Required to Receive

the Enclosed Medication Guide.

The Entire Carton is to be Dispensed

as a Unit.

Needle Cap for Pen Contains Dry

Natural Rubber.

Adalimumab-adbm PEN

Injection

40 mg/0.4 mL

For Subcutaneous Use Only

Rx only

2 Single-Dose Prefilled Pens

Quallent

Pharmaceuticals℠

NDC 82009-146-22

ATTENTION PHARMACIST:

Each Patient is Required to Receive

the Enclosed Medication Guide.

The Entire Carton is to be Dispensed

as a Unit.

Needle Cap for Syringe Contains Dry

Natural Rubber.

Adalimumab-adbm

Injection

40 mg/0.4 mL

For Subcutaneous Use Only

Rx only

2 Single-Dose Prefilled Syringes

Quallent

Pharmaceuticals℠

NDC 82009-148-22

ATTENTION PHARMACIST:

Each Patient is Required to Receive

the Enclosed Medication Guide.

The Entire Carton is to be Dispensed

as a Unit.

Needle Cap for Pen Contains Dry

Natural Rubber.

Adalimumab-adbm PEN

Injection

40 mg/0.8 mL

For Subcutaneous Use Only

Rx only

2 Single-Dose Prefilled Pens

Quallent

Pharmaceuticals℠

NDC 82009-150-22

ATTENTION PHARMACIST:

Each Patient is Required to Receive

the Enclosed Medication Guide.

The Entire Carton is to be Dispensed

as a Unit.

Needle Cap for Syringe Contains Dry

Natural Rubber.

Adalimumab-adbm

Injection

40 mg/0.8 mL

For Subcutaneous Use Only

Rx only

2 Single-Dose Prefilled Syringes

Quallent

Pharmaceuticals℠

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

The safety and efficacy of adalimumab were assessed in a randomized, double-masked, placebo-controlled study of 90 pediatric subjects from 2 to < 18 years of age with active JIA-associated non-infectious uveitis (PUV-I). Subjects received either placebo or 20 mg adalimumab (if < 30 kg) or 40 mg adalimumab (if ≥ 30 kg) every other week in combination with a dose of methotrexate. Concomitant dosages of corticosteroids were permitted at study entry followed by a mandatory reduction in topical corticosteroids within 3 months.

The primary endpoint was 'time to treatment failure'. The criteria determining treatment failure were worsening or sustained non-improvement in ocular inflammation, or worsening of ocular co-morbidities.

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 Adalimumab-adbm is not recommended [see Drug Interactions (7.2)].

A randomized, double-blind, 52-week clinical study of 2 dose concentrations of adalimumab (Study PCD-I) was conducted in 192 pediatric subjects (6 to 17 years of age) with moderately to severely active Crohn's disease (defined as Pediatric Crohn's Disease Activity Index (PCDAI) score >30). Enrolled subjects had over the previous two-year period an inadequate response to corticosteroids or an immunomodulator (i.e., azathioprine, 6-mercaptopurine, or methotrexate). Subjects who had previously received a TNF blocker were allowed to enroll if they had previously had loss of response or intolerance to that TNF blocker.

Subjects received open-label induction therapy at a dose based on their body weight (≥40 kg and <40 kg). Subjects weighing ≥40 kg received 160 mg (at Week 0) and 80 mg (at Week 2). Subjects weighing <40 kg received 80 mg (at Week 0) and 40 mg (at Week 2). At Week 4, subjects within each body weight category (≥40 kg and <40 kg) were randomized 1:1 to one of two maintenance dose regimens (high dose and low dose). The high dose was 40 mg every other week for subjects weighing ≥40 kg and 20 mg every other week for subjects weighing <40 kg. The low dose was 20 mg every other week for subjects weighing ≥40 kg and 10 mg every other week for subjects weighing <40 kg.

Concomitant stable dosages of corticosteroids (prednisone dosage ≤40 mg/day or equivalent) and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted throughout the study.

At Week 12, subjects who experienced a disease flare (increase in PCDAI of ≥15 from Week 4 and absolute PCDAI >30) or who were non-responders (did not achieve a decrease in the PCDAI of ≥15 from baseline for 2 consecutive visits at least 2 weeks apart) were allowed to dose-escalate (i.e., switch from blinded every other week dosing to blinded every week dosing); subjects who dose-escalated were considered treatment failures.

At baseline, 38% of subjects were receiving corticosteroids, and 62% of subjects were receiving an immunomodulator. Forty-four percent (44%) of subjects had previously lost response or were intolerant to a TNF blocker. The median baseline PCDAI score was 40.

Of the 192 subjects total, 188 subjects completed the 4 week induction period, 152 subjects completed 26 weeks of treatment, and 124 subjects completed 52 weeks of treatment. Fifty-one percent (51%) (48/95) of subjects in the low maintenance dose group dose-escalated, and 38% (35/93) of subjects in the high maintenance dose group dose-escalated.

At Week 4, 28% (52/188) of subjects were in clinical remission (defined as PCDAI ≤10).

The proportions of subjects in clinical remission (defined as PCDAI ≤10) and clinical response (defined as reduction in PCDAI of at least 15 points from baseline) were assessed at Weeks 26 and 52.

At both Weeks 26 and 52, the proportion of subjects in clinical remission and clinical response was numerically higher in the high dose group compared to the low dose group (Table 14). The recommended maintenance regimen is 20 mg every other week for subjects weighing <40 kg and 40 mg every other week for subjects weighing ≥40 kg. Every week dosing is not the recommended maintenance dosing regimen [see Dosage and Administration (2.4)].

The recommended subcutaneous dosage of Adalimumab-adbm for adult patients with plaque psoriasis (Ps) or uveitis (UV) [see Indications and Usage (1.7, 1.9)] is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. The use of adalimumab products in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies.

The recommended subcutaneous dosage of Adalimumab-adbm for pediatric patients 2 years of age and older with polyarticular juvenile idiopathic arthritis (JIA) or pediatric uveitis [see Indications and Usage (1.2, 1.9)], based on weight, is shown below. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with Adalimumab-adbm.

Adalimumab products have not been studied in patients with polyarticular JIA or pediatric uveitis less than 2 years of age or in patients with a weight below 10 kg.

The recommended subcutaneous dosage of Adalimumab-adbm for adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) [see Indications and Usage (1.1, 1.3, 1.4)] is 40 mg administered every other week. Methotrexate (MTX), other non-biologic DMARDs, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with Adalimumab-adbm. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosage of Adalimumab-adbm to 40 mg every week or 80 mg every other week.

