Hulio Product Monograph

1 INDICATIONS

Indications have been granted on the basis of similarity between Hulio and the reference biologic drug Humira^®.

Hulio is indicated for:

Rheumatoid Arthritis

• reducing the signs and symptoms, inducing major clinical response and clinical remission, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. Hulio can be used alone or in combination with methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs).

When used as first-line treatment in recently diagnosed patients who have not been previously treated with MTX, Hulio should be given in combination with MTX. Hulio can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is contraindicated.

Polyarticular Juvenile Idiopathic Arthritis

• in combination with methotrexate, reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients, 2 years of age and older who have had an inadequate response to one or more DMARDs. Hulio can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with MTX is not appropriate (see 14 CLINICAL TRIALS, 14.5 CLINICAL TRIALS - REFERENCE BIOLOGIC DRUG, Pediatric, Polyarticular Juvenile Idiopathic Arthritis, Study Results). Adalimumab injection has not been studied in pediatric patients with polyarticular juvenile idiopathic arthritis aged less than 2 years.

Psoriatic Arthritis

• reducing the signs and symptoms of active arthritis and inhibiting the progression of structural damage and improving the physical function in adult psoriatic arthritis patients. Hulio can be used in combination with MTX in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

• reducing signs and symptoms in adult patients with active ankylosing spondylitis who have had an inadequate response to conventional therapy.

Adult Crohn’s Disease

• reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy, including corticosteroids and/or immunosuppressants. Hulio is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Pediatric Crohn’s Disease

• reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 13 to 17 years of age weighing ≥ 40 kg with severely active Crohn’s disease and/or who have had an inadequate response or were intolerant to conventional therapy (a corticosteroid and/or aminosalicylate and/or an immunosuppressant) and/or a tumour necrosis factor alpha antagonist.

Adult Ulcerative Colitis

• treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy including corticosteroids and/or azathioprine or 6-mercaptopurine (6-MP) or who are intolerant to such therapies. The efficacy of adalimumab injection in patients who have lost response to or were intolerant to TNF blockers has not been established.

Pediatric Ulcerative Colitis

• inducing and maintaining clinical remission in pediatric patients 5 years of age and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy including corticosteroids and/or azathioprine or 6-MP or who are intolerant to such therapies.

Hidradenitis Suppurativa

• treatment of active moderate to severe hidradenitis suppurativa in adult and adolescent patients (12 to 17 years of age weighing ≥ 30 kg) who have not responded to conventional therapy (including systemic antibiotics).

Plaque Psoriasis

• treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, Hulio should be used after phototherapy has been shown to be ineffective or inappropriate.

Adult Uveitis

• treatment of non-infectious uveitis (intermediate, posterior and panuveitis) in adult patients with inadequate response to corticosteroids or as corticosteroid sparing treatment in corticosteroid-dependent patients.

Pediatric Uveitis

• treatment of chronic non-infectious anterior uveitis in pediatric patients from 2 years of age who have had an inadequate response to or are intolerant to conventional therapy, or in whom conventional therapy is inappropriate.

Pediatrics

Pediatrics (< 18 years of age):

Polyarticular Juvenile Idiopathic Arthritis

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

Pediatric Crohn’s Disease

The safety and efficacy of adalimumab injection were authorised in pediatric patients 13 to 17 years of age weighing ≥ 40 kg with severely active Crohn’s disease and/or who have had an inadequate response or were intolerant to conventional therapy (see 14 CLINICAL TRIALS, 14.5 CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG, Pediatric, Pediatric Crohn’s Disease).

Adolescent Hidradenitis Suppurativa

There are no clinical trials with adalimumab injection in adolescent patients with hidradenitis suppurativa (HS). The dosage of adalimumab injection in these patients has been determined based on pharmacokinetic/pharmacodynamic modeling and simulation (see 14 CLINICAL TRIALS, 14.5 CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG, Pediatric, Adolescent Hidradenitis Suppurativa).

Pediatric Uveitis

Adalimumab injection has not been studied in pediatric patients with uveitis less than 2 years of age. Very limited data are available for pediatric patients with uveitis between 2 and < 3 years of age.

Pediatric Ulcerative Colitis

Adalimumab injection has not been studied in pediatric patients with UC less than 5 years of age.

Geriatrics

Geriatrics (> 65 years of age):

Evidence from clinical studies and experience suggests that use of adalimumab injection in the geriatric population is not associated with differences in effectiveness. A brief discussion can be found under (7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations, 7.1.4 Geriatrics).

2 CONTRAINDICATIONS

• Patients with known hypersensitivity to Hulio (adalimumab injection) or any of its components. For a complete listing, see the (6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).
• Patients with severe infections such as sepsis, tuberculosis and opportunistic infections. See (3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Infections).
• Patients with moderate to severe heart failure (NYHA class III/IV). See (7 WARNINGS AND PRECAUTIONS, Cardiovascular, Patients with Congestive Heart Failure).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

Dosing Considerations

Pediatrics

Polyarticular Juvenile Idiopathic Arthritis

See 4 DOSAGE AND ADMINISTRATION, 4.2 Recommended Dosage and Dosage Adjustment, Pediatrics, Polyarticular Juvenile Idiopathic Arthritis.

Safety and effectiveness in pediatric patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg have not been established.

Pediatric Crohn’s Disease

See 4 DOSAGE AND ADMINISTRATION, 4.2 Recommended Dosage and Dosage Adjustment, Pediatrics, Pediatric Crohn’s Disease.

The majority (102/192) of pediatric patients with Crohn’s disease studied were 13 to 17 years of age weighing ≥ 40 kg.

Adolescent Hidradenitis Suppurativa

See 4 DOSAGE AND ADMINISTRATION, 4.2 Recommended Dosage and Dosage Adjustment, Pediatrics, Adolescent Hidradenitis Suppurativa.

There are no clinical trials with adalimumab injection in adolescent patients with hidradenitis suppurativa (HS). The dosage of Hulio in these patients has been determined based on pharmacokinetic/ pharmacodynamic modeling and simulation.

Pediatric Uveitis

See 4 DOSAGE AND ADMINISTRATION, 4.2 Recommended Dosage and Dosage Adjustment, Pediatrics, Pediatric Uveitis.

Safety and effectiveness in pediatric patients with uveitis less than 2 years of age have not been established. Very limited data are available for pediatric patients with uveitis between 2 and < 3 years of age.

Pediatric Ulcerative Colitis

See 4 DOSAGE AND ADM INISTRATION, 4.2 Recommended Dosage and Dosage Adjustment, Pediatrics, Pediatric Ulcerative Colitis.

Safety and effectiveness in pediatric patients with UC less than 5 years of age have not been established.

Geriatrics

Evidence from clinical studies and experience suggests that use of adalimumab injection in the geriatric population is not associated with differences in effectiveness. No dose adjustment is needed for this population. A brief discussion can be found under (7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations, 7.1.4 Geriatrics).

Sex

No sex-related pharmacokinetic differences were observed after correction for a patient’s body weight. Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab injection pharmacokinetics.

Ethnic Origin

No differences in immunoglobulin clearance would be expected among ethnic origin. From limited data in non-Caucasians, no important kinetic differences were observed for adalimumab injection. Dosage adjustment is not required.

Hepatic Insufficiency

No pharmacokinetic data are available in patients with hepatic impairment. No dose recommendation can be made.

Renal Insufficiency

No pharmacokinetic data are available in patients with renal impairment. No dose recommendation can be made.

Disease States

Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab injection pharmacokinetics. See (10 CLINICAL PHARMACOLOGY, 10.3 Pharmacokinetics, Special Populations and Conditions, Disease States).

Concomitant Medications

Methotrexate, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics or other DMARDs may be continued during treatment with Hulio. When treated with Hulio as monotherapy, some rheumatoid arthritis patients who experience a decrease in their response to Hulio 40 mg every other week may benefit from an increase in dose intensity to Hulio 40 mg every week.

Recommended Dose and Dosage Adjustment

Note: See Table 4 at end of section for available presentations of Hulio for each indication in pediatrics and adults.

Pediatrics

Polyarticular Juvenile Idiopathic Arthritis

The recommended dose of Hulio for patients with polyarticular JIA from 2 years of age is based on body weight (Table 1). Hulio is administered every other week via subcutaneous injection. Hulio can be used in combination with MTX or as monotherapy in case of intolerance to MTX or when continued treatment with MTX is not appropriate.

Table 1. Hulio Dose for Patients with Polyarticular JIA

Available data suggest that clinical response is usually achieved within 12 weeks of treatment. Efficacy and safety in patients who do not respond by Week 16 have not been established.

There is no relevant use of Hulio in children aged <2 years in this indication.

Pediatric Crohn’s Disease

The recommended Hulio induction dose regimen for pediatric patients with severely active Crohn’s disease and moderately active Crohn’s disease with no response to conventional therapy is 160 mg at Week 0, followed by 80 mg at Week 2 administered by subcutaneous injection. The first dose of 160 mg can be given in one day (four 40 mg injections) or split over two consecutive days (two 40 mg injections each day). The second dose of 80 mg at Week 2 is given as two 40 mg injections in one day.

The recommended Hulio maintenance dose regimen is 20 mg every other week beginning at Week 4.

For pediatric patients who experience a disease flare or non-response, dose escalation to 40 mg every other week may be considered. See (14 CLINICAL TRIALS, 14.5 CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG, Pediatric Crohn’s Disease).

The use of Hulio in pediatric patients with Crohn’s disease ages 13 to 17 has been evaluated up to one year in clinical studies.

If a patient has not responded by Week 12, continued therapy should be carefully reconsidered.

Adolescent Hidradenitis Suppurativa

The recommended Hulio dose regimen for adolescent patients with HS (12 to 17 years of age weighing ≥ 30 kg) is 80 mg at Week 0 followed by 40 mg every other week starting at Week 1 via subcutaneous injection.

In adolescent patients with inadequate response to Hulio 40 mg every other week, an increase in dosing frequency to 40 mg every week may be considered. See (14 CLINICAL TRIALS, 14.5 CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG, Pediatric, Adolescent Hidradenitis Suppurativa).

Antibiotics may be continued during treatment with Hulio if necessary.

Continued therapy beyond 12 weeks should be carefully reconsidered in a patient with no improvement within this time period.

Pediatric Uveitis

The recommended dose of Hulio in combination with methotrexate for pediatric patients with chronic non-infectious anterior uveitis 2 years of age and older is based on body weight (Table 2). In pediatric uveitis, there is no experience in the treatment with Hulio without concomitant treatment with MTX.

Table 2. Hulio Dose for Pediatric Patients with Uveitis

When Hulio is initiated in patients ≥ 6 years of age, an optional loading dose of 40 mg for patients < 30 kg or 80 mg for patients ≥ 30 kg may be administered one week prior to the start of maintenance therapy. No clinical data are available on the use of a loading dose for Hulio in children < 6 years of age.

There are no data in the use of adalimumab injection in children aged less than 2 years for this indication.

Pediatric Ulcerative Colitis

The recommended dose of Hulio for patients from 5 to 17 years of age with UC is based on body weight (Table 3). Hulio is administered via subcutaneous injection. Hulio

may be available in different strengths and/or presentations.

Table 3. Hulio Dose for Pediatric Ulcerative Colitis

a. Pediatric patients who turn 18 years of age while on Hulio should continue their prescribed maintenance dose.

Doses of 160 mg can be given as four 40 mg injections. Doses of 80 mg can be given as two 40 mg injections. Doses of 40 mg can be given as two 20 mg injections or one 40 mg injection.

Continued therapy beyond 8 weeks should be carefully considered in patients not showing signs of response within this time period.

There is no relevant use of adalimumab injection in children aged less than 5 years in this indication.

Adults

Rheumatoid Arthritis

The recommended dose of Hulio for adult patients with rheumatoid arthritis is 40 mg administered every other week as a subcutaneous injection.

Psoriatic Arthritis

The recommended dose of Hulio for adult patients with psoriatic arthritis is 40 mg administered every other week as a subcutaneous injection.

For the rheumatoid arthritis and psoriatic arthritis indications, available data suggest that the clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.

Ankylosing Spondylitis

The recommended dose of Hulio for patients with ankylosing spondylitis is Hulio 40 mg administered every other week via subcutaneous injection. Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, analgesics or disease modifying anti-rheumatic drugs can be continued during treatment with Hulio.

Crohn’s Disease

The recommended Hulio induction dose regimen for adult patients with Crohn’s disease is 160 mg at Week 0, followed by 80 mg at Week 2 administered by subcutaneous injection. The first dose of 160 mg can be given in one day (four 40 mg injections) or split over two consecutive days (two 40 mg injections). The second dose of 80 mg at Week 2 is given as two 40 mg injections in one day.

The recommended Hulio maintenance dose regimen for adult patients with Crohn’s disease is 40 mg every other week beginning at Week 4.

During treatment with Hulio, other concomitant therapies (e.g., corticosteroids and/or immunomodulatory agents) should be optimized.

For patients who experience a disease flare, dose escalation may be considered. See (14 CLINICAL TRIALS, 14.5 CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG, Adults, Crohn’s Disease, Study Results).

Some patients who have not responded by Week 4 (induction period) may benefit from continued maintenance therapy through Week 12. Available data suggest that the clinical response is usually achieved at Week 4 of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.

The use of adalimumab injection in Crohn’s disease has been evaluated up to one year in controlled clinical studies. In open-label studies, 510/1,594 patients were evaluated for three years, and 118/1,594 patients for at least five years.

Ulcerative Colitis

The recommended Hulio induction dose regimen for adult patients with UC is 160 mg at Week 0, followed by 80 mg at Week 2 administered by subcutaneous injection. The first dose of 160 mg can be given in one day (four 40 mg injections) or split over two consecutive days (two 40 mg injections each day). The second dose of 80 mg at Week 2 is given as two 40 mg injections in one day. Beginning at Week 4, continue with a dose of 40 mg every other week. Hulio should only be continued in patients who have responded during the first 8 weeks of therapy.

Aminosalicylates and/or corticosteroids may be continued during treatment with Hulio. Azathioprine and 6-MP may be continued during treatment with Hulio if necessary (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Serious Warnings and Precautions).

During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines.

Hidradenitis Suppurativa

The recommended Hulio initial dose for adult patients with hidradenitis suppurativa is 160 mg, followed by 80 mg two weeks later administered by subcutaneous injection. The first dose of 160 mg at Week 0 can be given in one day (four 40 mg injections) or split over two consecutive days (two 40 mg injections each day). The second dose of 80 mg at Week 2 is given as two 40 mg injections in one day.

The recommended Hulio maintenance dose regimen for adult patients with HS is 40 mg every week beginning four weeks after the initial dose.

Antibiotics may be continued during treatment with Hulio if necessary.

In patients without any benefit after 12 weeks of treatment, continued therapy should be reconsidered.

Plaque Psoriasis

The recommended dose of Hulio for adult patients with psoriasis is an initial dose of 80 mg administered subcutaneously (two 40 mg injections), followed by 40 mg subcutaneously given every other week starting one week after the initial dose.

Continued therapy beyond 16 weeks should be carefully reconsidered in a patient not responding within this time period.

Uveitis

The recommended dose of Hulio for adult patients with non-infectious uveitis is an initial dose of 80 mg administered subcutaneously (two 40 mg injections), followed by 40 mg subcutaneously given every other week starting one week after the initial dose.

Hulio can be initiated in combination with corticosteroids and/or other non-biologic immunomodulatory agents. Corticosteroids may be tapered in accordance with clinical practice starting two weeks after initiating treatment with Hulio. There is limited experience with the initiation of treatment with adalimumab injection alone.

