Biological response modifiers (BRMs) – TNF inhibitors

Mechanism of Action
Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis, including juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis patients and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis (Ps) plaques. In plaque psoriasis, treatment with HUMIRA may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which HUMIRA exerts its clinical effects is unknown.

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

INDICATIONS AND USAGE
HUMIRA is a tumor necrosis factor (TNF) blocker indicated for treatment of:
Rheumatoid Arthritis (RA):
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 RA.
Juvenile Idiopathic Arthritis (JIA):
Reducing signs and symptoms of moderately to severely active polyarticular JIA in pediatric patients 4 years of age and older.

Psoriatic Arthritis (PsA):
Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active PsA.

Ankylosing Spondylitis (AS):
Reducing signs and symptoms in adult patients with active AS.

Crohn’s Disease (CD):
Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. Reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Ulcerative Colitis (UC):
Inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine (6-MP). The effectiveness of HUMIRA has not been established in patients who have lost response to or were intolerant to TNF blockers.

Plaque Psoriasis (Ps):
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.

DOSAGE AND ADMINISTRATION
Administered by subcutaneous injection.

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis:
40 mg every other week.
Some patients with RA not receiving methotrexate may benefit from increasing the frequency to 40 mg every week.

Juvenile Idiopathic Arthritis:
15 kg (33 lbs) to < 30 kg (66 lbs): 20 mg every other week
≥ 30 kg (66 lbs): 40 mg every other week

Crohn's Disease and Ulcerative Colitis:
Initial dose (Day 1): 160 mg (four 40 mg injections in one day or two 40 mg injections per day for two consecutive days)
Second dose two weeks later (Day 15): 80 mg
Two weeks later (Day 29): Begin a maintenance dose of 40 mg every other week.
For patients with Ulcerative Colitis only: Only continue HUMIRA in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy.

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

How Supplied
Injection: 40 mg/0.8 mL in a single-use prefilled pen (HUMIRA Pen)
Injection: 40 mg/0.8 mL in a single-use prefilled glass syringe
Injection: 20 mg/0.4 mL in a single-use prefilled glass syringe

INDICATIONS AND USAGE
CIMZIA is a tumor necrosis factor (TNF) blocker indicated for:

 --Reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
--Treatment of adults with moderately to severely active rheumatoid arthritis.

DOSAGE AND ADMINISTRATION
CIMZIA is administered by subcutaneous injection. The initial dose of CIMZIA is 400 mg (given as two subcutaneous injections of 200 mg).

Crohn's Disease:
400 mg initially and at Weeks 2 and 4. If response occurs, follow with 400 mg every four weeks

Rheumatoid Arthritis:
400 mg initially and at Weeks 2 and 4, followed by 200 mg every other week; for maintenance dosing, 400 mg every 4 weeks can be considered

How Supplied:
200 mg lyophilized powder for reconstitution, in a single-use glass vial, with 1 mL of sterile Water for Injection, USP.
200 mg/mL solution in a single-use prefilled glass syringe.

INDICATIONS AND USAGE
Enbrel is a tumor necrosis factor (TNF) blocker indicated for the treatment of:
Rheumatoid Arthritis (RA)
Polyarticular Juvenile Idiopathic Arthritis (JIA) in patients aged 2 years or older.
Psoriatic Arthritis (PsA)
Ankylosing Spondylitis (AS)
Plaque Psoriasis (PsO)

DOSAGE AND ADMINISTRATION
Enbrel is administered by subcutaneous injection.
Adult RA and PsA
50 mg once weekly with or without methotrexate (MTX)

Ankylosing Spondylitis (AS)
50 mg once weekly

Adult Plaque Psoriasis (PsO)
50 mg twice weekly for 3 months, followed by 50 mg once weekly

Juvenile Idiopathic Arthritis (JIA)
0.8 mg/kg weekly, with a maximum of 50 mg per week

Administration
Administer subcutaneously. Rotate injection sites. New injections should be given at least one inch from an old site and never into areas where the skin is tender, bruised, red, or hard.
Powder for reconstitution: Follow package instructions carefully for reconstitution. Note: The needle cover of the diluent syringe (multidose vial) may contain dry natural rubber (latex) which should not be handled by persons sensitive to this substance. The maximum amount injected at any single site should not exceed 25 mg.

Prefilled syringe: May be allowed to reach room temperature prior to injection.

DOSAGE FORMS AND STRENGTHS
50 mg Single-use Prefilled Syringe
0.98 mL of a 50 mg/mL solution of etanercept

50 mg Single-use Prefilled SureClick® Autoinjector
0.98 mL of a 50 mg/mL solution of etanercept

25 mg Single-use Prefilled Syringe
0.51 mL of a 50 mg/mL solution of etanercept

25 mg Multiple-use Vial
25 mg of etanercept

Drug Update:  SIMPONI (golimumab) injection, for subcutaneous use
[Drug information  /   PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)
Initial U.S. Approval:  2013

Mechanism of Action: Golimumab is a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNFa. This interaction prevents the binding of TNFa to its receptors, thereby inhibiting the biological activity of TNFa (a cytokine protein). There was no evidence of the golimumab antibody binding to other TNF superfamily ligands; in particular, the golimumab antibody did not bind or neutralize human lymphotoxin. Golimumab did not lyse human monocytes expressing transmembrane TNF in the presence of complement or effector cells.