SERIOUS INFECTIONS

Patients treated with adalimumab products, including Adalimumab-adbm, are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Discontinue Adalimumab-adbm if a patient develops a serious infection or sepsis.

Reported infections include:

• Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before Adalimumab-adbm use and during therapy. Initiate treatment for latent TB prior to Adalimumab-adbm 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. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
• Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria.

Carefully consider the risks and benefits of treatment with Adalimumab-adbm prior to initiating therapy in patients with chronic or recurrent infection.

Monitor patients closely for the development of signs and symptoms of infection during and after treatment with Adalimumab-adbm, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Storage and Stability

Do not use beyond the expiration date on the container. Adalimumab-adbm must be refrigerated at 36°F to 46°F (2°C to 8°C). DO NOT FREEZE. Do not use if frozen even if it has been thawed.

Store in original carton until time of administration to protect from light.

If needed, for example when traveling, Adalimumab-adbm may be stored at room temperature up to a maximum of 77°F (25°C) for a period of up to 14 days, with protection from light. Adalimumab-adbm should be discarded if not used within the 14-day period. Record the date when Adalimumab-adbm is first removed from the refrigerator in the spaces provided on the carton and dose tray.

Do not store Adalimumab-adbm in extreme heat or cold.

INSTRUCTIONS FOR USE

Adalimumab-adbm (ada-LIM-u-mab adbm)

injection, for subcutaneous use

Single-Dose Adalimumab-adbm Prefilled Syringe

This product is CYLTEZO^® (adalimumab-adbm).

Adalimumab-adbm is a single-dose prefilled syringe that delivers a fixed dose of medicine. The prefilled syringe cannot be reused.

Important: Read these instructions before using a Adalimumab-adbm prefilled syringe.

• Do not use a Adalimumab-adbm prefilled syringe until you have been shown the right way to give the injections and have read and understood this Instructions for Use. If your doctor decides that you or a caregiver may be able to give your injections at home, you should receive training on the right way to prepare and give the injection. To help you remember when to inject Adalimumab-adbm, you can mark your calendar ahead of time.
• Do not remove the cap until you are ready to inject.

How should I store Adalimumab-adbm?

• Store Adalimumab-adbm in the refrigerator at 36°F to 46°F (2°C to 8°C). Store Adalimumab-adbm in the original carton until use to protect it from light.
• Do not freeze Adalimumab-adbm. Do not use Adalimumab-adbm if frozen, even if it has been thawed.
• Refrigerated Adalimumab-adbm may be used until the expiration date printed on the Adalimumab-adbm carton, dose tray, or prefilled syringe. Do not use Adalimumab-adbm after the expiration date.
• If needed, for example, when you are traveling, you may also store Adalimumab-adbm at room temperature up to 77°F (25°C) for up to 14 days. Store Adalimumab-adbm in the original carton until use to protect it from light.
• Throw away Adalimumab-adbm if it has been kept at room temperature and not been used within 14 days.
• Record the date you first remove Adalimumab-adbm from the refrigerator in the spaces provided on the carton and dose tray.
• Do not store Adalimumab-adbm in extreme heat or cold.
• Do not use a prefilled syringe if the liquid is milky, discolored, or has flakes or particles in it.
• Do not drop or crush Adalimumab-adbm. The prefilled syringe is glass.

Keep Adalimumab-adbm, injection supplies, and all other medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 USA

US License Number 2006

Manufactured for: Quallent Pharmaceuticals Health LLC, Grand Cayman, Cayman Islands

CYLTEZO ^® is a registered trademark of and is used under license from Boehringer Ingelheim International GmbH.

Other trademarks referenced are owned by third parties not affiliated with Boehringer Ingelheim Pharmaceuticals, Inc.

For more information about Adalimumab-adbm, go to www.quallentpharmaceuticals.com or call 1-877-605-7243.

Copyright © 2024 Boehringer Ingelheim International GmbH

ALL RIGHTS RESERVED

COL13735BD052024

Revised: 04/2024

Adalimumab-adbm is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients 2 years of age and older.

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.

Consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdose management recommendations.

• National Cancer Institute. Surveillance, Epidemiology, and End Results Database (SEER) Program. SEER Incidence Crude Rates, 17 Registries, 2000-2007.

Adalimumab-adbm is a tumor necrosis factor blocker. Adalimumab-adbm is a recombinant human IgG1 monoclonal antibody 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. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.

Adalimumab-adbm injection is supplied as a sterile, preservative-free solution of adalimumab-adbm for subcutaneous administration. The drug product is supplied as either a single-dose, prefilled pen (Adalimumab-adbm Pen) or as a single-dose, 1 mL prefilled glass syringe. Enclosed within the pen is a single-dose, 1 mL prefilled glass syringe. The solution of Adalimumab-adbm is clear to slightly opalescent and colorless to slightly yellow, with a pH of about 5.5.

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 Adalimumab-adbm contains adalimumab-adbm (40 mg), glacial acetic acid (0.03 mg), polysorbate 80 (0.2 mg), sodium acetate trihydrate (0.47 mg), trehalose dihydrate (30.3 mg), and Water for Injection, USP.

Each 40 mg/0.8 mL prefilled syringe or prefilled pen delivers 0.8 mL (40 mg) of drug product. Each 0.8 mL of Adalimumab-adbm contains adalimumab-adbm (40 mg), glacial acetic acid (0.13 mg), polysorbate 80 (0.8 mg), sodium acetate trihydrate (2.4 mg), trehalose dihydrate (65.0 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 Adalimumab-adbm contains adalimumab-adbm (20 mg), glacial acetic acid (0.06 mg), polysorbate 80 (0.4 mg), sodium acetate trihydrate (1.21 mg), trehalose dihydrate (32.5 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 Adalimumab-adbm contains adalimumab-adbm (10 mg), glacial acetic acid (0.03 mg), polysorbate 80 (0.2 mg), sodium acetate trihydrate (0.61 mg), trehalose dihydrate (16.3 mg), and Water for Injection, USP.

Consider the risks and benefits of TNF-blocker treatment including Adalimumab-adbm 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.

Treatment with adalimumab products may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome or autoimmune hepatitis [see Adverse Reactions (6.1, 6.3)]. If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with Adalimumab-adbm, discontinue treatment and evaluate the patient.