It is recommended that the benefit and risk of continued long-term treatment should be evaluated on a yearly basis.

Table 4. Available Presentations for Each Adult and Pediatric Indication

Definition(s): PFS = pre-filled syringe; N/A = not applicable

Administration

Hulio is intended for use under the guidance and supervision of a physician. Patients may self inject Hulio if their physician determines that it is appropriate and with medical follow-up, as necessary, after proper training in subcutaneous injection technique.

Pre-filled Syringe or Pre-filled Pen

The solution in the pre-filled pen or pre-filled syringe should be carefully inspected visually for particulate matter and discolouration prior to subcutaneous administration. If particulates and discolourations are noted, the product should not be used. Hulio does not contain preservatives; therefore, unused portions of drug remaining in the syringe should be discarded.

The Hulio Pen and the pre-filled syringe are available with a 29 gauge ½ inch needle and a cap that is not made with natural rubber latex.

Patients using the pre-filled syringes should be instructed to inject the full amount in the syringe, which provides 20 mg or 40 mg of Hulio, according to the directions provided in the PATIENT MEDICATION INFORMATION.

Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red or hard. See (PATIENT MEDICATION INFORMATION).

Missed Dose

Patients who miss a dose of Hulio should be advised to inject this missed dose as soon as they become aware of it, and then follow with their next scheduled dose.

5 OVERDOSAGE

The maximum tolerated dose of adalimumab injection has not been established in humans. Multiple 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.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

To help ensure the traceability of biologic products, including biosimilars, health professionals should recognise the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 5 Dosage Forms, Strengths, Composition and Packaging

Hulio (adalimumab injection) is supplied as a sterile solution for subcutaneous administration in the following packaging configurations:

Pen

Hulio Pen is available as a Pen in a carton containing two alcohol preps and two single-use Pen. Each single-use Pen contains a 1 mL pre-filled plastic syringe with a fixed 29 gauge ½ inch needle with a protective clear cap with a small inner gray cap providing 40 mg of adalimumab dissolved in 0.8 mL sterile solution (50 mg/mL). All contents of the Pen carton (including Pen, accessories and packaging) are not made with natural rubber latex.

Pre-Filled Syringe

Hulio is also available as a pre-filled syringe in a carton containing two alcohol preps and two single-use pre-filled syringe. Each single-use pre-filled syringe contains a 1 mL pre-filled plastic syringe with a fixed 29 gauge ½ inch needle with a needle cap providing 20 mg of adalimumab dissolved in 0.4 mL sterile solution (50 mg/mL). All contents of the pre-filled syringe carton (including syringe, accessories and packaging) are not made with natural rubber latex.

Hulio is also available as a pre-filled syringe in a carton containing two alcohol preps and two single-use pre-filled syringe. Each single-use pre-filled syringe contains a 1 mL pre-filled plastic syringe with a fixed 29 gauge ½ inch needle with a needle cap providing 40 mg of adalimumab dissolved in 0.8 mL sterile solution (50 mg/mL). All contents of the pre-filled syringe carton (including syringe, accessories and packaging) are not made with natural rubber latex.

7 WARNINGS AND PRECAUTIONS

Please see 3 Serious Warnings and Precautions Box at the beginning of Part I: Health Professional Information.

General

Concurrent Administration of Biologic DMARDs or TNF-Antagonists

Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocking agent, etanercept, with no added benefit compared to etanercept alone. Because of the nature of the adverse events seen with the combination of etanercept and anakinra, similar toxicities may also result from the combination of anakinra and other TNF-blocking agents. Therefore, the combination of Hulio (adalimumab injection) and anakinra is not recommended. See (9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions).

Concomitant administration of Hulio with other biologic DMARDs (e.g., anakinra and abatacept) or other TNF antagonists is not recommended based upon the increased risk for infections and other potential pharmacological interactions. See (9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions).

Switching Between Biological DMARDs

When switching from one biologic to another, patients should continue to be monitored for signs of infection.

Surgery

There is limited safety experience of surgical procedures in patients treated with adalimumab injection. The long half-life of adalimumab injection should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Hulio should be closely monitored for infections, and appropriate actions should be taken. There is limited safety experience in patients undergoing arthroplasty while receiving adalimumab injection.

Carcinogenesis and Mutagenesis

Long-term animal studies of adalimumab injection have not been conducted to evaluate the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic effects of adalimumab injection were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. See (16 NON-CLINICAL TOXICOLOGY, General Toxicology, Mutagenicity and Carcinogenicity, In vitro Genotoxicity).

Cardiovascular

Patients with Congestive Heart Failure

Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with

TNF-blockers. Cases of worsening CHF have also been observed with adalimumab injection. Adalimumab injection has not been formally studied in patients with CHF; however, in clinical trials of another TNF-blocker, a higher rate of serious CHF-related adverse events was observed. Physicians should exercise caution when using Hulio in patients who have heart failure and monitor them carefully. Hulio is contraindicated in moderate to severe heart failure (see 2 CONTRAINDICATIONS).

Gastrointestinal

Small Bowel Obstruction

Failure to respond to treatment for Crohn’s disease may indicate the presence of fixed fibrotic stricture that may require surgical treatment. Available data suggest that adalimumab injection does not worsen or cause strictures.

Hematologic

Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF-blocking agents. Adverse events of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with adalimumab injection. The causal relationship of these reports to adalimumab injection remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g., persistent fever, bruising, bleeding, pallor) while on Hulio. Discontinuation of Hulio therapy should be considered in patients with confirmed significant hematologic abnormalities.

Hypersensitivity Reactions

Allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed in approximately 1% of patients receiving adalimumab injection in clinical trials. See (8 ADVERSE REACTIONS). Reports of serious allergic reactions, including anaphylaxis, have been received following adalimumab injection administration. If an anaphylactic reaction or other serious allergic reactions occur, administration of Hulio should be discontinued immediately and appropriate therapy initiated.

The Hulio Pen and the pre-filled syringe are available with a 29 gauge ½ inch needle and a cap that is not made with natural rubber latex. See (6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).

Immune

Autoimmunity

Treatment with Hulio may result in the formation of autoantibodies and rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus- like syndrome following treatment with Hulio, treatment should be discontinued. See

(8 ADVERSE REACTIONS, 8.1 Adverse Drug Reaction Overview, Autoantibodies).

Immunosuppression

The possibility exists for TNF-blocking agents, including Hulio, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 64 patients with rheumatoid arthritis who were treated with adalimumab injection, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T- and B-cells and NK-cells, monocyte/macrophages, and neutrophils. The impact of treatment with Hulio on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood. See (7 WARNINGS AND PRECAUTIONS, Infections and Malignancies) and

(8 ADVERSE REACTIONS, 8.1 Adverse Drug Reaction Overview, Infections and

Malignancies).

Immunizations

In a randomized, double-blind, placebo-controlled study in 226 adult rheumatoid arthritis patients treated with adalimumab injection, antibody responses to concomitant pneumococcal and influenza vaccines were assessed. Protective antibody levels to the pneumococcal antigens were achieved by 86% of patients in the adalimumab injection group compared to 82% in the placebo group. A total of 37% of adalimumab injection-treated patients and 40% of placebo-treated patients achieved at least a 2-fold increase in antibody titer to at least three out of five pneumococcal antigens. In the same study, 98% of patients in the adalimumab injection group and 95% in the placebo group achieved protective antibody levels to the influenza antigens. A total of 52% of adalimumab injection-treated patients and 63% of placebo-treated patients achieved at least a 4-fold increase in antibody titer to at least two out of three influenza antigens.

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 Hulio therapy.

Patients on Hulio 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 injection.

Administration of live vaccines to infants exposed to adalimumab injection in utero is not recommended for five months following the mother’s last Hulio injection during pregnancy. See (7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations, 7.1.1 Pregnant Women).

Infections

Tuberculosis

Tuberculosis, including reactivation and new onset of tuberculosis, has been reported in patients receiving adalimumab injection. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Before initiation, during and after treatment with Hulio, patients should be evaluated for active and inactive (“latent”) tuberculosis infection with a tuberculin skin test. Treatment of latent tuberculosis infections should be initiated prior to therapy with Hulio. When tuberculin skin testing is performed for latent tuberculosis infection, an induration size of 5 mm or greater should be considered positive, even if vaccinated previously with Bacille Calmette-Guérin (BCG).

If active tuberculosis is diagnosed, Hulio therapy must not be initiated.

The possibility of undetected latent tuberculosis should be considered, especially in patients who have immigrated from or traveled to countries with a high prevalence of tuberculosis or who had close contact with a person with active tuberculosis. If latent infection is diagnosed, appropriate treatment must be started with anti-tuberculosis prophylactic treatment, in accordance with the Canadian Tuberculosis Standards and Centers for Disease Control and Prevention guidelines, before the initiation of Hulio. Use of anti-tuberculosis prophylactic treatment should also be considered before the initiation of Hulio in patients with several or significant risk factors for tuberculosis despite a negative test for tuberculosis and in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. The decision to initiate anti-tuberculosis therapy in these patients should only be made after taking into account both the risk for latent tuberculosis infection and the risks of anti-tuberculosis therapy. If necessary, consultation should occur with a physician with expertise in the treatment of tuberculosis.

Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients receiving adalimumab injection. Also, active tuberculosis has developed in patients receiving adalimumab injection whose screening for latent tuberculosis infection was negative, and some patients who have been successfully treated for active tuberculosis have redeveloped active tuberculosis while being treated with TNF-blocking agents.

Patients receiving Hulio should be monitored for signs and symptoms of active tuberculosis, particularly because tests for latent tuberculosis infection may be falsely negative. The risk of false negative tuberculin skin test results should be considered, especially in patients who are severely ill or immunocompromised. Patients should be instructed to seek medical advice if signs/symptoms suggestive of a tuberculosis infection (e.g., persistent cough, wasting/weight loss, low grade fever, listlessness) occur during or after therapy with Hulio, and physicians should monitor for signs and symptoms of active tuberculosis, including patients who are tuberculosis skin test negative.

Other Opportunistic Infections

Opportunistic infections, including invasive fungal infections, have been observed in patients receiving adalimumab injection. These infections are not consistently recognized in patients taking TNF-blockers and this has resulted in delays in appropriate treatment, sometimes resulting in fatal outcomes.

Patients taking TNF-blockers are more susceptible to serious fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis, and other opportunistic infections. Those who develop fever, malaise, weight loss, sweats, cough, dyspnea, and/or pulmonary infiltrates, or other serious systemic illness with or without concomitant shock should promptly seek medical attention for a diagnostic evaluation.

For patients who reside or travel in regions where mycoses are endemic, invasive fungal infections should be suspected if they develop the signs and symptoms of possible systemic fungal infection. Patients are at risk of histoplasmosis and other invasive fungal infections and hence clinicians should consider empiric antifungal treatment until the pathogen(s) are identified. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy. Patients who develop a severe fungal infection are also advised to stop the TNF-blocker until infections are controlled.

Hepatitis B Virus (HBV) Reactivation

Very rare cases of hepatitis B virus (HBV) reactivation have been associated with anti-TNF therapy. Clinically active HBV infection occurred following a latency period ranging from 3 to 20 months after initiation of therapy. In the majority of cases, patients were also taking other immunosuppressive drugs, including methotrexate, azathioprine, and/or corticosteroids. Hence, establishing a causal relationship to anti-TNF agents is confounded by the presence of these other medications. Where outcome information was provided, most patients were reported to have improved after antiviral treatment and/or discontinuation of the anti-TNF agent. However, fatal outcomes have also occurred in reported cases. Patients at risk of HBV infection should be evaluated for prior evidence of HBV infection before initiating anti-TNF therapy. Those identified as chronic carriers (i.e., surface antigen positive) should be monitored for signs and symptoms of active HBV infection throughout the course of therapy and for several months following discontinuation of therapy. Reactivation of HBV is not unique to anti-TNF-alpha agents and has been reported with other immunosuppressive drugs.

Malignancies

In the controlled portions of clinical trials of some TNF-blocking agents, including adalimumab injection, more cases of malignancies have been observed among patients receiving those TNF-blockers compared to control patients.

In the controlled and uncontrolled open-label portions of clinical trials of adalimumab injection, the more frequently observed malignancies, other than lymphoma and non-melanoma skin cancer, were breast, colon, prostate, lung, and melanoma.

Cases of acute and chronic leukemia have been reported in association with post-marketing TNF-blocker use in rheumatoid arthritis and other indications. Patients with rheumatoid arthritis may be at a higher risk (up to 2-fold) than the general population for the development of leukemia, even in the absence of TNF-blocking therapy.

Malignancies in Pediatric Patients and Young Adults

Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (i.e., including adalimumab injection). Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous post-marketing reports.

Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF-blockers including adalimumab injection. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF-blocker cases have occurred in patients with Crohn’s disease or UC and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-MPconcomitantly with a TNF-blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF-blocker or a TNF-blocker in combination with these other immunosuppressants. The potential risk with the combination of azathioprine or 6-mercaptopurine and Hulio should be carefully considered.

No malignancies were observed in the indicated pediatric patient population with Crohn’s disease treated with adalimumab injection (n=102) for 52 weeks in a clinical trial.

No malignancies were observed in pediatric patients aged 3 to 17 years with active JIA-associated chronic non-infectious anterior uveitis who were treated with adalimumab injection (n=90, randomized 2:1 to adalimumab injection:placebo) for up to18 months in a clinical trial.

No malignancies were observed in 93 pediatric patients with an exposure of up to 52 weeks during an adalimumab injection trial in pediatric patients with UC.

Treatment-emergent malignancies occurred in 2/480 adalimumab injection-treated UC patients in the double-blind controlled portion of two clinical trials (range of treatment duration from Weeks 0 to 52). The malignancies were squamous cell carcinoma and gastric cancer. Gastric cancer was considered serious and the patient discontinued as a result.

With current data it is not known if adalimumab injection treatment influences the risk for developing dysplasia or colon cancer. All patients with ulcerative colitis who are at risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations.

Lymphoma

In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving TNF-blockers compared to control patients.

However, for adalimumab injection, the occurrence of lymphoma was rare, and the follow-up period of placebo patients was shorter than for patients receiving TNF-antagonist therapy. The size of the control group and limited duration of the controlled portions of studies precludes the ability to draw firm conclusions. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation.

In combining the controlled and uncontrolled open-label portions of the 23 clinical trials in adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, psoriasis, and uveitis, with a median duration of approximately 2.4 years, including 8764 patients and 27,196 patient-years of therapy, the observed rate of lymphomas (95% CI) is 1.2 [0.9, 1.7] per 1000 patient-years. This is approximately 3-fold higher than expected in the general population.

During the controlled and open-label periods of 14 trials with adalimumab injection, the overall standard incidence ratio (SIR) of malignancies was 0.99 [95% confidence interval (CI), 0.81 to 1.20]. With current knowledge in this area, a possible risk for development of lymphomas or other malignancies in patients treated with a TNF-antagonist cannot be excluded.

No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving adalimumab injection. Additional caution should be exercised when considering Hulio treatment in these patients.

Non-Lymphoma Malignancy

During the controlled portions of 21 adalimumab injection trials in adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, psoriasis, and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% CI) of 6.9 (4.4, 10.6) per 1,000 patient-years among 5196 adalimumab injection-treated patients versus a rate of 6.4 (3.5, 11.9) per 1,000 patient-years among 3347 control patients (median duration of treatment of 4.0 months for adalimumab injection-treated patients and 3.9 months for control-treated patients).

