HYRIMOZ

Adalimumab is a

Subcutaneous administered biological disease modifier for the treatment of rheumatoid arthritis and other chronic debilitating diseases mediated by tumor necrosis factor. 2, 3 It was originally launched by Abbvie in the U.S. and approved in by the FDA.

This drug is frequently known as

It is produced by recombinant

DNA technology using a mammalian cell expression system.

This drug is available in a prefilled syringe form and convenient pen form for subcutaneous self-administered doses.

Several biosimilars to adalimumab.

Adalimumab-atto was the first adalimumab biosimilar approved by the FDA in 2016.

Adalimumab-adaz was approved by the FDA on October 31, 2018.

Other biosimilars include adalimumab-fkjp.

• which was approved in July 2022 -, 17 adalimumab-bwwd.

• which was approved in August 2022 -, 18, adalimumab-aacf.

• which was approved in October 2023 31 and adalimumab-ryvk.

• which was approved in February 2024 32.

A biosimilar marketed as

Hyrimoz, a high-concentration formulation of adalimumab, is also available. 20, 21.

A high-concentration, citrate-free formulation of Cyltezo® (adalimumab-adbm), a biosimilar to Humira®, was approved by the FDA in May for the treatment of multiple chronic inflammatory diseases.

Adalimumab is indicated for the following conditions: 31 Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). 16, 17, 18, 19, 20, 21, 31 Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. 16, 17, 18, 19, 20, 21, 31 Psoriatic Arthritis (PsA) in adults. 16, 17, 18, 19, 20, 21, 31 Ankylosing Spondylitis (AS) in adults. 16, 17, 18, 19, 20, 21, 31 Moderately to severely active Crohn's Disease (CD) in adults and pediatric patients six years of age and older. 16, 17, 18, 19, 20, 21, 31 Moderately to severely active Ulcerative Colitis (UC) in adults.

Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. 16, 17, 18, 19, 20, 21, 31 Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. 16, 17, 18, 19, 20, 21, 31 Moderate to severe Hidradenitis Suppurativa (HS) in adults.

Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older.

Adalimumab has also been used off-label to treat Pyoderma gangrenosum. 5,

After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein and erythrocyte sedimentation rate ) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis.

A decrease in CRP levels was also observed in patients diagnosed with Crohn's disease.

Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab.

A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. 1, 3, 15.

The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects.

The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%.

The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5-10.0 mg/kg following a single intravenous dose.

The distribution volume (Vss) ranged from 4.7-6.0 L following intravenous administration of doses ranging from 0.25-10 mg/kg in RA patients.

Adalimumab is most likely removed by opsonization via the reticuloendothelial system.

The mean terminal half-life was approximately 2 weeks, ranging from 10-20 days across studies.

The single-dose pharmacokinetics of adalimumab in

RA patients were determined in several studies with intravenous doses ranging from 0.25-10 mg/kg.

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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.

• 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.

Pediatric Weight 2 Years of Age and Older Recommended Dosage 10 kg (22 lbs) to less than 15 kg (33 lbs) 10 mg every other week 15 kg (33 lbs) to less than 30 kg (66 lbs) 20 mg every other week 30 kg (66 lbs) and greater 40 mg every other week.

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

Pediatric Weight 2 Years of Age and Older Recommended Dosage 10 kg (22 lbs) to less than 15 kg (33 lbs) 10 mg every other week 15 kg (33 lbs) to less than 30 kg (66 lbs) 20 mg every other week 30 kg (66 lbs) and greater 40 mg every other week Crohn's Disease.

• 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: Pediatric Weight Recommended Dosage Days and 15 Starting on Day 29 17 kg (37 lbs) to less than 40 kg (88 lbs) Day 1: 80 mg Day 15: 40 mg 20 mg every other week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) Day 15: 80 mg 40 mg every other week Ulcerative Colitis:

• Adults: 160 mg on Day 1 (given in one day or split over two consecutive days), 80 mg on Day and 40 mg every other week starting on Day 29.

Discontinue in patients without evidence of clinical remission by eight weeks (Day 57).

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

• Adults: o Day 1: 160 mg (given in one day or split over two consecutive days) o Day 15: 80 mg o Day and subsequent doses: 40 mg every week or 80 mg every other week 2.1 Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis The recommended subcutaneous dosage of IDACIO for adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) 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 IDACIO.

