Adalimumab (Micromedex)

DrugPoint® SummaryAdalimumab   (see details in DRUGDEX®)

 

 Dosing & Indications    

 Adult Dosing   (see details in DRUGDEX®)  

evaluate patients for latent tuberculosis (tuberculin skin test) prior to therapy; treatment of latent infection should be started prior to adalimumab therapy

Ankylosing spondylitis: 40 mg subQ every other week alone or in combination with NSAIDs, glucocorticoids, methotrexate or other DMARDs

Crohn's disease (Moderate to Severe), In patients with an inadequate response to conventional therapy: 160 mg subQ at week 0 (may administer as 4 injections in 1 day or 2 injections daily for 2 consecutive days), 80 mg subQ at week 2 (Day 15), then 40 mg subQ every other week starting at week 4 (Day 29)

Plaque psoriasis (Moderate to Severe), Chronic: initial, 80 mg subQ, followed by 40 mg subQ every other week starting one week after the initial dose

Psoriasis with arthropathy: 40 mg subQ every other week alone or in combination with other disease-modifying antirheumatic drugs

Rheumatoid arthritis (Moderate to Severe): 40 mg subQ every other week; other disease-modifying antirheumatic drugs (DMARDs) may be continued during therapy; may increase to 40 mg subQ every week in patients not receiving concomitant methotrexate

  

 Pediatric Dosing   (see details in DRUGDEX®) Back to top 

evaluate patients for latent tuberculosis (tuberculin skin test) prior to therapy; treatment of latent infection should be started prior to adalimumab therapy

all juvenile idiopathic arthritis patients should be brought up to date with current immunizations prior to initiating adalimumab therapy

Crohn's disease (Moderate to Severe), In patients with an inadequate response to conventional therapy: (40 kg or greater): 160 mg subQ loading dose once at wk 0 and 2 followed by a maintenance dosage of 80 mg subQ once every other wk for 48 wk (starting on week 4) was used in a clinical trial

Crohn's disease (Moderate to Severe), In patients with an inadequate response to conventional therapy: (40 kg or less): 80 mg subQ loading dose once at wk 0 and 2 followed by a maintenance dosage of 40 mg subQ once every other wk for 48 wk (starting on week 4) was used in a clinical trial

Juvenile idiopathic arthritis: Age 4 to 17 years, weight 15 kg (33 pounds) to less than 30 kg (66 pounds): 20 mg subQ every other week

Juvenile idiopathic arthritis: Age 4 to 17 years, weight 30 kg (66 pounds) or greater: 40 mg subQ every other week

Juvenile idiopathic arthritis: Concomitant methotrexate, glucocorticoids, salicylates, NSAIDs, or analgesics may be continued

  

 Dose Adjustments   (see details in DRUGDEX®) Back to top 

lupus-like syndrome: discontinue therapy if lupus-like syndrome develops

    

 FDA-Labeled Indications   (see details in DRUGDEX®) Back to top 

Ankylosing spondylitis

Crohn's disease (Moderate to Severe), In patients with an inadequate response to conventional therapy

Juvenile idiopathic arthritis

Plaque psoriasis (Moderate to Severe), Chronic

Psoriasis with arthropathy

Rheumatoid arthritis (Moderate to Severe)

 Black Box Warning   (see details in DRUGDEX®)

Back to top

Subcutaneous (Kit)

Patients treated with adalimumab are at increased risk for infections, some progressing to serious infections leading to hospitalization or death. These infections have included bacterial sepsis, tuberculosis, invasive fungal and other opportunistic infections. Evaluate for latent tuberculosis and treat if necessary prior to initiation of therapy. Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, of which adalimumab is a member .

 Contraindications/Warnings    

 Do Not Confuse Back to top 

Humira Pen - HumaPen

  

 Contraindications   (see details in DRUGDEX®) Back to top 

specific contraindications have not been determined

  

 Precautions   (see details in DRUGDEX®) Back to top 

children, adolescents, and young adults; lymphoma and other cancers have been reported

serious infections (eg, tuberculosis, invasive fungal infections, and other opportunistic infections), including fatalities, have been reported, especially with concomitant immunosuppressant use; do not initiate therapy in patients with active infections (including chronic or localized infections); discontinue therapy if a serious infection or sepsis develops

TB, reactivation or new-onset; may occur; increased risk in patients with potential exposure due to travel or residence in endemic areas or close personal contact with active TB or with history of latent or active disease, regardless of previous Bacille Calmette-Guerin vaccination

anaphylaxis and angioneurotic edema have been reported; requires discontinuation of therapy

autoantibody formation, including lupus-like syndrome; has occurred; discontinue therapy if symptoms occur

CNS demyelinating disorders, new onset or worsening of preexisting condition may occur

concomitant use with anakinra is not recommended

concomitant use with live vaccine not recommended

congestive heart failure, new-onset or worsening; has been reported; monitoring recommended; discontinuation may be necessary

hematologic abnormalities (eg, pancytopenia, aplastic anemia) have occurred; may require discontinuation of therapy

hepatitis B, chronic carriers; increased risk of reactivation, some cases fatal, including several months after therapy termination; monitoring recommended; discontinuation and supportive treatment may be necessary

juvenile rheumatoid arthritis patients should be brought up-to-date on all immunization requirements, when possible, prior to beginning treatment with adalimumab

latex sensitivity; needle cover of prefilled syringe contains latex

malignancies, history or new-onset including lymphomas and acute and chronic leukemia ; increased risk of developing other malignancies

rheumatoid arthritis, particularly highly active disease; higher risk for developing lymphoma

report suspected adverse events to Abbott Laboratories at 1-800-633-9110, or to the US Food and Drug Administration (FDA) at 1-800-FDA-1088 or www.fda.gov/medwatch

  

 Pregnancy Category   (see details in DRUGDEX®) Back to top 

B (FDA)

C (AUS)

  

 Breast Feeding   (see details in DRUGDEX®) Back to top 

Thomson: Infant risk cannot be ruled out.

 Drug Interactions (single)   (see details in DRUGDEX®)      

 Major Back to top 

Abatacept (theoretical)

Anakinra (theoretical)

Bacillus of Calmette and Guerin Vaccine, Live (theoretical)

Influenza Virus Vaccine, Live (theoretical)

Measles Virus Vaccine, Live (theoretical)

Mumps Virus Vaccine, Live (theoretical)

Poliovirus Vaccine, Live (theoretical)

Rilonacept (theoretical)

Rotavirus Vaccine, Live (theoretical)

Rubella Virus Vaccine, Live (theoretical)

Smallpox Vaccine (theoretical)

Typhoid Vaccine (theoretical)

Varicella Virus Vaccine (theoretical)

Yellow Fever Vaccine (theoretical)

 Adverse Effects   (see details in DRUGDEX®)    

 Common Back to top 

Cardiovascular: Hypertension (5% )

Dermatologic: Injection site pain (12% to 19% ), Injection site reaction (8% to 20% ), Rash (12% )

Immunologic: Antibody development, to adalimumab (1% to 12% ), Antinuclear antibody positive (12% )

Neurologic: Headache (12% )

Respiratory: Sinusitis (11% ), Upper respiratory infection (17% )

    

 Serious Back to top 

Dermatologic: Erythema multiforme, Primary cutaneous vasculitis, Stevens-Johnson syndrome

Hematologic: Aplastic anemia (rare ), Erythrocytosis (less than 5% ), Leukopenia (less than 5% ), Pancytopenia (less than 5% ), Thrombocytopenia (rare )

Immunologic: Anaphylaxis (rare ), Immune hypersensitivity reaction (approximately 1% ), Malignant lymphoma (rare )

Neurologic: Demyelinating disease of central nervous system (rare ), Multiple sclerosis (less than 5% ), Paresthesia (less than 5% ), Subdural hematoma (less than 5% )

Respiratory: Interstitial lung disease, Pulmonary fibrosis, Tuberculosis (rare )

Other: Angioedema, Cancer, Infectious disease

 Name Info    

 US Trade Names Back to top 

Humira

All Trade Names  

 Class   (see details in DRUGDEX®) Back to top 

Antirheumatic

Tumor Necrosis Factor Inhibitor

    

 Regulatory Status Back to top 

RX

    

 Generic Availability Back to top 

No

 Mechanism of Action/Pharmacokinetics  

 Mechanism of Action   (see details in DRUGDEX®) Back to top 

Systemic: Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta).

Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration. Adalimumab decreases C-reactive protein, erythrocyte sedimentation rate, IL-6, and matrix metalloproteinases MMP-1 and MMP-3.

  

 Pharmacokinetics   (see details in DRUGDEX®) Back to top 

  Absorption

Systemic: Bioavailability: 64%

  Distribution

Systemic: Vd: 4.7 to 6 L

  Elimination Half Life

Systemic: 2 wk (range 10 to 20 d)

 Administration/Monitoring  

 Administration   (see details in DRUGDEX®) Back to top 

Subcutaneous

do not handle the needle cover of the syringe if allergic to latex

injection site is usually on the front of thighs or abdomen (avoid area 2 inches around the navel)

rotate sites of injection each time at least 1 inch from the previous site; do not inject in tender, bruised, red, or hard areas of skin

gently squeeze the injection skin site and place the needle end of the syringe at 90 degrees angle flat against the raised area of skin

administer the desired dose and discard any unused portions of drug

  

 Monitoring   (see details in DRUGDEX®) Back to top 

improved range of motion, decreased early morning stiffness and painful/swollen joints, C-reactive protein levels, erythrocyte sedimentation rate

CBC, routine blood chemistry; periodically during long-term therapy

patients with chronic hepatitis B/chronic HBV carriers: signs and symptoms of active hepatitis B infection during therapy and following discontinuation of therapy

signs/symptoms of new or worsening heart failure

signs/symptoms of fungal infections and other serious systemic infections during and after treatment

 How Supplied

Back to top

Humira

Kit: 40 MG/0.8 ML

Subcutaneous Solution: 20 MG/0.4 ML, 40 MG/0.8 ML

 Toxicology    

 Clinical Effects Back to top 

ADALIMUMAB

USES: Adalimumab is indicated for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis. PHARMACOLOGY: Adalimumab is a recombinant human IgG1 monoclonal antibody that binds to tumor necrosis factor (TNF) alpha and blocks its interaction with endogenous cell surface TNF receptors. EPIDEMIOLOGY: Overdose is very rare. TOXICITY: There are no reports of toxicity following acute overdose. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. ADVERSE EFFECTS: COMMON (greater than 10%) - Infections (eg; upper respiratory, sinusitis), injection site reaction, headache, and rash. LESS COMMON (5% to 10%): Nausea, abdominal pain, hematuria, hypercholesterolemia, increased alkaline phosphatase, and back pain. Although the causal relationship to adalimumab is not clear, the following adverse reactions were also reported during studies: New onset or worsening congestive heart failure, leucocytoclastic vasculitis, hypertension, angioneurotic edema, cellulitis, psoriasis, erysipelas, cutaneous vasculitis, Stevens-Johnson syndrome, erythema multiforme, optic neuritis, pancytopenia, aplastic anemia, thrombocytopenia, leukopenia, polycythemia, anaphylaxis, paresthesia, tremor, hepatic necrosis, elevated liver enzymes, and interstitial lung disease, including pulmonary fibrosis.

    

 Treatment Back to top 

ADALIMUMAB

Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive. Monitor patients for clinical signs of infection. MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe

thrombocytopenia, bleeding. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.

Decontamination: Decontamination is not necessary; adalimumab is administered parenterally.

Antidote: None

Airway management: Endotracheal intubation and mechanical ventilation may be required in patients with severe allergic reactions, but this is rare.

Myelosuppression: Severe neutropenia: filgrastim 5 mcg/kg/day subcutaneously, or sargramostim 250 mcg/m(2)/day infused over 4 hours. Transfusions as needed for severe thrombocytopenia, bleeding.

Acute allergic reaction: MILD/MODERATE: Monitor airway. Administer antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine (ADULT: 0.3 to 0.5 mL of a 1:1000 solution subcutaneously; CHILD: 0.01 mL/kg, maximum 0.5 mL; may repeat in 20 to 30 min), corticosteroids, ECG monitoring and IV fluids.

Monitoring of patient: Monitor patients for clinical signs of infection. Monitor vital signs, ECG, and liver enzymes after significant overdose. Monitor serial CBC with differential and platelet counts.

Patient disposition: OBSERVATION CRITERIA: Mild to moderately symptomatic patients should be sent to health care facility for evaluation and treatment as necessary. ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted. CONSULT CRITERIA: Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.

    

 Range of Toxicity Back to top 

ADALIMUMAB

TOXICITY: A toxic dose has not been established. In clinical trials, adalimumab doses up to 10 mg/kg have been administered to patients with no evidence of dose-limiting toxicities. THERAPEUTIC DOSE: ADULTS - 40 to 160 mg SubQ, doses and dosing intervals may vary depending on the indication. CHILDREN - Age 4 to 17 years, weight 15 kg (33 pounds) to less than 30 kg (66 pounds): 20 mg subQ every other week. Age 4 to 17 years, weight 30 kg (66 pounds) or greater: 40 mg subQ every other week.

 Clinical Teaching 

 Clinical Teaching Back to top 

Advise patient of increased risk of lymphoma and other malignancies .

Advise patient to avoid vaccines during therapy due to drug-induced immunosuppression .

Instruct patient to report a latex-sensitivity prior to administration, as needle cover of prefilled syringe contains dry natural rubber (latex derivative) .

Drug may cause headache, rash, nausea, upper respiratory infection, and injection site reaction .

Instruct patient to report signs/symptoms of infection (including tuberculosis) or lupus-like syndrome (arthralgias, myalgias, fatigue, skin rashes) .

Advise patient to report signs/symptoms of heart failure (new onset or exacerbation of disease) .

Tell patient to report signs/symptoms of hepatitis B during and after drug therapy .

Advise patient to report signs/symptoms of pancytopenia or cytopenia .

Advise patient to rotate injection sites .

Patient should avoid concomitant use of anakinra due to possible development of serious infections .

Last Modified: May 21, 2010

u)  Tuberculosis5)  Clinical Applicationsa)  FDA Approved Indications1)  Ankylosing spondylitis2)  Crohn's disease (Moderate to Severe), In patients with an inadequate response to conventional therapy3)  Juvenile idiopathic arthritis4)  Plaque psoriasis (Moderate to Severe), Chronic5)  Psoriasis with arthropathy6)  Rheumatoid arthritis (Moderate to Severe)

 1.0   Dosing Information

Drug Properties

Storage and Stability

Adult Dosage

Pediatric Dosage

 1.1   Drug Properties A)  Information on specific products and dosage forms can be obtained by referring to the Tradename List (Product Index)B)  SynonymsAdalimumabC)  Physicochemical Properties1)  Molecular Weighta)  148 kilodaltons(Prod Info HUMIRA(TM) subcutaneous injection, 2003a) 2)  pHa)  Systemic: Approximately 5.2(Prod Info HUMIRA(TM) subcutaneous injection, 2003a)

 1.2   Storage and Stability A)  Preparation1)  Subcutaneous routea)  Preparation1)  The prefilled syringe should be inspected visually before injection and should not be used if it is discolored or if particulates are visible. Since adalimumab does not contain preservatives, unused portions of the drug should be discarded. Do not handle the needle cover of the syringe if allergic to latex (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).b)  Administration1)  Inject the full amount in the syringe (40 milligrams) subcutaneously. Sites of injection should be rotated and injections should never be given in areas where the skin may be tender, bruised, red, or hard (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).2)  The injection site is usually on the front of thighs or abdomen (avoid area 2 inches around the navel). Rotate sites of injection each time at least 1 inch from the previous site; do not inject in tender, bruised, red, or hard areas of skin (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)3)  Gently squeeze the injection skin site and place the needle end of the syringe at 90 degrees angle flat against the raised area of skin (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)4)  Administer the desired dose and discard any unused portions of drug (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)B)  Parenteral route1)  The manufacturer (Humira(TM)) recommends refrigeration at 2 to 8 degrees C (36 to 46 degrees F). Vials/syringes should not be frozen. The product should be protected from light and not used beyond the expiration date on the container (Prod Info Humira(TM), 2002).

 1.3   Adult Dosage

Normal Dosage

Dosage in Other Disease States

1.3.1   Normal Dosage

Intravenous route

Subcutaneous route

1.3.1.A   Intravenous route

1.3.1.A.1   Rheumatoid arthritis (Moderate to Severe) a)  Subcutaneous treatment is preferred.b)  Intravenous doses of 0.5 to 1 milligram/kilogram (mg/kg) every 2 or 2.5 weeks have been effective as monotherapy or combined with methotrexate in patients with active rheumatoid arthritis (Rau et al, 1998a; Weisman et al, 2000a). The antibody has been given slowly over 3 to 5 minutes (van de Putte et al, 1998a).

1.3.1.B   Subcutaneous route

Ankylosing spondylitis

Crohn's disease (Moderate to Severe), In patients with an inadequate response to conventional therapy

Plaque psoriasis (Moderate to Severe), Chronic

Psoriasis with arthropathy

Rheumatoid arthritis (Moderate to Severe)

1.3.1.B.1   Ankylosing spondylitis a)  The recommended dose for the treatment of ankylosing spondylitis is 40 milligrams (mg) subcutaneously every other week; other agents may be continued during adalimumab treatment (e.g., methotrexate, glucocorticoids, salicylates, nonsteroidal antiinflammatory agents, analgesics, other DMARDs). Concomitant use with anakinra is NOT recommended (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

1.3.1.B.2   Crohn's disease (Moderate to Severe), In patients with an inadequate response to conventional therapy a)  The recommended dose of adalimumab for the treatment of moderately to severely active Crohn's disease in patients who have had an inadequate response to conventional therapy is 160 milligrams (mg) subcutaneously (subQ) at week 0 (may be administered as 4 injections in 1 day or 2 injections daily for 2 consecutive days), followed by 80 mg subQ at week 2, then maintenance therapy with 40 mg subQ every other week starting at week 4. Clinical studies have not evaluated the use of adalimumab beyond 1 year. Other agents, such as aminosalicylates, corticosteroids, and immunomodulatory agents, may be continued (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

1.3.1.B.3   Plaque psoriasis (Moderate to Severe), Chronic a)  The recommended dose for the treatment of moderate to severe chronic plaque psoriasis is an initial dose of 80 milligrams (mg) subcutaneously once followed by 40 mg subcutaneously given every other week (starting one week after the initial dose). Controlled clinical studies have not evaluated the use of adalimumab for moderate to severe chronic plaque psoriasis beyond 1 year (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

1.3.1.B.4   Psoriasis with arthropathy a)  The recommended dose in adult patients with psoriatic arthritis is 40 milligrams (mg) administered subcutaneously every other week. Treatment with other medications such as methotrexate, glucocorticoids, salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, and other disease-modifying antirheumatic drugs (DMARDs) may be continued during therapy with adalimumab (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

1.3.1.B.5   Rheumatoid arthritis (Moderate to Severe) a)  The manufacturer recommends a subcutaneous dose of 40 milligrams (mg) every other week; other agents may be continued during adalimumab treatment (e.g., methotrexate, glucocorticoids, salicylates, nonsteroidal antiinflammatory agents, analgesics, other DMARDs). . Concomitant use with anakinra is NOT recommended (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).b)  In patients not receiving concurrent methotrexate, an increase in the dose frequency of adalimumab to 40 mg once weekly may provide greater benefit (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).c)  In clinical trials, subcutaneous adalimumab 20 or 40 mg every other week has been added to stable doses of methotrexate, improving response rates (Furst et al, 2001; Keystone et al, 2001a). Improvement has tended to be greater with the 40-mg dose, although this was not statistically significant. Higher doses (i.e., 80 mg) did not improve responses compared to lower doses (Keystone et al, 2001a). In one combination trial, adalimumab was given every other week to every other month, depending on clinical response (Sorbera et al, 2001b). In a phase III study, 40 mg every other week was added to prior DMARD therapy (at least 4 DMARDs), producing improvement in the ACR response (Anon, 2002a).d)  Treatment with adalimumab has been given for up to 4 years (Sorbera et al, 2001b).