Elevated TNFa levels in the blood, synovium, and joints have been implicated in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. TNFa is an important mediator of the articular inflammation that is characteristic of these diseases. The exact mechanism by which golimumab treats ulcerative colitis is unknown. Golimumab modulated the in vitro biological effects mediated by TNF in several bioassays, including the expression of adhesion proteins responsible for leukocyte infiltration (E-selectin, ICAM-1 and VCAM-1) and the secretion of proinflammatory cytokines (IL-6, IL-8, G-CSF and GM-CSF).

WARNING: SERIOUS INFECTIONS AND MALIGNANCY
See full prescribing information for complete boxed warning.

• Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial sepsis, invasive fungal (such as histoplasmosis), and other opportunistic infections have occurred in patients receiving SIMPONI
• Discontinue SIMPONI if a patient develops a serious infection or sepsis
• Perform test for latent TB; if positive, start treatment for TB prior to starting SIMPONI
• Monitor all patients for active TB during treatment, even if initial latent TB test is negative
• Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which SIMPONI is a member

WARNINGS AND PRECAUTIONS

• Serious Infections: Do not start SIMPONI during an active infection. If an infection develops, monitor carefully, and stop SIMPONI if infection becomes serious
• Invasive Fungal Infections: For patients who develop a systemic illness on SIMPONI, consider empiric antifungal therapy for those who reside in or travel to regions where mycoses are endemic
• Hepatitis B Reactivation: Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop SIMPONI and begin anti-viral therapy
• Malignancies: Incidence of lymphoma was greater than in the general U.S. population. Cases of other malignancies have been observed among patients receiving TNF-blockers
• Heart Failure: Worsening, or new onset, may occur. Stop SIMPONI if new or worsening symptoms occur
• Demyelinating Disease: Exacerbation or new onset, may occur
• Hypersensitivity Reactions: Serious systemic hypersensitivity reactions including anaphylaxis may occur

INDICATIONS AND USAGE
SIMPONI is a tumor necrosis factor (TNF) blocker indicated for the treatment of adult patients with:

• Moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate
• Active psoriatic arthritis (PsA) alone, or in combination with methotrexate
• Active ankylosing spondylitis (AS)
• Moderate to severe Ulcerative colitis (UC) with an inadequate response or intolerant to prior treatment or requiring continuous steroid therapy
  • inducing and maintaining clinical response
  • improving endoscopic appearance of the mucosa during induction
  • inducing clinical remission
  • aachieving and sustaining clinical remission in induction responders

DOSAGE AND ADMINISTRATION
Dosage in Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis
The SIMPONI dose regimen is 50 mg administered by subcutaneous injection once a month.

For patients with rheumatoid arthritis (RA), SIMPONI should be given in combination with methotrexate and for patients with psoriatic arthritis (PsA) or ankylosing spondylitis (AS), SIMPONI may be given with or without methotrexate or other non-biologic Disease Modifying Antirheumatic Drugs (DMARDs). For patients with RA, PsA, or AS, corticosteroids, non-biologic DMARDs, and/or NSAIDs may be continued during treatment with SIMPONI.

Dosage in Moderately to Severely Active Ulcerative Colitis
The recommended SIMPONI induction dosage regimen is a 200 mg subcutaneous injection at Week 0, followed by 100 mg at Week 2 and then maintenance therapy with 100 mg every 4 weeks.

Monitoring to Assess Safety
Prior to initiating SIMPONI and periodically during therapy, evaluate patients for active tuberculosis and tested for latent infection [see Warnings and Precautions (5.1)]. Prior to initiating SIMPONI, patients should be tested for hepatitis B viral infection [see Warnings and Precautions (5.1)].

Important Administration Instructions
SIMPONI is intended for use under the guidance and supervision of a healthcare provider. After proper training in subcutaneous injection technique, a patient may self inject with SIMPONI if a physician determines that it is appropriate. Instruct patients to follow the directions provided below [see Instructions for Use]:

• To ensure proper use, allow the prefilled syringe or autoinjector to sit at room temperature outside the carton for 30 minutes prior to subcutaneous injection. Do not warm SIMPONI in any other way.
• Prior to administration, visually inspect the solution for particles and discoloration through the viewing window. SIMPONI is clear to slightly opalescent and colorless to light yellow. Do not use SIMPONI, if the solution is discolored, or cloudy, or if foreign particles are present.
• Do not use any leftover product remaining in the prefilled syringe or prefilled autoinjector.
• Instruct patients sensitive to latex, to not handle the needle cover on the prefilled syringe as well as the needle cover of the prefilled syringe within the autoinjector cap because it contains dry natural rubber (a derivative of latex).
• At the time of dosing, if multiple injections are required, administer the injections at different sites on the body.
• Rotate injection sites and never give injections into areas where the skin is tender, bruised, red, or hard.