In the treatment of

RA, some patients not taking concomitant MTX may derive additional benefit from increasing the dosage of IDACIO to 40 mg every week or 80 mg every other week. 2.2 Juvenile Idiopathic Arthritis The recommended subcutaneous dosage of IDACIO for patients 2 years of age and older with polyarticular juvenile idiopathic arthritis (JIA) is based on weight as shown below.

MTX, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment with IDACIO.

Weight (2 Years of Age and older) Recommended Dosage 10 kg (22 lbs) to less than 15 kg (33 lbs) 10 mg every other week 15 kg (33 lbs) to less than 30 kg (66 lbs) 20 mg every other week 30 kg (66 lbs) and greater 40 mg every other week The only dosage form for IDACIO that allows weight-based dosing for pediatric patients below 30 kg is the single-dose glass vial kit for institutional use only.

Adalimumab products have not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg. 2.3 Crohn’s Disease Adults The recommended subcutaneous dosage of IDACIO for adult patients with Crohn’s disease (CD) is 160 mg initially on Day 1 (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15).

Two weeks later (Day 29) begin a dosage of 40 mg every other week.

Aminosalicylates and/or corticosteroids may be continued during treatment with IDACIO.

Azathioprine, 6-mercaptopurine (6-MP) or MTX may be continued during treatment with IDACIO if necessary.

Pediatrics The recommended subcutaneous dosage of

IDACIO for pediatric patients 6 years of age and older with Crohn’s disease (CD) is based on body weight as shown below: Pediatric Weight Recommended Dosage Days 1 through 15 Starting on Day 29 17 kg (37 lbs) to less than 40 kg (88 lbs) Day 1: 80 mg Day 15: 40 mg 20 mg every other week 40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days) Day 15: 80 mg 40 mg every other week The only dosage form for IDACIO that allows weight-based dosing for pediatric patients below 40 kg is the single-dose glass vial kit for institutional use only 2.4 Ulcerative Colitis Adults The recommended subcutaneous dosage of IDACIO for adult patients with ulcerative colitis is 160 mg initially on Day 1 (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15).

Two weeks later (Day 29) continue with a dosage of 40 mg every other week.

IDACIO in adult patients without evidence of clinical remission by eight weeks (Day 57) of therapy.

Azathioprine and 6-mercaptopurine (6-MP) may be continued during treatment with IDACIO if necessary. 2.5 Plaque Psoriasis or Adult Uveitis The recommended subcutaneous dosage of IDACIO for adult patients with plaque psoriasis (Ps) or Uveitis (UV) 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. 2.6 Hidradenitis Suppurativa Adults The recommended subcutaneous dosage of IDACIO for adult patients with hidradenitis suppurativa (HS) is an initial dose of 160 mg (given in one day or split over two consecutive days), followed by 80 mg two weeks later (Day 15).

Begin 40 mg weekly or 80 mg every other week dosing two weeks later (Day 29). 2.7 Monitoring to Assess Safety Prior to initiating IDACIO and periodically during therapy, evaluate patients for active tuberculosis and test for latent infection. 2.8 General Considerations for Administration IDACIO Pen or prefilled syringe is intended for use under the guidance and supervision of a physician.

A patient may self-inject IDACIO or a caregiver may inject IDACIO using either the IDACIO 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.

IDACIO may be taken out of the refrigerator for to 30 minutes before injecting to allow the liquid to come to room temperature.

Do not remove the cap or cover while allowing it to reach room temperature.

Carefully inspect the solution in the IDACIO Pen, or prefilled syringe or single dose institutional use vial for particulate matter and discoloration prior to subcutaneous administration.

If particulates and discolorations are noted, do not use the product.

IDACIO does not contain preservatives.

Therefore, discard unused portions of drug remaining in the syringe.

Instruct patients using the IDACIO

Pen or prefilled syringe to inject the full amount in the syringe, according to the directions provided in the 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.

IDACIO syringe plunger stopper and needle cover are not made with natural rubber latex.

IDACIO single-dose institutional use vial kit is for administration within an institutional setting only, such as a hospital, physician’s office, or clinic.

Withdraw the dose using the vial adapter, the sterile syringe and needle provided.

Only administer one dose per vial.

The vial does not contain preservatives; discard unused portion.

IDACIO vial and syringe stopper are not made with natural rubber latex.

Read these Administration Instructions before using the Idacio Vial kit.

IDACIO is supplied in a carton containing 1 sterile single-use syringe, 1 sterile needle, 1 vial adapter, 2 alcohol preps and 1 glass vial providing 40 mg/0.8 mL of IDACIO ( Figure A ) The contents of the Idacio Vial Kit are for single-dose (one-time) use only.

Discard unused portion.