During the controlled portions of 21 adalimumab injection rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, psoriasis, and uveitis trials, the rate (95% CI) of non-melanoma skin cancers was 8.9 (6.1, 13.1) per 1,000 patient-years among adalimumab injection-treated patients and 3.2 (1.3, 7.7) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% CI) of 2.7 (1.4, 5.5) per 1,000 patient-years among adalimumab injection-treated patients and 0.6 (0.1, 4.6) per 1,000 patient-years among control patients. The rate (95% CI) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among adalimumab injection-treated patients and 0.6 (0.1, 4.6) per 1,000 patient-years among control patients.

The observed rate of malignancies, other than lymphoma and non-melanoma skin cancers, is approximately (95% CI) 8.5 (7.4, 9.7) per 1,000 patient years in the controlled portion of clinical trials and in ongoing and completed open-label extension studies. The observed rate of non-melanoma skin cancers is (95% CI) approximately 9.6 (8.5, 10.9) per 1,000 patient years, and the observed rate of lymphomas is (95% CI) approximately 1.3 (0.9, 1.8) per 1,000 patient years. The median duration of these studies is approximately 3.3 years and included 6276 adult patients who were on adalimumab injection for at least one year or who developed a malignancy within a year of starting therapy, representing over 26,044 patient years of therapy.

All patients, and in particular psoriasis patients with a medical history of extensive immunosuppressant therapy or psoriasis patients with a history of Psoralen Ultra-Violet A (PUVA) treatment should be examined for the presence of non-melanoma skin cancer prior to and during treatment with Hulio.

Monitoring and Laboratory Tests

There is no known interference between adalimumab injection and laboratory tests.

Neurologic

Use of TNF-blocking agents, including adalimumab injection, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease, including multiple sclerosis, and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of Hulio in patients with pre-existing or recent onset central nervous system demyelinating disorders; discontinuation of Hulio should be considered if any of these disorders develop.

There is a known association between intermediate uveitis and central demyelinating disorders. Neurologic evaluation should be performed in patients with non-infectious intermediate uveitis prior to the initiation of Hulio therapy to assess for pre-existing central demyelinating disorders.

Special Populations

7.1.1 Pregnant Women

The extent of exposure in pregnancy during clinical trials is very limited, consisting only of individual cases.

An embryo-fetal perinatal developmental toxicity study has been performed in cynomolgus monkeys at dosages up to 100 mg/kg (266 times human area under the curve (AUC) when given 40 mg adalimumab injection subcutaneously with methotrexate every week, or 373 times human AUC when given 40 mg adalimumab injection subcutaneously without MTX) and has revealed no evidence of harm to the fetuses due to adalimumab injection. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, Hulio should be used during pregnancy only if clearly needed.

In a prospective cohort pregnancy exposure registry, conducted by the Organization of Teratology Information Specialists (OTIS)/MotherToBaby in the U.S. and Canada between 2004 and 2016, the risk of major birth defects in live-born infants was compared in 69 women with RA and 152 women with CD treated with adalimumab at least during the first trimester with 74 women with RA and 32 women with CD not treated with adalimumab during pregnancy. 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.

No pattern of major birth defects was observed. This study cannot reliably establish whether there is an association between adalimumab and the risk for 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.

Adalimumab injection may cross the placenta into the serum of infants born to women treated with adalimumab injection during pregnancy. Consequently, these infants may be at increased risk for infection. Administration of live vaccines to infants exposed to adalimumab injection in utero is not recommended for five months following the mother’s last adalimumab injection during pregnancy.

Labor and Delivery

There are no known effects of adalimumab injection on labor or delivery.

7.1.2 Breast-feeding

Limited information from case reports in the published literature indicates the presence of adalimumab in human milk at concentrations of 0.1% to 1% of the maternal serum level. Published data suggest that the systemic exposure of adalimumab to a breastfed infant is expected to be low because adalimumab is a large molecule and is degraded in the gastrointestinal tract. However, the effects of local exposure in the gastrointestinal tract are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for adalimumab and any potential adverse effects on the breastfed child from adalimumab or from the underlying maternal condition.

7.1.3 Pediatrics

Pediatrics (< 18 years of age)

Polyarticular Juvenile Idiopathic Arthritis

The efficacy and safety of adalimumab injection have been studied in pediatric patients aged 4 to 17 years (n=171) and 2 to 4 years (n=32). No overall differences were observed in the efficacy and safety between the two age groups. Adalimumab injection has not been studied in pediatric patients with polyarticular JIA less than 2 years of age or in pediatric patients with a weight below 10 kg.

Pediatric Crohn’s Disease

The majority (102/192) of pediatric patients with Crohn’s disease studied were 13 to 17 years of age weighing ≥ 40 kg.

Pediatric Uveitis

The efficacy and safety of adalimumab injection have been studied in pediatric patients with uveitis aged 2 to 17 years (n=90, randomized 2:1 to adalimumab injection:placebo). Very limited data are available for pediatric patients with uveitis between 2 and < 3 years of age. Serious adverse events were more frequent in children 4 years of age and younger.

Pediatric Ulcerative Colitis

The efficacy and safety of adalimumab injection have been studied in pediatric patients with ulcerative colitis aged 5 to 17 years (N = 93).

7.1.4 Geriatrics

A total of 519 rheumatoid arthritis patients 65 years of age and older, including 107 patients 75 years and older, received adalimumab injection in clinical Studies DE009, DE011, DE019 and DE031. No overall differences in effectiveness were observed between these patients and younger patients. The frequency of serious infection and malignancy among adalimumab injection-treated patients over age 65 was higher than for those under the age of 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.

8 ADVERSE REACTIONS

The adverse drug reaction profiles reported in clinical studies that compared Hulio to the reference biologic drug were comparable. The description of adverse reactions in this section is based on clinical experience with the reference biologic drug.

Adverse Reaction Overview

The most serious adverse reactions were (see 7 WARNINGS AND PRECAUTIONS)):

• serious infections
• neurologic events
• malignancies

The most common adverse reaction in rheumatoid arthritis patients treated with adalimumab injection was injection site reactions. In controlled trials for rheumatoid arthritis, polyarticular JIA, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn’s disease, adult and pediatric ulcerative colitis, adult hidradenitis suppurativa, psoriasis, and adult uveitis, 13% of patients treated with adalimumab injection developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 7% of patients receiving control treatment. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.

The proportion of rheumatoid arthritis patients who discontinued treatment due to adverse events during the double-blind, placebo-controlled portion of rheumatoid arthritis Studies DE009, DE011, DE019 and DE031 was 7.0% for patients taking adalimumab injection, and 4.0% for placebo-treated patients. The most common adverse events leading to discontinuation of adalimumab injection were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).

Among patients with rheumatoid arthritis in placebo-controlled studies, deaths occurred in 8 of

1,380 (0.58%) adalimumab injection-treated patients compared to 1 of 690 (0.14%) placebo-treated patients. The rate of deaths in both treatment arms is less than expected in the normal population with a standard mortality ratio (SMR) of 0.87 (95% CI, 0.38, 1.72) in the adalimumab injection group and 0.25 (95% CI, 0.00, 1.37) in the placebo group.

In Study DE019, 553 patients were exposed to at least one dose of adalimumab injection and 202 patients completed 10 years of study. A total of 24 patients died during the 10-year exposure period to adalimumab injection (4 during the double-blind phase, 14 during the open-label extension phase and an additional 6 after study drug termination). Among the treatment-emergent deaths, the most common reasons were: 4 sepsis, 3 cancers and 3 respiratory system events. However, the total number of deaths was not higher than that calculated according to age adjusted Standardized Mortality Rates.

Of the 553 patients, 23.0% discontinued due to an adverse event. The most common adverse events associated with discontinuation of study drug were pneumonia and breast cancer (n = 5 each). Fatigue, pneumonia, cellulitis, and histoplasmosis (n = 3 each) were the most common treatment-related adverse events leading to discontinuation of study drug.

In total, 49% of patients treated with adalimumab injection experienced a serious adverse event; 15.7% were considered at least possibly related to study drug. The most common serious adverse events were rheumatoid arthritis disease flare (n = 35, 6.3%), pneumonia (n = 26, 4.7%) and myocardial infarction (n = 10, 1.8%); of these, only pneumonia was considered to be at least possibly related to study drug.

The most frequently reported treatment-emergent adverse events were infections (total n = 448, 81%; serious n = 85, 15.4%) and injection site reactions (n = 115, 20.8%).

Adverse events of special interest among the 553 patients included 35 patients with malignancies other than non-melanoma skin cancer (including 5 cases of lymphoma); and 3 patients with tuberculosis. Serious adverse events of special interest included 5 patients each with pulmonary embolism and diverticulitis; 2 patients with multiple sclerosis; and 1 patient with hypersensitivity reaction.

Adalimumab injection has also been studied in 542 patients with early rheumatoid arthritis (disease duration less than three years) who were methotrexate naïve (Study DE013). No new safety signals were seen in this patient population compared to the safety profile seen in adalimumab injection Studies DE009, DE011, DE019 and DE031. In this study, deaths occurred in 5 of 542 (0.92%) adalimumab injection-treated patients compared to 1 of 257 (0.39%) methotrexate-treated patients. The rate of deaths in both treatment arms is less than expected in the normal population with a standard mortality ratio (SMR) of 0.57 (95% CI, 0.18, 1.32) in the adalimumab injection group and 0.22 (95% CI, 0.00, 1.23) in the methotrexate group.

Adalimumab injection has also been studied in 395 patients with psoriatic arthritis in two placebo-controlled studies and in an open-label extension study, in 393 patients with ankylosing spondylitis in two placebo-controlled studies and in over 1,500 patients with Crohn’s disease in five placebo-controlled and two open-label extension studies. The safety profile for patients with psoriatic arthritis treated with adalimumab injection 40 mg every other week was similar to the safety profile seen in patients with rheumatoid arthritis, adalimumab injection Studies DE009,

DE011, DE019, DE031 and DE013. During the controlled period of the psoriatic arthritis studies, no deaths occurred in the adalimumab injection-treated or placebo-treated patients. During the psoriatic arthritis open-label study, two deaths occurred in 382 patients with 795.7 patient-years of exposure. The rate of deaths is less than expected in the normal population with a standard mortality ratio (SMR) of 0.39 (95% CI, 0.04, 1.43). Among patients enrolled in the psoriasis open-label study, 5 deaths occurred in 1,468 patients with 4,068.6 patient-years of exposure.

Adalimumab injection has also been studied in 1,010 adult patients with ulcerative colitis (UC) in two randomized, double-blind, placebo-controlled studies (M06-826, 8 weeks and M06-827, 52 weeks) and an open-label extension study. No new safety signals were seen in the adult ulcerative colitis patient population. During the controlled period of the adult ulcerative colitis studies, no deaths occurred in the adalimumab injection-treated or placebo-treated patients. In the overall adalimumab injection adult ulcerative colitis development program of 1,010 patients with 2007.4 patient years of exposure (622 patients were treated for >1 year), 2 treatment-emergent deaths occurred during the long-term open-label extension study (cardio-respiratory arrest and right ventricular failure). There were no new safety signals compared to the known safety profile of adalimumab injection in the double-blind controlled portion of adult ulcerative colitis studies.

Adalimumab injection has also been studied in 727 adult patients with hidradenitis suppurativa (HS) in three randomized, double-blind, placebo-controlled studies and an open-label extension study. No deaths were reported during the placebo-control periods. In the overall adalimumab injection HS development program of 727 patients with 635.7 patient years of exposure (281patients were treated for >1 year), 2 treatment-emergent deaths occurred (cardio-respiratory arrest and autoimmune pancreatitis). No new safety signals were seen in the HS adult patient population.

Adalimumab injection has also been studied in 464 adult patients with uveitis in two randomized, double-masked, placebo-controlled studies (M10-877 and M10-880) and an open-label extension study (M11-327). No new safety signals for adalimumab injection were identified in the uveitis adult patient population. In the overall adalimumab injection adult uveitis development program of 464 adalimumab injection adult patients with 1308.2 patient-years of exposure, 6 treatment-emergent deaths were reported (chronic renal failure, aortic dissection/acute tamponade, B-cell lymphoma, brain abscess, pancreatic carcinoma, and accident). Two deaths occurred during the controlled period of the adult uveitis studies and 4 during the open-label extension study.

Autoantibodies

Patients had serum samples tested for autoantibodies at multiple time points in Studies DE009, DE011, DE019, DE031 and DE013. In those rheumatoid arthritis controlled trials, 11.9% of patients treated with adalimumab injection and 8.1% of placebo- or active control-treated patients who had negative baseline antinuclear antibody (ANA) titers, developed positive titers at Week 24. Two patients out of 3441 treated with adalimumab injection developed clinical signs suggestive of new onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with adalimumab injection on the development of autoimmune diseases is unknown.

Immunogenicity

Formation of anti-adalimumab injection antibodies is associated with increased clearance and reduced efficacy of adalimumab injection. There is no apparent correlation between the presence of anti-adalimumab injection antibodies and adverse events.

Pediatrics

In clinical trials with adalimumab injection therapy for polyarticular JIA, the proportion of patients achieving PedACR response was lower in anti-adalimumab injection antibody (AAA)-positive patients compared with AAA-negative patients.

In patients with polyarticular JIA who were 4 to 17 years (Study DE038), anti-adalimumab injection antibodies were identified in 27/171 subjects (15.8%) treated with adalimumab injection. In patients not given concomitant MTX, the incidence was 22/86 (25.6%), compared to 5/85 (5.9%) when adalimumab injection was used as add-on to MTX. In patients with polyarticular JIA who were 2 to <4 years of age or 4 years of age and older weighing <15 kg (Study M10-444), anti-adalimumab injection antibodies were identified in 7% (1/15) of patients, and the one patient was receiving concomitant MTX.

In patients 13 to 17 years of age with severely active Crohn’s disease, anti-adalimumab injection antibodies were identified in 3.5% (4/114) of patients receiving adalimumab injection.

In patients 5 to 17 years of age with moderately to severely active ulcerative colitis, anti-adalimumab antibodies were identified in 3% (3/100) of patients receiving adalimumab injection.

Adults

Rheumatoid arthritis patients in Studies DE009, DE011, and DE019 were tested at multiple time points for antibodies to adalimumab injection during the 6- to 12-month period. Approximately 5% (58/1062) of adult rheumatoid arthritis patients receiving adalimumab injection developed low-titer antibodies to adalimumab injection at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant MTX had a lower rate of antibody development than patients on adalimumab injection monotherapy (1% versus 12%). With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the American College of Rheumatology (ACR 20) response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of adalimumab injection is unknown.

In patients with psoriatic arthritis, anti-adalimumab injection antibodies were identified in 38/376 patients (10%) treated with adalimumab injection. In patients not given concomitant methotrexate, the incidence was 13.5% (24/178 patients), compared to 7% (14/198 patients) when adalimumab injection was used as add-on to methotrexate.

In patients with ankylosing spondylitis, anti-adalimumab injection antibodies were identified in 17/204 patients (8.3%) treated with adalimumab injection. In patients not given concomitant methotrexate, the incidence was 16/185 (8.6%), compared to 1/19 (5.3%) when adalimumab injection was used as add-on to methotrexate.

In patients with Crohn’s disease, anti-adalimumab injection antibodies were identified in 2.6% (7/269) of patients receiving adalimumab injection.

In patients with ulcerative colitis, anti-adalimumab injection antibodies were identified in 5.0% (19/379) of patients receiving adalimumab injection. The clinical significance of this is unknown.

