BIOLOGICALS









Belimumab (Benlysta®)

Dosage forms

Single-use vials
  • Comes in 120 mg and 400 mg vials
Single-dose autoinjector
  • 200 mg
  • Comes in carton with 4 autoinjectors
Single-use prefilled syringe
  • 200 mg
  • Comes in carton with 4 syringes

Dosing - Intravenous

SLE or lupus nephritis in adults and SLE in children ≥ 5 years old
  • Starting: 10 mg/kg at 2-week intervals for 3 doses
  • Maintenance: 10 mg/kg every 4 weeks

Dosing - Subcutaneous

Systemic lupus erythematosus (adults)
  • Dosing: 200 mg subcutaneously once weekly
  • Inject in abdomen or thigh
  • If transitioning from intravenous therapy, administer the first subcutaneous dose 1 to 4 weeks after the last intravenous dose
Lupus nephritis (adults)
  • Dosing: 400 mg (two 200 mg injections) once weekly for 4 doses, then 200 mg once weekly thereafter
  • Inject in abdomen or thigh
  • A patient with lupus nephritis may transition from intravenous therapy to subcutaneous therapy any time after the patient completes the first 2 intravenous doses. If transitioning, administer the first subcutaneous dose of 200 mg 1 to 2 weeks after the last intravenous dose.

Efficacy


Other

Vials
  • Benlysta is given by IV infusion over a period of 1 hour
  • Premedication (e.g. antihistamines, Tylenol, steroids) is recommended to prevent infusion reactions
Autoinjector and prefilled syringe
  • Keep refrigerated in original carton
  • May be stored outside of the refrigerator up to 86°F (30°C) for up to 12 hours if protected from sunlight

Mechanism of action

  • B-cell depleting agent - B-lymphocyte stimulator (BLyS) is a growth factor required for B-cell survival, maturation, and activation. Belimumab is a fully humanized IgG monoclonal antibody that binds and inactivates soluble BLyS. By inactivating BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.

FDA-approved indications

  • Systemic lupus erythematosus - patients aged 5 years and older with active, ANA-positive SLE who are receiving standard therapy
  • Lupus nephritis - adult patients with active lupus nephritis who are receiving standard therapy

Side effects


Side effect Belimumab
(N=674)
Placebo
(N=675)
Nausea 15% 12%
Diarrhea 12% 9%
Fever 10% 8%
Nasopharyngitis 9% 7%
Bronchitis 9% 5%
Insomnia 7% 5%
Pain in extremity 6% 4%
Pharyngitis 5% 3%
Leukopenia 4% 2%
Gastroenteritis 3% 1%
Other
  • Infusion reactions - up to 17% of patients; common reactions include headache, nausea, and skin reactions


Contraindications / Precautions

  • Cyclophosphamide - DO NOT COMBINE. Benlysta has not been studied in patients receiving intravenous cyclophosphamide.
  • Biologicals - DO NOT COMBINE. Benlysta has not been studied in patients receiving other biologicals.
  • Mortality - in intravenous trials, more deaths occurred in Benlysta-treated patients than placebo-treated patients. Out of 2,133 patients in 3 clinical trials, rates of death were as follows: Placebo - 3/675 (0.4%) | Benlysta 1 mg/kg 5/673 (0.7%) | Benlysta 4 mg/kg 0/111 (0%) | Benlysta 10 mg/kg 6/674 (0.9%). No single cause of death predominated. In subcutaneous trials, the rate of death for Benlysta-treated patients was 0.5% compared to 0.7% of placebo-treated patients.
  • Serious infections - Benlysta may increase the risk of serious infections. In intravenous trials, serious infections occurred in 6% of Benlysta-treated patients and 5.2% of placebo-treated patients. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. In trials involving subcutaneous administration, serious infections occurred in 4.1% of Benlysta-treated patients and 5.4% of placebo-treated patients.
  • Progressive Multifocal Leukoencephalopathy (PML) - JC virus infections resulting in PML and death have occurred. Consider PML diagnosis in patients with new-onset or deteriorating neurological signs and symptoms.
  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis and death have occurred. In trials, hypersensitivity reactions on the same day of infusion were reported in 13% of Benlysta-treated patients and 11% of placebo-treated patients. Reactions included rash, itching, angioedema, hypotension, and dyspnea. Subcutaneous administration has also been associated with serious reactions similar to those observed with intravenous administration.
  • Infusion reactions - in trials, adverse events on the same day of infusion were reported in 17% of Benlysta-treated patients and 15% of placebo-treated patients. Common reactions (> 3% of patients) included headache, nausea, and skin reactions. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of Benlysta-treated patients and 0.4% of placebo-treated patients. Serious reactions included bradycardia, myalgia, headache, rash, urticaria, and hypotension. Premedication before infusions may help to reduce the risk of reactions.
  • Depression - in intravenous trials, psychiatric events including depression, anxiety, and insomnia occurred in 16% of Benlysta-treated patients and 12% of placebo-treated patients. In subcutaneous trials, psychiatric events were reported in 6% of Benlysta-treated patients and 11% of placebo-treated patients. Serious psychiatric events have been reported in up to 1% of patients being treated with Benlysta. Use caution in susceptible patients.
  • Malignancy - Benlysta may increase the risk of malignancy. In controlled trials of IV Benlysta, malignancies (excluding non-melanoma skin cancers) occurred in 0.2% of Benlysta-treated patients and 0.3% of placebo-treated patients.
  • Immunizations - live vaccines should not be given 30 days before or concurrently with Benlysta. See live or attenuated vaccines for more.
  • Belimumab antibodies - in trials, anti-belimumab antibodies were detected in 4 of 563 (0.7%) patients treated with 10 mg/kg and 27 of 559 (4.8%) patients treated with 1 mg/kg. Neutralizing antibodies were detected in 3 patients receiving 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. The clinical relevance of anti-belimumab antibodies is unknown.
  • Lupus nephritis - patients with severe lupus nephritis were excluded from trials. The effects of Benlysta in these patients are unknown.
  • CNS lupus - patients with CNS lupus were excluded from trials. The effects of Benlysta in these patients are unknown.
  • Kidney disease - dosage adjustment is not recommended
  • Liver disease - has not been studied. Dosage adjustment is not recommended.

Rituximab | Rituxan® | Truxima® | Ruxience® | Riabni®

Dosage forms

Single-use vials (Rituxan®)
  • Comes in 100 mg and 500 mg vials
  • Drug concentration is 10 mg/ml
Biosimilars
  • Rituximab-abbs (Truxima®)
  • Rituximab-pvvr (Ruxience®)
  • Rituximab-arrx (Riabni®)
  • All come in 100 mg and 500 mg single-use vials

Dosing

Rheumatoid arthritis
  • Dosing: one course of Rituxan is two 1000 mg doses given 2 weeks apart
  • One course may be given every 24 weeks based on clinical response
  • Courses should not be given sooner than every 16 weeks
  • Rituxan should be given with methotrexate
Immune thrombocytopenia (off-label)
  • Dosing: 100 mg/week for 4 weeks OR 375 mg/m2/week for 4 weeks
  • Dosing is the same in children and adults
  • Response is highly variable. Only recommended as third- or fourth-line agent.
  • See immune thrombocytopenia for more
Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)
  • Dosing 375 mg/m2 intravenous infusion once weekly for 4 weeks
  • Methylprednisolone 1000 mg IV per day for 1 to 3 days followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day and tapered per clinical need) are recommended to treat severe vasculitis symptoms. This regimen should begin within 14 days prior to or with the initiation of Rituximab and may continue during and after the 4 week course of Rituximab treatment.
  • Safety and efficacy of treatment with subsequent courses of Rituxan have not been established

Lab monitoring

Before therapy
  • Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). The American College of Rheumatology recommends treating latent TB for at least one month before starting rituximab. Active TB should be treated completely before starting rituximab.
  • Hepatitis B - hepatitis B reactivation leading to death has occurred during rituxan therapy. Screen all patients for hepatitis B infection by measuring HBsAg and anti-HBc before initiating treatment with Rituxan. For positive results (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult a hepatitis B expert before starting therapy. Monitor patients with current or prior infection closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Hepatitis C - screen patients for hepatitis C before initiating therapy
  • Pregnancy test - verify pregnancy status in women of reproductive potential
Blood dyscrasias
  • In patients with RA, check CBC with platelets at 2 - 4 month intervals during Rituxan therapy
  • Recommendations in patients with malignancies differ

Efficacy


Other

  • Rituxan is given as an IV infusion
  • Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions

Mechanism of action

  • B-cell depleting agent - Rituxan is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. Rituxan targets the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. Upon binding to CD20, Rituxan mediates B-cell lysis.

FDA-approved indications

  • Rheumatoid arthritis - in combination with methotrexate for the treatment of adult patients with moderately- to severely- active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies
  • Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) - in combination with glucocorticoids in adults and pediatric patients ≥ 2 years old
  • Pemphigus vulgaris - adult patients with moderate to severe pemphigus vulgaris
  • Non–Hodgkin's lymphoma
  • Chronic Lymphocytic Leukemia (CLL)

Side effects


Side effect Rituximab Placebo
Hypertension 8% 5%
Nausea 8% 5%
Arthralgia 6% 4%
Fever 5% 2%
Dyspepsia 3% < 1%
Other
  • Infusion reactions - up to 32% of patients during first infusion; reactions include fever, chills, rigors, pruritus, urticaria/rash, angioedema, sneezing, throat irritation, cough, bronchospasm, and hypertension; reactions decreased with subsequent infusions


Contraindications / Precautions

NOTE: Precautions presented here are for patients with RA. Precautions in patients with malignancies may differ.
  • Pregnancy - infants exposed to rituximab in-utero are at risk for B-cell lymphocytopenia. Women with reproductive potential should use contraception while being treated with rituximab and for at least 12 months after the last dose.
  • Nursing - there is no data on the presence of rituximab in breast milk, but IgG is present in human milk. Women should not breastfeed while on rituximab and for at least 6 months after the last dose.
  • Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). The American College of Rheumatology recommends treating latent TB for at least one month before starting rituximab. Active TB should be treated completely before starting rituximab. [2]
  • Infusion reactions - fatal infusion reactions have occurred. Patients should be premedicated with methylprednisolone 100 mg IV or its equivalent 30 minutes prior to each infusion.
  • Mucocutaneous reactions - fatal mucocutaneous reactions have occurred. Reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.
  • Hepatitis B reactivation - hepatitis B reactivation leading to death has occurred. Screen all patients for hepatitis B infection by measuring HBsAg and anti-HBc before initiating treatment with Rituxan. For positive results (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult a hepatitis B expert before starting therapy. Monitor patients with current or prior infection closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Progressive Multifocal Leukoencephalopathy (PML) - JC virus infections resulting in PML and death have occurred. The majority of cases occurred in patients receiving chemotherapy or as part of a hematopoietic stem cell transplant. Consider PML in any patient presenting with new-onset neurologic manifestations.
  • Serious infections - Rituxan may increase the risk of serious infections including invasive fungal infections, bacterial infections, viral infections, and others. In RA trials, the rate of serious infections in Rituxan-treated patients was 4.31 per 100 patient-years. The most common serious infections were pneumonia or lower respiratory tract infections, cellulitis and urinary tract infections.
  • Use with other biologicals or DMARDs other than methotrexate - has not been studied. Use caution.
  • Cardiac reactions - cardiac reactions including arrhythmia and heart attack have occurred in patients treated with Rituxan. Susceptible patients should have cardiac monitoring during infusions.
  • Rituxan antibodies - in pemphigus trials lasting up to 18 months, anti-Rituxan antibodies were detected in up to 56% of patients. In trials for other indications, the incidence has been less (Non-Hodgkin's Lymphoma - 1.1% | RA - 11% | GPA/MPA - 23%). It's unknown if antibody development is associated with reduced efficacy and/or an increase in hypersensitivity reactions.
  • Vaccines - patients may receive non-live vaccines. Administer non-live vaccines at least 4 weeks prior to a course of Rituxan. Vaccine response may be lower in patients receiving Rituxan. Do not give live or attenuated vaccines.
  • Hypophosphatemia - in trials, newly-occurring hypophosphatemia (< 2.0 mg/dl) was observed in 21% of Rituxan-treated patients. The majority of the observed hypophosphatemia occurred at the time of the infusions and was transient.
  • Hyperuricemia - in trials, newly-occurring hyperuricemia (> 10 mg/dl) was observed in 1.5% of Rituxan-treated patients compared to 0.3% of placebo-treated patients.
  • Liver disease - has not been studied
  • Kidney disease - has not been studied