DDOSAGE FORMS AND STRENGTHS

• 50 mg/0.5 mL in a single dose prefilled SmartJect® autoinjector
• 50 mg/0.5 mL in a single dose prefilled syringe
• 100 mg/1 mL in a single dose prefilled SmartJect® autoinjector
• 100 mg/1 mL in a single dose prefilled syringe

INDICATIONS AND USAGE
REMICADE is a tumor necrosis factor (TNF) blocker indicated for:

Crohn's Disease:
reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease.

Pediatric Crohn's Disease:
reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Ulcerative Colitis:
reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Pediatric Ulcerative Colitis:
reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Rheumatoid Arthritis in combination with methotrexate:
reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active disease.

Ankylosing Spondylitis:
reducing signs and symptoms in patients with active disease.

Psoriatic Arthritis:
reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function.

Plaque Psoriasis:
treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate.

DOSAGE AND ADMINISTRATION
REMICADE is administered by intravenous infusion over a period of not less than 2 hours.

Crohn's Disease
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some adult patients who initially respond to treatment may benefit from increasing the dose to 10 mg/kg if they later lose their response.

Pediatric Crohn's Disease
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Ulcerative Colitis
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Pediatric Ulcerative Colitis
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Rheumatoid Arthritis
In conjunction with methotrexate, 3 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some patients may benefit from increasing the dose up to 10 mg/kg or treating as often as every 4 weeks.

Ankylosing Spondylitis
5 mg/kg at 0, 2 and 6 weeks, then every 6 weeks.

Psoriatic Arthritis and Plaque Psoriasis
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

DOSAGE FORMS AND STRENGTHS
100 mg of lyophilized infliximab in a 20 mL vial for intravenous infusion.

Drug UPDATES:  Inflectra™ (infliximab-dyyb) For Injection
[Drug information  /  PDF]    REVIEW PACKAGE INSERT FOR POSSIBLE UPDATES
PACKAGE INSERT -Dosing:  Click (+) next to Dosage and Administration section (drug info link)

>Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis) and infections due to other opportunistic pathogens. (5.1)
>Discontinue INFLECTRA if a patient develops a serious infection. (5.1)
>Perform test for latent TB; if positive, start treatment for TB prior to starting INFLECTRA. Monitor all patients for active TB during treatment, even if initial latent TB test is negative. (5.1)
>Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including infliximab products. (5.2)
>Postmarketing cases of fatal hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF blockers, including infliximab products. Almost all had received azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of cases were reported in patients with Crohn's disease or ulcerative colitis, most of whom were adolescent or young adult males. (5.2)

Initial U.S. Approval:  2016

Mechanism of Action: Infliximab products neutralize the biological activity of TNFa by binding with high affinity to the soluble and transmembrane forms of TNFa and inhibit binding of TNFa with its receptors. Infliximab products do not neutralize TNFß (lymphotoxin-a), a related cytokine that utilizes the same receptors as TNFa. Biological activities attributed to TNFa include: induction of proinflammatory cytokines such as IL-1 and IL-6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or chondrocytes. Cells expressing transmembrane TNFa bound by infliximab products can be lysed in vitro or in vivo. Infliximab products inhibit the functional activity of TNFa in a wide variety of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils, B and T lymphocytes and epithelial cells. The relationship of these biological response markers to the mechanism(s) by which infliximab products exert their clinical effects is unknown. Anti-TNFa antibodies reduce disease activity in the cotton-top tamarin colitis model, and decrease synovitis and joint erosions in a murine model of collagen-induced arthritis. Infliximab products prevent disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFa, and when administered after disease onset, allows eroded joints to heal.

INDICATIONS AND USAGE:

INFLECTRA is a tumor necrosis factor (TNF) blocker indicated for:

Crohn's Disease (1.1):
reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease.

Pediatric Crohn's Disease (1.2):
reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Ulcerative Colitis (1.3):
reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Rheumatoid Arthritis (1.4) in combination with methotrexate:
reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active disease.

Ankylosing Spondylitis (1.5):
reducing signs and symptoms in patients with active disease.

Psoriatic Arthritis (1.6):
reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function.

Plaque Psoriasis (1.7):
treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate.

DOSAGE AND ADMINISTRATION:
INFLECTRA is administered by intravenous infusion over a period of not less than 2 hours.

Crohn's Disease (2.1)
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some adult patients who initially respond to treatment may benefit from increasing the dose to 10 mg/kg if they later lose their response.

Pediatric Crohn's Disease (2.2)
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Ulcerative Colitis (2.3)
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Rheumatoid Arthritis (2.4)
In conjunction with methotrexate, 3 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some patients may benefit from increasing the dose up to 10 mg/kg or treating as often as every 4 weeks.

Ankylosing Spondylitis (2.5)
5 mg/kg at 0, 2 and 6 weeks, then every 6 weeks.

Psoriatic Arthritis (2.6) and Plaque Psoriasis (2.7)
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

HOW SUPPLIED:
For injection: 100 mg of lyophilized infliximab-dyyb in a 20 mL vial for intravenous infusion.