Figure A Prior to

• Remove the Idacio Vial Kit from the refrigerator and let it sit at room temperature for at least 30 minutes.

• Check the expiration date.

• Remove Vial Kit contents from the carton and inspect for damage.

Do not use if any kit component or packaging has been damaged.

• Check the vial contents to make sure that the liquid is clear, colorless, and free of particles and flakes.

Prepare syringe just prior to administration and inject immediately.

Do not store

Idacio in the syringe.

Step 1: Prepare Vial and Vial Adapter 1.1 Remove plastic flip off cap from vial and disinfect the rubber stopper.

Do not touch the top of the vial after cleaning 1.2 Without removing the vial adapter from its packaging, peel off the top cover (Figure B).

Do not touch the vial adapter Figure B 1.3 With the vial adapter still in its packaging, push the vial adapter onto the vial top until it snaps in place (Figure C).

C 1.4 Remove the vial adapter packaging (Figure D).

Step 2: Connect Syringe to Vial Adapter 2.1 Remove syringe from outer packaging.

Do not touch the syringe tip.

E 2.2 Hold the base of the vial adapter and connect the syringe to the vial adapter by turning it clockwise (Figure E).

Step 3: Withdraw the Dose 3.1 Invert the vial completely with the vial adapter and syringe still connected (Figure F).

F 3.2 Slowly withdraw the prescribed dose of Idacio into the syringe for administration (Figure G).

Remove air bubbles from the syringe.

Do not pull the plunger rod out.

Step 4: Disconnect the syringe 4.1 Turn over the vial and syringe.

Hold the base of the vial adapter and disconnect the syringe from the vial adapter by turning it counterclockwise (Figure H).

Do not touch the syringe tip Figure H Step 5: Attach Needle Figure I 5.1 Peel open the outer needle packaging to uncover the yellow syringe connector (Figure J).

J 5.2 Insert the syringe tip into the syringe connector.

Turn the syringe connector in a clockwise direction to tighten (Figure K).

K 5.3 Pull the outer needle packaging off (Figure L).

Do not remove the clear needle cap.

L 5.4 Pull back the needle safety cover toward the syringe (Figure M).

Do not remove the needle cover from the connector.

Step 6: Administer medication 6.1 When you are ready to inject Idacio remove the clear needle cap by pulling it straight off and throw it away (Figure N).

Do not recap the needle.

N 6.2 Administer the dose subcutaneously. 6.3 Place your thumb or index finger on the center of the textured finger pad and push the pink needle safety cover forward over the needle until you hear it click or feel it lock (Figure O).

Step 7: Discard Used Syringe and Needle 7.1 Discard used syringe and needle into an appropriate sharps container. adali-img-01.jpg adali-img-02.jpg adali-img-03.jpg adali-img-04.jpg adali-img-05.jpg adali-img-06.jpg adali-img-07.jpg adali-img-08.jpg adali-img-09.jpg adali-img-10.jpg adali-img-11.jpg adali-img-12.jpg adali-img-13.jpg adali-img-14.jpg adali-img-15.jpg.

(adalimumab-aacf) injection is supplied as a preservative-free, sterile, clear and colorless to pale yellow solution for subcutaneous administration.

The following packaging configurations are available.

• 40 mg/0.8 mL (2 count) IDACIO is supplied in a carton containing 2 alcohol preps and one tray.

The tray contains two single-dose pens, each containing a 1 mL prefilled glass syringe with a 29 gauge staked ½ inch needle, providing 40 mg/0.8 mL of IDACIO.

The syringe plunger stopper and needle cover are not made with natural rubber latex.

NDC number is 65219-554-08.

• IDACIO Pen 40 mg/0.8 mL.

• Starter Package for Plaque Psoriasis or Uveitis (4 Count) IDACIO is supplied in a carton containing 4 alcohol preps and 2 trays (Starter Package for Plaque Psoriasis or Uveitis).

Each tray contains two single-dose pens, each pen containing a 1 mL prefilled glass syringe with a 29 gauge staked ½ inch needle, providing 40 mg/0.8 mL of IDACIO.

NDC number is 65219-554-28.

• Starter Package for Crohn's Disease, Ulcerative Colitis, or Hidradenitis Suppurativa (6 Count) IDACIO is supplied in a carton containing 6 alcohol preps and 3 trays (Starter Package for Crohn’s Disease, Ulcerative Colitis, or Hidradenitis Suppurativa).