Anakinra (Kineret®)

Dosage forms

Prefilled syringe
  • Comes in 100 mg dose
  • Comes in pack of 28 syringes

Dosing

Rheumatoid arthritis
  • Dosing: 100 mg once daily
  • Dose should be given at the same time every day
Cryopyrin-associated periodic syndromes
  • Starting: 1 - 2 mg/kg daily
  • The dose can be individually adjusted to a maximum of 8 mg/kg daily to control active inflammation
  • Adjust doses in 0.5 to 1 mg/kg increments
  • Once daily administration is generally recommended, but the dose may be split into twice daily administrations
Deficiency of interleukin-1 receptor antagonist (DIRA)
  • Starting: 1 - 2 mg/kg daily
  • The dose can be individually adjusted to a maximum of 8 mg/kg daily to control active inflammation
  • Adjust doses in 0.5 to 1 mg/kg increments

Efficacy


Lab monitoring

Neutropenia
  • Check neutrophil count before starting therapy
  • Check neutrophil count monthly for 3 months when starting therapy, and thereafter quarterly for a period up to 1 year

Other

  • Keep refrigerated
  • Allow syringe to warm to room temperature for 30 minutes before injecting
  • Solution should be colorless. There may be trace amounts of small, translucent-to-white amorphous particles of protein in the solution.
  • Inject subcutaneously in the thigh, abdomen, or outer upper arms. Rotate injection sites.

Mechanism of action

  • Kineret is a recombinant, nonglycosylated form of the human interleukin-1 receptor antagonist (IL-1Ra). Kineret binds to IL-1 receptors and blocks the activity of IL-1 alpha and beta.
  • Rheumatoid arthritis mechanism - IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses. IL-1 has a broad range of activities including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption. The levels of the naturally occurring IL-1Ra in synovium and synovial fluid from RA patients are not sufficient to compete with the elevated amount of locally produced IL-1.
  • Cryopyrin-associated periodic syndromes mechanism - Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with cryopyrin-associated periodic syndromes such as NOMID. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activated inflammasome results in proteolytic maturation and secretion of IL-1β, which has an important role in the systemic inflammation and manifestations of NOMID.
  • Deficiency of interleukin-1 receptor antagonist (DIRA) mechanism - DIRA is an autosomal recessive monogenic autoinflammatory disease caused by mutations in the IL1RN gene leading to loss of secretion of the interleukin-1 receptor antagonist (IL-1Ra). The deficiency of IL-1Ra results in unopposed IL-1α and IL-1β pro-inflammatory signaling causing systemic inflammation with skin and bone involvement.

FDA-approved indications

  • Rheumatoid arthritis
  • Cryopyrin-associated periodic syndromes - treatment of neonatal-onset multisystem inflammatory disease (NOMID)
  • Deficiency of Interleukin-1 Receptor Antagonist (DIRA)

Side effects


Side effect Anakinra Placebo
Headache 12% 9%
Diarrhea 7% 5%
Other
  • Injection site reactions - up to 71% of patients; common reactions include erythema, ecchymosis, inflammation, and pain; reactions typically last 14 - 28 days; reactions typically occur within first 4 weeks of therapy


Contraindications / Precautions

  • Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). The American College of Rheumatology recommends treating latent TB for at least one month before starting anakinra. Active TB should be treated completely before starting anakinra. [2]
  • Serious infections - Kineret may increase the risk of serious infections including tuberculosis, invasive fungal infections, bacterial infections, viral infections, and others. In trials lasting 1 year, the incidence of serious infections in Kineret-treated patients was 3% compared to 2% in placebo-treated patients. Patients with asthma may be at higher risk.
  • TNF inhibitors - DO NOT COMBINE. May increase risk of serious infection.
  • Neutropenia - in trials, 8% of Kineret-treated patients had a decrease in WBCs of at least one WHO toxicity grade compared to 2% of placebo-treated patients. Absolute neutrophil counts < 1000 cells/μL occurred in 0.4% of Kineret-treated patients. See Lab monitoring for further recommendations.
  • Eosinophilia - in trials, 9% of Kineret-treated patients had an increase in eosinophils of at least one WHO toxicity grade compared to 3% of placebo-treated patients.
  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis have been reported. Patients with DIRA are lacking IL-1 receptor antagonist and may be at increased risk of hypersensitivity reactions, particularly during the first several weeks after starting Kineret. Use extra caution in these patients.
  • Malignancies - may increase the risk for malignancies
  • Vaccines - patients may receive non-live vaccines. Do not give live or attenuated vaccines.
  • Kineret antibodies - in trials, anti-Kineret antibodies were detected in up to 49% of patients. It's unclear if antibody development is associated with reduced efficacy.
  • CYP enzyme activity - suppression of inflammatory mediators by Kineret may increase CYP enzyme activity and decrease blood levels of drugs metabolized by CYP enzymes
  • Liver disease - has not been studied
  • Kidney disease
    • CrCl < 30 ml/min: consider dosing every other day

Sarilumab (Kevzara®)

Dosage forms

Single-dose pen
  • 150 mg
  • 200 mg
  • Comes in package of 2 pens
Single-dose syringe
  • 150 mg
  • 200 mg
  • Comes in package of 2 syringes

Dosing

Rheumatoid arthritis
  • Dosing: 200 mg SQ every two weeks
  • May be used as monotherapy or in combination with methotrexate or other conventional DMARDs

Efficacy


Lab monitoring

Neutropenia
  • Do not initiate in patients with ANC < 2000 cells/mm³
  • Check neutrophil count 4 - 8 weeks after starting therapy and every 3 months thereafter
Thrombocytopenia
  • Do not initiate in patients with platelet count < 150,000/mm³
  • Check platelet count 4 - 8 weeks after starting therapy and every 3 months thereafter
Elevated LFTs
  • Do not initiate in patients with AST or ALT > 1.5 X ULN
  • Check LFTs 4 - 8 weeks after starting therapy and every 3 months thereafter
Increased cholesterol
  • Check lipid parameters 4 - 8 weeks after starting therapy and every 24 weeks thereafter
Dose adjustments

Other

Syringe
  • Keep refrigerated
  • May be stored at room temperature up to 14 days
  • Inject subcutaneously in the thigh, abdomen, or outer upper arms. Rotate injection sites.

Mechanism of action

  • Interleukin-6-receptor inhibitor - Interleukin-6 (IL-6) is a pro-inflammatory mediator found in joints affected by inflammatory processes such as rheumatoid arthritis. Sarilumab is a human recombinant monoclonal antibody of the IgG1 subclass that binds to the IL-6 receptor. Sarilumab binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors.

FDA-approved indications

  • Rheumatoid arthritis

Side effects


Side effect Sarilumab Placebo
Neutropenia 10% 0.2%
ALT increase 5% 2%
Injection site erythema 4% 0.9%
Upper respiratory infection 3% 2%
UTI 3% 2%
Injection site pruritus 2% 0.2%
Leukopenia 2% 0%


Contraindications / Precautions

  • Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). For another IL-6-receptor inhibitor (tocilizumab), the American College of Rheumatology recommends treating latent TB for at least one month before starting therapy. Active TB should be treated completely before starting therapy. [2]
  • Serious infections - sarilumab may increase the risk of serious infections including tuberculosis, invasive fungal infections, bacterial infections, viral infections, and others. In 52-week trials, 4.3 serious infections per 100 patient-years occurred in sarilumab-treated patients compared to 3.1 serious infections per 100 patient-years in placebo-treated patients.
  • JAK inhibitors and other biologic DMARDs - sarilumab has not been investigated in combination with JAK inhibitors or biological DMARDs such as TNF antagonists. Avoid combination due to possible increased immunosuppression and risk of infection.
  • Hepatitis B - patients infected with hepatitis B may have reactivation of disease while taking sarilumab. Test patients before initiating therapy. Monitor infected patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Herpes zoster - reactivation of herpes zoster has occurred in patients using sarilumab
  • Gastrointestinal perforations - gastrointestinal (GI) perforations have been reported in trials. Most cases were reported as complications of diverticulitis. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids.
  • Neutropenia - neutropenia (< 1000 cells/mm³) occurred in 6% of patients in trials. Do not initiate sarilumab in patients with ANC < 2000 cells/mm³. See Lab monitoring for further recommendations.
  • Thrombocytopenia - thrombocytopenia (< 100,000/mm³) occurred in 1% of patients in trials. Do not initiate sarilumab in patients with platelet count < 150,000/mm³. See Lab monitoring for further recommendations.
  • Elevated liver enzymes - elevated liver enzymes (> 3 X ULN) occurred in 43% of patients in trials. Do not initiate sarilumab in patients with AST or ALT > 1.5 X ULN. See Lab monitoring for further recommendations.
  • Elevated lipid parameters - average lipid increases of 16 mg/dl, 27 mg/dl, and 3 mg/dl in LDL, triglycerides, and HDL, respectively, were seen in trials. See Lab monitoring for further recommendations.
  • Hypersensitivity reactions - hypersensitivity reactions were reported in 0.3% of sarilumab-treated patients in trials. Injection site redness, rash, and urticaria were the most frequent hypersensitivity reactions.
  • Malignancies - sarilumab may increase the risk for malignancies
  • Sarilumab antibodies - in trials, anti-sarilumab antibodies were detected in up to 9.2% of patients. No correlation was observed between antibody development and either loss of efficacy or adverse reactions.
  • Vaccines - patients may receive non-live vaccines. Do not give live or attenuated vaccines.
  • CYP enzyme activity - suppression of inflammatory mediators by sarilumab may increase CYP enzyme activity and decrease blood levels of drugs metabolized by CYP enzymes
  • Liver disease - DO NOT USE in active liver disease or hepatic impairment
  • Kidney disease
    • CrCl ≥ 30 ml/min: no dose adjustment necessary
    • CrCl < 30 ml/min: has not been studied

Tocilizumab (Actemra®)

Dosage forms

Prefilled syringe
  • Comes in 162 mg dose
Autoinjector (ACTPen®)
  • Comes in 162 mg dose
Single-use vial
  • 80 mg
  • 200 mg
  • 400 mg
  • Comes in 20 mg/ml concentration

Dosing

Rheumatoid arthritis
  • Prefilled syringe and autoinjector (subcutaneous)
    • Weight < 220 pounds (100 kg): 162 mg every other week. May increase to every week based on response.
    • Weight ≥ 220 pounds (100 kg): 162 mg every week
  • Infusion
    • Dosing: 4 mg/kg every 4 weeks
    • May increase to 8 mg/kg every 4 weeks based on response
    • Doses exceeding 800 mg per infusion are not recommended
Giant Cell Arteritis
  • 162 mg SQ once weekly in combination with a tapering course of glucocorticoids
  • A dose of 162 mg SQ once every other week in combination with a tapering course of glucocorticoids may be prescribed based on clinical considerations
  • Tocilizumab can be used alone following discontinuation of glucocorticoids
Polyarticular Juvenile Idiopathic Arthritis (PJIA)
  • Weight < 66 lbs (30 kg): 10 mg/kg every 4 weeks by IV infusion
  • Weight ≥ 66 lbs (30 kg): 8 mg/kg every 4 weeks by IV infusion
  • May be used alone or in combination with methotrexate
Systemic Juvenile Idiopathic Arthritis (SJIA)
  • Weight < 66 lbs (30 kg): 12 mg/kg every 2 weeks by IV infusion
  • Weight ≥ 66 lbs (30 kg): 8 mg/kg every 2 weeks by IV infusion
  • May be used alone or in combination with methotrexate
Cytokine Release Syndrome (CRS)
  • Weight < 66 lbs (30 kg): 12 mg/kg by IV infusion
  • Weight ≥ 66 lbs (30 kg): 8 mg/kg by IV infusion
  • May be given alone or in combination with corticosteroids
  • If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, up to 3 additional doses may be administered. The interval between consecutive doses should be at least 8 hours.
  • Doses exceeding 800 mg per infusion are not recommended in CRS patients
  • Subcutaneous administration is not approved for CRS
Systemic sclerosis-associated interstitial lung disease (SSc-ILD)
  • Dosing: 162 mg subcutaneously once weekly
  • The autoinjector has not been studied in SSc-ILD
  • Intravenous administration is not approved for SSc-ILD