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 Adalimumab-adbm or MTX [see Clinical Pharmacology (12.3)].

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 adalimumab products. Adalimumab products have 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 Adalimumab-adbm in patients who have heart failure and monitor them carefully.

Avoid the use of live vaccines with Adalimumab-adbm [see Warnings and Precautions (5.10)].

The safety and effectiveness of Adalimumab-adbm have not been established in pediatric patients with psoriatic arthritis, ankylosing spondylitis, or plaque psoriasis.

The safety and effectiveness of Adalimumab-adbm have been established for:

• reducing signs and symptoms of moderately to severely active polyarticular JIA in pediatric patients 2 years of age and older.
• the treatment of moderately to severely active Crohn's disease in pediatric patients 6 years of age and older.
• the treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older.
• the treatment of non-infectious intermediate, posterior, and panuveitis in pediatric patients 2 years of age and older.

A pediatric assessment for Adalimumab-adbm demonstrates that Adalimumab-adbm is safe and effective for pediatric patients in an indication for which Humira (adalimumab) is approved. However, Adalimumab-adbm is not approved for such indication due to marketing exclusivity for Humira (adalimumab).

Due to their inhibition of TNFα, adalimumab products administered during pregnancy could affect immune response in the in utero-exposed newborn and infant. Data from eight infants exposed to adalimumab 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 adalimumab products [see Warnings and Precautions (5.2)].

In clinical studies of RA (Studies RA-I, RA-II, RA-III, and RA-IV), a total of 519 subjects 65 years of age and older, including 107 subjects 75 years of age and older, received adalimumab. No overall difference in effectiveness was observed between these subjects and younger adult subjects.

The frequency of serious infection and malignancy among adalimumab-treated subjects 65 years of age and older was higher than for those less than 65 years of age. Consider the benefits and risks of Adalimumab-adbm in patients 65 years of age and older. In patients treated with Adalimumab-adbm, closely monitor for the development of infection or malignancy [see Warnings and Precautions (5.1, 5.2)].

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 subjects 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 Adalimumab-adbm 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.

It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Adalimumab-adbm therapy. Patients on Adalimumab-adbm may receive concurrent vaccinations, except for live vaccines.

The safety of administering live or live-attenuated vaccines in infants exposed to adalimumab products in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants [see Use in Specific Populations (8.1, 8.4)].

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of adalimumab or of other adalimumab products.

There are two assays that have been used to measure anti-adalimumab antibodies. With the ELISA, antibodies to adalimumab could be detected only when serum adalimumab concentrations were <2 mcg/mL. The ECL assay can detect anti-adalimumab antibody titers independent of adalimumab concentrations in the serum samples. The incidence of anti-adalimumab antibody (AAA) development in patients treated with adalimumab are presented in Table 2.

Adalimumab-adbm is indicated for the treatment of moderately to severely active Crohn's disease in adults and pediatric patients 6 years of age and older.

None.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Serious Infections [see Warnings and Precautions (5.1)]
• Malignancies [see Warnings and Precautions (5.2)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Hepatitis B Virus Reactivation [see Warnings and Precautions (5.4)]
• Neurologic Reactions [see Warnings and Precautions (5.5)]
• Hematological Reactions [see Warnings and Precautions (5.6)]
• Heart Failure [see Warnings and Precautions (5.8)]
• Autoimmunity [see Warnings and Precautions (5.9)]

• Abatacept: Increased risk of serious infection. (5.1, 5.11, 7.2)
• Anakinra: Increased risk of serious infection. (5.1, 5.7, 7.2)
• Live vaccines: Avoid use with Adalimumab-adbm. (5.10, 7.3)

Adalimumab-adbm 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. Adalimumab-adbm should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Warnings and Precautions (5)].

The Adalimumab-adbm Pen is a single-dose prefilled pen that delivers a fixed dose of medicine. The Adalimumab-adbm Pen cannot be reused.

Important: Read these instructions before using a Adalimumab-adbm Pen.

• Do not use a Adalimumab-adbm Pen until you have been shown the right way to give the injections and have read and understood this Instructions for Use. If your doctor decides that you or a caregiver may be able to give your injections of Adalimumab-adbm at home, you should receive training on the right way to prepare and inject Adalimumab-adbm. To help you remember when to inject Adalimumab-adbm, you can mark your calendar ahead of time.
• Do not remove the cap until you are ready to inject.

How should I store Adalimumab-adbm?

• Store Adalimumab-adbm in the refrigerator at 36°F to 46°F (2°C to 8°C). Store Adalimumab-adbm in the original carton until use to protect it from light.
• Do not freeze Adalimumab-adbm. Do not use Adalimumab-adbm if frozen, even if it has been thawed.
• Refrigerated Adalimumab-adbm may be used until the expiration date printed on the Adalimumab-adbm carton, dose tray, or pen. Do not use Adalimumab-adbm after the expiration date.
• If needed, for example, when you are traveling, you may also store Adalimumab-adbm at room temperature up to 77°F (25°C) for up to 14 days. Store Adalimumab-adbm in the original carton until use to protect it from light.
• Throw away Adalimumab-adbm if it has been kept at room temperature and not been used within 14 days.
• Record the date you first remove Adalimumab-adbm from the refrigerator in the spaces provided on the carton and dose tray.
• Do not store Adalimumab-adbm in extreme heat or cold.
• Do not use a Adalimumab-adbm Pen if the liquid is milky, discolored, or has flakes or particles in it.
• Do not drop or crush Adalimumab-adbm. The prefilled syringe inside the pen is glass.

Keep Adalimumab-adbm, injection supplies, and all other medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 USA

US License Number 2006

Manufactured for: Quallent Pharmaceuticals Health LLC, Grand Cayman, Cayman Islands

CYLTEZO^® is a registered trademark of and is used under license from Boehringer Ingelheim International GmbH.

Other trademarks referenced are owned by third parties not affiliated with Boehringer Ingelheim Pharmaceuticals, Inc.

For more information about Adalimumab-adbm, go to www.quallentpharmaceuticals.com or call 1-877-605-7243.

Copyright © 2024 Boehringer Ingelheim International GmbH

ALL RIGHTS RESERVED

COL13736BD052024

Revised: 04/2024

After treatment with adalimumab, a decrease in concentrations 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 concentrations was also observed in patients with Crohn's disease, ulcerative colitis and hidradenitis suppurativa. Serum concentrations of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.