Each tray contains two single-dose pens, each pen containing a 1 mL prefilled glass syringe with a 29 gauge staked ½ inch 65219-628-89needle, providing 40 mg/0.8 mL of IDACIO.

NDC number is 65219-554-38.

The tray contains two single-dose, 1 mL prefilled glass syringes with a 29 gauge staked ½ inch needle, each syringe providing 40 mg/0.8 mL of IDACIO.

NDC number is 65219-556-18.

• 40 mg/0.8 mL.

IDACIO is supplied in a carton containing 1 sterile single-use syringe, 1 sterile needle, 1 vial adapter, 2 alcohol preps and 1 glass vial providing 40 mg/0.8 mL of IDACIO.

The vial stopper is not made with natural rubber latex.

NDC number is 65219-558-08.

Do not use beyond the expiration date on the container.

IDACIO must be refrigerated at 36°F to 46°F (2°C to 8°C).

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, IDACIO may be stored at room temperature up to a maximum of 77°F (25°C) for a period of up to 28 days, with protection from light.

IDACIO should be discarded if not used within the 28-day period.

Record the date when

IDACIO is first removed from the refrigerator in the spaces provided on the carton.

Do not store

IDACIO in extreme heat or cold.

Available studies with use of adalimumab during pregnancy do not reliably establish an association between adalimumab and major birth defects.

Clinical data are available from the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry in pregnant women with rheumatoid arthritis (RA) or Crohn’s disease (CD) treated with adalimumab.

Registry results showed a rate of 10% for major birth defects with first trimester use of adalimumab in pregnant women with RA or CD and a rate of 7.5% for major birth defects in the disease-matched comparison cohort.

The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects.

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

In an embryo-fetal perinatal development study conducted in cynomolgus monkeys, no fetal harm or malformations were observed with intravenous administration of adalimumab during organogenesis and later in gestation, at doses that produced exposures up to approximately 373 times the maximum recommended human dose (MRHD) of 40 mg subcutaneous without methotrexate.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Disease-associated maternal and embryo/fetal risk Published data suggest that the risk of adverse pregnancy outcomes in women with RA or inflammatory bowel disease (IBD) is associated with increased disease activity.

Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Fetal/Neonatal Adverse Reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester.

Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to adalimumab products in utero.

A prospective cohort pregnancy exposure registry conducted by OTIS/MotherToBaby in the U.S. and Canada between and 2016 compared the risk of major birth defects in live-born infants of 221 women (69 RA, 152 CD) treated with adalimumab during the first trimester and 106 women (74 RA, 32 CD) not treated with adalimumab.

The proportion of major birth defects among live-born infants in the adalimumab-treated and untreated cohorts was 10% (8.7% RA, 10.5% CD) and 7.5% (6.8% RA, 9.4% CD), respectively.

This study cannot reliably establish whether there is an association between adalimumab and major birth defects because of methodological limitations of the registry, including small sample size, the voluntary nature of the study, and the non-randomized design.

In an independent clinical study conducted in ten pregnant women with IBD treated with adalimumab, adalimumab concentrations were measured in maternal serum as well as in cord blood (n=10) and infant serum (n=8) on the day of birth.

The last dose of adalimumab was given between and 56 days prior to delivery.

Adalimumab concentrations were 0.16-19.7 mcg/mL in cord blood, 4.28-17.7 mcg/mL in infant serum, and 0-16.1 mcg/mL in maternal serum.

In all but one case, the cord blood concentration of adalimumab was higher than the maternal serum concentration, suggesting adalimumab actively crosses the placenta.

In addition, one infant had serum concentrations at each of the following: 6 weeks (1.94 mcg/mL), 7 weeks (1.31 mcg/mL), 8 weeks (0.93 mcg/mL), and 11 weeks (0.53 mcg/mL), suggesting adalimumab can be detected in the serum of infants exposed in utero for at least 3 months from birth.

In an embryo-fetal perinatal development study, pregnant cynomolgus monkeys received adalimumab from gestation days to 97 at doses that produced exposures up to 373 times that achieved with the MRHD without methotrexate (on an AUC basis with maternal IV doses up to 100 mg/kg/week).

Adalimumab did not elicit harm to the fetuses or malformations.

A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received adalimumab in clinical studies RA-I through IV.

No overall difference in effectiveness was observed between these patients and younger patients.

The frequency of serious infection and malignancy among adalimumab treated patients 65 years of age and older was higher than for those less than 65 years of age.

Consider the benefits and risks of

IDACIO in patients 65 years of age and older.

In patients treated with

IDACIO, closely monitor for the development of infection or malignancy.