1.3.6   Dosage in Other Disease States A)  Therapy should be discontinued if a lupus-like syndrome develops (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

 1.4   Pediatric Dosage

Normal Dosage

Dosage in Other Disease States

1.4.1   Normal Dosage

Subcutaneous route

Juvenile idiopathic arthritis

1.4.1.A   Subcutaneous route

1.4.1.A.1   Crohn's disease (Moderate to Severe), In patients with an inadequate response to conventional therapy a)  Weight of 40 Kilograms or Greater1)  An adalimumab loading dose of 160 milligrams (mg) subcutaneously (subQ) once at weeks 0 and 2 followed by a maintenance dosage of 80 mg subQ once every other week for 48 weeks (starting on week 4) was given to pediatric patients who weighed 40 kilograms or greater in one clinical trial (Viola et al, 2009).b)  Weight of Less than 40 Kilograms1)  An adalimumab loading dose of 80 milligrams (mg) subcutaneously (subQ) once at weeks 0 and 2 followed by a maintenance dosage of 40 mg subQ once every other week for 48 weeks (starting on week 4) was given to most patients who weighed less than 40 kilograms in one clinical trial (Viola et al, 2009).

1.4.1.B   Juvenile idiopathic arthritis 1)  The recommended dose in patients age 4 years and older, weighing 15 kilograms (kg) (33 pounds) to less than 30 kg (66 pounds) is 20 mg subcutaneously (subQ) every other week. In patients weighing 30 kg (66 pounds) or greater, the recommended dose is 40 mg subQ every other week. Concomitant therapy with methotrexate, glucocorticoids, salicylates, NSAIDs, or analgesics may be continued during adalimumab treatment (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

1.4.5   Dosage in Other Disease States A)  Therapy should be discontinued if a lupus-like syndrome develops (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

 2.0   Pharmacokinetics

Onset and Duration

Drug Concentration Levels

ADME

 2.1   Onset and Duration A)  Onset1)  Initial Responsea)  RHEUMATOID ARTHRITIS, INTRAVENOUS: 24 hours to 7 days (van de Putte et al, 1998; Barrera et al, 2001; Kempeni, 1999).1)  Represents time to acute clinical improvement (Disease Activity Score (DAS)) following a single intravenous dose.2)  Peak Responsea)  RHEUMATOID ARTHRITIS, INTRAVENOUS: 1 to 2 weeks (van de Putte et al, 1998; Kempeni, 1999; Kempeni, 2000).1)  Represents time to maximal (acute) clinical improvement (Disease Activity Score (DAS)) following a single intravenous dose.b)  RHEUMATOID ARTHRITIS, SUBCUTANEOUS: within 3 months (van de Putte et al, 1999; van de Putte et al, 2000; Schattenkirchner et al, 1998).1)  Represents time to maximal sustained benefit during treatment with weekly doses; values are based on time-points of patient evaluation.B)  Duration1)  Single Dosea)  RHEUMATOID ARTHRITIS, INTRAVENOUS: up to 12 weeks (van de Putte et al, 1998).1)  Value represents duration of acute clinical improvement (Disease Activity Score (DAS)) in some patients following a single intravenous dose; benefits persisted for one month or less in most.

 2.2   Drug Concentration Levels A)  Therapeutic Drug Concentration1)  Not established; plasma-level monitoring is not used clinically.B)  Time to Peak Concentration1)  INTRAVENOUS: Plasma levels of adalimumab have increased proportionately with increasing doses (Kempeni, 1999). Quantitative data are unavailable.

2)  SUBCUTANEOUS: Following a single subcutaneous dose of 40 mg in healthy subjects, a mean peak plasma level of 4.7 mcg/mL was observed, occurring in 131 hours (Prod Info Humira(TM), 2002b).3)  Plasma levels during repeat subcutaneous administration have been comparable to those observed during repeat intravenous dosing (Schattenkirchner et al, 1998; Sorbera et al, 2001).

 2.3   ADME

Absorption

Distribution

Excretion

Elimination Half-life

2.3.1   Absorption A)  Bioavailability1)  SUBCUTANEOUS, SOLUTION: 64% (Prod Info Humira(TM), 2002b).

2.3.2   Distribution A)  Distribution Sites1)  OTHER DISTRIBUTION SITESa)  SYNOVIAL FLUID, 31 to 96% of plasma levels (RA patients) (Prod Info Humira(TM), 2002b).B)  Distribution Kinetics1)  Volume of Distributiona)  approximately 70 mL/kg (intravenous doses) (Kempeni, 1999; Sorbera et al, 2001).

2.3.4   Excretion A)  Total Body Clearance1)  0.18 to 0.27 mL/min (intravenous dosing) (Kempeni, 1999; Sorbera et al, 2001).a)  A slight increase in the clearance of methotrexate has been observed during combined therapy with intravenous adalimumab in rheumatoid arthritis patients (Weisman et al, 2000).b)  The clearance of adalimumab is reduced during concurrent methotrexate therapy. The manufacturer suggests that dose adjustments are not required for either methotrexate or adalimumab (Prod Info Humira(TM), 2002b).c)  Clearance has tended to be higher in the presence of anti-adalimumab antibodies; clearance tends to be lower in older patients (40 to greater than 75 years) (Prod Info Humira(TM), 2002b).

2.3.5   Elimination Half-life A)  Parent Compound1)  ELIMINATION HALF-LIFEa)  10 to 18 days (intravenous doses) (Sorbera et al, 2001; Weisman et al, 2000; van de Putte et al, 1998; Kempeni, 1999).1)  Not dose-dependent.

 3.0   Cautions

Contraindications

Precautions

Adverse Reactions

Teratogenicity/Effects in Pregnancy/Breastfeeding

Drug Interactions

3.0.A   Black Box WARNING1)  Subcutaneous (Kit)Serious InfectionsPatients treated with adalimumab are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.Adalimumab should be discontinued if a patient develops a serious infection or sepsis.Reported infections include:

Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before adalimumab use and during therapy. Treatment for latent infection should be initiated prior to adalimumab use.Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric antifungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.Bacterial, viral and other infections due to opportunistic pathogens.The risks and benefits of treatment with adalimumab should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with adalimumab, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.MalignanciesLymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, of which adalimumab is a member (Prod Info HUMIRA(R) subcutaneous injection, 2009).

 3.1   Contraindications A)  specific contraindications have not been determined (Prod Info HUMIRA(R) subcutaneous injection, 2009)

 3.2   Precautions A)  children, adolescents, and young adults; lymphoma and other cancers have been reported (Prod Info HUMIRA(R) subcutaneous injection, 2009)B)  serious infections (eg, tuberculosis, invasive fungal infections, and other opportunistic infections), including fatalities, have been reported, especially with concomitant immunosuppressant use; do not initiate therapy in patients with active infections (including chronic or localized infections); discontinue therapy if a serious infection or sepsis develops (Prod Info HUMIRA(R) subcutaneous injection, 2009)C)  TB, reactivation or new-onset; may occur; increased risk in patients with potential exposure due to travel or residence in endemic areas or close personal contact with active TB or with history of latent or active disease, regardless of previous Bacille Calmette-Guerin vaccination (Prod Info HUMIRA(R) subcutaneous injection, 2009)D)  anaphylaxis and angioneurotic edema have been reported; requires discontinuation of therapy (Prod Info HUMIRA(R) subcutaneous injection, 2009)E)  autoantibody formation, including lupus-like syndrome; has occurred; discontinue therapy if symptoms occur (Prod Info HUMIRA(R) subcutaneous injection, 2009)F)  CNS demyelinating disorders, new onset or worsening of preexisting condition may occur (Prod Info HUMIRA(R) subcutaneous injection, 2009)G)  concomitant use with anakinra is not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2009)H)  concomitant use with live vaccine not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2009)I)  congestive heart failure, new-onset or worsening; has been reported; monitoring recommended; discontinuation may be necessary (Prod Info HUMIRA(R) subcutaneous injection, 2009)J)  hematologic abnormalities (eg, pancytopenia, aplastic anemia) have occurred; may require discontinuation of therapy (Prod Info HUMIRA(R) subcutaneous injection, 2009)K)  hepatitis B, chronic carriers; increased risk of reactivation, some cases fatal, including several months after therapy termination; monitoring recommended; discontinuation and supportive treatment may be necessary (Prod Info HUMIRA(R) subcutaneous injection, 2009)L)  juvenile rheumatoid arthritis patients should be brought up-to-date on all immunization requirements, when possible, prior to beginning treatment with adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2009)M)  latex sensitivity; needle cover of prefilled syringe contains latex (Prod Info HUMIRA(R) subcutaneous injection, 2009)N)  malignancies, history or new-onset including lymphomas and acute and chronic leukemia (US Food and Drug Administration, 2009); increased risk of developing other malignancies (Prod Info HUMIRA(R) subcutaneous injection, 2009)O)  rheumatoid arthritis, particularly highly active disease; higher risk for developing lymphoma (Prod Info HUMIRA(R) subcutaneous injection, 2009)P)  report suspected adverse events to Abbott Laboratories at 1-800-633-9110, or to the US Food and Drug Administration (FDA) at 1-800-FDA-1088 or www.fda.gov/medwatch (Prod Info HUMIRA(R) subcutaneous injection, 2009)

 3.3   Adverse Reactions

Cardiovascular Effects

Dermatologic Effects

Endocrine/Metabolic Effects

Gastrointestinal Effects

Hematologic Effects

Hepatic Effects

Immunologic Effects

Musculoskeletal Effects

Neurologic Effects

Ophthalmic Effects

Renal Effects

Reproductive Effects

Respiratory Effects

Other

3.3.1   Cardiovascular Effects

Congestive heart failure

Hypertension

Vasculitis

3.3.1.A   Congestive heart failure 1)  Cases of new onset or worsening congestive heart failure (CHF) have been reported with tumor necrosis factor (TNF) blockers. Although adalimumab has not been formerly studied in patients with CHF, cases of worsening CHF have been observed with adalimumab treatment. In a clinical trial with another TNF blocker, a higher rate of serious CHF-related adverse events was reported. Caution should be exercised when using adalimumab in patients with CHF and these patients should be monitored carefully (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.1.B   Hypertension 1)  Incidence: 5% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), hypertension was reported in 5% of the adalimumab group compared with 3% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.1.C   Vasculitis 1)  A 44 year old Indian women with a 16-year medical history of rheumatoid arthritis developed leucocytoclastic vasculitis within 24 hours of her second dose of subcutaneous adalimumab 40 mg. She presented with a pruritic eruption on the dorsal aspect of both feet and around both medial malleoli. The rash subsided after 5 days. There was no evidence of an infective cause for the eruption. The only other abnormality was an increased C-reactive protein. The patient's underlying rheumatoid arthritis could have been a trigger for the eruption or it may have been the adalimumab. The only medication the patient was currently taking was oral prednisone 5 mg daily. The patient had never experienced any previous vasculitis eruptions. The patient was not rechallenged with adalimumab (Orpin et al, 2006).

3.3.2   Dermatologic Effects

Cellulitis

Erysipelas

Erythema multiforme

Injection site pain

Injection site reaction

Malignant melanoma

Primary cutaneous vasculitis

Psoriasis

Rash

Skin cancer

Stevens-Johnson syndrome

Summary

Urticaria

3.3.2.A   Cellulitis 1)  Incidence: less than 5% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)2)  Cellulitis was reported in less than 5% of patients with rheumatoid arthritis who received adalimumab (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

3.3.2.B   Erysipelas 1)  Incidence: less than 5% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)2)  Erysipelas was reported in less than 5% of patients with rheumatoid arthritis who received adalimumab (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

3.3.2.C   Erythema multiforme 1)  During postmarketing surveillance, erythema multiforme has been reported with adalimumab use (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008; United States Food and Drug Administration, 2008). In general, presenting symptoms of the serious skin reactions were mainly rash and skin lesions on the trunk, legs, arms, shoulder, back, hands, and face (United States Food and Drug Administration, 2008).2)  The United States Food and Drug Administration (FDA) has received postmarketing reports 7 cases of severe skin reactions following adalimumab administration, including 4 cases of erythema multiforme (EM), 2 cases of Stevens-Johnson syndrome (SJS), and 1 case of both EM and SJS. The majority of patients affected were female (85%) and were being treated for rheumatoid arthritis (71%). Two patients were also receiving methotrexate therapy. The median time to skin reaction onset was 60 days, with 3 cases reported within the first 2 months of therapy. There were no fatalities, although hospitalization was required in one case. The skin reactions resolved with drug discontinuation in 4 patients and no attempts at rechallenge were reported (United States Food and Drug Administration, 2008).3)  Erythema multiforme (EM) was diagnosed in a 49-year-old man with rheumatoid arthritis one month after beginning adalimumab therapy. The patient was also taking methadone, prednisone, multivitamins, and iron, although the start/stop times in relation to the adalimumab were not reported. After receiving the second adalimumab injection, red skin lesions on the arms and body developed and were identified as EM following a skin biopsy. The patient recovered upon discontinuation of adalimumab (United States Food and Drug Administration, 2008).

3.3.2.D   Injection site pain 1)  Incidence: 12% to 19% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)2)  In a placebo-controlled clinical study in patients with rheumatoid arthritis, injection-site pain was reported in 12% of patients in the adalimumab group (n=705) and 12% of patients in the placebo group (n=690) (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).3)  In clinical trials in pediatric patients (aged 4 to 17 years) with polyarticular juvenile idiopathic arthritis (n=171), injection-site pain was reported in 19% of patients treated with adalimumab (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

3.3.2.E   Injection site reaction 1)  Incidence: 8% to 20% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)2)  The most common adverse event associated with adalimumab therapy during clinical trials was mild injection site reaction. In placebo-controlled trials, injection-site reaction, which included erythema and/or itching, hemorrhage, pain or swelling, was reported in 20% of the adalimumab-treated patients compared with 14% of the placebo-treated patients. 3)  In a large, placebo-controlled clinical study in patients with rheumatoid arthritis, injection-site reaction (not including erythema and/or itching, hemorrhage, pain or swelling) was reported in 8% of patients in the adalimumab group (n=705) compared to 1% of patients in the placebo group (n=690) (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

4)  In clinical trials in pediatric patients (aged 4 to 17 years) with polyarticular juvenile idiopathic arthritis (n=171), injection-site reaction was reported in 16% of patients treated with adalimumab (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).5)  Injection-site reactions were reported in 15% of patients receiving repeat doses of subcutaneous adalimumab in one trial compared with 3% of placebo recipients (Keystone et al, 2001).

3.3.2.F   Malignant melanoma 1)  Results from meta and exposure adjusted pooled analyses involving 8808 patients with rheumatoid arthritis found no increase in the odds of non-cutaneous cancers plus melanoma associated with recommended doses of adalimumab, etanercept, or infliximab. Results of 18 randomized controlled trials with over 7846 years of follow-up were included in the analyses. The odds ratio for non-cutaneous cancers plus melanoma using the unadjusted meta-analytic method was 1.31 (95% confidence interval, 0.69 to 2.48). In the studies that reported incidence of malignancies, 34 of 4099 patients who were randomized to recommended doses over 3805 patient-years developed malignancies (0.8%). Of these malignancies, 12 occurred after crossover while 10 were unable to be allocated to the controlled or uncontrolled portion of the trial. Of the 2672 control patients, 15 (0.6%) developed a malignancy over 2124 patient-years. Overall, there was no increased risk for lymphomas, non-melanoma skin cancers, or the composite endpoint of non-cutaneous cancer and melanoma at recommended doses (Leombruno et al, 2008).2)  More cases of malignancies have occurred in patients receiving adalimumab than in controls; however the number and type are similar to what would be expected in the general population. In controlled portions of adalimumab trials of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis, malignancies other than lymphoma and non-melanoma skin cancer including, breast, colon, prostate, lung, and melanoma, were observed at a rate of 0.6 per 100 patient-years (95% confidence interval (CI), 0.3 to 1) among 3853 adalimumab-treated patients (median treatment duration of 5.5 months) compared with a rate of 0.4 per 100 patient-years (95% CI, 0.2 to 1) for 2183 control-treated patients (median treatment duration of 3.9 months) (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

3.3.2.G   Primary cutaneous vasculitis 1)  During postmarketing surveillance, cutaneous vasculitis has been reported with adalimumab use (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

3.3.2.H   Psoriasis 1)  A review of 69 cases of new onset psoriasis included 17 cases of pustular and 15 cases of palmoplantar psoriasis in patients using tumor necrosis factor (TNF) blockers to treat autoimmune and rheumatic conditions other than psoriasis or psoriatic arthritis. Two cases occurred in pediatric patients. The onset of psoriasis occurred from weeks to years after initiating treatment with TNF blockers. Twelve cases required hospitalization. None of the cases had a history of psoriasis prior to beginning TNF blocker therapy (US Food and Drug Administration, 2009).

3.3.2.I   Rash 1)  Incidence: 12% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)2)  In a placebo-controlled clinical study in patients with rheumatoid arthritis, rash was reported in 12% of patients in the adalimumab group (n=705) compared to 6% of patients in the placebo group (n=690) (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

3.3.2.J   Skin cancer 1)  Results from meta and exposure adjusted pooled analyses involving 8808 patients with rheumatoid arthritis found no increase in the odds of non-melanoma skin cancers associated with recommended doses of adalimumab, etanercept, or infliximab. Results of 18 randomized controlled trials with over 7846 years of follow-up were included in the analyses. The odds ratio for non-melanoma skin cancer using the unadjusted meta-analytic method was 1.27 (95% confidence interval, 0.67 to 2.42). In the studies that reported incidence of malignancies, 34 of 4099 patients who were randomized to recommended doses over 3805 patient-years developed malignancies (0.8%). Of these malignancies, 12 occurred after crossover while 10 were unable to be allocated to the controlled or uncontrolled portion of the trial. Of the 2672 control patients, 15 (0.6%) developed a malignancy over 2124 patient-years. Overall, there was no increased risk for lymphomas, non-melanoma skin cancers, or the composite endpoint of non-cutaneous cancer and melanoma at recommended doses (Leombruno et al, 2008).2)  More cases of malignancies have occurred in patients receiving adalimumab than in controls; however the number and type are similar to what would be expected in the general population. In controlled trials of patients treated with adalimumab for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis, non-melanoma skin cancers occurred at a rate of 0.9 per 100 patient-years (95% confidence interval (CI), 0.57 to 1.35 ) among 3853 adalimumab-treated patients compared to a rate of 0.3 per 100 patient-years (95% CI, 0.08 to 0.8) among 2183 control patients (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

3.3.2.K   Stevens-Johnson syndrome 1)  Serious skin reactions, including Stevens-Johnson syndrome (SJS), have been reported rarely with the use of tumor necrosis factor-alpha antagonists, including adalimumab. In general, presenting symptoms of the serious skin reactions were mainly rash and skin lesions on the trunk, legs, arms, shoulder, back, hands, and face. Additionally, oral mucositis or ulceration, genital ulceration, and/or fever were present in some SJS cases (United States Food and Drug Administration, 2008).2)  The United States Food and Drug Administration has received postmarketing reports of 7 cases of serious skin

reactions following adalimumab administration, including 4 cases of erythema multiforme (EM), 2 cases of Stevens-Johnson syndrome (SJS), and 1 case of both EM and SJS. The majority of patients affected were female (85%) and were being treated for rheumatoid arthritis (71%). Two patients were also receiving methotrexate therapy. The median time to skin reaction onset was 60 days, with 3 cases reported within the first 2 months of adalimumab therapy. There were no fatalities, although hospitalization was required in one case. The skin reactions resolved with drug discontinuation in 4 patients and no attempts at rechallenge were reported. (United States Food and Drug Administration, 2008).

3.3.2.L   Summary 1)  In clinical trials, the most common adverse event in patients receiving adalimumab was injection-site reaction with erythema and/or itching, hemorrhage, pain, or swelling (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008). Additionally, rare cases of serious skin reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported in patients receiving adalimumab (United States Food and Drug Administration, 2008; Prod Info HUMIRA(R) solution for subcutaneous injection, 2008). Melanoma and non-melanoma skin cancers have also occurred with adalimumab therapy; however the incidences were similar to what would be expected in the general population (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

3.3.2.M   Urticaria 1)  A case report of a 41-year-old female with a 15-year history of plaque-type psoriasis was started on adalimumab 40 mg subcutaneously twice a week for two weeks, weekly for the next 10 weeks, and then every other week. The patient reported a wheel-like flare with each injection followed by a pruritic, urticarial eruption (primarily on neck and arms) 10 hours post-injection. The reactions became less severe with each injection and required no treatment. After her tenth injection, the only skin reaction was at the injection site and the psoriasis responded dramatically to therapy (George et al, 2006).