In patients with moderate to severe HS, anti-adalimumab injection antibodies were identified in 10/99 patients (10.1%) treated with adalimumab injection.

In patients with psoriasis, anti-adalimumab injection antibodies were identified in 77/920 patients (8.4%) treated with adalimumab injection monotherapy.

In patients with plaque psoriasis, the rate of antibody development with adalimumab injection monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab injection could be detected only when serum adalimumab injection levels were < 2 mcg/mL. Among these patients whose serum adalimumab injection levels were < 2 mcg/mL (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In patients with plaque psoriasis on long-term adalimumab injection monotherapy who participated in a withdrawal and retreatment study and whose serum adalimumab injection levels were < 2 mcg/mL (approximately 12% of total patients studied), the immunogenicity rate was 16%; the overall rate of antibody development prior to withdrawal was 1.9%, and 2.3% after retreatment.

In patients with non-infectious uveitis, anti-adalimumab injection antibodies were identified in 4.8% (12/249) of patients treated with adalimumab injection. However, due to the limitation of the assay conditions, antibodies to adalimumab injection could be detected only when serum adalimumab injection levels were < 2 mcg/mL. Among the patients whose serum adalimumab injection levels were < 2 mcg/mL (approximately 23% of total patients studied), the immunogenicity rate was 21.1%.

The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab injection in an enzyme-linked immunosorbent assay (ELISA),and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to adalimumab injection with the incidence of antibodies to other products may be misleading.

Infections

Pediatrics

In a controlled trial for polyarticular JIA (Study DE038), the rate of adverse events of infections was 238.5 per 100 patient-years in the adalimumab injection-treated JIA patients compared to 269.5 per 100 patient-years in control (placebo) treated patients, and the rate of serious infections was 6.1 per 100 patient-years in the adalimumab injection-treated JIA patients compared to 0 events in control (placebo) treated patients.

In an open-label trial for polyarticular JIA (Study M10-444), the rate of adverse events of infections was 206.2 per 100 patient-years while receiving adalimumab injection and the rate of serious infections was 6.7 per 100 patient-years while receiving adalimumab injection.

In a randomized double-blind trial (M06-806) for the indicated pediatric patient population with Crohn’s disease, the rate of infections was 161.4 per 100 patient-years for the High-Dose group and 225.9 per 100 patient-years for the Low-Dose group. The rates of serious infections were 9.5 per 100 patient-years for the High-Dose group and 3.7 per 100 patient-years for the Low-Dose group. The rates of infections were 55.8% (29/52) and 52.0% (26/50) for High-Dose and Low-Dose groups, respectively. The rates of serious infections were 5.8% (3/52) and 2.0% (1/50) for High-Dose and Low-Dose groups, respectively and included anal abscess, gastroenteritis, and histoplasmosis disseminated in the High-Dose group and Bartholin’s abscess in the Low-Dose group.

In a randomized controlled trial (SYCAMORE) for pediatric patients with active JIA-associated chronic non-infectious anterior uveitis, the rate of adverse events of infections was 236.4 per 100 patient-years (77%) for the adalimumab injection-treated group compared to 164.5 per 100 patient years (40%) for the control (placebo) group. The rate of serious infections was 17.1 per 100 patient-years (13%) in the adalimumab injection-treated uveitis patients compared to 0 events in control (placebo) treated patients.

In a randomized controlled trial for pediatric patients with moderate to severe ulcerative colitis, the rate of adalimumab injection treatment-emergent adverse events of infections was 117.9 per 100 patient-years of overall adalimumab injection exposure in the trial, occurring in 47.3% of patients. The rate of adalimumab injection treatment-emergent serious infections was 7.7 per 100 patient-years of overall adalimumab injection exposure, occurring in 5.4% of patients.

Adults

In 23 controlled trials for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, psoriasis, and uveitis the rate of infection was 147.4 per 100 patient-years in 5630 adalimumab injection-treated patients and 142.7 per 100 patient-years in 3587 control-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on adalimumab injection after the infection resolved.

The incidence of serious infections was 3.4 per 100 patient-years in adalimumab injection-treated patients and 3.2 per 100 patient-years in placebo and active control-treated patients.

In controlled and open-label studies with adalimumab injection, serious infections such as legionellosis (0.02 per 100 patient-years) have been reported. No cases of listeriosis have been reported and therefore, an estimated rate of 0.01 per 100 patient-years was calculated. Both infections have been reported spontaneously during the post-marketing period.

In controlled and open-label studies with adalimumab injection, serious infections (including fatal infections, which occurred rarely) have been reported, which include reports of tuberculosis (including miliary and extra-pulmonary locations) and invasive opportunistic infections (e.g., disseminated histoplasmosis, pneumocystis carinii pneumonia, and aspergillosis). Most of the cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease.

In the double-blind controlled portion of two clinical trials with adalimumab injection in patients with UC, serious infections occurred in 4/480 patients treated with adalimumab injection; they were appendicitis (n=1), anal abscess (n=1), catheter sepsis (n=1) and salmonellosis (n=1). Serious infections occurred in 8 placebo patients. Opportunistic infections occurred in 7/480 patients treated with adalimumab injection; they were candidiasis (n=3), oesophageal candidiasis (n=1) and oral candidiasis (n=3). Opportunistic infections occurred in 3 placebo patients.

In the double-blind controlled portion of three clinical trials with adalimumab injection in patients with HS, serious infections occurred in 4/419 patients treated with adalimumab injection; they were Escherichia infection (n=1), genital infection bacterial (n=1), infection (n=1), pilonidal cyst (n=1) and pyelonephritis (n=1). Serious infections occurred in 2/366 placebo patients.

In the double-masked controlled portion of two clinical trials with adalimumab injection in patients with uveitis, serious infections occurred in 7/250 (2.8%) patients treated with adalimumab injection; they were pneumonia (n = 2), and 1 each of bronchitis, pilonidal cyst, pneumonia Legionella, tuberculosis, upper respiratory tract infection and urinary tract infection. Serious infections occurred in 4/250 (1.6%) placebo patients. Opportunistic infections occurred in 7/250 patients treated with adalimumab injection; they were active tuberculosis (n = 1), latent tuberculosis (n = 4) and oral candidiasis (n = 2). Latent tuberculosis occurred in 1 placebo-treated patient. In the open-label extension study (M11-327), the exposure-adjusted incidence rate of serious infections was increased in patients who received concomitant systemic corticosteroids and immunosuppressants in addition to treatment with adalimumab injection.

Injection Site Reactions

In controlled trials in adults and children, 13% of patients treated with adalimumab injection developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 7% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.

Based on two Phase II clinical studies (n=60 and n=62), injection site pain immediately after dosing of adalimumab injection 40 mg/0.4 mL was reduced by a median of 84% in comparison with adalimumab injection 40 mg/0.8 mL, based on mean score of visual analogue scale (VAS), in patients with moderately to severely active rheumatoid arthritis who were either biologic-naïve or current users of adalimumab injection 40 mg/0.8 mL that rated their average injection site pain as at least 3 cm (on a 0-10 cm VAS).

Malignancies

More cases of malignancy have been observed in adalimumab injection-treated patients compared to control-treated patients in clinical trials. See (7 WARNINGS AND PRECAUTIONS, Malignancies).

Neurologic Events

In 21 controlled trials for adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, and psoriasis the rate of new onset or exacerbation of central nervous system demyelinating disease (including multiple sclerosis and optic neuritis) and peripheral demyelinating disease (including Guillain-Barre syndrome) was less than 0.4 per 1000 patient-years in 5,380 adalimumab injection-treated patients and 0.7 per 1000 patient-years in 3,337 control-treated patients. In controlled and open-label studies for adult patients treated with adalimumab injection, the rate (95% CI) of demyelinating diseases was 0.7 (0.4, 1.1) per 1000 patient-years. Demyelinating diseases were reported spontaneously during the post-marketing period.

In the double-masked controlled portion of two clinical trials with adalimumab injection in adult patients with uveitis, 1 (0.4%) case of multiple sclerosis was reported in 250 patients treated with adalimumab injection. In the adult uveitis development program including the open-label study, the rate (95% CI) of demyelinating diseases (i.e., multiple sclerosis and optic neuritis) was 5.4 (2.2, 11.0) per 1000 patient-years.

See (7 WARNINGS AND PRECAUTIONS, Neurologic Events).

Psoriasis: New Onset and Worsening

Cases of new onset psoriasis, including pustular psoriasis and palmoplantar psoriasis, and cases of worsening of pre-existing psoriasis have been reported with the use of TNF-blockers, including adalimumab injection. Many of these patients were taking concomitant immunosuppressants (e.g., methotrexate, corticosteroids). Some of these patients required hospitalization. Most patients had improvement of their psoriasis following discontinuation of their TNF-blocker. Some patients have had recurrences of the psoriasis when they were re-challenged with a different TNF-blocker. Discontinuation of adalimumab injection should be considered for severe cases and those that do not improve or that worsen despite topical treatments.

Liver Enzyme Elevations

In controlled Phase 3 trials of adalimumab injection (40 mg subcutaneous every other week), in patients with RA and PsA with a control period duration ranging from 4 to 104 weeks, alanine aminotransferase (ALT) elevations ≥ 3 x ULN occurred in 3.7% of adalimumab injection-treated patients and 1.6% of control-treated patients. Since many of the patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between adalimumab injection and the liver enzyme elevations is not clear.

In controlled Phase 3 trials of adalimumab injection (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week), in adult patients with Crohn’s disease with a control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of adalimumab injection-treated patients and 0.9% of control-treated patients.

In controlled Phase 3 trials of adalimumab injection (initial doses of 160 mg and 80 mg on Days 1 and 15, respectively, followed by 40 mg every other week), in adult patients with UC with a control period duration ranging from 1 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 1.5% of adalimumab injection-treated patients and 1.0% of control-treated patients. The incidence of ALT elevations ≥5 x ULN was 0.5% in adalimumab injection-treated patients and 0.2% in control-treated patients.

In controlled Phase 3 trials of adalimumab injection (initial dose of 80 mg then 40 mg every other week), in patients with plaque psoriasis with a control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of adalimumab injection-treated patients and 1.8% of control-treated patients.

In controlled Phase 3 trials of adalimumab injection (40 mg every other week), in patients with ankylosing spondylitis with a control period of 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 2.4% of adalimumab injection-treated patients and 0.7% of control-treated patients.

In controlled trials of adalimumab injection (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in adult patients with hidradenitis suppurativa with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of adalimumab injection-treated patients and 0.6% of control-treated patients.

In controlled Phase 3 trials of adalimumab injection (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in patients with adult uveitis with an exposure of 165.4 patient-years and 119.8 patient-years in adalimumab injection-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of adalimumab injection-treated patients and 2.4% of control-treated patients.

In the controlled Phase 3 trial of adalimumab injection in patients with pediatric ulcerative colitis (N = 93) which evaluated efficacy and safety of a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every other week (N = 31) and a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every week (N = 32), following body weight adjusted induction dosing of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N = 63), or an induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0, placebo at Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N = 30), ALT elevations ≥ 3 X ULN occurred in 1.1% (1/93) of patients.

Across all adult indications in clinical trials, patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved on continued treatment. However, there have been very rare post-marketing reports of severe hepatic reactions including liver failure as well as less severe liver disorders that may precede liver failure, such as hepatitis including autoimmune hepatitis, in patients receiving TNF blockers, including adalimumab injection. The causal relationship to adalimumab injection treatment remains unclear.

Concurrent treatment with azathioprine/6-mercaptopurine

In adult Crohn’s disease studies, higher incidences of malignant and serious infection-related adverse events were seen with the combination of adalimumab injection and azathioprine/6-mercaptopurine compared with adalimumab injection alone.

Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Rheumatoid Arthritis

Description of Data Sources

The data described below reflect exposure to adalimumab injection in 3,046 patients, including more than 2,000 patients exposed for six months, and more than 1,500 exposed for more than one year (Studies DE009, DE011, DE019, DE031 and DE013). Adalimumab injection was studied in placebo-controlled trials and in long-term follow-up studies for up to 60 months duration in patients with moderately to severely active rheumatoid arthritis who had failed previous DMARD therapy; the mean age was 54 years, 77% were female and 91% Caucasian

(Studies DE009, DE011, DE019, DE031). A further study (Study DE013) was in patients with recently diagnosed rheumatoid arthritis who had not previously been treated with methotrexate. Most patients received adalimumab injection 40 mg every other week.

Relative Frequency of Adverse Drug Reactions

Table 6 summarizes adverse drug reactions reported at a rate of at least 1% in patients treated with adalimumab injection 40 mg every other week, as well as all doses of adalimumab injection tested, compared to placebo or methotrexate (Study DE013). Adverse reaction rates in patients treated with adalimumab injection 40 mg weekly were similar to rates in patients treated with adalimumab injection every other week. In Study DE019, the types and frequencies of adverse drug reactions in the 10-year open-label extension were similar to those observed in the one-year double-blind portion.

Table 6. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During the Control Period in Rheumatoid Arthritis Studies (Studies DE009, DE011, DE019, DE031, DE013)

Definition(s): s.c. = subcutaneous; eow = every other week

Psoriatic Arthritis

Table 7 summarizes adverse drug reactions reported in placebo-controlled and open-label studies at a rate of at least 1% in psoriatic arthritis patients treated with adalimumab injection 40 mg every other week.

Table 7. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During the Control and Open-Label Periods in Psoriatic Arthritis Studies (Studies M02-518, M02-570, and M02-537)

Definition(s): s.c. = subcutaneous; eow = every other week

Ankylosing Spondylitis

Adalimumab injection has been studied in 393 patients with ankylosing spondylitis in two placebo-controlled studies. The safety profile for patients with ankylosing spondylitis treated with adalimumab injection 40 mg every other week was similar to the safety profile seen in patients with rheumatoid arthritis, adalimumab injection Studies DE009, DE011, DE019, and DE031. Table 8 summarizes adverse drug reactions reported at a rate of at least 1% in ankylosing spondylitis patients treated with adalimumab injection 40 mg every other week compared to placebo.

Table 8. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During the Control Period in Ankylosing Spondylitis Studies (Studies M03-607 and M03-606)

Definition(s): s.c. = subcutaneous; eow = every other week

Crohn’s Disease

Adalimumab injection has been studied in over 1,500 patients with Crohn’s disease in five placebo-controlled and two open-label extension studies. The safety profile for patients with Crohn’s disease treated with adalimumab injection was similar to the safety profile seen in patients with rheumatoid arthritis including the safety profile for patients in placebo-controlled Study M05-769. No new safety signals occurred during the open-label long-term studies with adalimumab injection exposure up to five years. The safety profile of adalimumab injection in Crohn’s disease remains unaltered.

Table 9 and Table 10 summarize adverse drug reactions reported at a rate of at least 1% in Crohn’s disease patients treated with adalimumab injection in induction and maintenance studies, respectively.

Table 9. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During Administration of Induction Study Medications in Crohn’s Disease Studies (Studies M02-403 and M04-691)

Table 10. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During Administration of Blinded Study Maintenance Medications in Crohn’s Disease Studies (Studies M02-404 and M02-433)

Definition(s): s.c. = subcutaneous; ew = every week; eow = every other week

Ulcerative Colitis

Adalimumab injection has been studied in 1,010 adult patients with ulcerative colitis (UC) in two placebo-controlled studies and one open-label extension study. The safety profile for adult patients with UC treated with adalimumab injection was similar to the safety profile observed in patients with Crohn’s Disease.