Efficacy


Lab monitoring

Neutropenia
  • Do not initiate in patients with ANC < 2000 cells/mm³
  • Check neutrophil count 4 - 8 weeks after starting therapy and every 3 months thereafter
Thrombocytopenia
  • Do not initiate in patients with platelet count < 100,000/mm³
  • Check platelet count 4 - 8 weeks after starting therapy and every 3 months thereafter
Elevated LFTs
  • Do not initiate in patients with AST or ALT > 1.5 X ULN
  • Check LFTs every 4 - 8 weeks during the first 6 months of therapy and every 3 months thereafter
Increased cholesterol
  • Check lipid parameters 4 - 8 weeks after starting therapy and every 24 weeks thereafter
Polyarticular and Systemic Juvenile Idiopathic Arthritis
  • Monitor neutrophils, platelets, ALT and AST at the time of the second administration and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Monitor lipids as above for approved adult indications
Dose adjustments

Other

Prefilled syringe
  • Keep refrigerated
  • Solution should be clear and colorless to pale yellow
  • Inject subcutaneously in the thigh, abdomen, or outer upper arms. Rotate injection sites.
Vials
  • Infuse over 60 minutes

Mechanism of action

  • Interleukin-6-receptor inhibitor - tocilizumab is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass. Tocilizumab binds IL-6 receptors and inhibits the action of IL-6.

FDA-approved indications

  • Rheumatoid arthritis
  • Giant Cell Arteritis
  • Polyarticular juvenile idiopathic arthritis
  • Systemic juvenile idiopathic arthritis
  • Systemic sclerosis-associated interstitial lung disease (SSc-ILD)
  • COVID-19 in adults and children ≥ 2 years old (emergency use authorization)

Side effects


Side effect Tocilizumab Placebo
Nasopharyngitis 7% 4%
Headache 7% 3%
Hypertension 6% 3%
ALT increase 6% 1%
Other
  • Injection site reactions - up to 10% of adult patients and 41% of pediatric patients; common reactions include erythema, pruritus, pain, and hematoma
  • Infusion reactions - up to 8% of patients; common reactions include headache, hypertension, and skin reactions


Contraindications / Precautions

  • Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). The American College of Rheumatology recommends treating latent TB for at least one month before starting tocilizumab. Active TB should be treated completely before starting tocilizumab. [2]
  • Serious infections - Actemra may increase the risk of serious infections including tuberculosis, invasive fungal infections, bacterial infections, viral infections, and others. In RA patients treated for 24 weeks, 3.6 serious infections per 100 patient-years occurred in Actemra-treated patients compared to 1.5 serious infections per 100 patient-years in placebo-treated patients.
  • Hepatotoxicity / Elevated LFTs - serious cases of hepatotoxicity, including some that have resulted in death, have been seen in patients using Actemra. Time to onset ranged from months to years after initiation of treatment. While most cases presented with marked elevations of transaminases (> 5 X ULN), some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases. Do not initiate Actemra in patients with AST or ALT > 1.5 X ULN. For patients who develop AST or ALT > 5 X ULN during therapy, discontinue Actemra. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (e.g., ALT > 3 X ULN, serum total bilirubin > 2 X ULN), Actemra treatment should be interrupted and investigation done to establish the probable cause. If another cause for liver function abnormalities is found, Actemra may be restarted after liver functions normalize. Elevated LFTs have been seen in up to 36% of patients using Actemra monotherapy and up to 48% of patients using Actemra with DMARDs. See Lab monitoring for recommendations on monitoring LFTs.
  • Hepatitis B - patients infected with hepatitis B may have reactivation of disease while taking Actemra. Test patients before initiating therapy. Monitor infected patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Herpes zoster - reactivation of herpes zoster has occurred in patients using Actemra
  • Gastrointestinal perforations - in trials, a small number of patients developed gastrointestinal perforations while using Actemra. Most cases were reported as complications of diverticulitis.
  • Neutropenia - seen in 3.4% of adult patients and up to 26% of pediatric patients who weigh < 30 kg. Do not initiate Actemra in patients with ANC < 2000 cells/mm³. See Lab monitoring for further recommendations.
  • Thrombocytopenia - seen in up to 1.7% of patients. Do not initiate Actemra in patients with platelet count < 100,000/mm³. See Lab monitoring for further recommendations.
  • Elevated lipid parameters - elevated lipid parameters are seen in a significant number of patients. See Lab monitoring for further recommendations.
  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis have been reported
  • Malignancies - may increase the risk for malignancies
  • Demyelinating diseases (e.g. multiple sclerosis) - may exacerbate demyelinating diseases. Use caution.
  • Actemra antibodies - in trials, anti-Actemra antibodies were detected in up to 2% of patients. In some patients, antibody development was associated with the development of hypersensitivity reactions. It's unclear if antibody development is associated with reduced efficacy.
  • Vaccines - patients may receive non-live vaccines. Do not give live or attenuated vaccines.
  • CYP enzyme activity - suppression of inflammatory mediators by Actemra may increase CYP enzyme activity and decrease blood levels of drugs metabolized by CYP enzymes
  • Liver disease - DO NOT USE in active liver disease
  • Kidney disease - has not been studied

Ustekinumab (Stelara®)

Dosage forms

Prefilled syringe
  • 45 mg
  • 90 mg
Single-use vial
  • 45 mg/0.5 ml
Vial for intravenous use
  • 130 mg/26 ml (5 mg/ml)

Dosing

Crohn's disease and Ulcerative Colitis
  • Initial: single intravenous dose based on the table below

Weight Dose # of vials (130 mg/26ml)
≤ 55 kg 260 mg 2
55 - 85 kg 390 mg 3
> 85 kg 520 mg 4

  • Maintenance: 90 mg SQ every 8 weeks starting 8 weeks after the initial IV dose
Psoriasis (adults)
  • Weight ≤ 220 lbs (100 kg): 45 mg SQ initially and 4 weeks later, followed by 45 mg every 12 weeks
  • Weight > 220 lbs (100 kg): 90 mg SQ initially and 4 weeks later, followed by 90 mg every 12 weeks
Psoriasis (6 - 17 years old)
  • Dosing: Weight-based dosing by subcutaneous injection at Weeks 0 and 4, then every 12 weeks thereafter
  • Weight-based dosing
    • > 100 kg: 90 mg
    • 60 - 100 kg: 45 mg
    • < 60 kg: 0.75 mg/kg. See Stelara PI [sec 2.1] for a table that lists volume of injection for the 45 mg/0.5 ml vial by body weight
Psoriatic arthritis
  • Dosing: 45 mg SQ initially and 4 weeks later, followed by 45 mg every 12 weeks
  • Patients weighing > 220 lbs (100 kg) with moderate-to-severe plaque psoriasis: 90 mg SQ initially and 4 weeks later, followed by 90 mg every 12 weeks

Efficacy


Other

Prefilled syringe
  • Keep refrigerated. If needed, pens may be stored in original carton at room temperature for up to 30 days. Discard if not used within 30 days and do not return to refrigerator once removed.
  • Inject subcutaneously in the thigh, gluteal regions, abdomen, or upper arms. Rotate injection sites.
Infusion
  • Infuse over at least one hour

Mechanism of action

  • Interleukin inhibitor - ustekinumab is a human IgG1қ monoclonal antibody that binds with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. Ustekinumab has been shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1. The cytokines IL-12 and IL-23 have been implicated as important contributors to the chronic inflammation that is a hallmark of Crohn's disease

FDA-approved indications

  • Crohn's disease - moderate-to-severe disease in patients who have failed treatment with immunomodulators, corticosteroids, or tumor necrosis factor inhibitors
  • Ulcerative colitis - in adult patients with moderately to severely active disease
  • Psoriasis - moderate-to-severe disease in patients ≥ 6 years old
  • Psoriatic arthritis - may be used alone or with methotrexate

Side effects


Side effect Ustekinumab Placebo
Nasopharyngitis 11% 8%
Injection site erythema 5% 0%
Vulvovaginal candidiasis 5% 1%
Bronchitis 5% 3%
Pruritus 4% 2%
Urinary tract infection 4% 2%
Sinusitis 3% 2%


Contraindications / Precautions

  • BCG vaccination - DO NOT GIVE during treatment or within one year following the end of treatment. Do not give ustekinumab to patients who have received the BCG vaccine within the previous year.
  • Live vaccines - DO NOT GIVE live or attenuated vaccines. Use caution when giving live vaccines to household members.
  • Non-live vaccines - non-live vaccines may not elicit the appropriate immune response in patients receiving ustekinumab
  • Concomitant immunosuppressants - in Crohn’s and ulcerative colitis studies, immunosuppressants (6-mercaptopurine, azathioprine, methotrexate) were used concomitantly in approximately 30% of patients and corticosteroids were used concomitantly in up to 50% of patients. Use of these concomitant therapies did not appear to influence the overall safety or efficacy.
  • Allergen immunotherapy - allergen immunotherapy may not elicit the appropriate immune response in patients receiving ustekinumab
  • Noninfectious pneumonia - cases of interstitial pneumonia, eosinophilic pneumonia and cryptogenic organizing pneumonia have been reported. Symptoms include cough, dyspnea, and interstitial infiltrates following one to three doses of ustekinumab. Patients typically improved with drug discontinuation and in some cases, corticosteroids.
  • Serious infections - ustekinumab may increase the risk of serious infections. In psoriasis trials lasting 13 weeks, serious infections were reported in 0.3% of ustekinumab-treated patients and 0.4% of placebo-treated patients.
  • Theoretical risk for particular infections - patients with genetic deficiencies of IL-12/IL-23 are vulnerable to disseminated infections from mycobacteria, salmonella, and the BCG vaccine. It is unknown if ustekinumab increases the risk of these infections.
  • Tuberculosis (TB) - test all patients for TB before use. Do not treat patients with active TB. Start treatment for latent TB before initiating ustekinumab. Monitor for signs of active TB during treatment.
  • Malignancies - ustekinumab may increase the risk for malignancies. In Crohn's disease trials lasting up to one year, malignancies other than nonmelanoma skin cancers were reported in 0.2% of ustekinumab-treated patients and 0% of placebo-treated patients.
  • Nonmelanoma skin cancers - ustekinumab may increase the risk of nonmelanoma skin cancer. In psoriasis trials lasting a median of 3.2 years, nonmelanoma skin cancers were reported in 1.5% of ustekinumab-treated patients. Rapid appearance of multiple cutaneous squamous cell carcinomas have been reported in patients receiving ustekinumab.
  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis have been reported in a small number of patients. In Crohn's disease trials, 0.1% of patients receiving SQ ustekinumab and 0.08% of patients receiving IV ustekinumab reported hypersensitivity reactions.
  • Noninfectious pneumonia - cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia have been reported during postmarketing surveillance. Clinical presentations included cough, dyspnea, and interstitial infiltrates following one to three doses. Patients improved with discontinuation of therapy and in certain cases administration of corticosteroids.
  • Posterior Reversible Encephalopathy Syndrome (PRES) - in trials, two cases of posterior reversible encephalopathy syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), were reported. Cases have also been reported in the postmarketing setting. Symptoms of PRES include headache, seizures, confusion and visual disturbances. Cases have typically occurred within a few days to several months of starting ustekinumab, but some have occurred after a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab.
  • Ustekinumab antibodies - in trials, anti-ustekinumab antibodies were detected in up to 12.4% of psoriasis patients, 2.9% of Crohn's patients, and 4.6% of ulcerative colitis patients. In psoriasis studies, antibody development was associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. Antibody development was not associated with the development of hypersensitivity reactions.
  • CYP enzyme activity - suppression of inflammatory mediators by ustekinumab may increase CYP enzyme activity and decrease blood levels of drugs metabolized by CYP enzymes
  • Liver disease - has not been studied
  • Kidney disease - has not been studied