3.3.3   Endocrine/Metabolic Effects

Alkaline phosphatase raised

Breast cancer

Hypercholesterolemia

Hyperlipidemia

3.3.3.A   Alkaline phosphatase raised 1)  Incidence: 5% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), increased alkaline phophatase level was reported in 5% of the adalimumab group compared with 3% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.3.B   Breast cancer 1)  More cases of malignancies have occurred in patients receiving adalimumab than in controls; however the number and type are similar to what would be expected in the general population. In controlled portions of adalimumab trials of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis, malignancies other than lymphoma and non-melanoma skin cancer including, breast, colon, prostate, lung, and melanoma, were observed at a rate of 0.6 per 100 patient-years (95% confidence interval (CI), 0.3 to 1) among 3853 adalimumab-treated patients (median treatment duration of 5.5 months) compared with a rate of 0.4 per 100 patient-years (95% CI, 0.2 to 1) for 2183 control-treated patients (median treatment duration of 3.9 months) (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008a).

3.3.3.C   Hypercholesterolemia 1)  Incidence: 6% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), hypercholesterolemia was reported in 6% of the adalimumab group compared with 4% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.3.D   Hyperlipidemia 1)  Incidence: 7% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), hyperlipidemia was reported in 7% of the adalimumab group compared with 5% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.4   Gastrointestinal Effects

Abdominal pain

Colon cancer

Nausea

3.3.4.A   Abdominal pain 1)  Incidence: 7% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), abdominal pain was reported in 7% of the adalimumab group compared with 4% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.4.B   Colon cancer 1)  More cases of malignancies have occurred in patients receiving adalimumab than in controls; however the number and type are similar to what would be expected in the general population. In controlled portions of adalimumab trials of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis, malignancies other than lymphoma and non-melanoma skin cancer including, breast, colon, prostate, lung, and melanoma, were observed at a rate of 0.6 per 100 patient-years (95% confidence interval (CI), 0.3 to 1) among 3853 adalimumab-treated patients (median treatment duration of 5.5 months) compared with a rate of 0.4 per 100 patient-years (95% CI, 0.2 to 1) for 2183 control-treated patients (median treatment duration of 3.9 months) (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008a).

3.3.4.C   Nausea 1)  Incidence: 9% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), nausea was reported in 9% of the adalimumab group compared with 8% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.5   Hematologic Effects

Aplastic anemia

Erythrocytosis

Leukemia

Leukopenia

Pancytopenia

Summary

Thrombocytopenia

3.3.5.A   Aplastic anemia 1)  Incidence: rare (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  Rare cases of pancytopenia, including aplastic anemia have been reported with the use of tumor necrosis factor (TNF) blockers. Causality to adalimumab has not been established. Patients should seek immediate medical attention if signs and symptoms of blood dyscrasias or infection occur and adalimumab discontinuation should be considered in patients with confirmed hematologic abnormalities (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)

3.3.5.B   Erythrocytosis 1)  Incidence: less than 5% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  Polycythemia occurred in less than 5% of patients treated with adalimumab for rheumatoid arthritis (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.5.C   Leukemia 1)  A review of 147 postmarketing reports of leukemia in all patients using tumor necrosis factor (TNF) blockers included 44 cases of acute myeloid leukemia, 31 cases of chronic lymphocytic leukemia and 23 cases of chronic myeloid leukemia. Four cases of leukemia were reported in pediatric patients. Concomitant immunosuppressive therapies were used in 61% of the cases. In 26 of the 30 deaths reported, the cause was attributed to leukemia and was associated with the use of TNF blockers. Leukemia occurred within the first 1 to 2 years of therapy (US Food and Drug Administration, 2009).

3.3.5.D   Leukopenia 1)  Incidence: less than 5% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  Leukopenia has been reported infrequently with the use of tumor necrosis factor (TNF) blockers. Causality to adalimumab has not been established. Patients should seek immediate medical attention if signs and symptoms of blood dyscrasias or infection occur and adalimumab discontinuation should be considered in patients with confirmed hematologic abnormalities (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.5.E   Pancytopenia 1)  Incidence: less than 5% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  Rare cases of pancytopenia have been reported with the use of tumor necrosis factor (TNF) blockers. Causality to adalimumab has not been established. Patients should seek immediate medical attention if signs and symptoms of blood dyscrasias or infection occur and adalimumab discontinuation should be considered in patients with confirmed hematologic abnormalities (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.5.F   Summary 1)  Pancytopenia including aplastic anemia has been reported rarely in association with the use of TNF alpha-blocking agents. Adverse hematologic events, including clinically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been reported infrequently following the administration of adalimumab. The causal relationship of these events to adalimumab is not clear. Patients should be advised to seek medical attention immediately if they develop signs or symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bleeding, bruising, pallor) while taking adalimumab. Consider discontinuation of adalimumab treatment in patients with confirmed significant hematologic abnormalities (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.5.G   Thrombocytopenia 1)  Incidence: rare (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  Thrombocytopenia has been reported infrequently with the use of tumor necrosis factor (TNF) blockers. Causality to adalimumab has not been established. Patients should seek immediate medical attention if signs and symptoms of blood dyscrasias or infection occur and adalimumab discontinuation should be considered in patients with confirmed hematologic abnormalities. Thrombocytopenia has also been reported with adalimumab use during postmarketing surveillance (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.6   Hepatic Effects

Autoimmune hepatitis

Relapsing type B viral hepatitis

3.3.6.A   Autoimmune hepatitis 1)  A 36-year-old female developed autoimmune hepatitis following the administration of adalimumab for the treatment of psoriatic arthritis. The patient presented with psoriasis and psoriatic arthritis. Liver function test were normal and antinuclear antibodies (ANA) undetectable at this time. She was administered adalimumab 50 mg (every other week). Following her first dose, the patient developed nausea and pain in her upper right quadrant. Approximately 3 months following the initiation of adalimumab, her abdominal pain worsened. Upon hospital admission, physical examination found mild hepatomegaly. Laboratory testing revealed elevated liver enzymes and IgG (2260 mg/dL), positive ANA (titer 1:80) and anti-deoxyribonucleic acid (DNA) 1.73 mcg/mL. An abdominal computed tomography showed hepatomegaly without biliary tract obstruction. A liver biopsy revealed signs of autoimmune hepatitis with enlarged portal tracts and hepatic rosettes. Adalimumab was discontinued and prednisone 60 mg in combination with azathioprine 1 mg/kg was initiated. At a 2 month follow-up visit, hepatitis had resolved and ANA titer was undetectable (Adar et al, 2010).

3.3.6.B   Relapsing type B viral hepatitis 1)  Hepatitis B virus (HBV) reactivation has been reported with tumor necrosis factor (TNF) blocker therapy, including adalimumab, in patients who are chronic carriers of the virus. Some cases have been fatal. The majority of these cases occurred in patients who were concomitantly treated with other drugs that suppress the immune system. Patients who are at risk for HBV infection should be evaluated for previous evidence of HBV infection prior to TNF blocker treatment. Caution should be exercised in prescribing a TNF blocker to patients who are carriers of HBV. If treatment with a TNF blocker is required, patients should be closely monitored for signs of active HBV infection throughout treatment and for several months after terminating therapy. If HBV is reactivated during adalimumab treatment, adalimumab should be discontinued and effective antiviral therapy should be initiated. Safety of resuming TNF blocker therapy after HBV reactivation is controlled is unknown. Therefore, adalimumab therapy should be resumed with caution and careful monitoring (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.7   Immunologic Effects

Anaphylaxis

Antibody development, to adalimumab

Antinuclear antibody positive

Herpes zoster

Immune hypersensitivity reaction

Lupus erythematosus

Malignant lymphoma

Varicella

3.3.7.A   Anaphylaxis 1)  Incidence: rare (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  During postmarketing surveillance, anaphylaxis has been reported with adalimumab use (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.7.B   Antibody development, to adalimumab 1)  Incidence: 1% to 12% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In rheumatoid arthritis studies in which 1062 patients treated with adalimumab were tested for antibodies to adalimumab during a 6- to 12-month period, low-titer in vitro neutralizing antibodies to adalimumab were reported in about 5% of adalimumab-treated patients at least once during treatment. Antibody development was 1% in patients receiving concomitant adalimumab and methotrexate compared with 12% in those receiving adalimumab monotherapy. With usual adalimumab doses of 40 mg every other week, the American College of Rheumatology (ACR) 20 response was reduced in those who were antibody-positive compared with those who were antibody-negative. No correlation between antibody response and adverse events has been reported. The rate of antibody development to adalimumab was similar in patients being treated with adalimumab for ankylosing spondylitis and psoriatic arthritis compared with those being treated for rheumatoid arthritis. However, the rate of antibody development to adalimumab was 7% for patients receiving concomitant adalimumab and methotrexate for psoriatic arthritis compared with 1% for those receiving concomitant therapy for rheumatoid arthritis. The rate of antibody development was 2.6% for patients receiving adalimumab for Crohn's disease (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.7.C   Antinuclear antibody positive 1)  Incidence: 12% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In rheumatoid arthritis studies in which 3046 patients with negative baseline antinuclear antibody (ANA) titers were treated with adalimumab, positive ANA titers were reported in 12% of the adalimumab group compared with 7% of the placebo group at week 24 (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.7.D   Herpes zoster 1)  Patients receiving anti-TNF-alfa inhibitors or conventional disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis showed an increased risk for herpes zoster when compared with a control group. German researchers analyzed data from 5040 patients registered with RABBIT, a prospective cohort study, from May 2001 to December 2006 with follow-up through 2011. Patients show a significantly higher incidence rate for herpes zoster treated with either anti-TNF-alfa inhibitor or DMARD treatment (9.8%; CI 95%, 7.5 to 12.6 per 1000 years and 5.1%; CI 95%, 3.2 to 7.8 per 1000 patient years, respectively). Monoclonal antibodies and etanercept showed rates of 11.1%; 95% CI, 7.9 to 15.1 per 1000 patient years and 8.1%; 95% CI, 5.0 to 12.4 per 1000 patient years, respectively. (Strangfeld et al, 2009).

3.3.7.E   Immune hypersensitivity reaction 1)  Incidence: approximately 1% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In postmarketing experience, anaphylaxis has been reported rarely following adalimumab administration. If an anaphylactic or other serious allergic reaction occurs, administration of adalimumab should be discontinued immediately and appropriate therapy instituted. In clinical trials, allergic reactions overall (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed in approximately 1% of patients (Prod Info HUMIRA(R) subcutaneous injection, 2005).

3.3.7.F   Lupus erythematosus 1)  Incidence: rare (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In rheumatoid arthritis controlled trials including 3046 patients treated with adalimumab, 2 patients developed clinical symptoms suggestive of a new onset lupus-like syndrome after 24 weeks of therapy with adalimumab. The patients improved clinically after the drug was discontinued, and no signs of lupus nephritis or central nervous system symptoms were reported (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.7.G   Malignant lymphoma

1)  Incidence: rare (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008a)2)  Children and Adolescentsa)  An increased risk of lymphoma and other malignancies was reported in children and adolescents receiving tumor necrosis factor (TNF) blockers. An 8-year review identified 48 US and non-US cases of malignancies in children and adolescents receiving TNF blockers with approximately half of the cases reported as lymphomas, including hepatosplenic T-cell (10 cases), Hodgkin's (6 cases), and non-Hodgkin's (7 cases) lymphoma. Leukemia (6 cases), malignant melanoma (3 cases), and solid organ cancers were also reported. Most of the cases (88%) were also receiving concurrent immunosuppressive therapy with agents such as azathioprine and methotrexate. Rare malignancies included leiomyosarcoma (1 case), hepatic malignancy (1 case), and renal cell carcinoma (1 case). Of the cases reported, 31 cases were associated with infliximab (5 cases with rheumatic conditions), 15 cases were associated with etanercept (14 cases with rheumatic conditions), and 2 cases were associated with adalimumab (1 case with rheumatic conditions). Overall, 11 cases of malignancy were fatal, and causes of death included hepatosplenic T-cell lymphoma (9 cases), T-cell lymphoma (1 case), and sepsis following remission of the lymphoma (1 case). No specific dose was identified as being associated with the development of the malignancies (US Food and Drug Administration, 2009; US Food and Drug Administration, 2009).3)  Results from meta and exposure adjusted pooled analyses involving 8808 patients with rheumatoid arthritis found no increase in the odds of lymphoma associated with recommended doses of adalimumab, etanercept, or infliximab. Results of 18 randomized controlled trials with over 7846 years of follow-up were included in the analyses. The odds ratio for lymphoma using the unadjusted meta-analytic method was 1.26 (95% confidence interval, 0.52 to 3.06). In the studies that reported incidence of malignancies, 34 of 4099 patients who were randomized to recommended doses over 3805 patient-years developed malignancies (0.8%). Of these malignancies, 12 occurred after crossover while 10 were unable to be allocated to the controlled or uncontrolled portion of the trial. Of the 2672 control patients, 15 (0.6%) developed a malignancy over 2124 patient-years. Overall, there was no increased risk for lymphomas, non-melanoma skin cancers, or the composite endpoint of non-cutaneous cancer and melanoma at recommended doses (Leombruno et al, 2008).4)  Lymphoma has occurred more frequently in patients treated with adalimumab than in patients treated with placebo, and at an approximately 3-fold higher rate than expected in the general population. In controlled trials of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis, 2 lymphomas occurred in the adalimumab group (n=3853) compared with 1 lymphoma in the control group (n=2183). In combined controlled and uncontrolled open-label portions of the clinical trials with a median duration of about 2 years, including 6539 patients and more than 16,000 patient-years of adalimumab therapy, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. Patients with rheumatoid arthritis, especially those with highly active disease, are at an increased risk for developing lymphoma (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008a).

3.3.7.H   Varicella 1)  In a case report, a 42-year-old female patient receiving adalimumab 40 milligrams subcutaneously biweekly for 70 weeks for the treatment of rheumatoid arthritis contracted primary varicella infection with associated hepatic involvement. The patient's medical history included concomitant medications (methotrexate, deflazacort, folate, omeprazole, aspirin, and amlodipine), unconfirmed chickenpox during childhood, normal hepatic function, and a 15-year history of rheumatoid arthritis. Despite denial of any recent chickenpox exposure, skin examination revealed generalized, umbilicated vesicles with fluid demonstrating a positive amplified band for varicella zoster virus on polymerase chain reaction. The patient's AST and ALT peaked at 896 and 731 international units/liter (IU/L), respectively. Following 4 days of intravenous acyclovir, the patient's symptoms began to resolve with complete recovery on the 7th day with AST and ALT of 77 and 240 IU/L (Lee et al, 2007).

3.3.8   Musculoskeletal Effects

3.3.8.A   Backache 1)  Incidence: 6% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), back pain was reported in 6% of the adalimumab group compared with 4% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.9   Neurologic Effects

Demyelinating disease of central nervous system

Headache

Multiple sclerosis

Paresthesia

Subdural hematoma

Tremor

3.3.9.A   Demyelinating disease of central nervous system 1)  Incidence: rare (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  Rare cases of new-onset or exacerbation of clinical and/or radiologic evidence of demyelinating disease have been reported in association with tumor necrosis factor (TNF) blockers, including adalimumab. Caution should be exercised in considering the use of adalimumab in patients with a history of CNS demyelinating disorders (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.9.B   Headache 1)  Incidence: 12% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), headache was reported in 12% of the adalimumab group compared with 8% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.9.C   Multiple sclerosis 1)  Incidence: less than 5% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  Multiple sclerosis occurred in less than 5% of patients treated with adalimumab for rheumatoid arthritis (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.9.D   Paresthesia 1)  Incidence: less than 5% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  Paresthesia occurred in less than 5% of patients treated with adalimumab for rheumatoid arthritis (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.9.E   Subdural hematoma 1)  Incidence: less than 5% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  Subdural hematoma occurred in less than 5% patients treated with adalimumab for rheumatoid arthritis (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.9.F   Tremor 1)  Incidence: less than 5% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  Tremor occurred in less than 5% patients treated with adalimumab for rheumatoid arthritis (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.10   Ophthalmic Effects

3.3.10.A   Optic neuritis 1)  Two cases of optic neuritis associated with adalimumab have been reported (Chung et al, 2006).2)  The first was a case report of a 55 year old man with no previous history of ocular disease whom presented with a decrease in central vision in his right eye after adalimumab 40 mg injections every other week for a total of eight injections over four months to treat a severe psoriatic rash on his trunk, legs and elbows as well as tenderness and swelling in wrists and fingers. The patient previously tried oral methotrexate 15 mg weekly which was reduced to 10 mg weekly when adalimumab was initiated. Ocular coherence tomography revealed abnormally thickened circumpapillary nerve fiber layer and magnetic resonance imaging (MRI) of the brain and orbits revealed enhancement in the intracanalicular portion of the right optic nerve. The patient was diagnosed with drug associated retrobulbar optic neuritis and adalimumab was discontinued. The patient's visual acuity improved within a week with 250 mg methylprednisolone intravenously four times daily for 3 days followed by an oral prednisone taper. The patient suffered no further neurologic events 1 year later. The patient was reported to have a past medical history of type II diabetes mellitus, psoriatic arthritis, and hyperlipidemia and the patient was receiving standard medications of the following: simvastatin, atenolol, aspirin, metformin, steroid creams, paroxetine, risperidone, and folate. The case report did not specify the indication or how long the patient had been taking paroxetine or risperidone (Chung et al, 2006). 3)  A 40-year-old man with rheumatoid arthritis presented with gradual right eye visual loss with pain on movement. The patient had been taking adalimumab 40 mg subcutaneously every other week for the past year. The patient had no previous ocular or neurologic disease history. A diagnosis of demyelinating optic neuritis was made after an MRI revealed mild enhancement of the intra-orbital right optic nerve and several predominantly periventricular hyperintense lesions and two non-enhancing demyelinating plaques. The patient's vision gradually recovered spontaneously 4 months after visual loss onset. Visual tests showed a mild central scotoma in the right eye with a mild temporal atrophy of the affected optic disc. Adalimumab was not discontinued due to good control of his rheumatoid arthritis. The report did not specify information about past medical history or concurrent medications (Chung et al, 2006).

3.3.13   Renal Effects

Hematuria

Urinary tract infectious disease

3.3.13.A   Hematuria 1)  Incidence: 5% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), hematuria was reported in 5% of the adalimumab group compared with 4% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.13.B   Urinary tract infectious disease 1)  Incidence: 8% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), urinary tract infection was reported in 8% of the adalimumab group compared with 5% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.14   Reproductive Effects

3.3.14.A   Prostate cancer 1)  More cases of malignancies have occurred in patients receiving adalimumab than in controls; however the number and type are similar to what would be expected in the general population. In controlled portions of adalimumab trials of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis, malignancies other than lymphoma and non-melanoma skin cancer including, breast, colon, prostate, lung, and melanoma, were observed at a rate of 0.6 per 100 patient-years (95% confidence interval (CI), 0.3 to 1) among 3853 adalimumab-treated patients (median treatment duration of 5.5 months) compared with a rate of 0.4 per 100 patient-years (95% CI, 0.2 to 1) for 2183 control-treated patients (median treatment duration of 3.9 months) (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008a).

3.3.15   Respiratory Effects

Interstitial lung disease

Lung cancer

Pulmonary fibrosis

Sinusitis

Summary

Tuberculosis

Upper respiratory infection

3.3.15.A   Interstitial lung disease 1)  Interstitial lung disease, including pulmonary fibrosis, has been reported with adalimumab use during postmarketing surveillance (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.15.B   Lung cancer 1)  More cases of malignancies have occurred in patients receiving adalimumab than in controls; however the number and type are similar to what would be expected in the general population. In controlled portions of adalimumab trials of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis, malignancies other than lymphoma and non-melanoma skin cancer including, breast, colon, prostate, lung, and melanoma, were observed at a rate of 0.6 per 100 patient-years (95% confidence interval (CI), 0.3 to 1) among 3853 adalimumab-treated patients (median treatment duration of 5.5 months) compared with a rate of 0.4 per 100 patient-years (95% CI, 0.2 to 1) for 2183 control-treated patients (median treatment duration of 3.9 months) (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008a).