The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10 mg/kg following administration of a single intravenous dose (adalimumab products are not approved for intravenous use). Following 20, 40, and 80 mg every other week and every week subcutaneous administration, adalimumab mean serum trough concentrations at steady state increased approximately proportionally with dose in RA patients. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Healthy subjects and patients with RA displayed similar adalimumab pharmacokinetics.

Adalimumab exposure in patients treated with 80 mg every other week is estimated to be comparable with that in patients treated with 40 mg every week.

Adalimumab-adbm is indicated for the treatment of moderately to severely active ulcerative colitis in adult patients.

Patients treated with adalimumab products, including Adalimumab-adbm, 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 Adalimumab-adbm and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions (5.7, 5.11) and Drug Interactions (7.2)].

Treatment with Adalimumab-adbm 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.

Adalimumab-adbm is a tumor necrosis factor (TNF) blocker 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. (1.1)
• Reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. (1.2)
• Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. (1.3)
• Reducing signs and symptoms in adult patients with active ankylosing spondylitis. (1.4)
• Treatment of moderately to severely active Crohn's disease in adults and pediatric patients 6 years of age and older. (1.5)
• Treatment of moderately to severely active ulcerative colitis in adult patients. (1.6)
  
  Limitations of Use: Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers.
• 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. (1.7)
• Treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older. (1.8)
• Treatment of non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients 2 years of age and older. (1.9)

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

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 Adalimumab-adbm with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions (5.7, 5.11)]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker. There is insufficient information regarding the concomitant use of Adalimumab-adbm and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of Adalimumab-adbm 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.

Adalimumab-adbm 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. Adalimumab-adbm can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).

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 Adalimumab-adbm 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 × 10^-10M).

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 Adalimumab-adbm in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of Adalimumab-adbm should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders.

Adalimumab-adbm is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

• Serious infections: Do not start Adalimumab-adbm during an active infection. If an infection develops, monitor carefully, and stop Adalimumab-adbm if infection becomes serious. (5.1)
• Invasive fungal infections: For patients who develop a systemic illness on Adalimumab-adbm, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic. (5.1)
• Malignancies: Incidence of malignancies was greater in adalimumab-treated patients than in controls (5.2)
• Anaphylaxis or serious hypersensitivity reactions may occur (5.3)
• Hepatitis B virus reactivation: Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop Adalimumab-adbm and begin anti-viral therapy. (5.4)
• Demyelinating disease: Exacerbation or new onset, may occur. (5.5)
• Cytopenias, pancytopenia: Advise patients to seek immediate medical attention if symptoms develop, and consider stopping Adalimumab-adbm. (5.6)
• Heart failure: Worsening or new onset, may occur. (5.8)
• Autoimmunity: Stop Adalimumab-adbm if lupus-like syndrome or autoimmune hepatitis develop. (5.9)

• Administer by subcutaneous injection (2)

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis (2.2):

• Adults: 40 mg every other week.

Some patients with RA not receiving methotrexate may benefit from increasing the dosage to 40 mg every week or 80 mg every other week.

Juvenile Idiopathic Arthritis or Pediatric Uveitis (2.3):

Crohn's Disease (2.4):

• Adults: 160 mg on Day 1 (given in one day or split over two consecutive days); 80 mg on Day 15; and 40 mg every other week starting on Day 29.
• Pediatric Patients 6 Years of Age and Older:

Ulcerative Colitis (2.5):

• Adults: 160 mg on Day 1 (given in one day or split over two consecutive days), 80 mg on Day 15 and 40 mg every other week starting on Day 29. Discontinue in patients without evidence of clinical remission by eight weeks (Day 57).

Plaque Psoriasis or Adult Uveitis (2.6):

• Adults: 80 mg initial dose, followed by 40 mg every other week starting one week after initial dose.

Hidradenitis Suppurativa (2.7):

• Adults:
  • Day 1: 160 mg (given in one day or split over two consecutive days)
  • Day 15: 80 mg
  • Day 29 and subsequent doses: 40 mg every week or 80 mg every other week
• Adolescents 12 years of age and older:

  Adolescent Weight	Recommended Dosage
  30 kg (66 lbs) to less than 60 kg (132 lbs)	Day 1: 80 mg Day 8 and subsequent doses: 40 mg every other week
  60 kg (132 lbs) and greater	Day 1: 160 mg (given in one day or split over two consecutive days) Day 15: 80 mg Day 29 and subsequent doses: 40 mg every week or 80 mg every other week

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 Adalimumab-adbm. Consider discontinuation of Adalimumab-adbm therapy in patients with confirmed significant hematologic abnormalities.

Adalimumab-adbm is indicated for the treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older.

Adalimumab-adbm is a clear to slightly opalescent and colorless to slightly yellow solution available as:

The following adverse reactions have been identified during post-approval use of adalimumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to adalimumab products exposure.

Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis

General disorders and administration site conditions: Pyrexia

Hepato-biliary disorders: Liver failure, hepatitis, autoimmune hepatitis

Immune system disorders: Sarcoidosis

Neoplasms benign, malignant and unspecified (including cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin)

Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident

Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism

Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia, lichenoid skin reaction

Vascular disorders: Systemic vasculitis, deep vein thrombosis

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 Adalimumab-adbm 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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reaction with adalimumab was injection site reactions. In placebo-controlled trials, 20% of subjects treated with adalimumab developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of subjects receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.

The proportion of subjects who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies in subjects with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for subjects taking adalimumab and 4% for placebo-treated subjects. The most common adverse reactions leading to discontinuation of adalimumab in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).

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 Adalimumab-adbm 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.

Adalimumab-adbm is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. Adalimumab-adbm can be used alone or in combination with methotrexate.

Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Use of TNF blockers, including Adalimumab-adbm, 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 Adalimumab-adbm 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 Adalimumab-adbm therapy in this situation and monitor patients closely.

Adalimumab-adbm injection is supplied as a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution for subcutaneous administration. The following packaging configurations are available.

Prior to initiating Adalimumab-adbm and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection [see Warnings and Precautions (5.1)].

The safety and efficacy of adalimumab were assessed in randomized, double-blind, placebo-controlled studies in 1696 adult subjects with moderate to severe chronic plaque psoriasis (Ps) who were candidates for systemic therapy or phototherapy.