Table 11 and Table 12 summarize adverse drug reactions reported at a rate of at least 1% in adult ulcerative colitis disease patients treated with adalimumab injection during induction and maintenance periods, respectively.

Table 11. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During Administration of Induction Study Medications in Adult Ulcerative Colitis Studies (Studies M06-826 and M06-827)

Table 12. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During the Double-blind Induction and Maintenance Periods of Adult Ulcerative Colitis Studies (Studies M06-826 and M06-827)

Serious adverse events resulting in hospitalizations were reported by 18% (67/379) in the adalimumab injection-treated patients compared to 26% (56/214) in the placebo group adjusted for patient years at risk.

During the double-blind controlled clinical trials, the most common (≥5%) adverse drug reactions in adult subjects receiving adalimumab injection 160/80 during induction were ulcerative colitis (n=35, 7.3%) and nasopharyngitis (n=26, 5.4%), and during maintenance were ulcerative colitis (n=38, 16.2 %), nasopharyngitis (n=26, 11.1%), abdominal pain (n=17, 7.3%), and arthralgia (n=17, 7.3%). There were 2/480 adalimumab injection-treated patients who experienced severe leukopenia of which one case was serious. The patient with serious leukopenia, which was considered secondary to 6-MP, had an associated viral infection.

During the double-blind controlled clinical trials, the most common serious adverse event occurring in >1 patient more often in the adalimumab injection-treated patients compared to placebo when adjusted for exposure was deep vein thrombosis reported in 2 patients (4%, 1.12 events/100 patient-years).

During the double-blind controlled clinical trials, severe adverse events reported in >1 patient occurring more often in the adalimumab injection-treated patients compared to placebo when adjusted for exposure were deep vein thrombosis reported in 3 patients (0.6%, 1.68 events/100 patient-years), and constipation, leukopenia and fatigue, which were reported in 2 patients (0.4%, 1.12 events/100 patients-years).

The most common adverse event associated with discontinuation reported in >1 subject during induction and maintenance was ulcerative colitis [n=18 (3.8%) and n=8 (3.4%), respectively].

Hidradenitis Suppurativa

Adalimumab injection has been studied in 727 adult patients with hidradenitis suppurativa in three placebo- controlled studies and one open-label extension study.

Table 13 summarizes adverse drug reactions reported at a rate of at least 1% in hidradenitis suppurativa patients treated with adalimumab injection during the placebo-controlled portion of the studies.

Table 13. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug in Controlled Hidradenitis Suppurativa Studies (Studies M10-467, M11-313 and M11-810)

Psoriasis

Adalimumab injection has been studied in 1,696 patients with psoriasis in placebo-controlled and open-label extension studies. The safety profile for patients with psoriasis treated with adalimumab injection was similar to the safety profile seen in patients with rheumatoid arthritis. Safety results of the long-term open-label study are consistent with the known safety profile of adalimumab injection in other psoriasis studies. Table 14 summarizes adverse drug reactions reported at a rate of at least 1% in psoriasis patients treated with an initial dose of adalimumab injection 80 mg followed by adalimumab injection 40 mg every other week compared to placebo or methotrexate.

Table 14. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events Possibly or Probably Related to Study Drug in Controlled Psoriasis Studies (Studies M03-656, M04-716 and M02-528)

Definition(s): s.c. = subcutaneous; eow = every other week; MTX = methotrexate

Uveitis

Adalimumab injection has been studied in 500 adult patients with uveitis in two placebo-controlled studies and one open-label extension study. The safety profile for adult patients with uveitis treated with adalimumab injection was consistent with the known safety profile of adalimumab injection. Safety results of the long-term open-label study are generally consistent with the known safety profile of adalimumab injection in the controlled uveitis studies; the exposure-adjusted incidence rates of severe and serious adverse events (including serious infections) were higher in patients who received concomitant systemic corticosteroids and immunosuppressants. Table 15 summarizes adverse drug reactions reported at a rate of at least 1% in adult patients with uveitis treated with an initial dose of adalimumab injection 80 mg followed by adalimumab injection 40 mg every other week compared to placebo.

Table 15. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events Possibly or Probably Related to Study Drug in Controlled Adult Uveitis Studies (Studies M10-877 and M10-880)

Definition(s): s.c. = subcutaneous; eow = every other week

During the double-masked controlled clinical trials, the most common (≥ 5%) adverse drug reactions in adult subjects receiving adalimumab injection were nasopharyngitis (n = 44, 17.6%), arthralgia (n = 38, 15.2%), headache (n = 30, 12.0%), fatigue (n = 26, 10.4%), urinary tract infection (n = 21, 8.4%), uveitis (n = 20, 8.0%), back pain (n = 19, 7.6%), insomnia (n = 18, 7.2%), cough (n = 18, 7.2%), eye pain (n = 18, 7.2%), and upper respiratory tract infection (n = 15, 6.0%).

During the double-masked controlled clinical trials, the most common serious adverse event occurring in >1 patient more often in the adalimumab injection-treated patients compared to placebo was pneumonia (n = 2). During the overall adalimumab injection uveitis development program, including the double-masked controlled, and open-label extension trials, the most frequently reported serious adverse event was cataract (n = 7 patients).

During the double-masked controlled clinical trials, severe adverse events reported in >1 patient occurring more often in the adalimumab injection-treated patients compared to placebo were diarrhea (n = 2) and pneumonia (n = 2). During the overall adalimumab injection uveitis development program, including the double-masked controlled, and open-label extension trials, the most common severe adverse events reported were hypertension (n = 5 patients), pneumonia, urinary tract infection, reduced visual acuity and severe vision loss (n = 4 patients each).

Other Common Clinical Trial Adverse Drug Reactions

Other clinical trial adverse reactions occurring at an incidence of ≥ 1% that were observed among the various indications include:

Eye Disorders: conjunctivitis, visual impairment

Renal and Urinary Disorders: hematuria, renal impairment

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Pediatrics

Polyarticular Juvenile Idiopathic Arthritis

Table 16. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During the Double Blind Placebo-Controlled Phase in the Polyarticular JIA Trial (Study DE038)

* Total only includes values for the terms that were considered possibly or probably related by the investigator.

^† Term was not considered possibly or probably related as assessed by the investigator; however, these terms were considered more common in patients treated with adalimumab injection vs. placebo in the clinical trial.

In Study DE038, adalimumab injection was studied in 171 patients aged 4 to 17 years with polyarticular JIA. Serious adverse events were observed in 28% of patients treated with adalimumab injection and included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia and appendicitis. Serious infections were observed in 6.4% of patients treated with adalimumab injection and included cases of herpes zoster, appendicitis, pneumonia, urinary tract infection, streptococcal pharyngitis, viral infection and cervicitis. A total of 45% of patients experienced an infection while receiving adalimumab injection with or without concomitant MTX in the first 16 weeks of treatment (see 7 WARNINGS AND PRECAUTIONS, Infections). Granuloma annulare was reported in two patients (see 7 WARNINGS AND PRECAUTIONS, Malignancies).

During the double-blind phase of Study DE038, the most common (≥ 5%) adverse reactions occurring in the JIA population treated with adalimumab injection were viral infection (18%), injection site pain (18%), upper respiratory tract infection (16%), injection site reaction (15%), contusion (13%), excoriation (10%), rhinitis (7%), vomiting (6%) and drug hypersensitivity (6%).

Throughout Study DE038, 6% of patients had mild to moderate allergic reaction adverse events primarily localized allergic hypersensitivity reactions and urticaria (see 7 WARNINGS AND PRECAUTIONS, Hypersensitivity Reactions).

In the JIA trial, 10% of patients treated with adalimumab injection who were negative at baseline for anti-double-stranded DNA antibodies developed positive titers after 48 weeks of treatment (see 8 ADVERSE REACTIONS, 8.1 Adverse Reaction Overview, Immunogenicity, Pediatric).

In Study M10-444, adalimumab injection was studied in 32 patients who were 2 to <4 years of age or 4 years of age and older weighing <15 kg with polyarticular JIA. The safety profile for this patient population was similar to the safety profile seen in Study DE038.

In Study M10-444, 78% of patients experienced an infection while receiving adalimumab injection. These included nasopharyngitis, bronchitis, upper respiratory tract infection, otitis media, and were mostly mild to moderate in severity. Serious infections were observed in 9% of patients receiving adalimumab injection in the study and included dental caries, rotavirus gastroenteritis, and varicella.

In Study M10-444, non-serious allergic reactions were observed in 6% of patients and included intermittent urticaria and rash, which were all mild in severity.

Pediatric Crohn’s Disease

Table 17 summarizes adverse drug reactions reported in Study M06-806 at a rate of at least 1% in the indicated pediatric patient population with Crohn’s disease treated with adalimumab injection.

Table 17. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug With Double-Blind Every Other Week Dosing in the Pediatric Crohn’s Disease Study (Study M06-806)

Definition(s): eow = every other week

All treatment-emergent serious adverse events were observed in 21% (11/52) of patients receiving High-Dose and 20% (10/50) of patients receiving Low-Dose. Serious infections were observed in 6% (3/52) of patients receiving High-Dose and 2% (1/50) of patients receiving Low-Dose. The serious adverse events in the High-Dose group included anaemia, Crohn’s disease, anal abscess, gastroenteritis, and histoplasmosis disseminated. The serious adverse events in the Low-Dose group included Crohn’s disease, pancreatitis acute, Bartholin’s abscess, and facial bones fracture.

A total of 56% (29/52) of patients receiving High-Dose and 52% (26/50) of patients receiving Low-Dose experienced an infection (see also 7 WARNINGS AND PRECAUTIONS, Infections). Overall adverse events were observed in 96% (50/52) of patients receiving High-Dose and 86% (43/50) of patients receiving Low-Dose.

Hidradenitis Suppurativa

There are no clinical trials conducted to evaluate the safety of adalimumab injection in adolescents with hidradenitis suppurativa (HS).

Pediatric Uveitis

Table 18 summarizes adverse drug reactions reported in the SYCAMORE study at a rate of at least 1% in the indicated pediatric patient population with active JIA-associated chronic non-infectious anterior uveitis treated with adalimumab injection in combination with methotrexate.

Table 18. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug in the SYCAMORE Pediatric Uveitis Study

In the SYCAMORE study, adalimumab injection was studied in 90 pediatric patients (randomized 2:1 to adalimumab injection:placebo) with active JIA-associated chronic non-infectious anterior uveitis. Overall, serious adverse events were observed in 22% of patients treated with adalimumab injection in combination with MTX and included varicella, streptococcal infections, viral infection, diarrhea, syncope, viral infection, scarlet fever, cellulitis, infected bites, lower respiratory tract infection, cataract, testes exploration, antiviral prophylaxis, food poisoning, and tonsillar hypertrophy. Serious infections were observed in 13% of patients with adalimumab injection. Serious adverse events were more frequent in children 4 years of age and younger.

Pediatric Ulcerative Colitis

Table 19 summarizes adverse drug reactions reported in the M11-290 study at a rate of at least

1% in the indicated pediatric patient population.

Table 19 Number and Percentage of Subjects ≥1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug in the Pediatric Ulcerative Colitis Trial (Study M11-290)

Less Common Clinical Trial Adverse Reactions (<1%)

Infrequent serious adverse drug reactions occurring at an incidence of less than 1% in patients treated with adalimumab injection in RA Studies DE009, DE011, DE019, DE031 and DE013, JIA Study DE038, PsA Studies M02-518 and M02-570, AS Studies M03-607 and M03-606, CD Maintenance Studies M02-404 and M02-433, adult UC Studies M06-826 and M06-827, HS Studies M10-467, M11-313 and M11-810, Ps Studies M03-656, M04-716, and M02-528, and adult uveitis Studies M10-877 and M10-880:

Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

There are no known laboratory tests that may be helpful in following the patient’s response or in identifying possible adverse reactions.

Pediatrics

In the polyarticular juvenile idiopathic arthritis trial (Study DE038), 10/171 (5.8%) and 5/171

(2.9%) of patients treated with adalimumab injection developed severe elevations of ALT and aspartate aminotransferase (AST) (exceeding > 3 times the upper limit of normal [ULN] of ALT and AST, respectively). Forty two (42)/171 (25%) developed elevations of creatine phosphokinase (CPK); with 10/171 (5.8%) patients with severe elevations.

Liver enzyme elevations were more frequent among those treated with the combination of adalimumab injection and MTX than treated with adalimumab injection alone (ALT: 9.5% vs. 2.3%; AST: 5.9% vs. 0%).

No ALT or AST elevations ≥ 3 x ULN occurred in the open-label study of adalimumab injection in patients with polyarticular JIA who were 2 to <4 years of age (Study M10-444).

In the Phase 3 trial of adalimumab injection in patients with pediatric Crohn’s disease which evaluated efficacy and safety of two body weight adjusted maintenance dose regimens following body weight adjusted induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 X ULN occurred in 2.9% of patients all of whom were exposed to concomitant immunosuppressants at baseline.

The rates of hepatic adverse events were 7.7% (4/52) in the High-Dose group and 8.0% (4/50) in the Low-Dose group for pediatric patients 13 to 17 years of age weighing ≥ 40 kg with Crohn’s disease.

Adults

In controlled rheumatoid arthritis clinical trials (Studies DE009, DE011, DE019, and DE031), elevations of alanine aminotransferase (ALT) were similar in patients receiving adalimumab injection or placebo. In patients with early rheumatoid arthritis (disease duration of less than three years) (Study DE013), elevations of ALT were more common in the combination arm (adalimumab injection + methotrexate) compared to the methotrexate monotherapy arm or the adalimumab injection monotherapy arm.

In psoriatic arthritis clinical trials, elevations in ALT were more common in psoriatic arthritis patients compared with patients in rheumatoid arthritis clinical studies.

In controlled Crohn’s disease clinical trials and ulcerative colitis, elevations of ALT were similar in patients receiving adalimumab injection or placebo.

In all indications, patients with raised ALT were asymptomatic and in most cases, elevations were transient and resolved on continued treatment.

Post-Market Adverse Reactions

The following post-market adverse drug reactions have been reported:

^† See (7 WARNINGS AND PRECAUTIONS)

* See (8 ADVERSE REACTIONS, 8.1 Adverse Reaction Overview)

** occurring in patients receiving a TNF-antagonist including adalimumab injection

9 DRUG INTERACTIONS

Serious Drug Interactions

Serious Drug Interactions

• Serious infections and sepsis, including fatalities, have been reported with the use of TNF-blocking agents, including adalimumab injection. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their rheumatoid arthritis, could predispose them to infections. Tuberculosis and invasive opportunistic fungal infections have been observed in patients treated with TNF-blocking agents, including adalimumab injection.

Drug Interactions Overview

Population pharmacokinetic analyses with data from over 1,200 rheumatoid arthritis patients revealed that co-administration of methotrexate had an intrinsic effect on the apparent clearance of adalimumab injection (CL/F). See (9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions). As expected, there was a trend toward higher apparent clearance of adalimumab injection with increasing body weight and in the presence of anti-adalimumab injection antibodies.

Other more minor factors were also identified: higher apparent clearance was predicted in rheumatoid arthritis patients receiving doses lower than the recommended dose, and in rheumatoid arthritis patients with high rheumatoid factor or C-reactive protein (CRP) concentrations. These factors are not likely to be clinically important.

Adalimumab injection has been studied in rheumatoid arthritis patients taking concomitant methotrexate. See (14 CLINICAL TRIALS, 14.5 CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG). The data do not suggest the need for dose adjustment of either adalimumab injection or MTX.