3.3.15.C   Pulmonary fibrosis 1)  During postmarketing surveillance, pulmonary fibrosis has been reported with adalimumab use (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.15.D   Sinusitis 1)  Incidence: 11% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), sinusitis was reported in 11% of the

adalimumab group compared with 9% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.15.E   Summary 1)  Tuberculosis has occurred rarely. Upper respiratory tract infections and sinusitis occurred in 17% and 11% of patients, respectively, receiving 40 mg every other week in placebo-controlled studies (slightly higher incidence than placebo) (Prod Info HUMIRA(R) subcutaneous injection, 2005).

3.3.15.F   Tuberculosis 1)  Incidence: rare (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  Tuberculosis, frequently disseminated or extrapulmonary at clinical presentation, has been reported in some patients. The incidence of tuberculosis was 0.07 to 0.26 per 100 patient-years from collective study data in global trials (n=13,000), and US and Canadian trials (n=4500). This included reports of miliary, lymphatic, peritoneal, and pulmonary tuberculosis, with some fatalities. Most cases occurred within the first 8 months following initiation of therapy; and may reflect recrudescence of latent disease. There was some evidence of a greater occurrence of tuberculosis reactivation at higher than recommended doses. Antituberculosis treatment of patients with latent tuberculosis infection may reduce the risk of reactivation in patients treated with adalimumab. However, there have been cases in which patients developed active tuberculosis while being treated with adalimumab following a screening for latent tuberculosis that was negative. The potential for undetected latent tuberculosis should be taken into account, particularly in patients who have migrated from or travelled to regions where tuberculosis is endemic and in patients who have been in close contact with a person with active tuberculosis. All patients should be evaluated for possible tuberculosis risk factors and tested for active or latent tuberculosis with a tuberculin skin test prior to initiating adalimumab and during treatment. Treatment of latent infection should be started prior to adalimumab therapy. Patients should be monitored for signs and symptoms of active tuberculosis, including those who tested negative for latent tuberculosis (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.15.G   Upper respiratory infection 1)  Incidence: 17% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), upper respiratory infection was reported in 17% of the adalimumab group compared with 13% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.16   Other

Summary

Angioedema

Cancer

Death

Infectious disease

Influenza-like symptoms

3.3.16.A   Summary 1)  Results from meta and exposure adjusted pooled analyses involving 8808 patients with rheumatoid arthritis found no increase in the odds of serious adverse events associated with recommended doses of adalimumab, etanercept, or infliximab. Results of 18 randomized controlled trials with over 7846 years of follow-up were included in the analyses. The odds ratio for serious adverse events using the unadjusted meta-analytic method was 1.11 (95% confidence interval, 0.94 to 1.32). In the studies that reported the incidence of serious adverse events, 499 of 3581 patients (13.9%) who were initially randomized to recommended doses over 3032 patient-years experienced a serious adverse event while 257 of 2178 control patients (11.8%) over 1452 patient-years experienced a serious adverse event. When 3 different risk estimation methods were used, there was no evidence of increased serious adverse events with any of the anti-tumor necrosis factor treatments when administered at recommended doses (Leombruno et al, 2008).

3.3.16.B   Angioedema 1)  During postmarketing surveillance, angioneurotic edema has been reported with adalimumab use (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.16.C   Cancer 1)  Children and Adolescents

a)  An increased risk of lymphoma and other malignancies was reported in children and adolescents receiving tumor necrosis factor (TNF) blockers. An 8-year review identified 48 US and non-US cases of malignancies in children and adolescents receiving TNF blockers with approximately half of the cases reported as lymphomas, including hepatosplenic T-cell (10 cases), Hodgkin's (6 cases), and non-Hodgkin's (7 cases) lymphoma. Leukemia (6 cases), malignant melanoma (3 cases), and solid organ cancers were also reported. Most of the cases (88%) were also receiving concurrent immunosuppressive therapy with agents such as azathioprine and methotrexate. Rare malignancies included leiomyosarcoma (1 case), hepatic malignancy (1 case), and renal cell carcinoma (1 case). Of the cases reported, 31 cases were associated with infliximab (5 cases with rheumatic conditions), 15 cases were associated with etanercept (14 cases with rheumatic conditions), and 2 cases were associated with adalimumab (1 case with rheumatic conditions). Overall, 11 cases of malignancy were fatal, and causes of death included hepatosplenic T-cell lymphoma (9 cases), T-cell lymphoma (1 case), and sepsis following remission of the lymphoma (1 case). No specific dose was identified as being associated with the development of the malignancies (US Food and Drug Administration, 2009; US Food and Drug Administration, 2009).2)  More cases of malignancies have occurred in patients receiving adalimumab than in controls; however the number and type are similar to what would be expected in the general population. In controlled portions of adalimumab trials of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis, malignancies other than lymphoma and non-melanoma skin cancer including, breast, colon, prostate, lung, and melanoma, were observed at a rate of 0.6 per 100 patient-years (95% confidence interval (CI), 0.3 to 1) among 3853 adalimumab-treated patients (median treatment duration of 5.5 months) compared with a rate of 0.4 per 100 patient-years (95% CI, 0.2 to 1) for 2183 control-treated patients (median treatment duration of 3.9 months). Non-melanoma skin cancers occurred at a rate of 0.9 per 100 patient-years (95% CI, 0.57 to 1.35) among the adalimumab-treated compared with a rate of 0.3 per 100 patient-years (95% CI, 0.08 to 0.8) among the control-treated patients (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008a).3)  Lymphoma has occurred more frequently in patients treated with adalimumab than in patients treated with placebo, and at an approximately 3-fold higher rate than expected in the general population. In controlled trials of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis, 2 lymphomas occurred in the adalimumab group (n=3853) compared with 1 lymphoma in the control group (n=2183). In combined controlled and uncontrolled open-label portions of the clinical trials with a median duration of about 2 years, including 6539 patients and more than 16,000 patient-years of adalimumab therapy, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. Patients with rheumatoid arthritis, especially those with highly active disease, are at an increased risk for developing lymphoma (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008a).

3.3.16.D   Death 1)  Results from meta and exposure adjusted pooled analyses involving 8808 patients with rheumatoid arthritis found no increase in the odds of death associated with recommended doses of adalimumab, etanercept, or infliximab. Results of 18 randomized controlled trials with over 7846 years of follow-up were included in the analyses. The odds ratio for death using the unadjusted meta-analytic method was 1.39 (95% confidence interval, 0.74 to 2.62). In the studies that reported mortality (n=17), 23 deaths occurred in 4097 patients (0.6%) who were initially randomized to recommended doses over 3800 patient-years while 2 deaths occurred in 414 patients originally randomized to placebo who crossed over to recommended dose therapy. Eleven deaths occurred in 2671 control patients (0.4%) over 2124 patient-years. When 3 different risk estimation methods were used, there was no evidence of increased mortality with any of the anti-tumor necrosis factor treatments when administered at recommended doses (Leombruno et al, 2008).

3.3.16.E   Infectious disease 1)  Results from meta and exposure adjusted pooled analyses involving 8808 patients with rheumatoid arthritis found no increase in the odds of serious infections associated with recommended doses of adalimumab, etanercept, or infliximab. Results of 18 randomized controlled trials with over 7846 years of follow-up were included in the analyses. The odds ratio for serious infection using the unadjusted meta-analytic method was 1.21 (95% confidence interval (CI), 0.89 to 1.63). In the studies that reported occurrence of serious infections, 133 serious infections occurred in 3729 patients (3.6%) who were randomized to recommended doses over 3714 patient-years while 72 serous infections occurred in 2618 control patients (2.8%) over 2116 patient-years. When 3 different risk estimation methods were used, there was no evidence of increased risk for serious infection with any of the anti-tumor necrosis factor treatments when administered at recommended doses. High-dose adalimumab therapy (mean dose 49 mg/week) and high-dose infliximab therapy (mean dose 1.16 mg/kg/week) was associated with a two-fold increase in the risk of serious infections. The unadjusted meta-analytic risk associated with high-dose therapy was 2.07 (95% CI, 1.31 to 3.26) while the risk using the pooled method analysis was 1.83 (95% CI, 1.18 to 2.85). The risk of high-dose therapy was not increased when the meta-analysis was adjusted for exposure (1.99; 95% CI, 0.90 to 4.37) (Leombruno et al, 2008).2)  Serious infections, including sepsis and cases of opportunistic infections, including fatalities, have been reported with adalimumab therapy during clinical trials and postmarketing surveillance (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007; Keystone et al, 2001; Rau et al, 1998) Serious infections have occurred in many patients receiving concurrent immunosuppressive therapy that, in addition to their rheumatoid arthritis, may predispose them to infections. In postmarketing surveillance, infections caused by viral, bacterial, fungal and protozoal pathogens have been observed. Infections have been reported in all organ systems and with adalimumab monotherapy or in combination with other immunosuppressive agents. Patients with active chronic or localized infections should not be initiated on adalimumab therapy. If an infection occurs during adalimumab treatment, the patient should be monitored closely. Adalimumab therapy should be discontinued if a serious infection develops. Caution should be exercised when considering adalimumab for patients with a history of infection or other conditions which may increase infection risk or in patients who have resided in countries where tuberculosis and histoplasmosis are endemic. Before initiating adalimumab therapy,

benefits and risks should be weighed (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).3)  In placebo-controlled trials of patients being treated with adalimumab for rheumatoid arthritis, the rate of infection, consisting primarily of upper respiratory tract, bronchitis, and urinary tract, was 1 per patient-year in the adalimumab group compared with 0.9 per patient-year in the placebo group. The rate of serious infections, including pneumonia, septic arthritis, prosthetic and postsurgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis, was 0.04 per patient-year and 0.02 per patient-year in patients treated with adalimumab and placebo, respectively. Invasive opportunistic infections were reported at a rate of 0.075 per 100 patient-years, and some cases proved fatal. Postmarketing data includes infections with viral, bacterial, fungal, and protozoal organisms (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

3.3.16.F   Influenza-like symptoms 1)  Incidence: 7% (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007)2)  In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), flu syndrome was reported in 7% of the adalimumab group compared with 6% of the placebo group (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).

 3.4   Teratogenicity/Effects in Pregnancy/Breastfeeding A)  Teratogenicity/Effects in Pregnancy1)  U.S. Food and Drug Administration's Pregnancy Category: Category B (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008) (All Trimesters)a)  Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).2)  Australian Drug Evaluation Committee's (ADEC) Category: C (Australian Government Department of Health and Ageing Therapeutic Goods Administration, 2006)a)  Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.See Drug Consult reference: PREGNANCY RISK CATEGORIES3)  Crosses Placenta: Unknown4)  Clinical Managementa)  Due to the lack of adequate, well-controlled studies with adalimumab in pregnant women, it is recommended that adalimumab be used during pregnancy only if clearly needed. A pregnancy registry has been established, and prescribers can register patients by calling 1-877-311-8972 (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).5)  Literature Reportsa)  In a case report, a 37-year-old pregnant female who received a single dose of adalimumab during the first 5 weeks of gestation, had an uneventful pregnancy and gave birth to a healthy baby who was developing normally 25 months later. . The patient was treated with adalimumab 40 mg twice per month and her rheumatoid arthritis (RA) was effectively controlled. Five weeks after initiating adalimumab, the patient became pregnant. She had received a single injection of adalimumab during the 5 weeks and decided to continue with the pregnancy. Fetal growth progressed normally and no fetal anomalies were detected. At 32 weeks gestation, the patient gave birth to a healthy infant who weighed 2.6 kg and was 47 cm long. There were no neonatal abnormalities. At 25 months of age, the child is growing and developing normally (Roux et al, 2007).b)  There are no adequate and well-controlled studies with adalimumab in pregnant women. In studies of cynomolgus monkeys, systemic exposure 373 times greater than the human AUC at 40 mg/week subcutaneously resulted in no adverse fetal effects (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).B)  Breastfeeding1)  Thomson Lactation Rating: Infant risk cannot be ruled out.a)  Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during breastfeeding. Weigh the potential benefits of drug treatment against potential risks before prescribing this drug during breastfeeding.2)  Clinical Managementa)  It is not known if adalimumab is excreted into human breast milk, and there is insufficient clinical experience with adalimumab to confirm its safety in breast-feeding. Because of the potential for serious adverse reactions in the nursing infant, a decision should be made whether to discontinue nursing or to discontinue the drug. The importance of the drug to the mother should be taken into consideration (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).

 3.5   Drug Interactions

3.5.1   Drug-Drug Combinations

Abatacept

Anakinra

Bacillus of Calmette and Guerin Vaccine, Live

Influenza Virus Vaccine, Live

Measles Virus Vaccine, Live

Mumps Virus Vaccine, Live

Poliovirus Vaccine, Live

Rilonacept

Rotavirus Vaccine, Live

Rubella Virus Vaccine, Live

Smallpox Vaccine

Typhoid Vaccine

Varicella Virus Vaccine

Yellow Fever Vaccine

3.5.1.A   Abatacept 1)  Interaction Effect: an increased risk of infections2)  Summary: Controlled clinical trials demonstrated that the concomitant use of abatacept and tumor necrosis factor (TNF) antagonists resulted in an increased risk for serious infection and provided no additional benefit. Therefore, concurrent therapy with abatacept and TNF antagonists, such as adalimumab, is not recommended. When treatment is being transitioned from adalimumab to abatacept, patients should be monitored for signs of infection (Prod Info ORENCIA(R) IV powder, 2008).3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Use of abatacept with tumor necrosis factor (TNF) inhibitors, such as adalimumab, is not recommended due to an increased risk for serious infection. When transitioning treatment from adalimumab to abatacept, monitor the patient for signs of infection (Prod Info ORENCIA(R) IV powder, 2008).7)  Probable Mechanism: unknown8)  Literature Reportsa)  In controlled clinical trials, infections and serious infections occurred more frequently in patients treated concomitantly with abatacept and tumor necrosis factor (TNF) antagonist therapy (63% and 4.4%, respectively) compared with those treated with TNF antagonist therapy alone (43% and 0.8%, respectively) (Prod Info ORENCIA(R) IV powder, 2008).

3.5.1.B   Anakinra 1)  Interaction Effect: an increased risk of serious infections2)  Summary: The concomitant use of anakinra and another TNF blocking agent (etanercept) has been associated with an increased risk for serious infection, neutropenia, and provided no additional benefit. The use of anikinra in combination with TNF blocking agents, including adalimumab, is not recommended (Prod Info Humira(R), 2004). In a 24-week study in which patients were receiving both anakinra and etanercept (another TNF blocking agent) or etanercept alone, the incidence of serious infection was 7% for the combination versus no serious infections reported with etanercept alone. The infections included bacterial pneumonia (4 cases) and cellulitis (4 cases). Neutropenia (ANC less than 1 x 10(9)/L) was observed in 2% of patients receiving the combination. In addition, the combination of anakinra and etanercept did not offer addition clinical benefit when compared with etanercept alone (ACR50 response 31% versus 41%, respectively) (Prod Info Kineret(R), 2004).3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Use of anakinra with TNF blocking agents such as adalimumab is not recommended due to an increased risk for serious infection and neutropenia.7)  Probable Mechanism: unknown

3.5.1.C   Bacillus of Calmette and Guerin Vaccine, Live 1)  Interaction Effect: an increased risk of secondary transmission of infection by the live vaccine2)  Summary: Although no data are available regarding the effects of vaccination, including secondary transmission of infection from live vaccines, in patients receiving adalimumab therapy, vaccination with live vaccines is not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2006). Based on its mechanism of action, the possibility exists for

adalimumab to affect host defenses against infections since the cellular immune response may be altered.3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Although data are not available on the effects of concurrent vaccination, the manufacturer does not recommend the administration of live vaccines in patients receiving adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2006).7)  Probable Mechanism: altered cellular immune response

3.5.1.D   Influenza Virus Vaccine, Live 1)  Interaction Effect: an increased risk of secondary transmission of infection by the live vaccine2)  Summary: Although no data are available regarding the effects of vaccination, including secondary transmission of infection from live vaccines, in patients receiving adalimumab therapy, vaccination with live vaccines is not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2006). Based on its mechanism of action, the possibility exists for adalimumab to affect host defenses against infections since the cellular immune response may be altered.3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Although data are not available on the effects of concurrent vaccination, the manufacturer does not recommend the administration of live vaccines in patients receiving adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2006).7)  Probable Mechanism: altered cellular immune response

3.5.1.E   Measles Virus Vaccine, Live 1)  Interaction Effect: an increased risk of secondary transmission of infection by the live vaccine2)  Summary: Although no data are available regarding the effects of vaccination, including secondary transmission of infection from live vaccines, in patients receiving adalimumab therapy, vaccination with live vaccines is not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2006). Based on its mechanism of action, the possibility exists for adalimumab to affect host defenses against infections since the cellular immune response may be altered.3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Although data are not available on the effects of concurrent vaccination, the manufacturer does not recommend the administration of live vaccines in patients receiving adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2006).7)  Probable Mechanism: altered cellular immune response

3.5.1.F   Mumps Virus Vaccine, Live 1)  Interaction Effect: an increased risk of secondary transmission of infection by the live vaccine2)  Summary: Although no data are available regarding the effects of vaccination, including secondary transmission of infection from live vaccines, in patients receiving adalimumab therapy, vaccination with live vaccines is not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2006). Based on its mechanism of action, the possibility exists for adalimumab to affect host defenses against infections since the cellular immune response may be altered.3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Although data are not available on the effects of concurrent vaccination, the manufacturer does not recommend the administration of live vaccines in patients receiving adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2006).7)  Probable Mechanism: altered cellular immune response

3.5.1.G   Poliovirus Vaccine, Live 1)  Interaction Effect: an increased risk of secondary transmission of infection by the live vaccine2)  Summary: Although no data are available regarding the effects of vaccination, including secondary transmission of infection from live vaccines, in patients receiving adalimumab therapy, vaccination with live vaccines is not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2006). Based on its mechanism of action, the possibility exists for adalimumab to affect host defenses against infections since the cellular immune response may be altered.3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Although data are not available on the effects of concurrent vaccination, the manufacturer does not recommend the administration of live vaccines in patients receiving adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2006).7)  Probable Mechanism: altered cellular immune response

3.5.1.H   Rilonacept 1)  Interaction Effect: an increased risk of serious infections2)  Summary: Clinical data are unavailable on the effects of concurrent rilonacept (an interleukin (IL)-1 blocking agent) and

tumor necrosis factor (TNF) inhibitors. However, the concomitant use of another IL-1 blocker with TNF inhibitors was associated with an increased risk of serious infection and neutropenia. Therefore, concomitant use of rilonacept and a TNF inhibitor, such as adalimumab, etanercept, and infliximab, is not recommended (Prod Info ARCALYST(TM) subcutaneous injection, 2008).3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Concomitant use of rilonacept with tumor necrosis factor (TNF) inhibitors is not recommended due to an increased risk of serious infections (Prod Info ARCALYST(TM) subcutaneous injection, 2008).7)  Probable Mechanism: unknown

3.5.1.I   Rotavirus Vaccine, Live 1)  Interaction Effect: an increased risk of secondary transmission of infection by the live vaccine2)  Summary: Although no data are available regarding the effects of vaccination, including secondary transmission of infection from live vaccines, in patients receiving adalimumab therapy, vaccination with live vaccines is not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2006). Based on its mechanism of action, the possibility exists for adalimumab to affect host defenses against infections since the cellular immune response may be altered.3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Although data are not available on the effects of concurrent vaccination, the manufacturer does not recommend the administration of live vaccines in patients receiving adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2006).7)  Probable Mechanism: altered cellular immune response

3.5.1.J   Rubella Virus Vaccine, Live 1)  Interaction Effect: an increased risk of secondary transmission of infection by the live vaccine2)  Summary: Although no data are available regarding the effects of vaccination, including secondary transmission of infection from live vaccines, in patients receiving adalimumab therapy, vaccination with live vaccines is not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2006). Based on its mechanism of action, the possibility exists for adalimumab to affect host defenses against infections since the cellular immune response may be altered.3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Although data are not available on the effects of concurrent vaccination, the manufacturer does not recommend the administration of live vaccines in patients receiving adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2006).7)  Probable Mechanism: altered cellular immune response