Study Ps-I evaluated 1212 subjects with chronic Ps with ≥10% body surface area (BSA) involvement, Physician's Global Assessment (PGA) of at least moderate disease severity, and Psoriasis Area and Severity Index (PASI) ≥12 within three treatment periods. In period A, subjects received placebo or adalimumab at an initial dose of 80 mg at Week 0 followed by a dose of 40 mg every other week starting at Week 1. After 16 weeks of therapy, subjects who achieved at least a PASI 75 response at Week 16, defined as a PASI score improvement of at least 75% relative to baseline, entered period B and received open-label 40 mg adalimumab every other week. After 17 weeks of open label therapy, subjects who maintained at least a PASI 75 response at Week 33 and were originally randomized to active therapy in period A were re-randomized in period C to receive 40 mg adalimumab every other week or placebo for an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 19 and the baseline Physician's Global Assessment score ranged from "moderate" (53%) to "severe" (41%) to "very severe" (6%).

Study Ps-II evaluated 99 subjects randomized to adalimumab and 48 subjects randomized to placebo with chronic plaque psoriasis with ≥10% BSA involvement and PASI ≥12. Subjects received placebo, or an initial dose of 80 mg adalimumab at Week 0 followed by 40 mg every other week starting at Week 1 for 16 weeks. Across all treatment groups the mean baseline PASI score was 21 and the baseline PGA score ranged from "moderate" (41%) to "severe" (51%) to "very severe" (8%).

Studies Ps-I and II evaluated the proportion of subjects who achieved "clear" or "minimal" disease on the 6-point PGA scale and the proportion of subjects who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at Week 16 (see Table 16 and 17).

Additionally, Study Ps-I evaluated the proportion of subjects who maintained a PGA of "clear" or "minimal" disease or a PASI 75 response after Week 33 and on or before Week 52.

Additionally, in Study Ps-I, subjects on adalimumab who maintained a PASI 75 were re-randomized to adalimumab (N=250) or placebo (N=240) at Week 33. After 52 weeks of treatment with adalimumab, more subjects on adalimumab maintained efficacy when compared to subjects who were re-randomized to placebo based on maintenance of PGA of "clear" or "minimal" disease (68% vs. 28%) or a PASI 75 (79% vs. 43%).

A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. Median time to relapse (decline to PGA "moderate" or worse) was approximately 5 months. During the withdrawal period, no subject experienced transformation to either pustular or erythrodermic psoriasis. A total of 178 subjects who relapsed re-initiated treatment with 80 mg of adalimumab, then 40 mg every other week beginning at week 1. At week 16, 69% (123/178) of subjects had a response of PGA "clear" or "minimal".

A randomized, double-blind study (Study Ps-III) compared the efficacy and safety of adalimumab versus placebo in 217 adult subjects. Subjects in the study had to have chronic plaque psoriasis of at least moderate severity on the PGA scale, fingernail involvement of at least moderate severity on a 5-point Physician's Global Assessment of Fingernail Psoriasis (PGA-F) scale, a Modified Nail Psoriasis Severity Index (mNAPSI) score for the target-fingernail of ≥8, and either a BSA involvement of at least 10% or a BSA involvement of at least 5% with a total mNAPSI score for all fingernails of ≥20. Subjects received an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeks followed by open-label adalimumab treatment for an additional 26 weeks. This study evaluated the proportion of subjects who achieved "clear" or "minimal" assessment with at least a 2-grade improvement on the PGA-F scale and the proportion of subjects who achieved at least a 75% improvement from baseline in the mNAPSI score (mNAPSI 75) at Week 26.

At Week 26, a higher proportion of subjects in the adalimumab group than in the placebo group achieved the PGA-F endpoint. Furthermore, a higher proportion of subjects in the adalimumab group than in the placebo group achieved mNAPSI 75 at Week 26 (see Table 18).

Nail pain was also evaluated and improvement in nail pain was observed in Study Ps-III.

WARNING: SERIOUS INFECTIONS AND MALIGNANCY

See full prescribing information for complete boxed warning.

SERIOUS INFECTIONS (5.1, 6.1):

• Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens.
• Discontinue Adalimumab-adbm if a patient develops a serious infection or sepsis during treatment.
• Perform test for latent TB; if positive, start treatment for TB prior to starting Adalimumab-adbm.
• Monitor all patients for active TB during treatment, even if initial latent TB test is negative.

MALIGNANCY (5.2):

• Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers including adalimumab products.
• Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have occurred in adolescent and young adults with inflammatory bowel disease treated with TNF blockers including adalimumab products.

The safety and efficacy of adalimumab was assessed in two randomized, double-blind, placebo-controlled studies in 413 subjects with psoriatic arthritis (PsA). Upon completion of both studies, 383 subjects enrolled in an open-label extension study, in which 40 mg adalimumab was administered every other week.

Study PsA-I enrolled 313 adult subjects with moderately to severely active PsA (>3 swollen and >3 tender joints) who had an inadequate response to NSAID therapy in one of the following forms: (1) distal interphalangeal (DIP) involvement (N=23); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of plaque psoriasis) (N=210); (3) arthritis mutilans (N=1); (4) asymmetric PsA (N=77); or (5) AS-like (N=2). Subjects on MTX therapy (158 of 313 subjects) at enrollment (stable dose of ≤30 mg/week for >1 month) could continue MTX at the same dose. Doses of adalimumab 40 mg or placebo every other week were administered during the 24-week double-blind period of the study.

Compared to placebo, treatment with adalimumab resulted in improvements in the measures of disease activity (see Tables 8 and 9). Among subjects with PsA who received adalimumab, the clinical responses were apparent in some subjects at the time of the first visit (two weeks) and were maintained up to 88 weeks in the ongoing open-label study. Similar responses were seen in subjects with each of the subtypes of psoriatic arthritis, although few subjects were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. Responses were similar in subjects who were or were not receiving concomitant MTX therapy at baseline.

Subjects with psoriatic involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses. At 24 weeks, the proportions of subjects achieving a 75% or 90% improvement in the PASI were 59% and 42% respectively, in the adalimumab group (N=69), compared to 1% and 0% respectively, in the placebo group (N=69) (p<0.001). PASI responses were apparent in some subjects at the time of the first visit (two weeks). Responses were similar in subjects who were or were not receiving concomitant MTX therapy at baseline.

Similar results were seen in an additional, 12-week study in 100 subjects with moderate to severe psoriatic arthritis who had suboptimal response to DMARD therapy as manifested by ≥3 tender joints and ≥3 swollen joints at enrollment.