Brodalumab (Siliq®)

Dosage forms

Prefilled syringe
  • 210 mg single-dose syringe
  • Comes in carton with 2 syringes
  • Store in refrigerator
  • May be kept at room temperature for a maximum of 14 days

Dosing

Plaque psoriasis
  • Dosing: 210 mg administered by subcutaneous injection at Weeks 0, 1, and 2 followed by 210 mg every 2 weeks
  • If no response is seen by 12 - 16 weeks, consider stopping
  • Inject in thigh, abdomen, or upper arm
  • Screen for TB prior to initiating

Efficacy

Plaque psoriasis

Mechanism of action

  • Brodalumab is a human monoclonal IgG2 antibody that selectively binds to human IL-17RA and inhibits its interactions with cytokines IL-17A, IL-17F, IL-17C, IL-17A/F heterodimer, and IL-25. IL-17RA is a protein expressed on the cell surface and is a required component of receptor complexes utilized by multiple IL-17 family cytokines. Blocking IL-17RA inhibits IL-17 cytokine-induced responses including the release of pro-inflammatory cytokines and chemokines.

FDA-approved indications

  • Plaque psoriasis - moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies

Side effects


Side effect Placebo
(N=879)
Brodalumab
(N=1496)
Arthralgia 3.3% 4.7%
Headache 3.5% 4.3%
Fatigue 1.1% 2.6%
Diarrhea 1.1% 2.2%
Oropharyngeal pain 1.1% 2.1%
Nausea 1.1% 1.9%
Myalgia 0.3%1.7%
Injection site reactions 1.3% 1.5%
Influenza 0.5% 1.3%
Neutropenia 0.5% 1.0%
Tinea infections (tinea pedis, versicolor, cruris) 0.2% 1.0%


Drug interactions

  • CYP450 substrates - during chronic inflammation, CYP450 enzyme levels may be altered. When inflammation is suppressed by brodalumab, CYP enzyme activity may change. Therefore, upon initiation or discontinuation of brodalumab in patients who are receiving CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for changes in effect (e.g. warfarin) and/or drug levels (e.g. cyclosporine).

Contraindications / Precautions

  • Crohn's disease - DO NOT USE. Brodalumab may worsen Crohn's disease and should be avoided in these patients.
  • Tuberculosis (TB) - test patients for TB before starting brodalumab. Do not give brodalumab to patients with active TB. Initiate treatment for latent TB prior to administering brodalumab. Consider anti-TB therapy prior to initiation of brodalumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor for active TB during therapy.
  • Suicidal ideation and behavior - in psoriasis trials, suicidal ideation and behavior (including 4 completed suicides) occurred in 34 of 4464 subjects treated with brodalumab (0.37 per 100 subject-years). Patients with a history of depression were at greatest risk. A REMS program about the risk of suicidal ideation and behavior with brodalumab has been established by the manufacturer. Prescribers and pharmacies must complete the program in order to prescribe brodalumab. See Siliq REMS program for more.
  • Serious infections - brodalumab may increase the risk of infections. In trials, serious infections occurred in 0.5% of brodalumab-treated patients and 0.2% of placebo-treated patients. Fungal infections were also more frequent, occurring in 2.4% and 0.9% of patients, respectively. If a serious infection occurs, discontinue brodalumab until the infection resolves.
  • Decreased neutrophils - brodalumab may cause a decrease in the neutrophil count. In trials, a reduction in the neutrophil count occurred in 6.8% of brodalumab-treated patients and 3.6% of placebo-treated patients. Neutropenia (< 1000 cells/mm3) occurred in 0.5% and 0% of patients, respectively. Most cases of neutropenia were transient.
  • Brodalumab antibodies - in trials lasting 52 weeks, anti-brodalumab antibodies were detected in 3% of patients. None of the detected antibodies were deemed to be neutralizing. It's unknown if antibody development will affect the efficacy of brodalumab or increase hypersensitivity reactions.
  • Vaccines - do not give live or attenuated vaccines. Immune response to inactivated vaccines may be attenuated.
  • Liver disease - has not been studied. Manufacturer makes no recommendation.
  • Kidney disease - has not been studied. Manufacturer makes no recommendation.

Ixekizumab (Taltz®)

Dosage forms

Prefilled syringe
  • 80 mg single-dose syringe
  • Comes in carton with 1 syringe
  • Store in refrigerator
  • May be kept at room temperature for a maximum of 5 days
Autoinjector
  • 80 mg single-dose autoinjector
  • Comes in carton with 1, 2, or 3 autoinjectors
  • Store in refrigerator
  • May be kept at room temperature for a maximum of 5 days

Dosing

Plaque psoriasis (adults)
  • Dosing: 160 mg (two 80 mg injections) by subcutaneous injection at Week 0, followed by 80 mg at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks
  • Inject in thigh, abdomen, or back of upper arm
  • Screen for TB prior to initiating
Plaque psoriasis (children 6 - 17 years old)
  • Dosing: see table below
  • Inject in thigh, abdomen, or back of upper arm
  • Screen for TB prior to initiating

Pediatric Patient's Weight Starting Dose (Week 0) Dose every 4 weeks thereafter
> 110 lbs (50 kg) 160 mg 80 mg
55 lbs (25 kg) to 110 lbs (50 kg) 80 mg 40 mg
< 55 lbs (25 kg) 40 mg 20 mg

Psoriatic arthritis (adults)
  • Dosing: 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every 4 weeks
  • For patients with coexisting moderate-to-severe plaque psoriasis, use the plaque psoriasis dosing
  • May be administered alone or in combination with a conventional disease-modifying antirheumatic drug (cDMARD) (e.g., methotrexate)
  • Inject in thigh, abdomen, or back of upper arm
  • Screen for TB prior to initiating
Ankylosing spondylitis (adults)
  • Dosing: 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every 4 weeks
  • Inject in thigh, abdomen, or back of upper arm
  • Screen for TB prior to initiating
Non-radiographic axial spondyloarthritis (adults)
  • Dosing: 80 mg by subcutaneous injection every 4 week
  • Inject in thigh, abdomen, or back of upper arm
  • Screen for TB prior to initiating

Efficacy

Plaque psoriasis and psoriatic arthritis

Mechanism of action

  • Ixekizumab is a humanized IgG4 monoclonal antibody that selectively binds with the interleukin 17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.

FDA-approved indications

  • Plaque psoriasis (≥ 6 years old and adults)
  • Psoriatic arthritis
  • Ankylosing spondylitis
  • Non-radiographic axial spondyloarthritis

Side effects


Side effect Ixekizumab 80 mg Q 2 weeks
(N=1167)
Placebo
(N=791)
Injection site reactions (e.g. erythema, pain) 17% 3%
Upper respiratory tract infection 14% 13%
Nausea 2% 1%
Tinea infections 2% <1%


Drug interactions

  • CYP450 substrates - during chronic inflammation, CYP450 enzyme levels may be altered. When inflammation is suppressed by ixekizumab, CYP enzyme activity may change. Therefore, upon initiation or discontinuation of ixekizumab in patients who are receiving CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for changes in effect (e.g. warfarin) and/or drug levels (e.g. cyclosporine).

Contraindications / Precautions

  • Infections - ixekizumab may increase the risk of infections. In trials lasting 60 weeks, infections occurred in 38% of ixekizumab-treated patients and 23% of placebo-treated patients. Serious infections occurred in 0.7% and 0.4% of patients, respectively. Upper respiratory tract infections, oral candidiasis, conjunctivitis and tinea infections were more frequent in the ixekizumab group than in the placebo group. If a serious infection occurs, discontinue ixekizumab until the infection resolves.
  • Tuberculosis (TB) - test patients for TB before starting ixekizumab. Do not give ixekizumab to patients with active TB. Initiate treatment for latent TB prior to administering ixekizumab. Consider anti-TB therapy prior to initiation of ixekizumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor for active TB during therapy.
  • Hypersensitivity reactions - in trials, serious hypersensitivity reactions including angioedema and urticaria occurred in ≤ 0.1% of ixekizumab-treated patients. Anaphylaxis has been reported in the postmarketing setting. Discontinue ixekizumab if reactions occur.
  • Inflammatory bowel disease - ixekizumab may worsen inflammatory bowel disease. In trials lasting 12 weeks, inflammatory bowel disease occurred more frequently in ixekizumab-treated patients (Crohn's disease 0.1%, ulcerative colitis 0.2%) than placebo-treated patients (0%). Discontinue ixekizumab if IBD occurs.
  • Neutropenia - ixekizumab may cause neutropenia. In trials lasting 60 weeks, neutropenia occurred in 11% of ixekizumab-treated patients and 3% of placebo-treated patients. The incidence of neutropenia was higher during the first 12 weeks of therapy. The majority of the cases were mild (1500 - 2000 cells/mm3).
  • Ixekizumab antibodies - in trials lasting up to 60 weeks, anti-ixekizumab antibodies were detected in 22% of patients. Of these patients, 10% were found to have neutralizing antibodies. Neutralizing antibodies were associated with a loss of efficacy.
  • Vaccines - do not give live or attenuated vaccines. Immune response to inactivated vaccines may be attenuated. Before starting therapy, consider completing all age-appropriate immunizations if possible.
  • Liver disease - has not been studied. Manufacturer makes no recommendation.
  • Kidney disease - has not been studied. Manufacturer makes no recommendation.

Secukinumab (Cosentyx®)

Dosage forms

Sensoready pen
  • 150 mg single-dose pen
  • Comes in carton with 1 or 2 pens
  • Store in refrigerator
Prefilled syringe
  • 75 mg
  • 150 mg
  • 150 mg dose comes in carton with 1 or 2 syringes
  • 75 mg dose comes in carton with 1 syringe
  • Store in refrigerator
Vial
  • 150 mg
  • Store in refrigerator

Dosing

Plaque psoriasis (adults)
  • Dosing: 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3, and 4 followed by 300 mg every 4 weeks
  • Each 300 mg dosage is given as 2 subcutaneous injections of 150 mg
  • For some patients, a dosage of 150 mg may be effective
  • Inject in thigh, abdomen, or back of upper arm
  • Screen for TB prior to initiating
Plaque psoriasis (pediatric patients ≥ 6 years old)
  • Dosing: administer dose based on body weight at weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter
    • < 110 lbs (50 kg): dose is 75 mg
    • ≥ 110 lbs (50 kg): dose is 150 mg
  • Inject in thigh, abdomen, or back of upper arm
  • Screen for TB prior to initiating
Psoriatic arthritis (adults)
  • May be given with or without a loading dose
  • Dosing with loading dose: 150 mg at Weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter
  • Dosing without a loading dose: 150 mg every 4 weeks
  • If a patient continues to have active psoriatic arthritis, consider a dosage of 300 mg every 4 weeks
  • For psoriatic arthritis patients with coexistent moderate to severe plaque psoriasis, use the dosing and administration recommendations for plaque psoriasis
  • May be administered with or without methotrexate
  • Inject in thigh, abdomen, or back of upper arm
  • Screen for TB prior to initiating
Ankylosing spondylitis (adults)
  • May be given with or without a loading dose
  • Dosing with loading dose: 150 mg at Weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter
  • Dosing without a loading dose: 150 mg every 4 weeks
  • If a patient continues to have active ankylosing spondylitis, consider a dosage of 300 mg every 4 weeks
  • Inject in thigh, abdomen, or back of upper arm
  • Screen for TB prior to initiating
Non-radiographic axial spondyloarthritis (adults)
  • May be given with or without a loading dose
  • Dosing with loading dose: 150 mg at Weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter
  • Dosing without a loading dose: 150 mg every 4 weeks
  • Inject in thigh, abdomen, or back of upper arm
  • Screen for TB prior to initiating

Efficacy

Plaque psoriasis and psoriatic arthritis (adults) Plaque psoriasis (pediatric patients ≥ 6 years old)

Mechanism of action

  • Secukinumab is a human IgG1 monoclonal antibody that selectively binds to the interleukin-17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Secukinumab inhibits the release of proinflammatory cytokines and chemokines.