3.5.1.K   Smallpox Vaccine 1)  Interaction Effect: an increased risk of secondary transmission of infection by the live vaccine2)  Summary: Although no data are available regarding the effects of vaccination, including secondary transmission of infection from live vaccines, in patients receiving adalimumab therapy, vaccination with live vaccines is not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2006). Based on its mechanism of action, the possibility exists for adalimumab to affect host defenses against infections since the cellular immune response may be altered.3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Although data are not available on the effects of concurrent vaccination, the manufacturer does not recommend the administration of live vaccines in patients receiving adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2006).7)  Probable Mechanism: altered cellular immune response

3.5.1.L   Typhoid Vaccine 1)  Interaction Effect: an increased risk of secondary transmission of infection by the live vaccine2)  Summary: Although no data are available regarding the effects of vaccination, including secondary transmission of infection from live vaccines, in patients receiving adalimumab therapy, vaccination with live vaccines is not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2006). Based on its mechanism of action, the possibility exists for adalimumab to affect host defenses against infections since the cellular immune response may be altered.3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Although data are not available on the effects of concurrent vaccination, the manufacturer does not recommend the administration of live vaccines in patients receiving adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2006).7)  Probable Mechanism: altered cellular immune response

3.5.1.M   Varicella Virus Vaccine

1)  Interaction Effect: an increased risk of secondary transmission of infection by the live vaccine2)  Summary: Although no data are available regarding the effects of vaccination, including secondary transmission of infection from live vaccines, in patients receiving adalimumab therapy, vaccination with live vaccines is not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2006). Based on its mechanism of action, the possibility exists for adalimumab to affect host defenses against infections since the cellular immune response may be altered.3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Although data are not available on the effects of concurrent vaccination, the manufacturer does not recommend the administration of live vaccines in patients receiving adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2006).7)  Probable Mechanism: altered cellular immune response

3.5.1.N   Yellow Fever Vaccine 1)  Interaction Effect: an increased risk of secondary transmission of infection by the live vaccine2)  Summary: Although no data are available regarding the effects of vaccination, including secondary transmission of infection from live vaccines, in patients receiving adalimumab therapy, vaccination with live vaccines is not recommended (Prod Info HUMIRA(R) subcutaneous injection, 2006). Based on its mechanism of action, the possibility exists for adalimumab to affect host defenses against infections since the cellular immune response may be altered.3)  Severity: major4)  Onset: unspecified5)  Substantiation: theoretical6)  Clinical Management: Although data are not available on the effects of concurrent vaccination, the manufacturer does not recommend the administration of live vaccines in patients receiving adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2006).7)  Probable Mechanism: altered cellular immune response

 4.0   Clinical Applications

Monitoring Parameters

Patient Instructions

Place In Therapy

Mechanism of Action / Pharmacology

Therapeutic Uses

Comparative Efficacy / Evaluation With Other Therapies

 4.1   Monitoring Parameters A)  Therapeutic1)  Laboratory Parametersa)  Rheumatoid Arthritis1)  ESR, C-reactive protein levels periodically2)  Physical Findingsa)  Rheumatoid Arthritis1)  Symptom improvement (e.g., pain/stiffness, swollen/tender joints)2)  Mobility and quality of life assessments3)  Radiographs of hands, wrist, and feet periodically (evidence of slowing of disease progression)B)  Toxic1)  Laboratory Parametersa)  Anti-adalimumab antibodies (ELISA) at least once during therapyb)  Anti-dsDNA antibody determinations in patients presenting with lupus-like symptoms (e.g., tiredness, rash, bone pain) during adalimumab therapyc)  Complete blood counts, routine blood chemistry periodically during long-term therapy2)  Physical Findingsa)  INFECTION1)  Monitor during and after treatment for the development of opportunistic infections including invasive fungal infections. Symptoms of possible fungal infection include fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, and/or serious systemic illness including shock (US Food and Drug Administration, 2008). Signs and symptoms suggestive of tuberculosis infection include weight loss or wasting, fever, and cougha)  Patients at greatest risk are those with a history of recurrent infection, on concomitant immunosuppressive therapy, with underlying conditions predisposing to infections, or patients who have resided in or traveled to tuberculosis and mycotic

endemic regions. Discontinue treatment in any patient developing a serious infection. There have been reports of pulmonary and disseminated histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis and other opportunistic infections while taking tumor necrosis factor-alpha blockers. Some infections have resulted in fatalities (US Food and Drug Administration, 2008).2)  Increased risk of Hepatitis B virus (HBV) reactivation in patients with chronic hepatitis B infection or chronic HBV carriers (surface antigen positive) and monitor for signs and symptoms of active infection during therapy and for several months after discontinuation of therapy. Active HBV infections have occurred during a latency period from 3 weeks to 20 months after therapy initiation and fatal outcomes have occurred (Health Canada, 2006).b)  Temperature, blood pressure periodicallyc)  Signs/symptoms of new or worsening heart failured)  Signs/symptoms of toxicity, including respiratory symptoms (infection), fever/chills, dizziness (hypotension), muscle pain, persistent nausea, signs of hypersensitivity (e.g., urticaria)

 4.2   Patient Instructions A)  Adalimumab (Injection)Adalimumab

Treats symptoms of rheumatoid arthritis (RA) and slows the joint damage caused by RA. This medicine also treats juvenile idiopathic arthritis in children 4 to 17 years of age, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis.

When This Medicine Should Not Be Used:You should not use this medicine if you have had an allergic reaction to adalimumab.

How to Use This Medicine:InjectableYour doctor will prescribe your exact dose and tell you how often it should be given. This medicine is given as a shot under your skin.A nurse or other trained health professional will give you this medicine.You may be taught how to give your medicine at home. Make sure you understand all instructions before giving yourself an injection. Do not use more medicine or use it more often than your doctor tells you to.Use a new needle and syringe each time you inject your medicine.You will be shown the body areas where this shot can be given. Use a different body area each time you give yourself a shot. Keep track of where you give each shot to make sure you rotate body areas.This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions. Ask your pharmacist for the Medication Guide if you do not have one. Your doctor might ask you to sign some forms to show that you understand this information.This medicine comes with patient instructions. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions.

If a Dose is Missed:If you miss a dose or forget to use your medicine, use it as soon as you can. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not use extra medicine to make up for a missed dose.

How to Store and Dispose of This Medicine:If you store this medicine at home, keep it in the refrigerator. Do not freeze. Protect the medicine from light. Keep your medicine and supplies in the original packages until you are ready to use them.Throw away used needles in a hard, closed container that the needles cannot poke through. Keep this container away from children and pets.Ask your pharmacist, doctor, or health caregiver about the best way to dispose of any leftover medicine, containers, and other supplies. You will also need to throw away old medicine after the expiration date has passed.Keep all medicine away from children and never share your medicine with anyone.

Drugs and Foods to Avoid:Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins, and herbal products.This medicine should not be taken together with anakinra (Kineret®). Also, make sure your doctor knows if you are using any medicines that weaken the immune system (such as steroids or cancer medicines).Talk to your doctor before getting flu shots or other vaccines while you are receiving this medicine. Vaccines may not work as well, or they could make you ill while you are using this medicine.

Warnings While Using This Medicine:Make sure your doctor knows if you are pregnant or breastfeeding, or if you or your child have kidney disease, liver disease, a history of cancer, congestive heart failure, diabetes, psoriasis, or any type of infection, including hepatitis B, tuberculosis, or an infection that keeps coming back. Tell your doctor if you have multiple sclerosis, problems with your immune system, or a history of Guillain-Barré syndrome. Also tell your doctor if you are scheduled for any surgery.This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis is life-threatening and requires immediate medical attention. Stop using this medicine and check with your doctor right away if you or your child have a

rash; itching; swelling of the face, tongue, and throat; trouble with breathing; or chest pain after you receive the medicine.Serious skin reactions can occur during treatment with this medicine. Check with your doctor right away if you or your child have any of the following symptoms while using this medicine: blistering, peeling, or loosening of the skin; chills; cough; diarrhea; fever; itching; joint or muscle pain; red skin lesions; sore throat; sores, ulcers, or white spots in your mouth or lips; or unusual tiredness or weakness.You or your child will need to have a skin test for tuberculosis before you start using this medicine. Tell your doctor if you or anyone in your home has ever had a positive reaction to a tuberculosis skin test or been exposed to tuberculosis.This medicine lowers the number of some types of blood cells in your body. Because of this, you may bleed or get infections more easily. To help with these problems, avoid being near people who are sick or have infections. Wash your hands often. Stay away from rough sports or other situations where you could be bruised, cut, or injured. Brush and floss your teeth gently. Be careful when using sharp objects, including razors and fingernail clippers.Call your doctor right away if you or your child start to have a persistent cough, weight loss, night sweats, shortness of breath, fever, chills, unusual tiredness or weakness, or flu-like symptoms such as a runny or stuffy nose, headache, or feeling generally ill. These may be signs that you have an infection.Some people who have used this medicine developed lupus-like symptoms during treatment and got better after this medicine was stopped. Make sure your doctor knows if you or your child start having chest pains, shortness of breath, joint pain, or a rash on your cheeks or arms that is sensitive to the sun.A small number of people (including children and teenagers) who have used this type of medicine have developed certain types of cancer (such as leukemia). Some patients also developed a rare type of cancer called lymphoma. Talk with your doctor if you or your child have unusual bleeding, bruising, or weakness; swollen lymph nodes in the neck, underarms, or groin; or unexplained weight loss. Also, check with your doctor right away if your skin has red, scaly patches, or raised bumps that are filled with pus.Check with your doctor right away if you or your child have more than one of these symptoms: chest pain; decreased urine output; dilated neck veins; extreme fatigue; irregular breathing; irregular heartbeat; shortness of breath; swelling of the face, fingers, feet, or lower legs; tightness in the chest; trouble with breathing; weight gain; or wheezing. These may be signs of a heart condition called congestive heart failure (CHF).Some people who have used this medicine developed lupus-like symptoms during treatment and got better after the medicine was stopped. Make sure your doctor knows if you or your child start having chest pains, shortness of breath, joint pain, or a rash on your cheeks or arms that is sensitive to the sun.The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex). This may cause allergic reactions in people who are sensitive to latex. Tell your doctor if you or your child have a latex allergy before you start using this medicine.Your doctor will need to check your blood at regular visits while you are using this medicine. Be sure to keep all appointments.

Possible Side Effects While Using This Medicine:Call your doctor right away if you notice any of these side effects:Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or throat, chest tightness, trouble breathing.Blistering, peeling, or red skin rash.Bone pain.Chest pain, fast or uneven heartbeat.Cold or flu symptoms such as a runny or stuffy nose, sore throat, or body aches.Dry mouth, increased thirst, or muscle cramps.Fever, chills, a cough that does not go away, or unexplained weight loss.Nausea, vomiting, loss of appetite, or pain in your upper stomach.Numbness, tingling, or burning pain in your hands, arms, legs, or feet.Pain in your lower leg (calf).Pain with urination or a change in how much or how often you urinate.Raised bumps on the skin filled with pus.Red, black, or tarry stools, or dark urine.Red, scaly patches on the skin.Shortness of breath, cold sweats, and bluish-colored skin.Sores or white patches on your lips, mouth, or throat.Swelling in your hands, ankles, or feet.Swollen lymph nodes in the neck, underarms, or groin.Unusual bleeding, bruising, weakness, or pale skin.Yellowing of your skin or the whites of your eyes.

If you notice these less serious side effects, talk with your doctor:Back pain or joint pain.Changes in vision.Headache.Mild skin rash.Redness, itching, bruising, bleeding, pain, or swelling where the shot was given.

If you notice other side effects that you think are caused by this medicine, tell your doctor.

 4.3   Place In Therapy A)  Ankylosing spondylitis: Indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).B)  Juvenile Idiopathic Arthritis: Indicated as monotherapy or with methotrexate to reduce signs and symptoms of moderately to severe active polyarticular juvenile idiopathic arthritis in patient age 4 years and older (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).C)  Psoriasis with arthropathy: Adalimumab is indicated for use in patients with psoriatic arthritis to reduce signs and symptoms of active arthritis, inhibit the progression of structural damage, and improve physical function. Adalimumab can be used as monotherapy or in combination with DMARDs (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).D)  Rheumatoid arthritis: Indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. May be used alone or in combination with disease-modifying antirheumatic drugs (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).E)  Crohn's disease: Indicated as induction and maintenance treatment in adult patients with moderately to severely active Crohn's disease who have inadequately responded to conventional therapy; also indicated to reduce the signs and symptoms and induce clinical remission in these patients if they have lost response to or are intolerant of infliximab therapy (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008). Effective when compared to placebo for induction and maintenance therapy in patients with moderate to severe Crohn’s disease who experience inadequate response to concomitant therapy (Hanauer et al, 2006; Sandborn et al, 2007; Colombel et al, 2007), including patients who have previously received tumor necrosis factor (TNF)-antagonist agents (Colombel et al, 2007). Safe and active in patients intolerant or refractory to infliximab in small, single-arm, open-label clinical trials (Sandborn et al, 2004; Youdim et al, 2004).F)  It is unclear if adalimumab will offer an advantage over infliximab (chimeric anti-tumor necrosis factor (TNF)-alpha monoclonal antibody) or etanercept (TNF-receptor (TNFR)-Fc fusion protein). Advantages over infliximab include subcutaneous administration and a potentially lower risk of allergic phenomena (adalimumab is a fully-human antibody). Although infliximab is approved only for concomitant use with methotrexate, this does not preclude its use as monotherapy. Infliximab may offer an advantage of less frequent dosing. Like adalimumab, etanercept is given subcutaneously, and can be self-administered by the patient; a disadvantage of etanercept is the usual requirement of more frequent dosing (eg, twice weekly).

 4.4   Mechanism of Action / Pharmacology A)  MECHANISM OF ACTION1)  Adalimumab is a recombinant fully-human immunoglobulin-1 (IgG1) anti-tumor necrosis factor (TNF)-alpha monoclonal antibody under investigation primarily for the treatment of rheumatoid arthritis (Salfield et al, 1998)(Santora et al, 1999; Sorbera et al, 2001). The antibody is specific for TNF-alpha and does not bind to other cytokines (Salfield et al, 1998)(Barrera et al, 2001). It does not possess nonhuman or artificially fused human sequences, suggesting a low propensity for immunogenicity (Kempeni, 2000; Sorbera et al, 2001).2)  The rationale for use of adalimumab is based on cumulative evidence that the pleotropic cytokine TNF-alpha plays a major role in numerous events in inflammatory synovitis and articular matrix degradation; TNF-alpha is overproduced in rheumatoid joints, principally by macrophages (Kempeni, 2000; Taylor, 2001; Sorbera et al, 2001).3)  Preclinical studies have demonstrated the ability of adalimumab to inhibit binding of human TNF-alpha to p55 and p75 receptors on human cells, and to inhibit/neutralize a wide range of TNF-alpha biologic activities (Sorbera et al, 2001; Kempeni, 1999; Kempeni, 2000). Inhibition of TNF-alpha cytotoxicity in murine L929 cells by 50% was observed with a mean adalimumab concentration of 0.13 nanomols (nM) (Sorbera et al, 2001). Intraperitoneal administration has prevented severe polyarthritis in transgenic mice expressing human TNF-alpha (Kempeni, 2000; Sorbera et al, 2001).4)  In human studies involving rheumatoid arthritis patients, adalimumab was demonstrated to reduce inflammation and decrease the acute phase reaction. Significant decreases in peripheral-blood levels of interleukin-1-beta mRNA, as well as circulating levels of interleukin-1 receptor antagonist and interleukin-6, were observed within 24 hours of a single intravenous dose, and correlated with clinical responses. Total circulating TNF-alpha (free and bound) increased postinfusion, most likely related to formation of TNF-antibody complexes. A significant fall in TNF receptors was reported at day 14 (Barrera et al, 2001). These data suggest that blockade of circulating interleukin-1-beta at the transcriptional level may be involved in the mechanism of action.5)  Limited preclinical data suggest the potential of adalimumab to protect against photoaging. A significant reduction in c-Jun and phosphorylated c-Jun expression was observed in dermal cells postinjection in rheumatoid arthritis patients who had received UVB irradiation. The authors suggest that this may lead a decrease in matrix-metalloproteinase expression, and a photoaging protectant effect (Tjioe et al, 2001).B)  REVIEW ARTICLES1)  Efficacy of agents designed to block effects of tumor necrosis factor (TNF)-alpha in rheumatoid arthritis patients (Taylor, 2001).2)  Treatment of rheumatoid arthritis, including use of adalimumab (Lorenz & Kalden, 2001, in German).3)  Use of anti-TNF-alpha modalities in rheumatoid arthritis and other conditions (Fautrel & Cherin, 2000, in French).

 4.5   Therapeutic Uses

Ankylosing spondylitis

Crohn's disease (Moderate to Severe), In patients with an inadequate response to conventional therapy

Juvenile idiopathic arthritis

Plaque psoriasis (Moderate to Severe), Chronic

Psoriasis with arthropathy

Rheumatoid arthritis (Moderate to Severe)

4.5.A   Ankylosing spondylitis FDA Labeled Indication1)  OverviewFDA Approval: Adult, yes; Pediatric, noEfficacy: Adult, Evidence favors efficacyRecommendation: Adult, Class IIbStrength of Evidence: Adult, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)3)  Adult:a)  Signs and symptoms of ankylosing spondylitis (AS) improved with adalimumab compared with placebo in a multicenter, randomized, double-blind study. Patients who met modified New York criteria for definite, active AS received adalimumab 40 milligrams (mg) subcutaneously every other week (n=208) or placebo (n=107) for 24 weeks. For inclusion, all patients met at least 2 of the following 3 criteria: scoring at least 4 on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), back pain of at least 4 on a 10-centimeter (cm) visual analogue scale (VAS), and a duration of morning stiffness of at least 1 hour. At weeks 12, 16, or 20, patients who did not achieve a 20% response according to the ASsessment in Ankylosing Spondylitis International Working Group criteria for improvement (ASAS20) could enter open-label treatment with adalimumab 40 mg every other week. The following disease-modifying antirheumatic drugs (DMARDs) at the following doses sulfasalazine 3 grams/day or less, methotrexate 25 mg/week or less, hydroxychloroquine at 400 mg/day or less, prednisone (or its equivalent) 10 mg/day or less, and non-steroidal anti-inflammatory drugs were allowed if the dosage had remained stable for at least 4 weeks before baseline visit. Exclusion criteria included but was not limited to previous treatment with anti-tumor necrosis factor therapy, cyclosporine, azathioprine, or DMARDs (other than the above mentioned) as well as intraarticular injection(s) with corticosteroids within 4 weeks prior to baseline. (vanderHeijde et al, 2005).The primary efficacy endpoint was percentage of ASA20 responders at week 12. The definition of an ASA20 response was 20% or more improvement and absolute improvement of at least 1 unit as compared with baseline in at least 3 of the following 4 domainsAssessed with a 10-cm VAS:Patient's global assessment of disease activity during the previous weekPatient's assessment of pain during the previous week (total back score)Function (represented by the BASFI score)Inflammation (represented by the mean of the severity and duration of the morning stiffness)Furthermore, there could be no deterioration (defined as a worsening of at least 20% or an absolute increase of at least 1 unit) in the remaining domain.The ASAS20 response rate was 58.2% (121 of 208) for adalimumab and 20.6% (22 of 107) for placebo (difference 37.6% (95% CI 27.4% to 47.8%) p less than 0.001). This was confirmed with a sensitivity analysis (missing values were not counted as nonresponders). Patients responded by 2 weeks, continued to improve through 8 weeks, and maintained response through 24 weeks.ASAS20 SUBCOMPONENTS FROM BASELINE TO WEEK 12

ASAS20 SubcomponentsBaseline to week 12Placebo (n=107) Adalimumab (n=208) p value

Patient's global assessment 6.5 +/- 6.3 -39.1 +/- 4.6 less than 0.001Total back score -9.5 +/- 4.3 -40.5 +/- 3.1 less than 0.001Function -8 +/- 4 -35.8 +/- 2.8 less than 0.001Inflammation -15.2 +/- 4.9 -41.6 +/- 3.5 less than 0.001KEY: p values = determined comparing adalimumab with placebo treatment; if a patient received early-escape open-label adalimumab prior to week 24, the last observation prior to early-escape open-label adalimumab was carried forward when week 24 data were analyzedASAS20 SUBCOMPONENTS FROM BASELINE TO WEEK 24

ASAS20 SubcomponentsBaseline to week 24

Placebo (n=107) Adalimumab (n=208) p value

Patient's global assessment 8.7 +/- 6.9 -37.8 +/- 5 less than 0.001

Total back score -10 +/- 4.3 -42.4 +/- 3.1 less than 0.001

Function -8.5 +/- 4.2 -37.7 +/- 3 less than 0.001

Inflammation -12.5 +/- 5 -42.9 +/- 3.6 less than 0.001

KEY: p values = determined comparing adalimumab with placebo treatment; if a patient received early-escape open-label adalimumab prior to week 24, the last observation prior to early-escape open-label adalimumab was carried forward when week 24 data were analyzed

From week 12, there was a total of 155 patients (49.2%), 74 placebo treated and 81 adalimumab, who switched to open-label adalimumab due to a lack of response (ASAS20 nonresponse). At week 16 during the open-label treatment, 44 of the 74 (59.5%) patients in the placebo group and 32 of the 81 (39.5%) patients in the adalimumab became ASAS20 responders. Many secondary outcomes improved with adalimumab compared with placebo. C-reactive protein decreased 1.3 milligrams/deciliter (mg/dL) +/- 0.1 mg/dL at 12 and 24 weeks for adalimumab and 0.1 mg/dL +/- 0.1 mg/dL at 12 and 24 weeks for placebo (p less than 0.001).CLINICAL SIGNS AND SYMPTOMS FROM BASELINE TO WEEK 12 AND FROM BASELINE TO WEEK 24

Secondary OutcomesBaseline to week 12 Baseline to week 24p value p value

BASDAI less than 0.001 less than 0.001BASMI less than 0.001 less than 0.001Chest expansion 0.504 0.580MASES 0.018 0.005BAS-G less than 0.001 less than 0.001Nocturnal pain less than 0.001 less than 0.001Physician's global assessment less than 0.001 less than 0.001Swollen joint count 0.81 0.87Tender joint count 0.481 0.4KEY: BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; MASES = Maastricht Ankylosing Spondylitis Enthesitis Score; BAS-G = Bath Ankylosing Spondylitis Patient Global Score (measures well-being over the previous week and previous 6 months); p values = determined comparing adalimumab with placebo treatment; if a patient received early-escape open-label adalimumab prior to week 24, the last observation prior to early-escape open-label adalimumab was carried forward when week 24 data were analyzedInjection site reaction occurred more frequently with adalimumab (10.1%) compared with placebo (2.8%) through week 24. Infection occurred in 31.7% of patients receiving adalimumab compared with 21.5% of patients receiving placebo. Serious infection occurred in 1 placebo patient.