Drug-Behavioural Interactions

Adalimumab injection may have a minor influence on the ability to drive and use machines. Dizziness (including vertigo, vision disorder and fatigue) may occur following administration of adalimumab injection.

Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 20. Established or Potential Drug-Drug Interactions

Definition(s): DMARDs = disease-modifying anti-rheumatic drugs; MTX = methotrexate; TNF = tumor necrosis factor

Drug-Food Interactions

Adalimumab injection is administered as a subcutaneous injection. Interactions with food are therefore not applicable.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

There are no known laboratory tests that may be helpful in following the patient’s response or in identifying possible adverse reactions.

10 CLINICAL PHARMACOLOGY

Mechanism of Action

Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF-expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally-occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis, including polyarticular JIA, psoriatic arthritis and ankylosing spondylitis patients and play an important role in both pathologic inflammation and joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques, which contribute to the inflammatory response, to the proliferation and decreased maturation of keratinocytes and to the associated vascular damages that are characteristic of the disease. Increased levels of TNF are also found in hidradenitis suppurativa lesions.

Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration [ELAM-1, VCAM-1, and ICAM-1 with a half maximal inhibitory concentration (IC₅₀) of 1 to 2 x 10^-10M].

Pharmacodynamics

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

The serum adalimumab injection concentration-efficacy relationship as measured by the American College of Rheumatology response criteria (ACR 20) appears to follow the Hill E_max equation as shown in Figure 1.

Figure 1. Serum Adalimumab Injection Concentration-Efficacy Relationship as Measured by the American College of Rheumatology Response Criteria (ACR 20)

The half maximal effective concentration (EC₅₀) estimates ranging from 0.8 to 1.4 mcg/mL were obtained through pharmacokinetic / pharmacodynamic modelling of swollen joint count, tender joint count and ACR 20 response from patients participating in Phase 2 and 3 trials.

Pharmacokinetics

Pediatrics

Following the administration of 24 mg/m² (up to a maximum of 40 mg) subcutaneously every other week to patients with polyarticular JIA who were 4 to 17 years, the mean trough steady-state (values measured from Week 20 to 48) serum adalimumab injection concentration was 5.5 ± 5.6 mcg/mL (102% CV) adalimumab injection monotherapy and 10.9 ± 5.2 mcg/mL (47.7% CV) with concomitant MTX. In patients with polyarticular JIA who were 2 to <4 years old or aged 4 and above weighing <15 kg dosed with adalimumab injection 24 mg/m², the mean trough steady-state serum adalimumab injection concentrations was 6.0 ± 6.1 mcg/mL (101% CV) adalimumab injection monotherapy and 7.9 ± 5.6 mcg/mL (71.2% CV) with concomitant MTX.

In pediatric patients 13 to 17 years of age weighing ≥ 40 kg with severely active Crohn’s disease and/or who have had an inadequate response or were intolerant to conventional therapy, the mean ± SD serum adalimumab injection trough concentration achieved at Week 4 was 15.7 ± 6.64 mcg/mL following administration of 160 mg adalimumab injection at Week 0 and 80 mg adalimumab injection at Week 2. The mean ± SD adalimumab injection trough concentrations at Week 4 were 17.2 ± 6.67 mcg/mL (n=45) for patients who were naïve to infliximab. The mean ± SD adalimumab injection trough concentrations at Week 4 were 14.4 ± 6.40 mcg/mL (n=51) for patients who were infliximab-experienced.

For patients who stayed on their randomized double-blind therapy, the mean ± SD adalimumab injection trough concentration at Week 52 was 9.43 ± 4.98 mcg/mL following administration of 40 mg adalimumab injection every other week and 3.59 ± 2.91 mcg/mL following administration of 20 mg adalimumab injection every other week. For patients who stayed on their randomized double-blind therapy and were naïve to infliximab, the mean ± SD adalimumab injection trough concentrations at Week 52 were 12.0 ± 3.89 mcg/mL (n=11) and 3.06 ± 2.02 mcg/mL (n=10) for the High-Dose and Low-Dose groups, respectively. For patients who stayed on their randomized double-blind therapy and were infliximab-experienced, the mean ± SD adalimumab injection trough concentrations at Week 52 were 6.85 ± 4.72 mcg/mL (n=11) and 4.27 ± 2.82 mcg/mL (n=8) for the High-Dose and Low-Dose groups, respectively.

Adalimumab injection exposure in adolescent hidradenitis suppurativa (HS) patients was predicted using population pharmacokinetic modeling and simulation based on cross-indication pharmacokinetics in other pediatric patients (pediatric psoriasis, juvenile idiopathic arthritis, pediatric Crohn’s disease, and enthesitis-related arthritis). Serum adalimumab injection concentrations in adolescent patients with HS receiving the recommended dosage regimen are predicted to be similar to those observed in adult subjects with HS (steady-state trough concentration of approximately 8 to 10 mcg/mL).

Adalimumab injection exposure in pediatric uveitis patients was predicted using population pharmacokinetic modelling and simulation based on cross-indication pharmacokinetics in other pediatric patients (N = 524) (pediatric psoriasis [age 5 to 18 years, n = 109], juvenile idiopathic arthritis [age 2 to 17 years, n = 181], pediatric Crohn’s disease [age 6 to 17 years, n = 189], and enthesitis-related arthritis [age 6 to 18 years, n = 45]). No clinical exposure data are available on the use of a loading dose in children < 6 years. The predicted exposures indicate that in the absence of methotrexate, a loading dose may lead to an initial increase in systemic exposure.

Following the subcutaneous administration of body weight-based dosing of 0.6 mg/kg (maximum dose of 40 mg) every other week to pediatric patients with ulcerative colitis, the mean trough steady-state serum adalimumab concentrations was 5.01 ± 3.28 mcg/mL at Week 52. For patients who received 0.6 mg/kg (maximum dose of 40 mg) every week, the mean (± SD) trough steady-state serum adalimumab concentrations were 15.7 ± 5.60 mcg/mL at Week 52.

Adults

The single-dose pharmacokinetics of adalimumab injection in rheumatoid arthritis patients were determined in several studies with intravenous doses ranging from 0.25 to 10.0 mg/kg. The distribution volume (Vss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab injection is approximately 12 mL/h. The mean terminal half-life was approximately two weeks, ranging from 10 to 20 days across studies. The pharmacokinetics of adalimumab injection were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose.

Adalimumab injection mean steady-state trough concentrations of approximately 5 mcg/mL and 8 to 9 mcg/mL, were observed in rheumatoid arthritis patients without and with methotrexate, respectively. The serum adalimumab injection trough levels at steady-state increased approximately proportionally with dose following 20, 40 and 80 mg every other week and every week subcutaneous dosing. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time.

Population pharmacokinetic analyses in patients with rheumatoid arthritis revealed that there was a trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab injection antibodies.

In patients with psoriatic arthritis, adalimumab injection mean steady-state trough concentrations of 8.5 to 12 mcg/mL and 6 to 10 mcg/mL were observed in patients with and without MTX, respectively.

In patients with Crohn’s disease, the loading dose of 160 mg adalimumab injection on Week 0 followed by 80 mg adalimumab injection on Week 2 achieves mean serum adalimumab injection trough concentrations of approximately 12 mcg/mL at Week 2 and Week 4. Mean steady-state trough levels of approximately 7 mcg/mL were observed at Week 24 and Week 56 in Crohn’s disease patients who received a maintenance dose of adalimumab injection 40 mg every other week.

Population pharmacokinetic analysis in patients with Crohn’s disease revealed a lower apparent clearance of adalimumab as compared to patients with rheumatoid arthritis.

In patients with ulcerative colitis, a loading dose of 160 mg adalimumab injection on Week 0 followed by 80 mg adalimumab injection on Week 2 achieved serum adalimumab injection trough concentrations of 11.8 ± 4.0 mcg/mL at Week 2 (n=167) and 12.3 ± 5.4 mcg/mL at Week 4 (n=160). At Week 52, trough levels of 8.0 ± 6.1 mcg/mL were observed in UC patients who received a maintenance dose of 40 mg adalimumab injection every other week (n=101). Trough levels at Week 52 were 10.8 ± 7.5 mcg/mL in UC patients achieving remission (n=39) and 6.2 ± 4.2 mcg/mL in UC patients not achieving remission (n=62).

In patients with HS, a dose of 160 mg adalimumab injection on Week 0 followed by 80 mg adalimumab injection on Week 2 achieved serum adalimumab injection trough concentrations of approximately 7 to 8 mcg/mL at Week 2 and Week 4. The mean steady-state trough concentration at Week 12 through Week 36 were approximately 8 to 10 mcg/mL during adalimumab injection 40 mg every week treatment.

In patients with psoriasis, the mean steady-state trough concentration was 5 mcg/mL during adalimumab injection 40 mg every other week monotherapy treatment.

In patients with uveitis, a loading dose of 80 mg adalimumab injection on Week 0 followed by 40 mg adalimumab every other week starting at Week 1, resulted in mean steady-state concentrations of approximately 8 to 10 mcg/mL.

Absorption

The maximum serum concentration (C_max) and the time to reach the maximum concentration (T_max) were 4.7 ± 1.6 mcg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab injection to healthy adult subjects. The average absolute bioavailability of adalimumab injection estimated from three studies following a single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab injection were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose.

Distribution

Adalimumab injection concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum.

Metabolism

No formal studies have been conducted to evaluate the metabolism of adalimumab. However, as adalimumab injection is an IgG1 antibody of entirely human sequences, it is expected that its metabolism would follow the course of other IgG molecules.

Elimination

No formal studies have been conducted to evaluate the excretion of adalimumab. However, as adalimumab injection is an IgG1 antibody of entirely human sequences, it is expected that its excretion would follow the course of other IgG molecules.

Special Populations and Conditions

Pediatrics: Adalimumab injection has not been studied in pediatric patients with polyarticular JIA less than 2 years of age or in patients with a weight <10 kg.

The majority (102/192) of pediatric patients with Crohn’s disease studied were 13 to 17 years of age weighing ≥ 40 kg.

There are no clinical trials with adalimumab injection in adolescent patients (12 to 17 years of age) with hidradenitis suppurativa (HS). Use of adalimumab injection in adolescent patients is supported by evidence from adequate and well-controlled studies of adalimumab injection in adult HS patients with supplemental pharmacokinetic modeling and simulation. The use of adalimumab injection has not been established in patients younger than 12 years of age with

HS.

Adalimumab injection has not been studied in pediatric patients with uveitis less than 2 years of age. Very limited data are available for pediatric patients with uveitis between 2 and < 3 years of age.

Adalimumab injection has not been studied in pediatric patients with ulcerative colitis less than 5 years of age.

Geriatrics: Population pharmacokinetic analyses in patients with rheumatoid arthritis revealed that there was a trend toward lower clearance with increasing age in patients aged 40 to > 75 years of age.

Sex: Population pharmacokinetic analyses in patients with rheumatoid arthritis revealed that no sex-related pharmacokinetic differences were observed after correction for a patient’s body weight.

Ethic Origin: No differences in immunoglobulin clearance would be expected among ethnic origin. From limited data in non-Caucasians, no important kinetic differences were observed for adalimumab injection.

Hepatic Insufficiency: No pharmacokinetic data are available in patients with hepatic impairment.

Renal Insufficiency: No pharmacokinetic data are available in patients with renal impairment.

Disease States: Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab injection pharmacokinetics. Population pharmacokinetic analyses predicted minor increases in apparent clearance in patients receiving doses lower than the recommended dose and in patients with high rheumatoid factor or C-reactive protein (CRP) concentrations. These increases are not likely to be clinically important. See (4 DOSAGE AND ADMINISTRATION, 4.1 Dosing Considerations, Disease States).

11 STORAGE, STABILITY AND DISPOSAL

Do not use beyond the expiration date on the container. Hulio must be refrigerated at 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, Hulio may be stored at room temperature up to a maximum of 25°C (77°F) for a single period of up to 56 days for 20 mg in 0.4 mL sterile solution and up to 56 days for 40 mg in 0.8 mL sterile solution, with protection from light. Hulio should be discarded if not used within that time period. Record the date when Hulio is first removed from the refrigerator in the spaces provided on the carton.

Do not store Hulio in extreme heat or cold.

12 SPECIAL HANDLING INSTRUCTIONS

Any unused product or waste material should be disposed of in accordance with local requirements.

A puncture-resistant container for disposal of needles and syringes (including the Pen) should be used. Patients or caregivers should be instructed in the handling technique as well as proper syringe and needle disposal and be cautioned against reuse of these items.

A healthcare professional (e.g., doctor, nurse or pharmacist) should be consulted for instructions on how to properly dispose of used needles and syringes (including the Pen). Special provincial or local laws regarding the proper disposal of needles and syringes should be followed. Needles or syringes (including the Pen) should NEVER be thrown in the household trash or recycling bin.

• Used needles and syringes (including the Pen) should be placed in a container made especially for this purpose (sharps container), or a hard plastic container with a screw-on cap or metal container with a plastic lid labelled “Used Syringes”. Glass or clear plastic containers should not be used.
• The container should always be kept out of the reach of children.
• When the container is about two-thirds full, the cap or lid should be taped down so that it does not come off. The container should be disposed of as instructed by a healthcare professional. CONTAINERS SHOULD NEVER BE THROWN IN THE HOUSEHOLD TRASH OR RECYCLING BIN.
• Unless otherwise instructed by a healthcare professional, used alcohol pads may be placed in the trash.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: adalimumab

Chemical name: Not applicable. Adalimumab is not a chemical. It is an immunoglobulin (recombinant human IgG1 monoclonal antibody).

Molecular formula and molecular mass: Adalimumab consists of 1,330 amino acids and has an apparent molecular weight of 148 kilodaltons (kDa), as determined by ESI-TOF/MS analysis.

Structural formula:

Physicochemical properties: Adalimumab is a human Immunoglobulin G subclass 1 (IgG1) type antibody composed of two heavy chain (HC) molecules and two light chain (LC) molecules. Total apparent molecular weight of 148 kilodaltons (kDa), as determined by ESI-TOF/MS analysis.

Hulio is supplied as a sterile, preservative-free solution for subcutaneous administration. The solution of adalimumab injection is clear to slightly opalescent and colourless to pale brownish-yellow, with a pH of 5.2.

Each Hulio PFS and AI consists of 50 mg/mL solution of adalimumab injection, with diluted hydrochloric acid, methionine, monosodium glutamate, polysorbate 80, sorbitol and water for injection (distilled).

Product Characteristics

Hulio (adalimumab injection) is a recombinant human immunoglobulin (IgG1) monoclonal antibody specific for human tumor necrosis factor (TNF). Adalimumab injection was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1:κ constant regions. Adalimumab injection is produced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kDa.

14 CLINICAL TRIALS

Comparative Trial Design and Study Demographics

Clinical studies conducted to support similarity between Hulio and the reference biologic drug included:

• A comparative pharmacokinetic (PK) clinical Phase 1 study (FKB327-001) in healthy subjects
• Two Phase 3 studies (FKB327-002 and FKB327-003) in RA patients receiving concomitant methotrexate (MTX)

An overview of the study design and demographic characteristics of patients enrolled in each clinical study are presented in Table 21.

Table 21. Summary of Trial Design and Patient Demographics

eow=every other week; EU=European Union; F=female; M=male; AI=auto-injector; OLE=open-label extension; PFS=pre-filled syringe; PK=pharmacokinetic; RA=rheumatoid arthritis; SC=subcutaneous; US=United States.