The efficacy and safety of adalimumab were assessed in five randomized, double-blind studies in subjects ≥18 years of age with active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Subjects had at least 6 swollen and 9 tender joints. Adalimumab was administered subcutaneously in combination with methotrexate (MTX) (12.5 to 25 mg, Studies RA-I, RA-III and RA-V) or as monotherapy (Studies RA-II and RA-V) or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study RA-IV).

Study RA-I evaluated 271 subjects who had failed therapy with at least one but no more than four DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks.

Study RA-II evaluated 544 subjects who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of adalimumab were given as monotherapy every other week or weekly for 26 weeks.

Study RA-III evaluated 619 subjects who had an inadequate response to MTX. Subjects received placebo, 40 mg of adalimumab every other week with placebo injections on alternate weeks, or 20 mg of adalimumab weekly for up to 52 weeks. Study RA-III had an additional primary endpoint at 52 weeks of inhibition of disease progression (as detected by X-ray results). Upon completion of the first 52 weeks, 457 subjects enrolled in an open-label extension phase in which 40 mg of adalimumab was administered every other week for up to 5 years.

Study RA-IV assessed safety in 636 subjects who were either DMARD-naïve or were permitted to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Subjects were randomized to 40 mg of adalimumab or placebo every other week for 24 weeks.

Study RA-V evaluated 799 subjects with moderately to severely active RA of less than 3 years duration who were ≥18 years old and MTX naïve. Subjects were randomized to receive either MTX (optimized to 20 mg/week by week 8), adalimumab 40 mg every other week or adalimumab/MTX combination therapy for 104 weeks. Subjects were evaluated for signs and symptoms, and for radiographic progression of joint damage. The median disease duration among subjects enrolled in the study was 5 months. The median MTX dose achieved was 20 mg.

The safety and efficacy of adalimumab were assessed in adult subjects with non-infectious intermediate, posterior and panuveitis excluding subjects with isolated anterior uveitis, in two randomized, double-masked, placebo-controlled studies (UV I and II). Subjects received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week after the initial dose. The primary efficacy endpoint in both studies was ‘time to treatment failure’.

Treatment failure was a multi-component outcome defined as the development of new inflammatory chorioretinal and/or inflammatory retinal vascular lesions, an increase in anterior chamber (AC) cell grade or vitreous haze (VH) grade or a decrease in best corrected visual acuity (BCVA).

Study UV I evaluated 217 subjects with active uveitis while being treated with corticosteroids (oral prednisone at a dose of 10 to 60 mg/day). All subjects received a standardized dose of prednisone 60 mg/day at study entry followed by a mandatory taper schedule, with complete corticosteroid discontinuation by Week 15.

Study UV II evaluated 226 subjects with inactive uveitis while being treated with corticosteroids (oral prednisone 10 to 35 mg/day) at baseline to control their disease. Subjects subsequently underwent a mandatory taper schedule, with complete corticosteroid discontinuation by Week 19.

Adalimumab-adbm is intended for use under the guidance and supervision of a physician. A patient may self-inject Adalimumab-adbm or a caregiver may inject Adalimumab-adbm using either the Adalimumab-adbm Pen or prefilled syringe if a physician determines that it is appropriate, and with medical follow-up, as necessary, after proper training in subcutaneous injection technique.

Adalimumab-adbm can be taken out of the refrigerator for 15 to 30 minutes before injecting to allow the liquid to come to room temperature. Do not remove the cap while allowing it to reach room temperature. Carefully inspect the solution in the Adalimumab-adbm Pen or prefilled syringe for particulate matter and discoloration prior to subcutaneous administration. If particulates and discolorations are noted, do not use the product. Adalimumab-adbm does not contain preservatives; therefore, discard unused portions of drug remaining from the syringe. NOTE: Instruct patients sensitive to latex not to handle the needle cap of the Adalimumab-adbm 40 mg/0.8 mL and 40 mg/0.4 mL Pen or 40 mg/0.8 mL, 40 mg/0.4 mL, 20 mg/0.4 mL, and 10 mg/0.2 mL prefilled syringe because they contain natural rubber latex [see How Supplied/Storage and Handling (16)].

Instruct patients using the Adalimumab-adbm Pen or prefilled syringe to inject the full amount in the syringe, according to the directions provided in the Instructions for Use [see Instructions for Use].

Injections should occur at separate sites in the thigh or abdomen. Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red or hard.

If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.

The safety and efficacy of adalimumab 40 mg every other week was assessed in 315 adult subjects in a randomized, 24 week double-blind, placebo-controlled study in subjects with active ankylosing spondylitis (AS) who had an inadequate response to glucocorticoids, NSAIDs, analgesics, methotrexate or sulfasalazine. Active AS was defined as subjects who fulfilled at least two of the following three criteria: (1) a Bath AS disease activity index (BASDAI) score ≥4 cm, (2) a visual analog score (VAS) for total back pain ≥40 mm, and (3) morning stiffness ≥1 hour. The blinded period was followed by an open-label period during which subjects received adalimumab 40 mg every other week subcutaneously for up to an additional 28 weeks.

Improvement in measures of disease activity was first observed at Week 2 and maintained through 24 weeks as shown in Figure 2 and Table 11.

Responses of subjects with total spinal ankylosis (n=11) were similar to those without total ankylosis.

Figure 2. ASAS 20 Response By Visit, Study AS-I

At 12 weeks, the ASAS 20/50/70 responses were achieved by 58%, 38%, and 23%, respectively, of subjects receiving adalimumab, compared to 21%, 10%, and 5% respectively, of subjects receiving placebo (p <0.001). Similar responses were seen at Week 24 and were sustained in subjects receiving open-label adalimumab for up to 52 weeks.

A greater proportion of subjects treated with adalimumab (22%) achieved a low level of disease activity at 24 weeks (defined as a value <20 [on a scale of 0 to 100 mm] in each of the four ASAS response parameters) compared to subjects treated with placebo (6%).

A second randomized, multicenter, double-blind, placebo-controlled study of 82 subjects with ankylosing spondylitis showed similar results.

Subjects treated with adalimumab achieved improvement from baseline in the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score (-3.6 vs. -1.1) and in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) score (7.4 vs. 1.9) compared to placebo-treated subjects at Week 24.

Two randomized, double-blind, placebo-controlled studies (Studies HS-I and II) evaluated the safety and efficacy of adalimumab in a total of 633 adult subjects with moderate to severe hidradenitis suppurativa (HS) with Hurley Stage II or III disease and with at least 3 abscesses or inflammatory nodules. In both studies, subjects received placebo or adalimumab at an initial dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every week starting at Week 4 and continued through Week 11. Subjects used topical antiseptic wash daily. Concomitant oral antibiotic use was allowed in Study HS-II.