4.5.B   Crohn's disease (Moderate to Severe), In patients with an inadequate response to conventional therapy FDA Labeled Indication1)  OverviewFDA Approval: Adult, yes; Pediatric, noEfficacy: Adult, Effective; Pediatric, Evidence favors efficacyRecommendation: Adult, Class IIa; Pediatric, Class IIbStrength of Evidence: Adult, Category B; Pediatric, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Adalimumab is indicated as induction and maintenance treatment in adult patients with moderately to severely active Crohn's disease who have inadequately responded to conventional therapy; also indicated to reduce the signs and symptoms and induce clinical remission in these patients if they have lost response to or are intolerant of infliximab therapy (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).Adalimumab therapy was effective when compared to placebo for induction therapy in patients with moderate to severe Crohn’s disease who experience inadequate response to concomitant therapy in the double-blind CLASSIC-I trial (n=299) (Hanauer et al, 2006).Adalimumab therapy was effective as maintenance therapy when compared to placebo in the randomized, double-blind, phase 2 CLASSIC-II trial (n=55) and the randomized, double-blind, phase 3 CHARM trial (n=854) (Sandborn et al, 2007; Colombel et al, 2007).Adalimumab therapy was safe and effective in patients intolerant or refractory to infliximab in several clinical trials (Sandborn et al, 2007a; Sandborn et al, 2004; Youdim et al, 2004).In a 48-week clinical trial (n=23), induction and maintenance treatment with adalimumab led to favorable clinical remission and response rates in pediatric patients with moderate to severe Crohn's disease (Viola et al, 2009).3)  Adult:a)  General Information1)  Adalimumab has demonstrated efficacy compared to placebo for induction and maintenance therapy in patients with moderate to severe Crohn’s disease who experience inadequate response to conventional therapy (Hanauer et al, 2006; Sandborn et al, 2007; Colombel et al, 2007). Additional clinical trials have reported safety and activity of adalimumab in patients intolerant or refractory to infliximab (Sandborn et al, 2007a; Sandborn et al, 2004; Youdim et al, 2004). Injection-site reactions are the most common adverse events associated with adalimumab in the treatment of moderate to severe

Crohn’s disease (Hanauer et al, 2006; Youdim et al, 2004; Papadakis et al, 2005). Two cases of tuberculosis in patients receiving adalimumab for Crohn's disease were reported in the CHARM trial (Colombel et al, 2007), although most other trials in this population have not resulted in any reports of tuberculosis or opportunistic infections (Hanauer et al, 2006; Youdim et al, 2004; Papadakis et al, 2005). Long-term safety concerns of adalimumab, including development of malignancies (Prod Info HUMIRA(R) solution, 2005), have not been determined in this population.b)  Clinical Trials1)  Induction therapy with adalimumab was more effective than placebo in achieving clinical remission in patients with moderate to severe Crohn’s disease in the multicenter, double-blind, placebo-controlled CLASSIC-I (Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn’s Disease) clinical trial. Patients (n=299; mean ages ranging from 37 +/- 13 years to 39 +/- 13 years) with a baseline Crohn’s Disease Activity Index (CDAI) score between 220 and 450 points were permitted to receive concomitant therapies including 5-aminosalicylates, prednisone, budesonide, azathioprine, 6-mercaptopurine, methotrexate, and/or antibiotics at stable doses, while patients who had previously received other anti-tumor necrosis factor (TNF) agents (including infliximab) and patients on cyclosporine or tacrolimus within the previous 8 weeks were excluded. Patients were randomized to 4 groups: placebo at weeks 0 and 2, adalimumab 40 mg subcutaneously (subQ) at week 0 and 20 mg subQ at week 2 (40 mg/20 mg), adalimumab 80 mg subQ at week 0 and 40 mg subQ at week 2 (80 mg/40 mg), or adalimumab 160 mg subQ at week 0 and 80 mg subQ at week 2 (160 mg/80 mg). The primary endpoint was clinical remission, defined as a CDAI score of less than 150 points, at week 4 in patients in the 2 highest dose groups of adalimumab compared to placebo. Clinical remission at week 4 was significantly improved in the 160 mg/80 mg group (36%) compared to the placebo group (12%; p=0.001), but not in the 40 mg/20 mg group (18%) or the 80 mg/40 mg group (24%). Based on subgroup analysis, use of concomitant immunosuppressants appeared to have no affect on clinical remission rates. At week 4, 100-point responses (a CDAI reduction of at least 100 points) occurred in 25%, 34%, 40%, and 50% of patients in the placebo, 40 mg/20 mg, 80 mg/40 mg, and 160 mg/80 mg groups, respectively, and was statistically significant compared to placebo only in the 160 mg/80 mg group (p=0.002). At week 4, 70-point responses (a CDAI reduction of at least 70 points) occurred in 37%, 54%, 59%, and 59%, of patients in the placebo, 40 mg/20 mg (p less than 0.05), 80 mg/40 mg (p=0.01), and 160 mg/80 mg (p=0.007) groups, respectively, and was statistically significant in each treatment group versus placebo. Mean CDAI scores were significantly lower than placebo in the 160 mg/80 mg group at weeks 2 and 4 and in the 80 mg/40 mg group at weeks 1, 2, and 4. Patient-reported outcomes, assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ) were significantly improved versus placebo in the 160 mg/80 mg group at weeks 1, 2, and 4 and in the 80 mg/40 mg group at weeks 2 and 4. Median serum C-reactive protein (CRP) was significantly improved in all dose groups at weeks 1, 2, and 4 versus placebo. Injection-site reactions, primarily consisting of burning and pain, were the most common adverse events, occurring in 16%, 26%, 24%, and 38% of patients in the placebo, 40 mg/20 mg, 80 mg/40 mg, and 160 mg/80 mg groups, respectively. Infections occurred in 16%, 10%, 17%, and 21% of patients in the placebo, 40 mg/20 mg, 80 mg/40 mg, and 160 mg/80 mg groups, respectively. No tuberculosis, opportunistic infections, lymphomas, or death occurred in any group. Other adverse events were similar across all groups. One patient in the 160 mg/80 mg group developed antibodies to adalimumab at week 2, but subsequently tested negative at week 4 (Hanauer et al, 2006).2)  Maintenance therapy with adalimumab appeared to be effective for the treatment of patients with moderate to severe Crohn’s disease in the randomized, double-blind, placebo-controlled CLASSIC-II clinical trial, a follow-up to the CLASSIC-I (Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn’s Disease) trial. All enrolled patients (n=276) had completed CLASSIC-I, received additional adalimumab at a dose of 40 milligrams (mg) subcutaneously (subQ) at weeks 0 (week 4 of CLASSIC-I) and 2, and were assessed at week 4. Patients not in clinical remission (n=204), defined as Crohn’s Disease Activity Index (CDAI) scores of 150 or greater, at weeks 0 and/or 4 continued on open-label adalimumab 40 mg subQ every other week. Patients who were in clinical remission (n=55), defined as CDAI scores of less than 150, at weeks 0 and 4 were randomized to receive placebo (n=18) or additional treatment with adalimumab 40 mg subQ weekly (n=18) or every other week (n=19), until week 55. Tapering of corticosteroids was mandated at week 8 in randomized patients while other concurrent medications were required to remain constant. Of 204 patients in the open-label cohort, 46% of patients achieved remission, defined as a CDAI score of less than 150 points, and 65% achieved a 100-point reduction in CDAI. Of 36 patients receiving steroids at baseline, 21 (58%) had discontinued them at week 56. In the randomized group, remission rates at week 56 were significantly higher (p less than 0.05) in each adalimumab group versus placebo: 44% (8/18), 79% (15/19), and 83% (15/18) in the placebo, adalimumab every other week, and adalimumab weekly groups, respectively. Complete discontinuation of steroids at week 56 occurred in 57% (4 of 7) of placebo patients, 67% (4/6) of patients receiving adalimumab every other week, and 88% (7/8) of patients receiving adalimumab weekly. Concomitant immunosuppression, including azathioprine, 6-mercaptopurine, or methotrexate, did not appear to impact the efficacy of adalimumab (table). Patients randomized to placebo experienced more adverse events, including serious adverse events, than those randomized to either adalimumab group (Sandborn et al, 2007).

Efficacy of adalimumab stratified by concomitant immunosuppressive useTreatment CDAI < 150

Total IMM+ IMM-Placebo N 8/18 1/3 7/15

% 44 33 4740 mg every other week N 15/19 4/4 11/15

% 79 100 7340 mg weekly N 15/18 4/5 11/13

% 83 80 85CDAI = Crohn's Disease Activity Index, IMM = immunosuppressive agent (includes azathioprine, 6-mercaptopurine, or methotrexate)

3)  Maintenance treatment with adalimumab in patients with moderate to severely active Crohn’s disease improved rates of remission and response compared to placebo in the phase 3, multicenter, double-blind Crohn's trial of the fully Humanized antibody Adalimumab for Remission Maintenance (CHARM) clinical trial. The primary endpoint of the study was to assess 2 doses of adalimumab in maintaining clinical remission, defined as a Crohn’s Disease Activity Index (CDAI) score of less than 150, at 26 and 56 weeks. Patients (n=854) with baseline CDAI scores of 220 to 450 points, received open-label induction therapy with adalimumab 80 milligrams (mg) subcutaneously (subQ) at week 0 and 40 mg subQ at week 2. Clinical response (a decrease in CDAI of at least 70 points) occurred in 499 (58%) patients, who were then randomized at week 4 to receive placebo (n=170), adalimumab 40 mg every other week (n=172), or adalimumab 40 mg weekly (n=157) through week 56. Tapering of steroids was permitted after week 8. At 26 weeks, remission occurred in 17%, 40%, and 47% of patients who received placebo, adalimumab every other week, and adalimumab weekly, respectively (p less than 0.001 for each comparison versus placebo). At week 56, remission occurred in 12%, 36%, and 41% of patients in the placebo, adalimumab every other week, and adalimumab weekly groups, respectively (p less than 0.001 for each comparison versus placebo). Median duration of clinical remission was 127 days, 378 days (p=0.002), and greater than 392 days (p less than 0.001) for the placebo, adalimumab every other week, and adalimumab weekly groups, respectively. At 26 weeks, CDAI reductions of 100 points occurred in 26.5%, 52%, and 52% of patients in the placebo, adalimumab every other week, and adalimumab weekly groups, respectively (p less than 0.001 for each comparison versus placebo). At 56 weeks, CDAI reductions of 100 points occurred in 16.5%, 41%, and 48% of patients in the placebo, adalimumab every other week, and adalimumab weekly groups, respectively (p less than 0.001 for each comparison versus placebo). Additionally, significantly greater (p less than 0.001) percentages of patients in each adalimumab group experienced 70-point reductions in CDAI scores compared to placebo at both 26 and 56 weeks. Clinical remission at 56 weeks was achieved in 10%, 31%, and 34% of patients who had previously received tumor necrosis factor (TNF)-antagonist therapy and 14%, 42%, and 48% of patients who were TNF-antagonist naive in the placebo, adalimumab every other week, and adalimumab weekly groups, respectively. Corticosteroid-free remission was achieved in 3%, 35%, and 30% at week 26 and 6%, 29%, and 23% at week 56 in the placebo, adalimumab every other week, and adalimumab weekly groups, respectively (p less than 0.01 for each comparison versus placebo). In the combined adalimumab groups, 30% of patients achieved complete fistula closure at 26 weeks compared to 13% of placebo patients (p=0.043) and 33% of adalimumab patients at week 56 achieved complete fistula closure compared to 13% of placebo patients (p=0.016). One case of multiple sclerosis and one death due to a pulmonary embolism (although not considered treatment-related) occurred during the open-label induction period. Infections occurred in significantly more (p less than 0.05) patients in the adalimumab every other week group (46.2%) compared to the placebo group (36.8%), but not significantly greater (p=0.089) in the adalimumab weekly group (44.4%). More patients in the adalimumab groups experienced injection site reactions than patients in the placebo group but reactions were typically mild to moderate. Two patients who received adalimumab 40 mg every other week developed tuberculosis (Colombel et al, 2007).4)  In a multicenter, double-blind, randomized, placebo-controlled trial (GAIN (Gauging Adalimumab Efficacy in Infliximab Nonresponders); n=325), adalimumab was superior to placebo for inducing remission and clinical response in patients with moderate to severe Crohn's disease, intolerant or refractory to infliximab therapy. Patients (35% male, mean ages ranging from 37 +/- 12 years to 39 years +/- 12 years) with a baseline Crohn’s Disease Activity Index (CDAI) score of 220 to 450 points were randomized to receive adalimumab 160 milligrams (mg) at week zero and 80 mg at week 2 (n=159) or matching placebo (n=166) subcutaneously, with follow-up through week 4. The mean CDAI score was 313 points at baseline (range, 0 to 600; higher score indicating more severe condition). Approximately 50% of the participants lost previous response to infliximab, nearly 60% developed intolerance to infliximab, and 12% became refractory and intolerant to infliximab therapy. Concomitant therapies were permitted. A total of 301 patients completed the trial (adalimumab, n=155; placebo, n=156). Based on the intent-to-treat analysis, 21% adalimumab-treated patients and 7% placebo-treated patients achieved clinical remission (primary endpoint, defined as a CDAI score of less than 150 points) at week 4 (absolute difference 14.2 percentage points, 95% confidence interval (CI), 6.7 to 21.6; p less than 0.001). Clinical response defined as a decrease in CDAI score of 70 points or more from baseline (70-point response) at weeks 1, 2, and 4 was 35%, 52%, and 52%, respectively, in the adalimumab group, and 21%, 33%, and 34%, respectively, in the placebo group. The absolute differences in the 70-point response between groups at weeks 1, 2, and 4 were 14.1 percentage points (95% CI, 4.5 to 23.7), 19.7 percentage points (95% CI, 9.1 to 30.2), and 17.8 percentage points (95%, 7.3 to 28.4), respectively. Response rates of 100-point decrease or more from baseline at weeks 1, 2, and 4 were 20%, 37%, and 38%, respectively, in the adalimumab group, and 12%, 18%, and 25%, respectively, in the placebo group. The absolute differences in the 100-point response between groups at weeks 1, 2, and 4 were 7.4 percentage points (95% CI, -0.5 to 15.4), 18.4 percentage points (95% CI, 8.9 to 27.9), and 13.7 percentage points (95% CI, 3.7 to 23.7), respectively. Mean CDAI scores were significantly lower in the adalimumab group than placebo at weeks 1, 2, and 4. Patient-reported outcomes, assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ), were significantly improved in the adalimumab group versus placebo at weeks 4 (score 150 versus 139, respectively; p less than 0.001). Median serum C-reactive protein (CRP) was significantly improved in the adalimumab group at week 4 versus placebo (5 milligrams per liter (mg/L) vs 7 mg/L) despite a higher baseline concentration (9 mg/L vs 7 mg/L). Relative to placebo, adalimumab was associated with a lower incidence of infections (16% and 24%; and a similar incidence of injection-site reactions (11% and 10%), primarily consisting of irritation and pain (Sandborn et al, 2007a).5)  Adalimumab was well-tolerated and active in patients with moderate to severe Crohn’s disease who were previously treated with infliximab in a phase 2 clinical trial. Patients (n=24; mean age, 34 +/- 11 years) with a mean baseline Crohn’s Disease Activity Index (CDAI) score of 286 +/- 105 had previously experienced a clinical response to infliximab but subsequently lost their response or were intolerant to therapy because of acute or delayed hypersensitivity reactions. Information regarding prior infliximab therapy, including time since last infliximab dose and number of infliximab doses, was not collected; although, no patient had a detectable serum concentration of infliximab at baseline. Patients receiving prednisone or budesonide at baseline were required to maintain stable doses through week 4 and then undergo weekly

tapering until discontinuation. Adalimumab 80 milligrams (mg) subcutaneously (subQ) was administered at week 0, followed by 40 mg subQ every other week through week 10. Dose escalation to 40 mg weekly through week 11 was permitted if clinical remission and complete fistula closure at week 4 or complete steroid withdrawal after week 4 were not achieved. The primary endpoint was clinical remission, defined as a CDAI score of less than 150 at week 4 in patients with a baseline CDAI score of 220 points or more. Concomitant medications consisted of corticosteroids, including budesonide (n=15; 63%), azathioprine, 6-mercaptopurine, or 6-thioguanine (n=7; 29%), methotrexate (n=3; 13%), 5-aminosalicylates (n=5; 21%), antibiotics (n=7; 29%), and combinations of a corticosteroid with azathioprine or 6-mercaptopurine (n=5; 21%). In the subset of patients with moderate to severe (CDAI score of 220 points or higher) Crohn’s disease (n=17), clinical remission occurred in 18%, 12%, and 29% at weeks 2, 4, and 12, respectively and clinical response (CDAI reduction of at least 100 points) occurred in 29%, 41%, and 59% at weeks 2, 4, and 12, respectively. Of these 17 patients, clinical remission rates were 13% (1 of 8) and 25% (2 of 8) at weeks 4 and 12, respectively, in patients who had previously lost response to infliximab and 11% (1 of 9) and 33% (3 of 9) at weeks 4 and 12, respectively, in patients who were intolerant to infliximab but had not lost response to therapy. The mean CDAI score in patients with moderate to severe Crohn’s disease was 281 +/- 47 at week 0, 230 +/- 73 at week 2, 275 +/- 134 at week 4, and 239 +/- 124 at week 12. Dose escalation occurred in 79% (19 of 24) of all patients due to incomplete responses at week 4 (Sandborn et al, 2004).4)  Pediatric:a)  In a 48-week clinical trial (n=23), induction and maintenance treatment with adalimumab led to favorable clinical remission and response rates in pediatric patients with moderate to severe Crohn's disease (CD). Patients (median age, 16.1 years (yr); range, 9 to 20 yr; erythrocyte sedimentation rate (ESR), 54 +/- 36 millimeters/hour (mm/hr); C-reactive protein level (CRP), 31.2 +/- 24 mg/milliliter (mL)) with active CD and a Pediatric Crohn's Disease Activity Index (PCDAI) score greater than 30 (baseline score, 36.5 +/- 5.7) who were refractory or intolerant to conventional CD treatment (corticosteroids or immunomodulators (IM)) or refractory (n=11) or intolerant (n=3) to infliximab were eligible for enrollment. Concomitant use with a corticosteroid such as methylprednisolone (n=18; mean daily dose, 0.9 +/- 0.2 milligrams/kilograms (mg/kg)) or an IM such as azathioprine (n=11; dose, 2.5 mg/kg/day) or methotrexate (n=2; 15 mg/week subcutaneously (subQ)) was permitted; however, methylprednisolone was gradually tapered after 4 weeks and IM were discontinued between study weeks 8 to 12. Patients received an adalimumab loading dose (weight of 40 kg or greater, 160 mg (n=13); weight less than 40 kg, 120 mg (n=2) or 80 mg (n=8)) subQ on study weeks zero and 2 followed by adalimumab maintenance therapy (weight of 40 kg or greater, 80 mg (n=13); weight less than 40 kg, 80 mg (n=2) or 40 mg (n=8)) subQ every other week for 48 weeks starting on week 4. At week 12, the maintenance dose could be decreased in patients with clinically controlled disease. Clinical remission (defined as the absence of symptoms and a PCDAI score of 10 or less) and clinical response (defined as a decrease in the PCDAI score from baseline by 50% or greater) rates (primary endpoints) are presented in Table 1. At week 48, the mean PCDAI score (9.9 +/- 2.7), ESR (13.1 +/- 4.4 mm/hr), and CRP level (2.7 +/- 1.3 mg/mL) were significantly (p less than 0.01) improved from baseline and oral corticosteroid use was significantly (p less than 0.01) decreased (mean daily dose, 0.07 +/- 0.1 mg/kg). Some patients developed an infection (lower abdominal abscess (n=1), staphylococcal folliculitis (n=1), and upper respiratory tract infection (n=6)) during the study period. No malignancies were reported (Viola et al, 2009).