Study FKB327-001 was a randomized, single-blind, three-arm, parallel group, single-dose study to compare the safety and PK of Hulio and US-Humira^® and EU-Humira^® in healthy subjects.

The study evaluated 180 healthy subjects (60 in each arm). A single subcutaneous injection of 40 mg Hulio, US-Humira^® or EU-Humira^® was given to subjects under fasting conditions and the subjects were then observed for 64 days after dosing during which the PK, safety, tolerability, and immunogenicity measurements were made. The PK parameters are summarized in Table 22.

Study FKB327-002 was a randomized, double-blind, parallel group, multi-centre clinical phase III study in adult patients with moderate to severe RA despite MTX therapy.

A total of 730 adult patients (18-93 years of age) with moderate to severe active disease despite MTX therapy were enrolled and randomized in 1:1 ratio to receive either Hulio 40 mg or US-Humira^® 40 mg every other week via subcutaneous injection up to Week 24.

The primary objective was to demonstrate comparability in the ACR20 response rate at Week 24 between Hulio and US-Humira^® using an equivalence margin of -12% to +15% on the difference in response rates.

Study FKB327-003 included patients who had completed Study FKB327-002 and who met limited entry criteria. This multi-center, Open Label Extension study was conducted in 2 parts:

Period I was a randomized, 2-arm comparison of Hulio PFS and US-Humira^® PFS administered as 40 mg eow from Week 0 to Week 28 (last dose in Period I). Patients were randomized in a 2:1 ratio to continue the same treatment, or to switch to the alternate treatment to that received in Study FKB327-002.

Period II was a single arm extension in which all patients received Hulio 40 mg sc eow, (the patients outside of the US using AI and those in the US using PFS), from Week 30 to Week 76, followed by a 4 week follow up period.

The primary objective was to compare the safety of long-term treatment with Hulio and Humira^® in patients with RA.

Comparative Study Results

14.2.1 Comparative Bioavailability Studies

14.2.1.1 Pharmacokinetics

Comparative Pharmacokinetic Study FKB327-001

Comparability criteria were met for the PK parameters C_max and AUC_0-t as the point estimate for the Hulio and US-Humira^® geometric mean ratios for C_max and the 90% CI for AUC_0-t were within the acceptance margins of 80.0% to 125.0% (see Table 22).

Table 22. Summary of Pharmacokinetic Parameters for Adalimumab Injection in Serum (Geometric Mean [CV]; ANOVA; Study FKB327-001)

¹ Hulio (N=60)

² US-Humira^® (N=60)

³ N=58 for Hulio and N=59 for US-Humira^®.

⁴ Expressed as the median (range) only.

⁵ Expressed as the arithmetic mean (CV%) only. N=58 for Hulio and N=59 for US-Humira^®.

14.2.2 Comparative Safety and Efficacy

14.2.2.1 Efficacy

Adult Rheumatoid Arthritis

Study Results (FKB327-002)

The analyses of the primary endpoint, ACR20, demonstrated that the 90% CIs of the difference between Hulio and US-Humira^® were within the pre-defined equivalence margin (-12% to +15%) (Table 23).

Table 23. Analysis of the ACR20 Response Rate at Week 24 in Study FKB327-002

ACR20=American College of Rheumatology 20% response criteria; CI=confidence interval; N=number of patients in the full analysis set; n=number of responders.

^a Missing Week 24 responses for the ACR and responses for patients who discontinued the treatment prior to Week 24 were imputed using non-responder imputation.

^b Percentages based on the number of patients with an evaluable ACR20 result at Week 24, after imputation.

^c CIs calculated using a normal approximation with no continuity correction.

14.2.2.2 Safety

The types, frequency and severity of adverse events were comparable between the biosimilar and the reference biologic drug.

Immunogenicity

Immunogenicity (Healthy Subjects)

Study FKB327-001 evaluated the relative treatment-emergent Anti-Drug Antibodies (ADA) response of Hulio vs. US-Humira^® and EU-Humira^® using an immune-competent population (healthy male and female adult subjects, n=60 per treatment group).

The incidence of subjects with post-dose ADA to adalimumab injection and post-Neutralizing Antibodies (nAb) to adalimumab injection in subjects with a positive ADA result over time was comparable amongst the treatment groups up to 65 days post-injection.

Immunogenicity (RA)

The ADA and nAb test results are summarized by treatment sequence in studies FKB327-002 and FKB327-003 in Table 24 and Table 25.

Table 24. Summary of ADA / nAb responses by treatment group in study FKB327-002

If data at last sampling time point (Day 169) is missing, result carried forward from previous time point.

* The denominator is number of patients of Safety Analysis Set in each treatment group. The incidence of ADA/nAb are at each time point separately.

Table 25. ADA / nAb activity in Study FKB327-003 by treatment sequence

F=FKB327; H=Humira^®

F-F-F, F-H-F, H-F-F and H-H-F refers to treatment sequence in Study FKB327-002 study followed by Period 1 and Period 2 of the open-label extension study FKB327-003

*A Denominator is number of patients of Safety Analysis Set in each treatment sequence

CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG

Adult

Rheumatoid Arthritis

Study Demographics and Trial Design

The efficacy and safety of adalimumab injection were assessed in five randomized, double-blind studies in patients ≥ 18 years of age with active rheumatoid arthritis diagnosed according to the American College of Rheumatology (ACR) criteria. Patients had at least six swollen and nine tender joints. Adalimumab injection was administered subcutaneously in combination with methotrexate (12.5 to 25 mg, Studies DE009, DE019 and DE013), or as monotherapy (Studies DE011 and DE013), or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study DE031).

Table 26 summarizes the controlled clinical trials that were done in patients with active rheumatoid arthritis.

Table 26. Summary of Controlled Clinical Trials Supporting Safety and Efficacy in Patients with Rheumatoid Arthritis

Definition(s): ew = every week; eow = every other week; MTX = methotrexate

Mean ages across the four studies ranged from 53.0 years (adalimumab injection group, Study DE011) to 56.2 years (adalimumab injection group, Study DE019). The mean age in Study DE013 was 51.9 years (adalimumab injection + methotrexate group) to 52.0 years (methotrexate group). Mean weight ranged from 68.5 kg (adalimumab injection group, Study DE011) to 80.3 kg (placebo group, Study DE019). The mean weight in Study DE013 was 74.4 kg (adalimumab injection group) to 76.8 kg (adalimumab injection + methotrexate group). As expected, based on the demographics of the disease, patients were predominantly female, with the percentage of female patients ranging from 73.0% (placebo group, Study DE019) to 83.3% (placebo group, Study DE009). Similarly, the percentage of females in Study DE013 ranged from 72.0% (adalimumab injection + methotrexate group) to 77.4% (adalimumab injection group). Patients were predominantly Caucasian, with the percentage of Caucasian patients ranging from 75.0% (placebo group, Study DE009) to 99.1% (placebo group, Study DE011). The percentage of Caucasian patients in Study DE013 ranged from 93.3% (adalimumab injection + methotrexate group) to 94.2 % (methotrexate group). The high percentage of Caucasian patients in Study DE011 was consistent with the populations of the geographic regions in which this study was conducted (i.e., Europe, Canada, and Australia). Overall, the demographic characteristics of the study patients were fairly representative of rheumatoid arthritis in the general population. There were no notable differences between the studies in any of the demographic characteristics analyzed.

Description of Clinical Studies

Adalimumab injection was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. Some patients were treated for up to 10 years. The efficacy and safety of adalimumab injection were assessed in five randomized, double-blind, well-controlled studies.

Study DE009 evaluated 271 patients with moderately to severely active rheumatoid arthritis who had failed therapy with at least one but no more than four DMARDs, and had inadequate response to methotrexate.

Study DE011 evaluated 544 patients with moderately to severely active rheumatoid arthritis who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of adalimumab injection were given by subcutaneous injection as monotherapy every other week or weekly for 26 weeks.

Study DE019 evaluated 619 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to methotrexate. Patients received placebo, 40 mg of adalimumab injection every other week with placebo injections on alternate weeks, or 20 mg of adalimumab injection weekly for up to Week 52. Study DE019 had an additional primary endpoint at Week 52 of inhibition of disease progression (as detected by X-ray results). Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of adalimumab injection was administered every other week for up to ten years. 202 patients completed 10 years of the study; the efficacy demonstrated at 5 years (reduction in signs and symptoms of RA, improvement in physical function, inhibition of structural joint damage, and rates of clinical response including remission) was maintained through 10 years with continued adalimumab injection in these patients. For efficacy results in these patients, see (14 CLINICAL TRIALS, 14.5 CLINICAL TRIALS – REFERENCE BIOLOGIC DRUG, Adult, Rheumatoid Arthritis, Study Results, Clinical Response, Studies DE009, DE011 and DE019; Radiographic Response; and Quality of Life and Physical Function Response). For a description of safety in these patients, see (8 ADVERSE REACTIONS, 8.1 Adverse Reaction Overview).

Study DE031 assessed safety in 636 patients with moderately to severely active rheumatoid arthritis 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. Patients were randomized to 40 mg of adalimumab injection or placebo every other week for 24 weeks.

Study DE013 evaluated 799 patients with moderate to severely active early rheumatoid arthritis (disease duration less than three years) who were ≥ 18 years old and methotrexate naïve. This study compared the efficacy of adalimumab injection + methotrexate combination therapy and methotrexate monotherapy in reducing the signs and symptoms and rate of progression of joint damage in rheumatoid arthritis. Patients were randomized to receive adalimumab injection 40 mg every other week + methotrexate combination therapy, adalimumab injection 40 mg every other week monotherapy, or methotrexate given weekly, for 104 weeks.

Study Results

Clinical Response

Studies DE009, DE011 and DE019

The percent of adalimumab injection-treated patients achieving ACR 20/50/70 responses was consistent across all three trials. The results of the three trials are summarized in Table 27.

Table 27. ACR Responses in Placebo-Controlled Trials (Percent of Patients)

* Study DE009 at Week 24, Study DE011 at Week 26, and Study DE019 at Weeks 24 and 52

** p < 0.01 for adalimumab injection versus placebo

Definition(s): MTX = methotrexate; ACR = American College of Rheumatology

The results of the components of the ACR response criteria for Studies DE011 and DE019 are shown in Table 28. ACR response rates and improvement in all components of ACR response were maintained to Week 104. Over the two years in Study DE019, 24% of adalimumab injection patients receiving 40 mg every other week achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6-month period. ACR responses were maintained in similar proportions of patients for up to five years with continuous adalimumab injection treatment in the open-label portion of Study DE019.

Table 28. Components of ACR Response in Studies DE011 and DE019

^† Visual analogue scale; 0 = best; 10 = worst

^‡ Disability index of the Health Assessment Questionnaire (HAQ); 0 = best; 3 = worst, measures the patient’s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity

* p < 0.001 for adalimumab injection versus placebo, based on mean change from baseline

Definition(s): MTX = methotrexate; CRP = C-reactive protein

The time course of ACR 20 response for Study DE019 is shown in Figure 2. In Study DE019, 85% of patients with ACR 20 responses at Week 24 maintained the response at Week 52. The time course of ACR 20 response for Studies DE009 and DE011 were similar.

Figure 2. Study DE019 ACR 20 Responses Over 52 Weeks

In the open-label extension for Study DE019, durable and sustained ACR 20, 50 and 70 responses have been observed through 5 and 10 years. Of 207 patients, 114 patients continued on adalimumab injection 40 mg every other week for 5 years. Among those, 86 patients (75.4%) had ACR 20 responses; 72 patients (63.2%) had ACR 50 responses; and 41 patients (36%) had ACR 70 responses. Of 207 patients, 81 patients continued on adalimumab injection 40 mg every other week for 10 years. Among those, 64 patients (79.0%) had ACR 20 responses; 56 patients (69.1%) had ACR 50 responses; and 43 patients (53.1%) had ACR 70 responses.

Study DE031

In Study DE031, 53% of patients treated with adalimumab injection 40 mg every other week plus standard of care had an ACR 20 response at Week 24 compared to 35% on placebo plus standard of care (p < 0.001). No unique adverse reactions related to the combination of adalimumab injection and other DMARDs were observed.

In all four studies, adalimumab injection-treated patients achieved ACR 20/50/70 responses faster and more often than placebo-treated patients. In Study DE009, there was a statistically significant difference in ACR 20 responses at Week 1 (first study visit) between patients treated with adalimumab injection (26.0%) and placebo (5.0%). Statistically significant differences in ACR 20 responses were also seen in Studies DE011, DE019 and DE031 at Week 2 (first study visit) between patients treated with adalimumab injection (36.4, 29.1 and 33.7%, respectively) and placebo (7.3, 13.0 and 8.6%, respectively). A similar pattern of the time to first ACR 50 and 70 responses was noted in all four studies.

Study DE013

In Study DE013, for early rheumatoid arthritis patients who were methotrexate naïve, the combination therapy with adalimumab injection + MTX led to faster and significantly greater ACR responses than methotrexate monotherapy at Week 52, and responses were sustained at Week 104. The clinical responses for Study DE013 are presented in Table 29.

At Week 52, all individual components of the ACR response criteria improved with adalimumab injection + MTX therapy, and improvements were maintained to Week 104.

Over the two-year study, 48.5% of patients who received adalimumab injection + methotrexate combination therapy achieved a major clinical response (ACR 70 for six continuous months) compared to 27.2% of patients who received MTX monotherapy (p < 0.001).

Table 29. Clinical Responses in Study DE013 (All Randomized Subjects)

a. p < 0.05 for adalimumab injection + MTX versus MTX for ACR 20

p < 0.001 for adalimumab injection + MTX versus MTX for ACR 50 and 70 and Major Clinical Response

b. p < 0.001 for adalimumab injection + MTX versus adalimumab injection

c. Major Clinical Response is achieving ACR 70 response for a continuous six-month period

Definition(s): MTX = methotrexate; ACR = American College of Rheumatology

At Week 52 and Week 104 of treatment in Study DE013, adalimumab injection + methotrexate combination therapy was superior to methotrexate monotherapy in achieving a low disease state in patients with recently diagnosed moderate to severe rheumatoid arthritis, as demonstrated by the number of patients who achieved clinical remission [disease activity score (DAS28) < 2.6] at Week 52 and change from baseline in DAS28 at Week 52 and Week 104.

DAS28 responses for Study DE013 are presented in Table 30.

Table 30. Change in DAS28 from Baseline at Weeks 52 and 104 in Study DE013 (All Randomized Subjects)

1. a. p < 0.001 for adalimumab injection + MTX versus MTX
2. b. b. p < 0.001 for adalimumab injection + MTX versus adalimumab injection

Definition(s): MTX = methotrexate; DAS = disease activity score; SD = standard deviation

Radiographic Response

In Study DE019, where adalimumab injection-treated patients had a mean duration of rheumatoid arthritis of approximately 11 years, structural joint damage was assessed radiographically and expressed as change in total Sharp score (TSS) and its components, the erosion score and joint space narrowing (JSN) score at Month 12 compared to baseline. At baseline, the median TSS was approximately 55 in the placebo and 40 mg every other week groups. The 12-month results are shown in Table 31. Adalimumab injection + methotrexate-treated patients demonstrated less radiographic progression than patients receiving methotrexate alone at Week 52.