Both studies evaluated Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12. HiSCR was defined as at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count relative to baseline (see Table 19). Reduction in HS-related skin pain was assessed using a Numeric Rating Scale in subjects who entered the study with an initial baseline score of 3 or greater on a 11-point scale.

In both studies, a higher proportion of adalimumab- than placebo-treated subjects achieved HiSCR (see Table 19).

In both studies, from Week 12 to Week 35 (Period B), subjects who had received adalimumab were re-randomized to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 40 mg every other week, or placebo). Subjects who had been randomized to placebo were assigned to receive adalimumab 40 mg every week (Study HS-I) or placebo (Study HS-II).

During Period B, flare of HS, defined as ≥25% increase from baseline in abscesses and inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects who were withdrawn from adalimumab treatment following the primary efficacy timepoint in two studies.

The safety and efficacy of multiple doses of adalimumab were assessed in adult subjects with moderately to severely active Crohn's disease, CD, (Crohn's Disease Activity Index (CDAI) ≥220 and ≤450) in randomized, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted, and 79% of subjects continued to receive at least one of these medications.

Induction of clinical remission (defined as CDAI <150) was evaluated in two studies. In Study CD-I, 299 TNF-blocker naïve subjects were randomized to one of four treatment groups: the placebo group received placebo at Weeks 0 and 2, the 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, the 80/40 group received 80 mg at Week 0 and 40 mg at Week 2, and the 40/20 group received 40 mg at Week 0 and 20 mg at Week 2. Clinical results were assessed at Week 4.

In the second induction study, Study CD-II, 325 subjects who had lost response to, or were intolerant to, previous infliximab therapy were randomized to receive either 160 mg adalimumab at Week 0 and 80 mg at Week 2, or placebo at Weeks 0 and 2. Clinical results were assessed at Week 4.

Maintenance of clinical remission was evaluated in Study CD-III. In this study, 854 subjects with active disease received open-label adalimumab, 80 mg at week 0 and 40 mg at Week 2. Subjects were then randomized at Week 4 to 40 mg adalimumab every other week, 40 mg adalimumab every week, or placebo. The total study duration was 56 weeks. Subjects in clinical response (decrease in CDAI ≥70) at Week 4 were stratified and analyzed separately from those not in clinical response at Week 4.

The safety and efficacy of adalimumab was assessed in two studies (Studies JIA-I and JIA-II) in subjects with active polyarticular juvenile idiopathic arthritis (JIA).

The safety and efficacy of adalimumab were assessed in adult subjects with moderately to severely active ulcerative colitis (Mayo score 6 to 12 on a 12 point scale, with an endoscopy subscore of 2 to 3 on a scale of 0 to 3) despite concurrent or prior treatment with immunosuppressants such as corticosteroids, azathioprine, or 6-MP in two randomized, double-blind, placebo-controlled clinical studies (Studies UC-I and UC-II). Both studies enrolled TNF-blocker naïve subjects, but Study UC-II also allowed entry of subjects who lost response to or were intolerant to TNF-blockers. Forty percent (40%) of subjects enrolled in Study UC-II had previously used another TNF-blocker.

Concomitant stable doses of aminosalicylates and immunosuppressants were permitted. In Studies UC-I and II, subjects were receiving aminosalicylates (69%), corticosteroids (59%) and/or azathioprine or 6-MP (37%) at baseline. In both studies, 92% of subjects received at least one of these medications.

Induction of clinical remission (defined as Mayo score ≤2 with no individual subscores >1) at Week 8 was evaluated in both studies. Clinical remission at Week 52 and sustained clinical remission (defined as clinical remission at both Weeks 8 and 52) were evaluated in Study UC-II.

In Study UC-I, 390 TNF-blocker naïve subjects were randomized to one of three treatment groups for the primary efficacy analysis. The placebo group received placebo at Weeks 0, 2, 4 and 6. The 160/80 group received 160 mg adalimumab at Week 0 and 80 mg at Week 2, and the 80/40 group received 80 mg adalimumab at Week 0 and 40 mg at Week 2. After Week 2, subjects in both adalimumab treatment groups received 40 mg every other week.

In Study UC-II, 518 subjects were randomized to receive either adalimumab 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week starting at Week 4 through Week 50, or placebo starting at Week 0 and every other week through Week 50. Corticosteroid taper was permitted starting at Week 8.

In both Studies UC-I and UC-II, a greater percentage of the subjects treated with 160/80 mg of adalimumab compared to subjects treated with placebo achieved induction of clinical remission. In Study UC-II, a greater percentage of the subjects treated with 160/80 mg of adalimumab compared to subjects treated with placebo achieved sustained clinical remission (clinical remission at both Weeks 8 and 52) (Table 15).

In Study UC-I, there was no statistically significant difference in clinical remission observed between the adalimumab 80/40 mg group and the placebo group at Week 8.

In Study UC-II, 17.3% (43/248) in the adalimumab group were in clinical remission at Week 52 compared to 8.5% (21/246) in the placebo group (treatment difference: 8.8%; 95% confidence interval (CI): [2.8%, 14.5%]; p<0.05).

In the subgroup of subjects in Study UC-II with prior TNF-blocker use, the treatment difference for induction of clinical remission appeared to be lower than that seen in the whole study population, and the treatment differences for sustained clinical remission and clinical remission at Week 52 appeared to be similar to those seen in the whole study population. The subgroup of subjects with prior TNF-blocker use achieved induction of clinical remission at 9% (9/98) in the adalimumab group versus 7% (7/101) in the placebo group, and sustained clinical remission at 5% (5/98) in the adalimumab group versus 1% (1/101) in the placebo group. In the subgroup of subjects with prior TNF-blocker use, 10% (10/98) were in clinical remission at Week 52 in the adalimumab group versus 3% (3/101) in the placebo group.

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 Adalimumab-adbm and anakinra is not recommended [see Drug Interactions (7.2)].

NDC 82009-144-22

ATTENTION PHARMACIST:

Each Patient is Required to Receive

the Enclosed Medication Guide.

The Entire Carton is to be Dispensed

as a Unit.

Needle Cap for Pen Contains Dry

Natural Rubber.