Table 1: Response to Adalimumab Therapy

Study Week Clinical Remission Clinical Response

2 36.3% 87%

4 60.8% 88%

12 30.5% 70%

24 50% 86%

48 65.2% 91%

4.5.C   Juvenile idiopathic arthritis FDA Labeled Indication1)  OverviewFDA Approval: Adult, no; Pediatric, yes (age 4 to 17 years)Efficacy: Pediatric, EffectiveRecommendation: Pediatric, Class IIaStrength of Evidence: Pediatric, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Indicated as monotherapy or with methotrexate to reduce signs and symptoms of moderately to severe active polyarticular juvenile idiopathic arthritis in patient age 4 years and older (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)Fewer patients receiving adalimumab with or without methotrexate experienced disease flare compared with placebo in a randomized, double-blind, stratified, placebo-controlled, multicenter, medication-withdrawal study of 171 patients age 4 to 17 years with active juvenile rheumatoid arthritis not responding adequately to treatment with NSAIDs (Lovell et al, 2008).Concomitant methotrexate, glucocorticoids, salicylates, NSAIDs, or analgesics may be continued during adalimumab therapy (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).3)  Pediatric:

a)  Fewer patients receiving adalimumab with or without methotrexate experienced disease flare compared with placebo in a randomized, double-blind, stratified, placebo-controlled, multicenter, medication-withdrawal study of 171 patients age 4 to 17 years with active juvenile rheumatoid arthritis not responding adequately to treatment with NSAIDs. The study had a 16-week open label lead-in phase, a 32-week double-blind withdrawal phase, and an open-label extension phase. In the open-label lead-in phase, patients received adalimumab 24 milligrams/square meter (mg/m(2))(maximum 40 mg) subcutaneously (subQ) every other week for 16 weeks with (n=85) or without (n=86) methotrexate. At week 16, patients with an American College of Rheumatology Pediatric 30% (ACR Pedi 30) response were randomized to receive subcutaneous adalimumab (n=68; 38 in the methotrexate group and 30 in the no methotrexate group) or placebo (n=65; 37 in the methotrexate group and 28 in the no methotrexate group) every other week in a 32-week, double-blind treatment phase. Patients in the double-blind phase were eligible to participate in the extension phase of the study to receive open-label treatment with adalimumab (24 mg/m(2) subQ every other week (maximum 40 mg) during the first part and fixed dose based on body weight during the second part (20 mg for patients weighing less than 30 kilograms (kg) and 40 mg for patients weighing greater than or equal to 30 kg). ACR Pedi 30 responses (improvement of 30% or more in at least three of the six core criteria for juvenile rheumatoid arthritis and a worsening of 30% or more in no more than one of the criteria) were measured throughout the study. The primary efficacy measure was disease flare which was defined as a worsening from baseline of at least 30% in greater than 3 to 6 Pediatric American College of Rheumatology (ACR) core criteria and improvement of more than 30% in no more than 1 of the 6 ACR criteria. An increase in the number of active joints to at least 2 was required if the number of joints with active arthritis was used as a criteria for flare. In the efficacy analysis following the double-blind phase of the study, there were significantly fewer patients who received adalimumab experiencing disease flare compared to placebo, (13 of 30 (43%) vs 20 of 28 (71%); p=0.03) without methotrexate, and (14 of 38 (37%) vs 24 of 37 (65%); p=0.02) with methotrexate. More patients treated with adalimumab and methotrexate had Pediatric ACR 30 (63% vs 38%, p=0.03), 50 (63% vs 38%; p=0.03), or 70 (63% vs 27%; p=0.002) responses at week 48 compared with placebo. Concomitant use of NSAIDs or prednisone (0.2 mg/kg/day or less, or 10 mg/day maximum) was allowed during the study and logistic-regression analysis showed that it did not influence the incidence of disease flares. Infections and injection-site reactions (mild to moderate) were the most frequently reported adverse events. Serious adverse events were reported in 14 patients (6 during the open-label lead-in phase, 1 during the double-blind phase, and 7 during the open-label extension phase). Of the serious adverse events, 7 were serious infections (1 case each of bronchopneumonia, herpes simplex virus infection, pharyngitis, pneumonia, and unspecified viral infection, and 2 cases of herpes zoster). Twelve patients discontinued treatment due to adverse events (9 during the open-label lead-in phase and 3 during the open-label extension phase). There were no reports of deaths, malignant conditions, opportunistic infections, cases of tuberculosis, demyelinating diseases, or lupuslike reactions during the study. Development of anti-adalimumab antibody occurred in 27 of 171 patients (16%) during the open-label and double-blind phases (5 of 85 (6%) receiving methotrexate and 22 of 86 (26%) not receiving methotrexate) but it did not lead to a greater rate of discontinuation of the study drug, or greater incidence of serious adverse events (Lovell et al, 2008).

4.5.D   Plaque psoriasis (Moderate to Severe), Chronic FDA Labeled Indication1)  OverviewFDA Approval: Adult, yes; Pediatric, noEfficacy: Adult, EffectiveRecommendation: Adult, Class IIaStrength of Evidence: Adult, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Adalimumab is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)In a 52-week, multicenter, randomized, double-blind, placebo-controlled study (n=1212) in patients with moderate to severe psoriasis, significantly more patients treated with adalimumab achieved a 75% or greater Psoriasis Area and Severity Index (PASI 75) response rate relative to baseline at 16 weeks compared to patients who received placebo. Additionally, significantly more patients who initially received adalimumab and had PASI 75 at 33 weeks, who were re-randomized to adalimumab maintained efficacy at 52 weeks compared to patients who re-randomized to placebo (Menter et al, 2008)In a 16-week, multinational, randomized, double-blind, double-dummy, placebo-controlled study (n=271) in patients with moderate to severe psoriasis, significantly more patients treated with adalimumab achieved a 75% or greater Psoriasis Area and Severity Index response rate (PASI 75) relative to baseline at 16 weeks compared to patients who received methotrexate or placebo (Saurat et al, 2008).Compared to placebo, adalimumab was associated with a significant clinical response for up to 60 weeks during a double-blind, randomized, controlled trial involving 147 patients with moderate to severe plaque psoriasis (Gordon et al, 2006)3)  Adult:a)  In a 52-week, multicenter, randomized, double-blind, placebo-controlled study (n=1212) in patients with moderate to severe psoriasis, significantly more patients treated with adalimumab achieved a 75% or greater Psoriasis Area and Severity Index response rate (PASI 75) relative to baseline at 16 weeks compared to patients who received placebo. Patients with moderate to severe plaque psoriasis (defined as 10% or more of body surface area (BSA) affected, a PASI score of 12 or greater, and a Physician's Global Assessment (PGA) of at least moderate severity at baseline) were randomized (2:1) to receive subcutaneous (SUBQ) injections of either adalimumab 80 milligrams (mg) once followed by 40 mg every other week (EOW) beginning on week 1 through week 15 (n=814; mean age, 44.1 +/- 13.2 years (yr)) or matched placebo given on the same schedule (n=398; mean age, 45.4 +/- 13.4 yr) (treatment period A). Concomitant low-

to mid-potency topical corticosteroids applied to palms, soles, face, and intertriginous areas were allowed during the study period. Patients who achieved a PASI 75 could continue to the open-label period B starting on week 17 until week 31 in which all patients received SUBQ adalimumab 40 mg EOW (adalimumab group, n=580; placebo group, n=26). Patients who achieved a PASI 75 at week 33 could continue to period C (an additional 19 weeks of treatment), with patients initially treated with placebo in period A (n=22) continuing on adalimumab 40 mg EOW and patients initially treated with adalimumab in period A being randomized (1:1) to either SUBQ adalimumab 40 mg EOW (n=250) or matched placebo (n=240) to determine the percentage of adalimumab-treated patients who would lose an adequate response after week 33. Patients who did not achieve a PASI 75 at 16 weeks (adalimumab group, n=203; placebo group, n=329) and patients with PASI responses greater than 50% relative to baseline (PASI 50) but less than PASI 75 at 33 weeks could receive SUBQ adalimumab 40 mg EOW in a separate, open-label extension study. At 16 weeks, 578 patients in the adalimumab group (71%) achieved a PASI 75 response (first primary endpoint) compared to 26 patients (7%) in the placebo group (p less than 0.001). The improved PASI 75 response was evident after 4 weeks of treatment (p less than 0.001) with a mean percentage PASI score improvement from baseline of 52% versus (vs) 9%, in the adalimumab and placebo arms, respectively (p less than 0.001). Significantly more patients who had received adalimumab in period A and were randomized to adalimumab in period C (at week 33) continued to have an adequate response compared to patients who had received adalimumab in period A and were randomized to placebo in period C, with 12 of 250 patients (5%) and 68 of 240 patients (28%), respectively, experiencing a loss of response (second primary endpoint, defined as a PASI score which was less than a 50% reduction relative to baseline and at least a 6-point increase in PASI score relative to week 33 PASI score; p less than 0.001) . Mild to moderate adverse effects during period A occurred in 59.5% of patients in the adalimumab group and 53% of patients in the placebo group, with an 1.8% incidence of serious events in each group. However, infectious adverse events (28.9% vs 22.4%; p=0.019) and upper respiratory tract infections (7.2% vs 3.5%; p=0.01) occurred more frequently in adalimumab-treated patients compared to placebo-treated patients (Menter et al, 2008).b)  In a 16-week, multinational, randomized, double-blind, double-dummy, placebo-controlled study (n=271) in patients with moderate to severe psoriasis, significantly more patients treated with adalimumab achieved a 75% or greater Psoriasis Area and Severity Index response rate (PASI 75) relative to baseline at 16 weeks compared to patients who received methotrexate or placebo. Patients with moderate to severe plaque psoriasis (defined as 10% or more of body surface area (BSA) affected and a PASI score of 10 or greater) that was plaque psoriasis for at least 1 year and stable plaque psoriasis for at least 2 months were enrolled. Enrolled patients were randomized (2:2:1) to receive subcutaneous (subQ) injections of adalimumab 80 milligrams (mg) once followed by 40 mg every other week beginning on week 1 through week 15 (n=108; mean age, 42.9 +/- 12.6 years (yr)); oral methotrexate initiated at 7.5 mg/week at week 0, 10 mg/week at week 2, 15 mg/ week at week 4 to 8, thereafter the dose could be increased up to a maximum of 25 mg/wk based on PASI response rate (n=110; mean age, 41.6 +/- 12 yr); or matching placebo given on the same schedule (n=53; mean age, 40.7 +/- 11.4 yr). The dose adjustments for methotrexate after week 8 were as follow: if a 50% or greater PASI (PASI 50) was not achieve at 8 weeks, then the dose was increased to 20 mg/week followed by a subsequent increase to 25 mg/wk if at 12 weeks PASI 50 was not achieved or no dose increase (maintain at 20 mg/wk) if at 12 weeks a PASI 50 was achieved. All patients received folate 5 mg orally once weekly. Concomitant low potency topical corticosteroids applied to palms, soles, face, and inframammary areas and groin were allowed during the study period. The mean weekly doses of methotrexate were 14.2 +/- 3 mg at week 4, 16.8 +/- 3 mg at week 8, 18.8 +/- 4.8 mg at week 12, and 19.2 +/- 4.9 mg at week 15. At 16 weeks, 79.6% of adalimumab treated patients achieved a PASI 75 response (primary endpoint) compared to 35.5% of methotrexate treated patients (risk difference (43.7%; 95% confidence interval (CI) 30.8% to 56.7%; p less than 0.001 vs adalimumab) and 18.9% in the placebo treated patients (risk difference 60.5%; 95% CI 44.5% to 76.6%; p less than 0.001 vs adalimumab). The improved PASI 75 response was evident after 2 weeks for adalimumab (4.6%) compared with methotrexate (0%) (p less than 0.05) and 4 weeks for adalimumab compared with placebo (p =0.001). A 100% or greater PASI (PASI 100) was achieved in 16.7%, 7.3%, and 1.9% for the adalimumab, methotrexate, and placebo treated patients, respectively (p=0.04 methotrexate vs adalimumab and p=0.004 placebo vs adalimumab). The percentage of patients with a physicians' global assessment of 'clear' or 'minimal', at week 16, were 73.1%, 30%, and 11.3% for adalimumab, methotrexate, and placebo, respectively (p less than 0.001 vs methotrexate and p less than 0.001 vs placebo). Total adverse events, most of which were mild to moderate severity, were reported in 73.8%, 80.9%, and 79.2% in the adalimumab, methotrexate, and placebo groups, respectively. No serious infections were reported. The majority of adverse events were non-serious infections followed by nasopharyngitis and headache for all groups (Saurat et al, 2008).c)  When compared with placebo, treatment with adalimumab significantly improved disease scores in patients with moderate to severe plaque psoriasis. During a double-blind, randomized, controlled trial, 147 patients received subcutaneous adalimumab at a dosage of 40 milligrams (mg) every other week (EOW; n=45) or 40 mg weekly (n=50) or placebo (n=52) for 12 weeks. Loading doses of adalimumab 80 mg were given initially to decrease the time to achieve an effective concentration. After 12 weeks, patients had the option of continuing in a 48-week extension trial during which patients who received placebo during the first 12 weeks were switched to adalimumab 40 mg every other week. Patients who continued therapy with adalimumab during the extension trial remained at their assigned dosages. Dose escalation to adalimumab 40 mg weekly was allowed for patients with less than a 50% response. All patients had received prior therapy with topical agents, but not tumor necrosis factor treatment. Low- to mid-potency topical corticosteroids were allowed during the study, but no other psoriasis therapies were permitted. The primary efficacy endpoint was the percentage of patients achieving at least a 75% improvement in Psoriasis Area and Severity Index (PASI) score (PASI 75) relative to baseline at weeks 12 and 24. Within one week after initiation of therapy, statistically significant improvements in PASI scores were noted with adalimumab therapy compared with placebo (p less than 0.001). After 12 weeks, 53% of patients receiving adalimumab 40 mg EOW and 80% of patients receiving adalimumab 40 mg weekly achieved at least PASI 75 relative to baseline, compared with 4% of patients treated with placebo (p less than 0.001). When placebo-treated patients were switched to adalimumab 40 mg EOW at week 12, 55% achieved at least PASI 75 by week 24 which was

similar to the response noted at week 12 for the adalimumab 40 mg EOW treatment group. The favorable clinical response associated with adalimumab therapy was maintained through 60 weeks of therapy. Clinical improvement in psoriasis did not vary by sex, age, or baseline weight. Additionally, comparable percentages of patients achieved PASI 75 whether they had moderate or severe psoriasis at baseline. Compared with placebo at week 12, PASI 100 was achieved in 11% and 26% of patients receiving adalimumab 40 mg EOW and every week, respectively (p less than 0.001). At week 24, the placebo/EOW group had a PASI 100 rate of 11% compared with 13% for patients in the EOW group. Overall, therapy with adalimumab was well tolerated. Adverse events were generally mild to moderate in severity and typically appeared to be unrelated or probably unrelated to treatment. Serious adverse events were reported in three patients receiving adalimumab EOW and 11 patients receiving adalimumab weekly compared to no patients receiving placebo. Detection of rare adverse events was limited due to the study being insufficiently powered (Gordon et al, 2006).