FDA-approved indications

  • Plaque psoriasis (adults and children ≥ 6 years old)
  • Psoriatic arthritis (adults)
  • Ankylosing spondylitis (adults)
  • Non-radiographic axial spondyloarthritis (adults)

Side effects


Side effect Secukinumab 300 mg
(N=691)
Secukinumab 150 mg
(N=692)
Placebo
(N=694)
Nasopharyngitis 11.4% 12.3% 8.6%
Diarrhea 4.1% 2.6% 1.4%
Upper respiratory tract infection 2.5% 3.2% 0.7%
Rhinitis 1.4% 1.4% 0.7%
Oral herpes 1.3% 0.1% 0.3%
Pharyngitis 1.2% 1.0% 0%
Urticaria 0.6% 1.2% 0.1%
Rhinorrhea 1.2% 0.3% 0.1%


Drug interactions

  • CYP450 substrates - during chronic inflammation, CYP450 enzyme levels may be altered. When inflammation is suppressed by secukinumab, CYP enzyme activity may change. Therefore, upon initiation or discontinuation of secukinumab in patients who are receiving CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for changes in effect (e.g. warfarin) and/or drug levels (e.g. cyclosporine).

Contraindications / Precautions

  • Infections - secukinumab may increase the risk of infections. In trials lasting 12 weeks, infections occurred in 28.7% of secukinumab-treated patients and 18.9% of placebo-treated patients. Serious infections occurred in 0.14% and 0.3% of patients, respectively. Nasopharyngitis (11.4% vs 8.6%), upper respiratory tract infections (2.5% vs 0.7%) and mucocutaneous infections with candida (1.2% vs 0.3%) were observed more commonly with secukinumab. If a serious infection occurs, discontinue secukinumab until the infection resolves.
  • Tuberculosis (TB) - test patients for TB before starting secukinumab. Do not give secukinumab to patients with active TB. Initiate treatment for latent TB prior to administering secukinumab. Consider anti-TB therapy prior to initiation of secukinumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor for active TB during therapy.
  • Inflammatory bowel disease - secukinumab may worsen inflammatory bowel disease. In trials lasting up to 52 weeks, Crohn's exacerbations (0.11%/year), ulcerative colitis exacerbations (0.08%/year), and new cases of ulcerative colitis (0.08%/year) occurred more frequently in secukinumab-treated patients than in placebo-treated patients (0%). Use caution in susceptible patients.
  • Hypersensitivity reactions - in trials, serious hypersensitivity reactions including anaphylaxis and urticaria were observed. Discontinue secukinumab if reactions occur.
  • Latex allergy - the removable cap of the secukinumab Sensoready pen and the secukinumab prefilled syringe contains natural rubber latex, which may cause an allergic reaction in latex-sensitive individuals.
  • Vaccines - do not give live or attenuated vaccines. Immune response to inactivated vaccines may be attenuated. Before starting therapy, consider completing all age-appropriate immunizations if possible.
  • Secukinumab antibodies - in trials lasting up to 52 weeks, anti-secukinumab antibodies were detected in < 1% of patients. Of these patients, 50% were deemed to have neutralizing antibodies. Neutralizing antibodies were not associated with a loss of efficacy.
  • Liver disease - has not been studied. Manufacturer makes no recommendation.
  • Kidney disease - has not been studied. Manufacturer makes no recommendation.

Guselkumab (Tremfya®)

Dosage forms

Autoinjector
  • 100 mg single-dose injector
  • Comes in carton with 1 injector
  • Store in refrigerator
Prefilled syringe
  • 100 mg single-dose syringe
  • Comes in carton with 1 syringe
  • Store in refrigerator

Dosing

Plaque psoriasis
  • Dosing: 100 mg by subcutaneous injection at Week 0, Week 4, and every 8 weeks thereafter
  • If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.
  • Inject in thigh, abdomen, or back of upper arm
Psoriatic arthritis
  • Dosing: 100 mg by subcutaneous injection at Week 0, Week 4, and every 8 weeks thereafter
  • Inject in thigh, abdomen, or back of upper arm
  • May be administered alone or in combination with a conventional disease-modifying antirheumatic drug (e.g. methotrexate)

Efficacy

Plaque psoriasis and psoriatic arthritis

Mechanism of action

  • Guselkumab is a human monoclonal IgG1λ antibody that selectively binds to the p19 subunit of interleukin 23 (IL-23) and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Guselkumab inhibits the release of proinflammatory cytokines and chemokines.

FDA-approved indications

  • Plaque psoriasis
  • Psoriatic arthritis

Side effects


Side effect Guselkumab
(N=823)
Placebo
(N=422)
Upper respiratory infections 14.3% 12.8%
Headache 4.6% 3.3%
Injection site reactions 4.5% 2.8%
Arthralgia 2.7% 2.1%
Diarrhea 1.6% 0.9%
Gastroenteritis 1.3% 0.9%
Tinea infections 1.1% 0
Herpes simplex infections 1.1% 0.5%


Drug interactions

  • CYP450 substrates - during chronic inflammation, CYP450 enzyme levels may be altered. When inflammation is suppressed by guselkumab, CYP enzyme activity may change. Therefore, upon initiation or discontinuation of guselkumab in patients who are receiving CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for changes in effect (e.g. warfarin) and/or drug levels (e.g. cyclosporine).

Contraindications / Precautions

  • Hypersensitivity reactions - serious hypersensitivity reactions including anaphylaxis have been reported in the postmarketing setting. Discontinue guselkumab if reactions occur.
  • Infections - guselkumab may increase the risk of infections. In trials lasting 16 weeks, infections occurred in 23% of guselkumab-treated patients and 21% of placebo-treated patients. Serious infections occurred in ≤ 0.2% of subjects in both groups. Upper respiratory tract infections, gastroenteritis, tinea infections, and herpes simplex infections were observed more commonly in the guselkumab group. If a serious infection occurs, discontinue guselkumab until the infection resolves.
  • Tuberculosis (TB) - test patients for TB before starting guselkumab. Do not give guselkumab to patients with active TB. Initiate treatment for latent TB prior to administering guselkumab. Consider anti-TB therapy prior to initiation of guselkumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor for active TB during therapy.
  • Vaccines - do not give live or attenuated vaccines. Immune response to inactivated vaccines may be attenuated. Before starting therapy, consider completing all age-appropriate immunizations if possible.
  • Elevated liver enzymes - in trials, elevated liver enzymes occurred in 2.6% of guselkumab-treated patients and 1.9% of placebo-treated patients. Most elevations were mild and none led to drug discontinuation.
  • Guselkumab antibodies - in trials lasting up to 156 weeks, anti-guselkumab antibodies were detected in 9% of patients. Of these patients, 6% were deemed to have neutralizing antibodies. In general, neutralizing antibodies were not associated with a loss of efficacy or development of injection-site reactions.
  • Liver disease - has not been studied. Manufacturer makes no recommendation.
  • Kidney disease - has not been studied. Manufacturer makes no recommendation.

Risankizumab (Skyrizi®)

Dosage forms

Prefilled syringe
  • 75 mg single-dose syringe
  • Comes in carton with 2 syringes
  • Store in refrigerator

Dosing

Plaque psoriasis
  • Dosing: 150 mg (two 75 mg injections) administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter
  • If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.
  • Inject in thigh, abdomen, or upper outer arm
  • Test for TB prior to initiating

Efficacy

Plaque psoriasis

Mechanism of action

  • Risankizumab-rzaa is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to the p19 subunit of human interleukin 23 (IL-23) cytokine and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Risankizumab-rzaa inhibits the release of pro-inflammatory cytokines and chemokines.

FDA-approved indications

  • Plaque psoriasis

Side effects


Side effect Risankizumab
(N=1306)
Placebo
(N=300)
Upper respiratory infections 13% 9.7%
Headache 3.5% 2%
Fatigue 2.5% 1%
Injection site reactions 1.5% 1%
Tinea infections 1.1% 0.3%


Contraindications / Precautions

  • Infections - risankizumab may increase the risk of infections. In trials lasting 16 weeks, infections occurred in 22.1% of risankizumab-treated patients and 14.7% of placebo-treated patients. Serious infections occurred in ≤ 0.4% of subjects in both groups. Upper respiratory tract infections and tinea infections were observed more commonly in the risankizumab group. If a serious infection occurs, discontinue risankizumab until the infection resolves.
  • Tuberculosis (TB) - test patients for TB before starting risankizumab. Do not give risankizumab to patients with active TB. Initiate treatment for latent TB prior to administering risankizumab. Consider anti-TB therapy prior to initiation of risankizumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor for active TB during therapy.
  • Vaccines - do not give live or attenuated vaccines. Immune response to inactivated vaccines may be attenuated. Before starting therapy, consider completing all age-appropriate immunizations if possible.
  • Risankizumab antibodies - in trials lasting up to 52 weeks, anti-risankizumab antibodies were detected in 24% of patients. Of these patients, 57% were deemed to have neutralizing antibodies. Higher neutralizing antibody titers were associated with reduced efficacy.
  • Liver disease - has not been studied. Manufacturer makes no recommendation.
  • Kidney disease - has not been studied. Manufacturer makes no recommendation.

Tildrakizumab (Ilumya™)

Dosage forms

Prefilled syringe
  • 100 mg single-dose syringe
  • Comes in carton with 1 syringe
  • Store in refrigerator
  • May be kept at room temperature for up to 30 days

Dosing

Plaque psoriasis
  • Dosing: 100 mg by subcutaneous injection at Weeks 0, 4, and every twelve weeks thereafter
  • If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regularly scheduled interval.
  • Inject in thigh, abdomen, or upper outer arm
  • Test for TB prior to initiating

Efficacy

Plaque psoriasis

Mechanism of action

  • Tildrakizumab is a humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines.

FDA-approved indications

  • Plaque psoriasis

Side effects


Side effect Tildrakizumab
(N=705)
Placebo
(N=355)
Upper respiratory infections 14% 12%
Injection site reactions 3% 2%
Diarrhea 2% 1%


Contraindications / Precautions

  • Hypersensitivity reactions - in clinical trials, cases of angioedema and urticaria occurred in patients who were treated with tildrakizumab. Discontinue tildrakizumab if hypersensitivity reactions occur.
  • Infections - tildrakizumab may increase the risk of infections. In trials, there was a less than 1% difference in the incidence of infections between the tildrakizumab group (23%) and the placebo group. Serious infections occurred in ≤ 0.3% of subjects in both groups.
  • Tuberculosis (TB) - test patients for TB before starting tildrakizumab. Do not give tildrakizumab to patients with active TB. Initiate treatment for latent TB prior to administering tildrakizumab. Consider anti-TB therapy prior to initiation of tildrakizumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor for active TB during therapy.
  • Vaccines - do not give live or attenuated vaccines. Immune response to inactivated vaccines may be attenuated. Before starting therapy, consider completing all age-appropriate immunizations if possible.
  • Tildrakizumab antibodies - in trials lasting up to 64 weeks, anti-tildrakizumab antibodies were detected in 6.5% of patients. Of these patients, 40% were deemed to have neutralizing antibodies. Neutralizing antibodies were associated with reduced efficacy.
  • Liver disease - has not been studied. Manufacturer makes no recommendation.
  • Kidney disease - has not been studied. Manufacturer makes no recommendation.