Table 31. Radiographic Mean Changes Over 12 Months in Study DE019 with Background Methotrexate

1. a. 40 mg administered every other week

* Based on analysis of ranked ANCOVA

** 95% confidence intervals for the differences in change scores between MTX and adalimumab injection

Definition(s): MTX = methotrexate; LOCF = last observation carried forward; JSN = joint space narrowing; CI = confidence interval

Data from the open-label extension of Study DE019 indicate that the reduction in rate of progression of structural damage is maintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients originally treated with 40 mg adalimumab injection every other week were evaluated radiographically. Among those, 59.3% (48 patients) showed no progression of structural damage defined by a change from baseline in the modified total Sharp score (mTSS) of 0.5 or less. At 10 years, 79 of 207 patients originally treated with 40 mg adalimumab injection every other week were evaluated radiographically. Among those, 50.6% (40 patients) showed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or less.

In Study DE013, adalimumab injection-treated patients had a mean duration of rheumatoid arthritis of less than nine months and had not previously received methotrexate. Structural joint damage was assessed radiographically and expressed as change in TSS. The Week 52 results are shown in Table 32. A statistically significant difference for change in modified total Sharp score, erosion score and JSN were observed at Week 52 and maintained at Week 104.

Table 32. Radiographic Mean Change (95% Confidence Interval) in Study DE013

1. a. p < 0.001 for adalimumab injection + MTX versus MTX at Week 52 and Week 104 and for adalimumab injection + MTX versus adalimumab injection at Week 104
2. b. p < 0.01 for adalimumab injection + MTX versus adalimumab injection at Week 52

Definition(s): MTX = methotrexate; JSN = joint space narrowing

The percentage of patients without progression (change from baseline in modified total Sharp score ≤ 0.5) was significantly higher with adalimumab injection + methotrexate combination therapy compared to methotrexate monotherapy at Week 52 (63.8 and 37.4% respectively, p < 0.001) and Week 104 (61.2 and 33.5% respectively, p < 0.001).

Quality of Life and Physical Function Response

In Studies DE009, DE011, DE019 and DE031, adalimumab injection showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire (HAQ) from baseline to the end of study, and significantly greater improvement than placebo in the health outcomes as assessed by the Short Form Health Survey (SF-36). Improvement was seen in both the Physical Component Summary (PCS) and the Mental Component Summary (MCS).

In Study DE019, the mean (CI) improvement in HAQ from baseline at Week 52 was -0.60 (-0.65, -0.55) for the adalimumab injection patients and -0.25 (-0.33, -0.17) for placebo + methotrexate (p < 0.001) patients. Eighty-two percent (82%) of adalimumab injection-treated patients who achieved a 0.5 or greater improvement in HAQ at Week 52 in the double-blind portion of the study maintained that improvement through Week 104 of open-label treatment, and a similar proportion of patients maintained this response through Week 260 (five years) and Week 520 (10 years). After five years, the proportion of subjects who were HAQ responders at the 0.22, 0.50, 0.75 and 1.0 levels were 76.5, 60.0, 47.5 and 30.8% respectively. A total of 149 patients who received adalimumab injection for 10 years were assessed for HAQ. After 10 years, the proportions of patients who were HAQ responders at the 0.22, 0.50, 0.75 and 1.0 levels were 73.8 (n = 110), 57.0 (n = 85), 44.3 (n = 66) and 26.2% (n = 39) respectively. Improvement in SF-36 was measured and maintained up to Week 156 (3 years).

In Study DE013, the active comparator-controlled study in early rheumatoid arthritis, the improvement in the HAQ disability index, and the physical component of the SF-36, showed greater improvement (p < 0.001) for the adalimumab injection + MTX combination therapy versus the MTX monotherapy at Week 52, which was maintained through Week 104.

At Week 52 and Week 104 of treatment, 69.4% (186/268) and 63.8% (171/268) of subjects, respectively, treated with adalimumab injection +MTX combination therapy had a decrease (i.e., improvement) in the disability index of the HAQ of ≥ 0.3 units. In comparison, 61.5% (158/257; p = 0.562) and 53.3% (137/257; p = 0.0146) of subjects treated with methotrexate monotherapy, and 55.1% (151/274; p < 0.001) and 48.2% (132/274; p < 0.001) of subjects treated with adalimumab injection monotherapy had a decrease in the disability index of the HAQ of ≥ 0.3 units at Weeks 52 and 104, respectively.

Psoriatic Arthritis

The efficacy of adalimumab injection was assessed in two randomized, double-blind, placebo-controlled studies in 413 patients. The primary study treated 313 adult patients with moderately to severely active psoriatic arthritis who had an inadequate response to nonsteroidal anti-inflammatory drug (NSAID) therapy. Of the 313 treated in this study, 158 (50.5%) were described as taking methotrexate at the time of randomization. Doses of adalimumab injection 40 mg every other week were administered for 24 weeks. Table 33 summarizes the controlled clinical trials that were done in patients with active psoriatic arthritis.

Table 33. Summary of Controlled Clinical Trials Supporting Safety and Efficacy in Patients with Psoriatic Arthritis

Definition(s): eow = every other week; MTX = methotrexate; BSA = body surface area

DMARDs = disease-modifying anti-rheumatic drugs

Mean ages across the two studies ranged from 47.7 years (placebo group, Study M02-570) to 50.4 years (adalimumab injection group, Study M02-570). Mean weight ranged from 85.5 kg

(placebo group, Study M02-518) and 91.5 kg (adalimumab injection group, Study M02-570). The percentage of females ranged from 43.1 % (adalimumab injection group, Study M02-570) and 45.1% (placebo group, Study M02-518). Patients were predominantly Caucasian, with the percentage of Caucasian patients ranging from 93.8% (placebo group, Study M02-518) to 98.0% (adalimumab injection group, Study M02-570). There were no notable differences between the studies in any of the demographic characteristics analyzed. Upon completion of both studies, 383 patients enrolled in an open label extension study (Table 34) in which adalimumab injection 40 mg is administered every other week.

Table 34. Summary of Open-Label Clinical Trials Evaluating Long-Term Safety and Efficacy in Patients with Psoriatic Arthritis

Definition(s): eow = every other week

Description of Clinical Studies

Study M02-518 evaluated the effectiveness and safety of adalimumab injection either alone or in combination with concomitant methotrexate in subjects with moderately to severely active PsA who have had an inadequate response or intolerance to NSAID therapy.

Study M02-570 evaluated the effectiveness and safety of adalimumab injection either alone or in combination with any concomitant DMARD (except cyclosporine or tacrolimus) in subjects with moderately to severely active psoriatic arthritis who have had an inadequate response to DMARD therapy.

Study M02-537 evaluates the long-term safety and efficacy of adalimumab injection 40 mg every other week in the treatment of psoriatic arthritis in subjects who completed the controlled Studies M02-518 and M02-570.

Study Results

Clinical Response

Studies M02-518, M02-570 and M02-537

Adalimumab injection was superior to placebo in all measures of disease activity (p < 0.001) as shown in Table 35 and Table 36. Among patients with psoriatic arthritis who received adalimumab injection, the clinical responses were apparent at the time of the first visit (Week 2), significant at Week 12, and maintained at Week 24 in the double-blind period of the study. Table 36 presents data from the ongoing open-label study regarding improvement in arthritic manifestations of psoriatic arthritis.

Patients with a psoriasis involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses. In these patients, the skin lesions of psoriasis were improved with adalimumab injection, relative to placebo, as measured by the PASI. Results were similar with and without concomitant methotrexate therapy. The small number of patients with moderate to severe psoriasis requires additional data to adequately assess the PASI response.

Table 35. ACR and PASI Response in Placebo-Controlled Psoriatic Arthritis Study (Study M02-518) (Percent of Patients)

† p < 0.001 for all comparisons between adalimumab injection and placebo

Definition(s): ACR = American College of Rheumatology; PASI = Psoriasis Area and Severity Index

Table 36. Components of Disease Activity in Psoriatic Arthritis (Study M02-518)

† As observed analysis presented, N at Week 24 may be less than 162 for placebo or 151 for adalimumab injection

‡ p < 0.001 for adalimumab injection versus placebo comparisons based on mean change from baseline

a. Visual analogue scale; 0 = best, 100 = worst

b. Disability index of the Health Assessment Questionnaire (HAQ); 0 = best, 3 = worst; measures the patient’s ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity

c. C-reactive protein (CRP) normal range: 0 to 0.287 mg/Dl

Radiographic Response

Radiographic changes in the hands, wrists, and feet were assessed in the psoriatic arthritis study at baseline and Week 24 during the double-blind period when patients were on adalimumab injection or placebo and at Week 48 when all patients were on open-label adalimumab injection. A modified total Sharp score (mTSS), which included distal interphalangeal joints (i.e., not identical to the TSS used for rheumatoid arthritis), was used by readers blinded to treatment group to assess the radiographs.

Week 24

The mean change in mTSS was evaluated and demonstrated that adalimumab injection-treated patients had significantly less progression in their X-rays, compared to placebo-treated patients. As shown in Table 37, the mean change from baseline in both the erosion and the joint space narrowing scores in the adalimumab injection treatment group was significantly superior to placebo. As with other TNF agents, the median change in Sharp scores for both patient groups were zero.

Table 37. Radiographic Mean Changes at Week 24 in Placebo-Controlled Psoriatic Arthritis Study (Study M02-518)^†

† Analysis of patients with X-ray films at both baseline and Week 24

Definition(s): JSN = joint space narrowing

Week 48

Adalimumab injection-treated patients demonstrated greater inhibition of radiographic progression at Week 48 compared to placebo-treated patients at Week 24 (see Table 38).

Table 38. Change in Modified Total Sharp Score^‡ in Psoriatic Arthritis (Study M02-537)

* p < 0.05 for the difference between adalimumab injection, Week 48 and placebo, Week 24 (primary analysis)

** p < 0.001 for the difference between adalimumab injection, Week 48 and placebo, Week 24 (primary analysis)

‡ X-rays with less than 50% assessments were imputed

Definition(s): JSN = joint space narrowing; SD = standard deviation

Physical Function Response

Disability and physical function were assessed in psoriatic arthritis study using Health Assessment Questionnaire Disability Index (HAQ-DI). The adalimumab injection-treated patients had significantly greater improvement in the disability index of the HAQ from baseline to Week 24, compared to placebo and were maintained up to Week 84 (see Table 39 and Table 40).

Table 39. Disability Index of the HAQ (Full Analysis Set) (Study M02-518)

* Statistically significant at the p = 0.001 level

a. p-value for differences between treatment groups from an ANOVA model with treatment group and baseline methotrexate use/extent of psoriasis (≥ 3% BSA, < 3% BSA) as factors

Definition(s): HAQ = Health Assessment Questionnaire; BSA = body surface area; eow = every other week; SD = standard deviation

Table 40. Mean Change From Baseline in Disability Index of HAQ by Visit (Observed) (Study M02-518 Subjects Randomized to Adalimumab Injection)

Note: The disability index of the Health Assessment Questionnaire (HAQ) has a range from 0 to 3 with a higher score indicating a greater extent of functional limitations

a. Last assessment prior to the first adalimumab injection

A subset of the subjects is still being followed in the ongoing study.

Results from the Short Form Health Survey (SF-36) support these findings, with statistically significant Physical Component Summary (PCS) scores, as well as statistically significant pain and vitality domain scores at Week 24, which were maintained to Week 72.

Ankylosing Spondylitis

Study Demographics and Trial Design

The safety and efficacy of adalimumab injection 40 mg every other week were assessed in 393 adult patients in two randomized, 24-week double-blind, placebo-controlled studies in patients with active ankylosing spondylitis who have had an inadequate response to or intolerance to one or more NSAIDs, and who may have additionally failed DMARD therapy. The larger study enrolled 315 adult patients with active ankylosing spondylitis [defined as fulfilling at least two of the following three criteria: (1) a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4 cm, (2) a visual analogue score (VAS) for total back pain ≥ 40 mm, and (3) morning stiffness ≥ 1 hour]. The primary efficacy endpoint was percentage of ASAS 20 responders at Week 12 measured by the Assessment in Ankylosing Spondylitis (ASAS) response criteria. Additional pre-determined endpoints included: response as defined by ASAS 5/6 criteria, ASAS 40/50/70 and partial remission, Bath Ankylosing Spondylitis Metrology Index (BASMI), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The blinded period was followed by an open-label period during which patients received adalimumab injection 40 mg every other week subcutaneously for up to an additional 80 weeks.

Study Results

Clinical Response

Results showed statistically significant reduction in signs and symptoms of ankylosing spondylitis in patients treated with adalimumab injection compared to placebo in Study M03-607. Significant improvement in measures of disease activity was first observed at Week 2 and maintained through Week 24 as shown in Figure 3 and Table 40.

Patients with total spinal ankylosis were included in the larger study (n = 11). Responses of these patients were similar to those without total ankylosis.

Figure 3. ASAS 20 Response by Visit, Study M03-607

At Week 12, the ASAS 20/50/70 responses were achieved by 58, 38, and 23%, respectively, of patients receiving adalimumab injection, compared to 21, 10, and 5% respectively, of patients

Adalimumab injection (N=208)

receiving placebo (p < 0.001). At Week 24, the ASAS 20/50/70 responses were achieved by 51, 35 and 24%, respectively, of patients receiving adalimumab injection, compared to 19, 11, and 8%, respectively, of patients receiving placebo (p < 0.001). These results were sustained in patients receiving open-label adalimumab injection through Week 52.

In a sub-group analysis by region an adalimumab injection versus placebo treatment group difference was observed between the United States (US) and European (EU) subjects (21.7 and 50.9% respectively). This difference in the treatment effect is driven by the different placebo ASAS 20 response rates (33.3% for US versus 10.2% for EU). However, the adalimumab injection ASAS 20 response rates were 55 and 61.1% in the US and EU respectively.

A low level of disease activity [defined as a value < 20 (on a scale of 0 to 100 mm) in each of the four ASAS response parameters] was achieved at Week 24 in 22% of adalimumab injection-treated patients versus 6% in placebo-treated patients (p < 0.001).

Other secondary and additional measures of efficacy such as response as defined by ASAS 5/6 criteria, ASAS 40, metrology (BASMI), enthesitis (MASES), and disease activity (BASDAI) were statistically significant at Weeks 12 and 24.

Table 41. Components of Ankylosing Spondylitis Disease Activity in Study M03-607

* Statistically significant as p < 0.001 for all comparisons between adalimumab injection and placebo at Week 24

a. Percent of subjects with at least a 20% and 10-unit improvement measured on a visual analogue scale (VAS) with 0 = “none” and 100 = “severe”

b. Mean of questions 5 and 6 of BASDAI

Definition(s): BASFI = Bath Ankylosing Spondylitis Functional Index; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; CRP = C-reactive protein (mg/dL)

Similar results (not all statistically significant) were seen in the second randomized trial, a multicentre, double-blind, placebo-controlled study of 82 patients with ankylosing spondylitis (Study M03-606).

Patients treated with adalimumab injection achieved statistically significant greater improvement from baseline in the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score (-3.15 versus -0.95, p < 0.001) and in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) score (6.93 versus 1.55, p < 0.001) compared to placebo-treated patients at Week 12, which were maintained through Week 24.

Crohn’s Disease

Study Demographics and Trial Design

The safety and efficacy of multiple doses of adalimumab injection were assessed in over 1,500 adult patients with moderately to severely active Crohn’s disease (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 80% of patients continued to receive at least one of these medications.

Table 42 summarizes the controlled clinical trials and Table 43 summarizes the open-label clinical trials that were done in patients with moderately to severely active Crohn’s disease.

Table 42. Summary of Controlled Clinical Trials Supporting Safety and Efficacy in Patients with Crohn’s Disease