Adalimumab-adbm PEN

Injection

40 mg/0.4 mL

For Subcutaneous Use Only

Rx only

2 Single-Dose Prefilled Pens

Quallent

Pharmaceuticals℠

NDC 82009-146-22

ATTENTION PHARMACIST:

Each Patient is Required to Receive

the Enclosed Medication Guide.

The Entire Carton is to be Dispensed

as a Unit.

Needle Cap for Syringe Contains Dry

Natural Rubber.

Adalimumab-adbm

Injection

40 mg/0.4 mL

For Subcutaneous Use Only

Rx only

2 Single-Dose Prefilled Syringes

Quallent

Pharmaceuticals℠

NDC 82009-148-22

ATTENTION PHARMACIST:

Each Patient is Required to Receive

the Enclosed Medication Guide.

The Entire Carton is to be Dispensed

as a Unit.

Needle Cap for Pen Contains Dry

Natural Rubber.

Adalimumab-adbm PEN

Injection

40 mg/0.8 mL

For Subcutaneous Use Only

Rx only

2 Single-Dose Prefilled Pens

Quallent

Pharmaceuticals℠

NDC 82009-150-22

ATTENTION PHARMACIST:

Each Patient is Required to Receive

the Enclosed Medication Guide.

The Entire Carton is to be Dispensed

as a Unit.

Needle Cap for Syringe Contains Dry

Natural Rubber.

Adalimumab-adbm

Injection

40 mg/0.8 mL

For Subcutaneous Use Only

Rx only

2 Single-Dose Prefilled Syringes

Quallent

Pharmaceuticals℠

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

The safety and efficacy of adalimumab were assessed in a randomized, double-masked, placebo-controlled study of 90 pediatric subjects from 2 to < 18 years of age with active JIA-associated non-infectious uveitis (PUV-I). Subjects received either placebo or 20 mg adalimumab (if < 30 kg) or 40 mg adalimumab (if ≥ 30 kg) every other week in combination with a dose of methotrexate. Concomitant dosages of corticosteroids were permitted at study entry followed by a mandatory reduction in topical corticosteroids within 3 months.

The primary endpoint was 'time to treatment failure'. The criteria determining treatment failure were worsening or sustained non-improvement in ocular inflammation, or worsening of ocular co-morbidities.

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 Adalimumab-adbm is not recommended [see Drug Interactions (7.2)].

A randomized, double-blind, 52-week clinical study of 2 dose concentrations of adalimumab (Study PCD-I) was conducted in 192 pediatric subjects (6 to 17 years of age) with moderately to severely active Crohn's disease (defined as Pediatric Crohn's Disease Activity Index (PCDAI) score >30). Enrolled subjects had over the previous two-year period an inadequate response to corticosteroids or an immunomodulator (i.e., azathioprine, 6-mercaptopurine, or methotrexate). Subjects who had previously received a TNF blocker were allowed to enroll if they had previously had loss of response or intolerance to that TNF blocker.

Subjects received open-label induction therapy at a dose based on their body weight (≥40 kg and <40 kg). Subjects weighing ≥40 kg received 160 mg (at Week 0) and 80 mg (at Week 2). Subjects weighing <40 kg received 80 mg (at Week 0) and 40 mg (at Week 2). At Week 4, subjects within each body weight category (≥40 kg and <40 kg) were randomized 1:1 to one of two maintenance dose regimens (high dose and low dose). The high dose was 40 mg every other week for subjects weighing ≥40 kg and 20 mg every other week for subjects weighing <40 kg. The low dose was 20 mg every other week for subjects weighing ≥40 kg and 10 mg every other week for subjects weighing <40 kg.

Concomitant stable dosages of corticosteroids (prednisone dosage ≤40 mg/day or equivalent) and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted throughout the study.

At Week 12, subjects who experienced a disease flare (increase in PCDAI of ≥15 from Week 4 and absolute PCDAI >30) or who were non-responders (did not achieve a decrease in the PCDAI of ≥15 from baseline for 2 consecutive visits at least 2 weeks apart) were allowed to dose-escalate (i.e., switch from blinded every other week dosing to blinded every week dosing); subjects who dose-escalated were considered treatment failures.

At baseline, 38% of subjects were receiving corticosteroids, and 62% of subjects were receiving an immunomodulator. Forty-four percent (44%) of subjects had previously lost response or were intolerant to a TNF blocker. The median baseline PCDAI score was 40.

Of the 192 subjects total, 188 subjects completed the 4 week induction period, 152 subjects completed 26 weeks of treatment, and 124 subjects completed 52 weeks of treatment. Fifty-one percent (51%) (48/95) of subjects in the low maintenance dose group dose-escalated, and 38% (35/93) of subjects in the high maintenance dose group dose-escalated.

At Week 4, 28% (52/188) of subjects were in clinical remission (defined as PCDAI ≤10).

The proportions of subjects in clinical remission (defined as PCDAI ≤10) and clinical response (defined as reduction in PCDAI of at least 15 points from baseline) were assessed at Weeks 26 and 52.

At both Weeks 26 and 52, the proportion of subjects in clinical remission and clinical response was numerically higher in the high dose group compared to the low dose group (Table 14). The recommended maintenance regimen is 20 mg every other week for subjects weighing <40 kg and 40 mg every other week for subjects weighing ≥40 kg. Every week dosing is not the recommended maintenance dosing regimen [see Dosage and Administration (2.4)].

The recommended subcutaneous dosage of Adalimumab-adbm for adult patients with plaque psoriasis (Ps) or uveitis (UV) [see Indications and Usage (1.7, 1.9)] is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. The use of adalimumab products in moderate to severe chronic Ps beyond one year has not been evaluated in controlled clinical studies.

The recommended subcutaneous dosage of Adalimumab-adbm for pediatric patients 2 years of age and older with polyarticular juvenile idiopathic arthritis (JIA) or pediatric uveitis [see Indications and Usage (1.2, 1.9)], based on weight, is shown below. MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with Adalimumab-adbm.

Adalimumab products have not been studied in patients with polyarticular JIA or pediatric uveitis less than 2 years of age or in patients with a weight below 10 kg.

The recommended subcutaneous dosage of Adalimumab-adbm for adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) [see Indications and Usage (1.1, 1.3, 1.4)] is 40 mg administered every other week. Methotrexate (MTX), other non-biologic DMARDs, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with Adalimumab-adbm. In the treatment of RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosage of Adalimumab-adbm to 40 mg every week or 80 mg every other week.