Anifrolumab (Saphnelo™)

Dosage forms

Vial
  • 300 mg/2 ml
  • Store in refrigerator

Dosing

Systemic lupus erythematosus (adults)
  • Dosing: 300 mg by IV infusion every 4 weeks
  • Missed doses: If a planned infusion is missed, administer anifrolumab as soon as possible. Maintain a minimum interval of 14 days between infusions.

Efficacy


Mechanism of action

  • Anifrolumab-fnia is a human IgG1κ monoclonal antibody that binds to subunit 1 of the type I interferon receptor (IFNAR) with high specificity and affinity. This binding inhibits type I IFN signaling, thereby blocking the biologic activity of type I IFNs. Anifrolumab-fnia also induces the internalization of IFNAR1, thereby reducing the levels of cell surface IFNAR1 available for receptor assembly. Blockade of receptor mediated type I IFN signaling inhibits IFN responsive gene expression as well as downstream inflammatory and immunological processes. Inhibition of type I IFN blocks plasma cell differentiation and normalizes peripheral T-cell subsets. Type I IFNs play a role in the pathogenesis of SLE. Approximately 60-80% of adult patients with active SLE express elevated levels of type I IFN inducible genes.

FDA-approved indications

  • Moderate to severe SLE in adults who are receiving standard therapy - The efficacy of anifrolumab has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. Use of anifrolumab is not recommended in these situations.

Side effects


Adverse Reaction Anifrolumab
(N=459)
Placebo
(N=466)
Upper respiratory tract infection 34% 23%
Bronchitis 11% 5.2%
Infusion-related reactions 9.4% 7.1%
Herpes Zoster 6.1% 1.3%
Cough 5.0% 3.2%
Respiratory tract infection 3.3% 1.5%
Hypersensitivity 2.8% 0.6%
Most common reactions were headache, nausea, vomiting, fatigue, and dizziness


Contraindications / Precautions

  • Hypersensitivity reactions - serious hypersensitivity reactions including anaphylaxis and angioedema have occurred. In trials, any hypersensitivity reaction occurred in 2.8% of anifrolumab-treated patients and 0.6% of placebo-treated patients, and serious reactions occurred in 0.6% of anifrolumab-treated patients. Anifrolumab should be administered in a healthcare facility that is equipped to manage these reactions. Patients with a history of serious reactions should not receive anifrolumab. Patients with milder reactions may need to be premedicated.
  • Other biologic therapies - anifrolumab has not been studied with other biologic therapies, and it should not be given with other biologics, including B-cell agents (e.g. belimumab).
  • Infections - anifrolumab may increase the risk of infections. In trials, serious infections occurred in 4.8% of anifrolumab-treated patients and 5.6% of placebo-treated patients, and fatal infections occurred in 0.4% and 0.2%, respectively. Respiratory infections and herpes zoster infections were more common in anifrolumab-treated patients (see Side effects above). Do not initiate anifrolumab in patients with an active infection and consider interrupting therapy in patients with significant ongoing infection.
  • Malignancies - immunosuppressants like anifrolumab may increase the risk of malignancies. In trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.7% of anifrolumab-treated patients and 0.6% of placebo-treated patients, and malignancies, including non-melanoma skin cancers, occurred in 1.3% and 0.6%, respectively.
  • Vaccines - do not give live or attenuated vaccines. Immune response to inactivated vaccines may be attenuated. Before starting therapy, consider completing all age-appropriate immunizations if possible.
  • Anifrolumab antibodies - in trials lasting 60 weeks, anti-anifrolumab antibodies were detected in 1.7% of patients. The effect of these antibodies on efficacy and hypersensitivity reactions is unknown.
  • Liver disease - anifrolumab has not been studied in liver disease, but hepatic dysfunction is not expected to affect the metabolism of anifrolumab
  • Kidney disease - anifrolumab has not been explicitly studied in kidney disease patients. In studies, anifrolumab clearance did not differ significantly between patients with mild, moderate, and normal kidney function. Anifrolumab is not cleared renally.

Intravenous immunoglobulin (IVIG)

Dosage forms

IVIG products available in the U.S.
  • Bivigam®
  • Carimune®
  • Flebogamma® Dif
  • Gammagard®
  • Gammagard® S/D
  • Gammaplex®
  • Gamunex-C®
  • Octagam®
  • Privigen®

Dosing

NOTE: Dosing recommendations vary slightly by product. Doses presented here are general recommendations.
Primary humoral immunodeficiency
  • 0.3 - 0.8 grams/kg every 3 - 4 weeks
Immune thrombocytopenia
  • 1 gram/kg as a one-time dose. May repeat if necessary.
  • Alternatively, 0.4 grams/kg/day can be given on 2 - 5 consecutive days as needed
Kawasaki syndrome
  • 1 gram/kg as a one-time dose
  • Alternatively, 0.4 grams/kg/day for 4 consecutive days
  • Dosing from Gammagard S/D PI
Multifocal motor neuropathy
  • 0.5 - 2.4 grams/kg/month
  • Dosing from Gammagard PI
Chronic Inflammatory Demyelinating Polyneuropathy
  • Loading dose: 2 grams/kg
  • Maintenance: 1 gram/kg every 3 weeks
  • Dosing from Gamunex-C PI
Guillain–Barré syndrome
  • 0.4 grams/kg/day for 5 consecutive days [3]
Myasthenia gravis
  • 1 - 2 grams/kg/dose [3]
Kidney transplant (highly sensitized to HLA)
  • 2 grams/kg/month for 4 months before transplant [3]

Efficacy


Other

  • IVIG is typically given intravenously over the course of 1 - 5 days depending on the dose and the patient
  • Some products (e.g. Gammagard) can be infused subcutaneously through a pump

Mechanism of action

  • Primary humoral immunodeficiency - IVIG replaces deficient antibodies
  • Autoimmune disorders - there are a number of theories on how IVIG causes immunosuppression. Proposed mechanisms include the following:
    • Binding and neutralization of autoantibodies
    • Blockade of Fcγ receptors on macrophages thereby inhibiting phagocytosis
    • Up regulation of Fcγ receptor IIB on macrophages. Fcγ receptor IIB down regulates the inflammatory cascade.
    • Binding of complement components and blocking their activation
    • Decreasing the half-life of autoantibodies [3,4]

FDA-approved indications

  • Primary humoral immunodeficiency
  • Immune thrombocytopenia
  • Kawasaki syndrome
  • Multifocal motor neuropathy
  • Chronic Inflammatory Demyelinating Polyneuropathy

Side effects

NOTE: Information below is from a study in Privigen PI where median dose was 0.430 grams/kg in patients with primary humoral immunodeficiency. Placebo comparison is not available so strength of association is unknown.
  • Headache - 45%
  • Fatigue - 16%
  • Nausea - 14%
  • Chills - 11%
  • Vomiting - 11%
  • Back pain - 10%
  • Pain - 9%
  • Fever - 9%
  • Diarrhea - 8%
  • Cough - 6%
  • Stomach discomfort - 6%

Contraindications / Precautions

NOTE: General contraindications/precautions are listed below. See the individual product PI for specific product information.
  • Sensitivity reactions - severe sensitivity reactions may occur, even in patients who have tolerated previous infusions. Appropriate precautions should be taken.
  • IgA deficiency - all IVIG products contain small amounts of IgA. Patients with IgA deficiency may have antibodies to IgA. These patients are at increased risk of severe hypersensitivity reactions to IVIG. Gammagard S/D contains the least amount of IgA.
  • Kidney dysfunction/failure - IVIG can cause kidney dysfunction/failure in some patients. IVIG products that contain sucrose (e.g. Carimune) carry a higher risk. Use caution in susceptible patients (e.g. pre-existing kidney disease, diabetes, ≥ 65 years old, volume depletion, sepsis, paraproteinemia, concomitant nephrotoxic drugs).
  • Thrombosis - IVIG may increase the risk of venous and arterial thrombosis. Use caution in patients with risk factors for thrombosis (e.g. immobilization, hypercoagulable states, history of thrombosis, estrogen use, indwelling catheters, hyperviscosity).
  • Increased serum viscosity - IVIG infusions increase serum proteins which may increase serum viscosity. Ensure adequate hydration and check blood viscosity in at-risk patients (e.g. cryoglobulins, very high triglycerides, monoclonal gammopathies).
  • Hyperproteinemia and pseudohyponatremia - IVIG infusions increase serum proteins. The increase in serum proteins may cause pseudohyponatremia because the plasma water fraction in blood samples is reduced leading to false sodium concentration measurements. Providers should distinguish true hyponatremia from pseudohyponatremia in patients receiving IVIG, because treatment of hyponatremia may increase blood viscosity.
  • Aseptic meningitis - aseptic meningitis has occurred in patients receiving IVIG. Symptoms (e.g. severe headache, nuchal rigidity, photophobia, painful eye movements) usually begin within several hours to 2 days of receiving treatment. Discontinuation of IVIG typically leads to resolution within 2 days.
  • Hemolysis - blood group antibodies in IVIG may cause hemolysis. Higher doses of IVIG (≥ 2 grams/kg) and non-O blood types in recipients may be risk factors. Check hemoglobin levels in high-risk patients before therapy, within 36 hours of the start of therapy, and at 7 - 10 days.
  • Transfusion-related acute lung injury (TRALI) - TRALI, a syndrome of noncardiogenic pulmonary edema, has occurred in patients receiving IVIG. Symptoms typically occur within 1 - 6 hours following treatment. If TRALI is suspected, testing for anti-neutrophil antibodies and anti-human leukocyte antigen (HLA) antibodies in both the IVIG product and the patient's serum should be performed.
  • Live vaccines - IVIG infusions may impair the efficacy of live vaccines such as mumps, rubella, and varicella for up to 6 months and measles for up to a year
  • Volume overload - IVIG infusions often contain a large volume of fluid. Use caution in susceptible patients (e.g. CHF, kidney disease)
  • Potential for infection transfer - because IVIG is a blood product, the potential for the transmission of infectious agents exists
  • Blood glucose monitoring - some IVIG products (e.g. Octagam) contain maltose which can be falsely interpreted as glucose by some glucometers
  • Serologic antibody tests - passively transferred antibodies from IVIG may cause false-positive serological testing (e.g. infection/immunity testing, direct or indirect antiglobulin testing, detection of beta-D-glucans for diagnosis of fungal infections)
  • Liver disease - manufacturer makes no recommendation
  • Kidney disease - use caution. May worsen kidney disease.