4.5.E   Psoriasis with arthropathy FDA Labeled Indication1)  OverviewFDA Approval: Adult, yes; Pediatric, noEfficacy: Adult, Evidence favors efficacyRecommendation: Adult, Class IIaStrength of Evidence: Adult, Category BSee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Adalimumab is indicated for use in patients with psoriatic arthritis to reduce signs and symptoms of active arthritis, inhibit the progression of structural damage and improve physical function (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)Effective in reducing the symptoms of active arthritis and improving patient-reported outcomes in patients (n=313) with moderately to severely active psoriatic arthritis in the randomized, double-blind, placebo-controlled, Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) (Mease et al, 2005; Gladman et al, 2007), with effects sustained over 48 weeks during the open-label extension phase (n=285) of the study (Gladman et al, 2007a)3)  Adult:a)  In a randomized, double-blind, placebo-controlled study, adalimumab was effective in reducing the symptoms of active arthritis in patients with psoriatic arthritis. The Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) enrolled 313 patients with moderately to severely active psoriatic arthritis (defined as greater than 3 swollen and greater than 3 tender joints) of several subtypes who had an inadequate response to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were administered either 40 milligrams (mg) of adalimumab (n=151) or placebo (n=162) subcutaneously every other week for 24 weeks. Patients who were on methotrexate (MTX) at the start of the enrollment were maintained at the same dose throughout the study duration. Results for measures of disease activity such as number of swollen and tender joints and pain were significantly improved for patients in the adalimumab group compared to the placebo group (p less than 0.001). At week 12, 58% adalimumab-treated patients and 14% placebo-treated patients achieved an American College of Rheumatology 20% improvement (ACR20) (between group difference 44%, 95% confidence interval (CI), 33% to 54%; p less than 0.001). The ACR20 response rates at week 24 were 57% and 15% in the adalimumab and placebo groups, respectively (between group difference 42%, 95% CI, 31% to 52%; p less than 0.001). The mean change in modified total Sharp scores (a scale assessing structural damage on radiographs of the hands and feet) in patients with baseline and week 24 radiographs, was -0.2 in the adalimumab arm compared to 1 in the placebo arm (p < 0.001). Patients in the adalimumab group experienced the beneficial effects at 2 weeks from the start of the study. Psoriatic Area and Severity Index (PASI) responses were used to assess patients with psoriatic involvement of at least 3% body surface area (BSA). In some patients, PASI responses were evident as early as 2 weeks into the treatment. At 24 weeks, 59% and 42% of patients in the adalimumab group (n=69) achieved 75% and 90% improvement in PASI, respectively compared to 1% and 0% of patients in the placebo group (n=69) (p less than 0.001). Concomitant baseline MTX therapy did not affect the level of response. Adalimumab was associated with higher incidence of nasopharyngitis (9.9% vs 9.3%) and injection-site reactions (6.6% vs 3.1%) than placebo (Mease et al, 2005).1)  In an intent-to-treat, open-label extension phase of the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) (n=285), the clinical and radiographic efficacy of adalimumab established at 24 weeks were sustained over 48 weeks among patients with moderate to severe psoriatic arthritis. Patients who completed 24 weeks of adalimumab (n=138) or placebo (n=147) blinded treatment in ADEPT entered the extension phase, during which they received adalimumab 40 milligrams (mg) subcutaneously every other week for up to 120 weeks or until adalimumab became commercially available. Those who failed to demonstrate at least 20% improvement in tender joint count and swollen joint count from baseline after 12 weeks of active treatment in the open-label phase (eg, at 36 weeks in the study) were allowed to increase the dosage of adalimumab to 40 mg weekly. At week 48, 56%, 44%, and 30% patients achieved an American College of Rheumatology 20% improvement (ACR20), ACR50, and ACR70, respectively. Among patients who were treated with placebo initially followed by adalimumab, the ACR20, ACR50, and ACR70 response rates were 48%, 34%, and 20%, respectively. Among the 69 adalimumab-treated patients evaluated with the Psoriasis Area and Severity Index (PASI), 67%, 58%, 46%, and 33% patients achieved a 50%, 75%, 90% and 100% PASI improvement response, respectively through 48 weeks. Patients in the placebo followed by adalimumab group achieved similar PASI response with respective rates at 61%, 53%, 44%, and 31%. At week 24, the mean change in the modified total Sharp score (mTSS) from baseline was -0.1 for adalimumab-treated patients (n=133) compared with 0.9 for placebo-treated patients (n=141). The inhibition of radiographic progression was maintained at 48 weeks (mean mTSS change 0.1, adalimumab group vs 1, placebo-adalimumab group). Concomitant baseline methotrexate therapy did not affect the level of rheumatologic and psoriatic response. The use of adalimumab beyond 24 weeks did not increase the prevalence of adverse events; upper respiratory tract infection (13.7%), nasopharyngitis (10.9%), and injection-site reactions (8.4%) were the most common during weeks

24 to 48 (Gladman et al, 2007a).2)  Patient-reported outcomes from the same trial were analyzed separately. Results were analyzed at 12 and 24 weeks; all results were similar between the 2 evaluation time points. At 12 weeks, patients who received adalimumab had a significantly improved mean change (-0.4 +/- 0.5, adalimumab; -0.1 +/- 0.5, placebo; p < 0.001) in the Health Assessment Questionnaire Disability Index (HAQ DI), which measures physical function and functional loss and has a minimum clinically important difference (MCID) of +/- 0.3. Complete resolution of functional loss (HAQ DI score of 0) occurred in 33.8% of the adalimumab group versus (vs) 14.3% of the placebo group at 12 weeks (p < 0.001). Patients treated with adalimumab experienced significantly improved mean changes in 7 of the 8 domains of the Short-Form 36 (SF-36) Health Survey, which measures functional status and general well-being, compared to patients treated with placebo; the only domain with no significant differences was role-emotional. The MCID (5 point change) of the physical component summary (PCS) of the SF-36 was achieved in 66.9% of the adalimumab group compared to 26.5% of the placebo group (p < 0.001) at 12 weeks while no significant differences were found between groups in the mental component summary (MCS) of the SF-36. Assessment of the Functional Assessment of Chronic Illness Therapy - Fatigue scale (FACIT-Fatigue) resulted in significantly greater mean changes in patients who received adalimumab compared to patients who received placebo at week 12 (p < 0.001) while significantly more patients who received adalimumab achieved the MCID of at least 4 points at 12 weeks (60.7% vs 30.4%; p < 0.001). Significant improvements in mean changes in visual analog scales (0 to 100 millimeter (mm)) were found in the adalimumab group compared to the placebo group in both patient-reported assessment of pain (-23 +/- 27 vs 1.6 +/- 24, respectively; p < 0.001) and patient-reported global assessment of disease activity (-19.6 +/- 29.4 vs 0.4 +/- 23.1, respectively; p < 0.001) at 12 weeks. The MCID (5-point change) of the Dermatology Life Quality Index (DLQI), used to assess dermatological-related functional limitations in patients with at least a 3% body surface area affected by psoriasis, occurred in 54.8% of the adalimumab group (n=66) and 21.7% of the placebo group (n=66; p=0.001) at 12 weeks. Complete resolution of dermatological-related functional loss (DLQI score of 0) occurred in 36.9% of the adalimumab group vs 4.9% of the placebo group at 12 weeks (p < 0.001) (Gladman et al, 2007).

4.5.F   Rheumatoid arthritis (Moderate to Severe) FDA Labeled Indication1)  OverviewFDA Approval: Adult, yes; Pediatric, noEfficacy: Adult, EffectiveRecommendation: Adult, Class IIaStrength of Evidence: Adult, Category ASee Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS2)  Summary:Indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. May be used alone or in combination with other disease-modifying antirheumatic drugs (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)Single or repeat intravenous and repeat subcutaneous doses of adalimumab have shown efficacy in active rheumatoid arthritis patients who responded poorly to prior therapy with disease-modifying antirheumatic agents (van de Putte et al, 2000a; van de Putte et al, 1999a; Schattenkirchner et al, 1998a; Anon, 2002a; Sorbera et al, 2001b; Kempeni, 1999a)Improves physical function in addition to reducing signs/symptoms and inhibiting progression of structural damage in patients with moderate to severe active rheumatoid arthritis (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)Combined therapy with methotrexate has produced significant improvement in patients responding poorly to the same doses of methotrexate alone (Schattenkirchner et al, 2000; Weisman et al, 2000a; Furst et al, 2001; Keystone et al, 2001a; Sorbera et al, 2001b)A slowing of radiographic disease progression was reported with monotherapy in one open study and with combined methotrexate plus adalimumab in a placebo-controlled study (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008)3)  Adult:a)  Pivotal Trials1)  Five manufacturer-sponsored, randomized, double-blind studies demonstrated that adalimumab improved measures of rheumatoid arthritis and health outcomes compared to placebo. These trials consisted of different adult patient populations. Study 1 (n=271) involved patients who failed therapy with at least one (but no more than 4) disease modifying antirheumatic agents (DMARDs) and had an inadequate response to methotrexate; Study 2 (n=544) patients failed at least one DMARD; Study 3 (n=619) patients had an inadequate response to methotrexate; Study 4 (n=636) patients were either DMARD naive or maintained (for the past 28 days) on stable doses of DMARDs; and Study 5 (n=799) patients were methotrexate-naive and randomized to methotrexate (optimized to 20 mg per week by week 8), adalimumab, or combination therapy with methotrexate and adalimumab. Doses of adalimumab included 20 milligrams every other week (Study 1), 20 mg weekly (Study 2, 3), 40 mg every other week (Study 1, 2, 3, 4, 5), 40 mg weekly (Study 2), or 80 mg every other week (Study 1). Study 2 patients received adalimumab monotherapy; patients receiving placebo in study 3 were also given methotrexate. For patients receiving adalimumab 40 mg every other week for 6 months, American College of Rheumatology (ACR) 20 response was achieved in 65% of the adalimumab group and 13% of placebo (Study 1, p less than 0.01); 46% and 19%, respectively (Study 2, p less than 0.01); 63% and 30%, respectively (Study 3, p less than 0.01); and 53% and 35%, respectively (Study 4, p less than 0.001). In Study 5, a major clinical response (defined by an ACR-70 response for a continuous 6-month period) was achieved in 49% of patients in the combination adalimumab plus methotrexate arm, compared to 25% in the adalimumab arm (p less than 0.001) and 28% in the methotrexate arm (p less than 0.001). Improvements were maintained to week 104. Study 3 continued therapy for a total of 12 months, at which

time, radiographic assessment was performed. The mean change in total sharp score (TSS) was 2.7 for placebo and 0.1 for adalimumab 40 mg every other week (mean difference 2.6, 95% confidence interval (CI) 1.4 to 3.8; p less than 0.001). Significant differences were also seen with erosion score (1.6 placebo, 0 for adalimumab, p less than 0.001) and joint space narrowing (JSN) score (1 placebo, 0.1 adalimumab, p=0.002). Physical function response was assessed using the disability index of the Health Assessment Questionnaire (HAQ-DI) and the Short Form Health Survey (SF 36). In Study 3, the mean improvement from baseline with the HAQ-DI at 52 weeks was 0.6 (95% CI, 0.55 to 0.65) for adalimumab and 0.25 (95% CI, 0.17 to 0.33) for placebo (p less than 0.001). Of the adalimumab patients who achieved a 0.5 or greater improvement in HAQ-DI at week 52, 82% maintained improvement through week 104 of the open label phase of the study; improvement in SF-36 was also maintained. Study 5 also assessed structural joint damage radiographically. TSS, erosion score, and JSN score were all significantly improved at 52 and 104 weeks in the adalimumab plus methotrexate arm as compared to either the adalimumab or methotrexate monotherapy arms. HAQ-DI and the physical component of SF-36 demonstrated greater improvement for the combination arm versus either the adalimumab or methotrexate monotherapy arms (p less than 0.001) at weeks 52 and 104 (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008).b)  Monotherapy1)  In phase I single-dose, placebo-controlled studies with adalimumab (0.5 to 10 milligrams/kilogram (mg/kg) intravenously) involving patients with a poor response to prior therapy with disease-modifying antirheumatic drugs (DMARDs), clinical improvement was seen within 24 hours in some patients, with peak effects occurring after 1 to 2 weeks; maximal benefit was obtained with a dose 1 mg/kg (van de Putte et al, 1998a; Kempeni, 1999a; Barrera et al, 2001a). In one trial (n=120) (van de Putte et al, 1998a), a decrease in the Disease Activity Score (DAS) by 1.2 or greater at any time after treatment (clinical response) was observed in 41%, 72%, 67%, 56%, and 78% of patients receiving single infusions of 0.5, 1, 3, 5, and 10 mg/kg, respectively; this DAS score was achieved in 19% of patients treated with placebo. At day 29 post-dosing, response rates were 6%, 28%, 33%, 44%, and 39%, respectively (0% placebo). Some responses persisted for 3 months.2)  Repeat intravenous or subcutaneous administration of adalimumab was reported effective in DMARD-refractory patients in placebo-controlled studies (up to 6 months) (van de Putte et al, 1999a; Schattenkirchner et al, 1998a; Anon, 2002a; Sorbera et al, 2001b; Kempeni, 1999a); results of open-label or blinded (non-placebo) extensions of these studies or single-dose studies, or less often studies of strictly uncontrolled design, have indicated sustained efficacy for up to 4 years (van de Putte et al, 2000a; Rau et al, 1998a; Kempeni, 2000a; Sorbera et al, 2001b; Anon, 2002a). Doses in these trials were 0.5 mg/kg or 20, 40, or 80 mg weekly subcutaneously, 40 mg biweekly, or 0.5 to 10 mg/kg intravenously every two weeks. In the weekly subcutaneous regimens, there was no statistical advantage of doses higher than 20 mg (van de Putte et al, 2000a). Evidence of the efficacy of adalimumab (given for up to one year) in slowing radiologic disease progression was reported in an open-label study (Rau et al, 1999); however, these results require confirmation (Kempeni, 2000a).3)  In one double-blind, placebo-controlled study involving 283 patients who had received 4 previous DMARDs (median)(van de Putte et al, 2000a), subcutaneous adalimumab was significantly superior to placebo in producing clinical improvement after 3 months of treatment. Improvement by at least 20% based on the American College of Rheumatology improvement criteria (ACR 20) was reported at 3 months in 14% of patients treated with placebo, and 49%, 59%, and 56% of those assigned to weekly adalimumab 20, 40, and 80 mg, respectively; ACR 50 responses were seen in 24%, 27%, and 19% with these respective adalimumab doses, compared to 3% receiving placebo. Decreases in tender joint counts (TJC) were also significantly greater with all doses of adalimumab (52 to 57%) than with placebo (8%). There was a trend toward greater reductions in swollen joint counts (SJC) with adalimumab 40 and 80 mg (56% and 54%, respectively) compared to the 20-mg dose (39%), although this was not significant; all doses reduced SJC to a significantly greater extent than placebo (15%). After 3 months, patients continued blinded adalimumab in same doses for 9 further months; placebo-treated patients were given still blinded adalimumab 40 mg weekly. Improvements in ACR 20, ACR 50, TJC, and SJC after the additional 9 months (12 months total) were similar to or slightly greater than those seen at 3 months. There was no statistically significant difference in efficacy between adalimumab doses in this trial.4)  In a randomized study provided by the manufacturer in patients who had failed therapy with at least one DMARD (n=544) (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008), American College of Rheumatology improvement criteria (ACR 20) responses were seen 46% and 53% after 6 months of treatment with subcutaneous doses of 40 mg every other week and 40 mg weekly, respectively (19% placebo); corresponding ACR 70 response rates at this time were 12% and 18% (2% placebo). All differences were statistically significant relative to placebo for both doses of adalimumab.5)  The placebo-controlled ARMADA trial (n=271) evaluated the efficacy of add-on subcutaneous adalimumab in patients who were partial responders on stable doses of methotrexate (mean, 16.8 mg weekly) (Keystone et al, 2001a). At 24 weeks, improvement by at least 20% based on the American College of Rheumatology improvement criteria (ACR 20) was observed in 48%, 66%, and 66% of patients receiving adalimumab 20, 40 and 80 mg every other week, respectively (15% placebo response). Corresponding ACR 50 response rates were 32%, 54%, and 43% (8% placebo), whereas ACR 70 response rates were 10%, 27%, and 19% (5% placebo); significantly more patients receiving adalimumab 40 or 80 mg achieved an ACR 70 response compared to adalimumab 20 mg or placebo. Decreases in swollen joint counts (SJC) and tender joint counts (TJC) were significantly greater with all doses of adalimumab (42 to 60%) compared to placebo, with a slight tendency toward dose-related efficacy, particularly for SJC. The frequency of injection-site reactions was higher in patients receiving adalimumab (15%, versus 3% with placebo). Further analysis of data in this trial (Furst et al, 2001) indicated a significant reduction in serum pro-matrix metalloproteinase-1 (pro-MMP-1) and pro-MMP-3 with all doses of adalimumab compared to placebo, which paralleled clinical benefits and suggested slowing of disease progression. After this 24-week phase, patients in this trial were given 40 mg subcutaneously every other week in an open-label extension. At 1 year, 25% of patients had an ACR 70 response; ACR 20 and 50 responses were seen in 70% and 48%, respectively (Anon, 2002a).c)  Combination Therapy

1)  Addition of intravenous (0.25 to 5 milligrams/kilogram (mg/kg)) or subcutaneous (1 mg/kg or 20 to 80 mg) adalimumab every other week to prior methotrexate therapy (usual, 16 mg weekly) has produced significant improvement in patients not responding optimally to methotrexate alone (Schattenkirchner et al, 2000; Weisman et al, 2000a; Furst et al, 2001; Keystone et al, 2001a; Sorbera et al, 2001b). Combined treatment has been given for up to 2 years. In one trial, adalimumab was given every other week to every other month, depending on clinical response (Sorbera et al, 2001b).

 4.6   Comparative Efficacy / Evaluation With Other Therapies

4.6.A   Methotrexate

Plaque psoriasis (Moderate to Severe), Chronic

Rheumatoid arthritis

4.6.A.1   Plaque psoriasis (Moderate to Severe), Chronic a)  In a 16-week, multinational, randomized, double-blind, double-dummy, placebo-controlled study (n=271) in patients with moderate to severe psoriasis, significantly more patients treated with adalimumab achieved a 75% or greater Psoriasis Area and Severity Index response rate (PASI 75) relative to baseline at 16 weeks compared to patients who received methotrexate or placebo. Patients with moderate to severe plaque psoriasis (defined as 10% or more of body surface area (BSA) affected and a PASI score of 10 or greater) that was plaque psoriasis for at least 1 year and stable plaque psoriasis for at least 2 months were enrolled. Enrolled patients were randomized (2:2:1) to receive subcutaneous (subQ) injections of adalimumab 80 milligrams (mg) once followed by 40 mg every other week beginning on week 1 through week 15 (n=108; mean age, 42.9 +/- 12.6 years (yr)); oral methotrexate initiated at 7.5 mg/week at week 0, 10 mg/week at week 2, 15 mg/ week at week 4 to 8, thereafter the dose could be increased up to a maximum of 25 mg/wk based on PASI response rate (n=110; mean age, 41.6 +/- 12 yr); or matching placebo given on the same schedule (n=53; mean age, 40.7 +/- 11.4 yr). The dose adjustments for methotrexate after week 8 were as follow: if a 50% or greater PASI (PASI 50) was not achieve at 8 weeks, then the dose was increased to 20 mg/week followed by a subsequent increase to 25 mg/wk if at 12 weeks PASI 50 was not achieved or no dose increase (maintain at 20 mg/wk) if at 12 weeks a PASI 50 was achieved. All patients received folate 5 mg orally once weekly. Concomitant low potency topical corticosteroids applied to palms, soles, face, and inframammary areas and groin were allowed during the study period. The mean weekly doses of methotrexate were 14.2 +/- 3 mg at week 4, 16.8 +/- 3 mg at week 8, 18.8 +/- 4.8 mg at week 12, and 19.2 +/- 4.9 mg at week 15. At 16 weeks, 79.6% of adalimumab treated patients achieved a PASI 75 response (primary endpoint) compared to 35.5% of methotrexate treated patients (risk difference (43.7%; 95% confidence interval (CI) 30.8% to 56.7%; p less than 0.001 vs adalimumab) and 18.9% in the placebo treated patients (risk difference 60.5%; 95% CI 44.5% to 76.6%; p less than 0.001 vs adalimumab). The improved PASI 75 response was evident after 2 weeks for adalimumab (4.6%) compared with methotrexate (0%) (p less than 0.05) and 4 weeks for adalimumab compared with placebo (p =0.001). A 100% or greater PASI (PASI 100) was achieved in 16.7%, 7.3%, and 1.9% for the adalimumab, methotrexate, and placebo treated patients, respectively (p=0.04 methotrexate vs adalimumab and p=0.004 placebo vs adalimumab). The percentage of patients with a physicians' global assessment of 'clear' or 'minimal', at week 16, were 73.1%, 30%, and 11.3% for adalimumab, methotrexate, and placebo, respectively (p less than 0.001 vs methotrexate and p less than 0.001 vs placebo). Total adverse events, most of which were mild to moderate severity, were reported in 73.8%, 80.9%, and 79.2% in the adalimumab, methotrexate, and placebo groups, respectively. No serious infections were reported. The majority of adverse events were non-serious infections followed by nasopharyngitis and headache for all groups (Saurat et al, 2008).

4.6.A.2   Rheumatoid arthritis a)  Indirect comparison of separate 48-week studies suggested that adalimumab monotherapy was more effective and safer than methotrexate monotherapy in patients with active rheumatoid arthritis. EULAR (European League Against Rheumatism) response rates were significantly higher with adalimumab (83 versus 40%) (Sorbera et al, 2001a). However, the types of studies compared and baseline data between groups were grossly different. A direct, prospective, randomized comparison of monotherapy with each agent is required.b)  In a large unpublished study involving patients who had responded poorly to methotrexate alone (n=619), an ACR 20 response was observed in 63% receiving methotrexate and subcutaneous adalimumab (40 mg every other) week for 6 months, which was significantly higher than in those receiving placebo plus methotrexate (30%); at one year of treatment, corresponding ACR 20 response rates were 59% and 24%. An ACR 70 response was seen in approximately 4% and 22% of patients in the placebo/methotrexate and methotrexate/adalimumab groups, respectively, at both 6 and 12 months of treatment. Radiologic assessments in this trial indicated significantly less radiographic progression of disease over 12 months with combined methotrexate/adalimumab compared to placebo/methotrexate; total Sharp scores (extent of structural joint damage) at one year were 0.1 and 2.7, respectively (Prod Info Humira(TM), 2002a).

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