Adalimumab (Humira®)

Dosage forms

Single-use pen
  • 40 mg/0.4 ml
  • 40 mg/0.8 ml
  • Comes in carton with 2 pens
Syringe
  • 10 mg/0.1 ml
  • 10 mg/0.2 ml
  • 20 mg/0.2 ml
  • 20 mg/0.4 ml
  • 40 mg/0.4 ml
  • 40 mg/0.8 ml
  • Comes in carton with 2 syringes
Starter packs
  • Adult Crohn's, Ulcerative colitis, Hidradenitis Suppurativa - six 40 mg pens (40 mg/0.8 ml or 40 mg/0.4 ml)
  • Adult Crohn's, Ulcerative colitis, Hidradenitis Suppurativa - three 80 mg pens (80 mg/0.8 ml)
  • Psoriasis, Uveitis - four 40 mg pens (40 mg/0.8 ml or 40 mg/0.4 ml)
  • Psoriasis, Uveitis - one 80 mg/0.8 ml pen and two 40 mg/0.4 ml pens
  • Pediatric Crohn's - 40 mg/0.8 ml (6 syringes); 80 mg/0.8 ml (3 syringes); 40 mg/0.8 ml (3 syringes); 80 mg/0.8 ml (one syringe) and 40 mg/0.4 ml (one syringe)

Dosing

Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis (adults)
  • Dosing: 40 mg every other week
  • In rheumatoid arthritis, some patients not taking methotrexate may derive additional benefit from increasing the dosage to 40 mg every week or 80 mg every other week
Crohn's disease (adults)
  • Day 1: 160 mg (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days)
  • Day 15: 80 mg
  • Day 29 and on: 40 mg every other week
  • Target trough concentration in IBD: ≥ 7.5 mcg/ml [5]
Crohn's disease (children ≥ 6 years)

Weight Treatment
17 kg (37 lbs) to < 40 kg (88 lbs) Induction
  • 80 mg initially on Day 1 and 40 mg two weeks later (Day 15)
Maintenance (start on Day 29)
  • 20 mg every other week
≥ 40 kg (88 lbs) Induction
  • 160 mg initially on Day 1 (given in one day or split over two consecutive days) and 80 mg two weeks later (Day 15)
Maintenance (start on Day 29)
  • 40 mg every other week
Ulcerative colitis (adults)
  • Day 1: 160 mg (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days)
  • Day 15: 80 mg
  • Day 29 and on: 40 mg every other week
  • Target trough concentration in IBD: ≥ 7.5 mcg/ml [5]
Ulcerative colitis (≥ 5 years old))

Pediatric Weight Recommended Dosage
Days 1 through 15 Starting on Day 29*
20 kg (44 lbs) to
less than 40 kg (88 lbs)
Day 1: 80 mg
Day 8: 40 mg
Day 15: 40 mg
40 mg every other week or 20 mg every week
40 kg (88 lbs) and greater Day 1: 160 mg (single dose or split over two consecutive days)
Day 8: 80 mg
Day 15: 80 mg
80 mg every other week or 40 mg every week
*Continue the recommended pediatric dosage in patients who turn 18 years of age and who are well-controlled on their HUMIRA regimen.
Plaque Psoriasis or Adult Uveitis (adults)
  • Day 1: 80 mg
  • Day 8 and on: 40 mg every other week
Juvenile Idiopathic Arthritis or Pediatric Uveitis (≥ 2 years old)

Weight Dose
10 kg (22 lbs) to < 15 kg (33 lbs) 10 mg every other week
(10 mg Prefilled Syringe)
15 kg (33 lbs) to < 30 kg (66 lbs) 20 mg every other week
(20 mg Prefilled Syringe)
≥ 30 kg (66 lbs) 40 mg every other week
(Humira Pen or 40 mg Prefilled Syringe)
Hidradenitis suppurativa (adults)
  • Day 1: 160 mg (given as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days)
  • Day 15: 80 mg
  • Day 29 and on: 40 mg every week or 80 mg every other week
Hidradenitis suppurativa (≥ 12 years old)
  • 30 kg (66 lbs) to < 60 kg (132 lbs): 80 mg on Day 1, 40 mg on Day 8, and then 40 mg every other week
  • ≥ 60 kg (132 lbs): 160 mg on Day 1 (given in one day or split over two consecutive days), 80 mg on Day 15, and then starting on Day 29, 40 mg every week or 80 mg every other week

Efficacy


Other

  • Keep refrigerated
  • Humira may be stored at room temperature up to a maximum of 77°F (25°C) for a period of up to 14 days with protection from light
  • Humira is injected subcutaneously into the thigh or abdomen. Rotate injection sites.
  • May leave at room temperature for 15 - 30 minutes before injecting
  • Solution should be clear and colorless

Mechanism of action

  • Tumor Necrosis Factor inhibitor - Humira is a human monoclonal antibody (IgG) specific for human tumor necrosis factor alpha (TNF-alpha). Humira binds TNF-alpha and blocks its interaction with cell receptors. Humira may also lyse TNF expressing cells in the presence of complement.

FDA-approved indications

  • Rheumatoid arthritis - adalimumab is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. Adalimumab can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).
  • Juvenile Idiopathic Arthritis - adalimumab is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older. Adalimumab can be used alone or in combination with methotrexate.
  • Psoriatic Arthritis - adalimumab is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. Adalimumab can be used alone or in combination with non-biologic DMARDs.
  • Ankylosing Spondylitis - adalimumab is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis
  • Crohn’s Disease - adalimumab is indicated for the treatment of moderately to severely active Crohn’s disease in adults and pediatric patients 6 years of age and older
  • Ulcerative Colitis - adalimumab is indicated for the treatment of moderately to severely active ulcerative colitis in adults and pediatric patients 5 years of age and older
  • Plaque Psoriasis - 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. Adalimumab should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.
  • Hidradenitis Suppurativa - adalimumab is indicated for the treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older
  • Uveitis - adalimumab is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients 2 years of age and older

Side effects


Side effect Adalimumab Placebo
Upper respiratory infection 17% 13%
Headache 12% 8%
Rash 12% 6%
Sinusitis 11% 9%
Accidental injury 10% 8%
Urinary tract infection 8% 5%
Abdominal pain 7% 4%
High cholesterol 6% 4%
Back pain 6% 4%
Increased alk phos 5% 3%
Hypertension 5% 3%
Other
  • Injection site reactions - 20% of patients; common reactions include redness, itching, bleeding, pain, and swelling.


Contraindications / Precautions

  • Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). The American College of Rheumatology recommends treating latent TB for at least one month before starting a TNF inhibitor. Active TB should be treated completely before starting a TNF inhibitor. [2]
  • Serious infections - TNF inhibitors may increase the risk of serious infections including tuberculosis, invasive fungal infections, bacterial infections, viral infections, and others. In controlled trials, the rate of serious infections was 4.4 per 100 patient-years in 7723 Humira-treated patients versus a rate of 2.9 per 100 patient-years in 4598 control-treated patients.
  • Hepatitis B - patients infected with hepatitis B may have reactivation of disease while taking TNF inhibitors. Test patients before initiating therapy. Monitor infected patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Malignancies - TNF inhibitors may increase the risk for certain cancers, particularly lymphoma. Concomitant immunosuppressants may increase the risk.
  • Demyelinating diseases (e.g. multiple sclerosis) - TNF inhibitors may exacerbate demyelinating diseases. Use caution.
  • Blood dyscrasias - blood dyscrasias including aplastic anemia have been reported
  • Abatacept and anakinra - DO NOT COMBINE. Increases risk of serious infection.
  • Heart failure - TNF inhibitors may cause new onset heart failure or worsen existing heart failure. Use caution.
  • Drug-induced lupus - TNF inhibitors have been associated with drug-induced lupus in a small number of patients
  • Autoantibodies - in controlled trials, 12% of Humira-treated patients and 7% of placebo-treated patients developed positive ANA titers during treatment
  • Elevated liver enzymes - in controlled trials, ALT elevations ≥ 3 x ULN occurred in 3.5% of Humira-treated patients and 1.5% of control-treated patients. Concomitant methotrexate may increase the risk.
  • Humira antibodies - anti-adalimumab antibodies have been found in up to 61% of patients treated with adalimumab. Antibodies have been associated with reduced serum adalimumab concentrations. The effects of antibody development on efficacy and safety are unknown.
  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis have been reported
  • Vaccines - patients may receive non-live vaccines. Do not give live or attenuated vaccines.
  • CYP enzyme activity - suppression of inflammatory mediators by TNF inhibitors may increase CYP enzyme activity and decrease blood levels of drugs metabolized by CYP enzymes. Use caution when initiating or stopping TNF inhibitors in patients taking concomitant CYP450 substrates with a narrow therapeutic index (e.g. warfarin, cyclosporine, theophylline). Monitor drug levels and drug effects (e.g. INR) when appropriate.
  • Liver disease - has not been studied
  • Kidney disease - has not been studied

Certolizumab (Cimzia®)

Dosage forms

Prefilled syringe
  • Comes in 200 mg dose
  • Comes in carton with 2 pens
Vial
  • 200 mg/ml
  • Comes in kit with vial of powdered drug that must be reconstituted before injecting

Dosing

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis
  • Starting: 400 mg at Weeks 0, 2, and 4
  • Maintenance: 200 mg every other week OR 400 mg every 4 weeks
Crohn's disease
  • Starting: 400 mg at Weeks 0, 2, and 4
  • Maintenance: 400 mg every 4 weeks
  • Target trough concentration in IBD: ≥ 20 mcg/ml [5]
Plaque psoriasis
  • Dosing: 400 mg every other week
  • For patients with body weight ≤ 90 kg, 400 mg at Weeks 0, 2, and 4 followed by 200 mg every other week may be considered
Non-radiographic axial spondyloarthritis
  • Starting: 400 mg at Weeks 0, 2, and 4
  • Maintenance: 200 mg every 2 weeks OR 400 mg every 4 weeks

Efficacy


Other

  • Keep refrigerated
  • Let medication warm to room temperature before injecting
  • Cimzia is injected subcutaneously into the thigh or abdomen. Rotate injection sites.

Mechanism of action

  • Tumor Necrosis Factor inhibitor - Cimzia is a recombinant, humanized antibody Fab' fragment with specificity for human tumor necrosis factor alpha (TNF-alpha). Cimzia binds TNF-alpha and neutralizes it.

FDA-approved indications

  • Rheumatoid arthritis
  • Psoriatic Arthritis
  • Ankylosing Spondylitis
  • Crohn’s Disease (adult)
  • Plaque psoriasis
  • Non-radiographic axial spondyloarthritis

Side effects



Side effect Certolizumab Placebo
Upper respiratory infections 20% 13%
Urinary tract infections 7% 6%
Arthralgia 6% 4%


Contraindications / Precautions

  • Concomitant abatacept or anakinra - DO NOT COMBINE. Increases risk of serious infection.
  • Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). The American College of Rheumatology recommends treating latent TB for at least one month before starting a TNF inhibitor. Active TB should be treated completely before starting a TNF inhibitor. [2]
  • Serious infections - TNF inhibitors may increase the risk of serious infections including tuberculosis, invasive fungal infections, bacterial infections, viral infections, and others. In controlled trials, the rate of serious infections was 3% per year in Cimzia-treated patients and 1% per year for placebo-treated patients. Serious infections included bacterial and viral infections, pneumonia, and pyelonephritis.
  • Hepatitis B - patients infected with hepatitis B may have reactivation of disease while taking TNF inhibitors. Test patients before initiating therapy. Monitor infected patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Malignancies - TNF inhibitors may increase the risk for certain cancers, particularly lymphoma. Concomitant immunosuppressants may increase the risk. In trials, malignancies were observed at a rate of 0.5 per 100 patient-years among 4,650 Cimzia-treated patients versus a rate of 0.6 per 100 patient-years among 1,319 placebo-treated patients.
  • Demyelinating diseases (e.g. multiple sclerosis) - TNF inhibitors may exacerbate demyelinating diseases. Use caution.
  • Elevated liver enzymes - Cimzia may raise liver enzymes. In trials, up to 4.3% of Cimzia-treated subjects had elevated liver enzymes compared to 2.5% of placebo-treated subjects.
  • Blood dyscrasias - blood dyscrasias including aplastic anemia have been reported
  • Heart failure - TNF inhibitors may cause new onset heart failure or worsen existing heart failure. Use caution.
  • Drug-induced lupus - TNF inhibitors have been associated with drug-induced lupus in a small number of patients
  • Autoantibodies - in controlled trials, 4% of Cimzia-treated patients and 2% of placebo-treated patients developed positive ANA titers during treatment
  • Cimzia antibodies - in long-term Crohn's disease trials, up to 23% of patients developed anti-Cimzia antibodies. In RA trials, 7% of patients developed anti-Cimzia antibodies. In the RA trials, antibody development was associated with lower drug plasma concentrations and reduced efficacy.
  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis have been reported
  • Vaccines - patients may receive non-live vaccines. Do not give live or attenuated vaccines.
  • CYP enzyme activity - suppression of inflammatory mediators by TNF inhibitors may increase CYP enzyme activity and decrease blood levels of drugs metabolized by CYP enzymes. Use caution when initiating or stopping TNF inhibitors in patients taking concomitant CYP450 substrates with a narrow therapeutic index (e.g. warfarin, cyclosporine, theophylline). Monitor drug levels and drug effects (e.g. INR) when appropriate.
  • Coagulation studies - Cimzia may cause an erroneously prolonged activated Partial Thromboplastin Time (aPTT)
  • Liver disease - has not been studied
  • Kidney disease - has not been studied

Etanercept | Enbrel® | Erelzi®

Dosage forms

Prefilled syringe (Enbrel®)
  • Comes in 25 mg and 50 mg doses
  • Comes in carton with 4 pens
Autoinjector (Enbrel®)
  • Comes in 50 mg dose
  • Comes in carton with 4 autoinjectors
Mini prefilled cartridges (Enbrel®)
  • Comes in 50 mg dose
  • Comes in carton with 4 cartridges
  • For use with AutoTouch reusable autoinjector
Vial (Enbrel®)
  • Comes in 25 mg multi-use vial
  • Comes in carton with 4 vials
  • Drug must be reconstituted
Prefilled syringe (Erelzi®)
  • Comes in 25 mg and 50 mg doses
  • Comes in carton with 1 or 4 pens
  • Erelzi is a biosimilar to Enbrel
  • Erelzi is etanercept-szzs
Sensoready Pen (Erelzi®)
  • Comes in 50 mg dose
  • Comes in carton with 1 or 4 pens
  • Erelzi is a biosimilar to Enbrel
  • Erelzi is etanercept-szzs

Dosing

Rheumatoid arthritis, Psoriatic arthritis, Ankylosing spondylitis (adults)
  • Dosing: 50 mg once weekly
Plaque psoriasis (adults)
  • Starting: 50 mg twice weekly for 3 months
  • Maintenance: 50 mg once weekly
  • Starting doses of 25 - 50 mg once weekly have also been shown to be effective
Plaque psoriasis (pediatric patients ≥ 4 years old)
  • ≥ 138 lbs (63 kg): 50 mg once weekly
  • < 138 lbs (63 kg): 0.8 mg/kg weekly
Polyarticular juvenile idiopathic arthritis (pediatric patients ≥ 2 years old)
  • ≥ 138 lbs (63 kg): 50 mg once weekly
  • < 138 lbs (63 kg): 0.8 mg/kg weekly

Efficacy


Other

  • Keep refrigerated
  • Let Enbrel/Erelzi warm to room temperature for 15 - 30 minutes before injecting
  • Inject subcutaneously in the thigh, abdomen, or outer upper arms. Rotate injection sites.
  • See medication guide and instructions for use for more information on storage and proper injection technique

Mechanism of action

  • Tumor Necrosis Factor inhibitor - Enbrel is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. Enbrel inhibits binding of TNF-alpha and TNF-beta to cell surface TNFRs.

FDA-approved indications

  • Rheumatoid arthritis (adults)
  • Polyarticular Juvenile Idiopathic Arthritis (≥ 2 years old)
  • Psoriatic Arthritis (adults)
  • Ankylosing Spondylitis (adults)
  • Plaque Psoriasis (adults and children ≥ 4 years old)

Side effects


Side effect Etanercept Placebo
Upper respiratory infections 38% 30%
Non-upper respiratory infections 21% 15%
Fever 3% 0%
Other
  • Injection site reactions - up to 37% of patients; reactions include redness, itching, pain, swelling, bleeding, and bruising; average duration of reactions is 3 - 5 days; reactions typically occurred in the first month and then decreased in frequency


Contraindications / Precautions

  • Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). The American College of Rheumatology recommends treating latent TB for at least one month before starting a TNF inhibitor. Active TB should be treated completely before starting a TNF inhibitor. [2]
  • Serious infections - TNF inhibitors may increase the risk of serious infections including tuberculosis, invasive fungal infections, bacterial infections, viral infections, and others. In controlled trials, rates of serious infections were 1.4% in Enbrel-treated patients and 0.8% in placebo-treated patients. In rheumatological trials, serious infections included pneumonia, cellulitis, septic arthritis, bronchitis, gastroenteritis, pyelonephritis, sepsis, abscess and osteomyelitis.
  • Hepatitis B - patients infected with hepatitis B may have reactivation of disease while taking TNF inhibitors. Test patients before initiating therapy. Monitor infected patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Malignancies - TNF inhibitors may cause a slight increase in the risk for certain cancers. In trials, the observed rate of lymphoma in etanercept-treated patients was 0.10 cases per 100 patient-years. This was 3-fold higher than the rate of lymphoma expected in the general U.S. population. Non-melanoma skin cancer rates in trials were 3.54 cases per 100 patient-years in etanercept-treated patients versus 1.28 cases per 100 patient-years in control patients. Risks for other malignancies may also be increased.
  • Demyelinating diseases (e.g. multiple sclerosis) - TNF inhibitors may exacerbate demyelinating diseases. Use caution.
  • Blood dyscrasias - blood dyscrasias including aplastic anemia have been reported
  • Abatacept and anakinra - DO NOT COMBINE. Increases risk of serious infection.
  • Cyclophosphamide - DO NOT COMBINE. May increase risk of malignancy.
  • Sulfasalazine - combination may decrease neutrophil count
  • Heart failure - TNF inhibitors may cause new onset heart failure or worsen existing heart failure. Use caution.
  • Drug-induced lupus - TNF inhibitors have been associated with drug-induced lupus in a small number of patients
  • Autoantibodies - in controlled trials, 11% of Enbrel-treated patients and 5% of placebo-treated patients developed positive ANA titers during treatment
  • Granulomatosis with Polyangiitis - etanercept should not be combined with other immunosuppressants in patients with granulomatosis with polyangiitis. In one study, the addition of etanercept to standard therapy (including cyclophosphamide) for granulomatosis with polyangiitis was associated with a higher incidence of non-cutaneous solid malignancies and did not improve outcomes.
  • Alcoholic hepatitis - Use caution. May increase mortality.
  • Etanercept antibodies - in adult trials, anti-etanercept antibodies were detected in up to 9% of patients. Antibody development did not appear to affect drug efficacy.
  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis have been reported
  • Vaccines - patients may receive non-live vaccines. Do not give live or attenuated vaccines. Etanercept may attenuate the desired immune response to vaccines. It's unknown if this affects vaccine efficacy.
  • CYP enzyme activity - suppression of inflammatory mediators by TNF inhibitors may increase CYP enzyme activity and decrease blood levels of drugs metabolized by CYP enzymes. Use caution when initiating or stopping TNF inhibitors in patients taking concomitant CYP450 substrates with a narrow therapeutic index (e.g. warfarin, cyclosporine, theophylline). Monitor drug levels and drug effects (e.g. INR) when appropriate.
  • Liver disease - has not been studied
  • Kidney disease - has not been studied

Golimumab | Simponi® | Simponi Aria®

Dosage forms

Prefilled syringe (Simponi)
  • Comes 50 mg and 100 mg doses
Autoinjector (Simponi)
  • Comes 50 mg and 100 mg doses
Vial (Simponi Aria)
  • 50 mg/4 ml single-use vial

Dosing - Simponi

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis
  • Dosing: 50 mg once a month
  • For patients with rheumatoid arthritis, Simponi should be given with methotrexate
Ulcerative colitis
  • Dosing: 200 mg at Week 0, followed by 100 mg at Week 2, and then maintenance therapy with 100 mg every 4 weeks

Dosing - Simponi Aria

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis (adults)
  • Dosing: 2 mg/kg given as an intravenous infusion over 30 minutes at Week 0 and 4, and every 8 weeks thereafter
  • For patients with rheumatoid arthritis, Simponi Aria should be given with methotrexate
  • For patients with psoriatic arthritis or ankylosing spondylitis, Simponi Aria may be given with or without methotrexate or other non-biologic disease modifying antirheumatic drugs.
Psoriatic Arthritis and Polyarticular Juvenile Idiopathic Arthritis (≥ 2 years old)
  • Dosing: 80 mg/m2 given as an intravenous infusion over 30 minutes at weeks 0 and 4, and every 8 weeks thereafter

Efficacy


Other

Syringe and autoinjector
  • Keep refrigerated
  • Let Simponi warm to room temperature for 30 minutes before injecting
  • Inject subcutaneously in the thigh, abdomen, or outer upper arms. Rotate injection sites.
  • Simponi should be clear to slightly opalescent and colorless to light yellow
Simponi Aria
  • Keep refrigerated
  • Must be infused intravenously over 30 minutes
  • Solution should be colorless to light yellow. The solution may develop a few fine translucent particles.

Mechanism of action

  • Tumor Necrosis Factor inhibitor - Simponi is a human IgG1қ monoclonal antibody specific for human tumor necrosis factor alpha (TNF-alpha). Simponi binds TNF-alpha and prevents it from binding with TNF-alpha receptors.

FDA-approved indications

Simponi (adults only)
  • Rheumatoid arthritis (in combination with methotrexate)
  • Psoriatic Arthritis
  • Ankylosing Spondylitis
  • Ulcerative colitis
Simponi Aria
  • Rheumatoid arthritis in adults. Use in combination with methotrexate.
  • Psoriatic arthritis in adults and children ≥ 2 years of age
  • Ankylosing Spondylitis in adults
  • Polyarticular juvenile idiopathic arthritis in patients ≥ 2 years old

Side effects


Side effect Golimumab Placebo
Upper respiratory infections 16% 13%
Viral infections (e.g. influenza and herpes) 5% 3%
Other
  • Injection site reactions - up to 6% of patients; most reactions were mild; most frequent reaction was redness
  • Infusion reactions (Simponi Aria) - 1.1% of patients; most common reaction was rash


Drug interactions

  • Other biologic products - DO NOT GIVE with abatacept or anakinra because the risk for serious infections may be increased. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. The concomitant use of golimumab with biologics approved to treat RA, psoriatic arthritis, and ankylosing spondylitis is not recommended because of the possibility of an increased risk of infection.
  • CYP450 substrates - during chronic inflammation, CYP450 enzyme levels may be altered. When inflammation is suppressed by golimumab, CYP enzyme activity may change. Therefore, upon initiation or discontinuation of golimumab in patients who are receiving CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for changes in effect (e.g. warfarin) and/or drug levels (e.g. cyclosporine).

Contraindications / Precautions

  • Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). The American College of Rheumatology recommends treating latent TB for at least one month before starting a TNF inhibitor. Active TB should be treated completely before starting a TNF inhibitor. [2]
  • Serious infections - TNF inhibitors may increase the risk of serious infections including tuberculosis, invasive fungal infections, bacterial infections, viral infections, and others. In controlled trials, the incidence of serious infections was 5.7 per 100 patient-years in Simponi-treated patients and 4.2 per 100 patient-years in placebo-treated patients.
  • Hepatitis B - patients infected with hepatitis B may have reactivation of disease while taking TNF inhibitors. Test patients before initiating therapy. Monitor infected patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Malignancies - TNF inhibitors may increase the risk for certain cancers, particularly lymphoma. Concomitant immunosuppressants may increase the risk.
  • Demyelinating diseases (e.g. multiple sclerosis) - TNF inhibitors may exacerbate demyelinating diseases. Use caution.
  • Blood dyscrasias - blood dyscrasias including aplastic anemia have been reported
  • Heart failure - TNF inhibitors may cause new onset heart failure or worsen existing heart failure. Use caution.
  • Drug-induced lupus - TNF inhibitors have been associated with drug-induced lupus in a small number of patients
  • Autoantibodies - in controlled trials, 4% of Simponi-treated patients and 2.6% of placebo-treated patients developed positive ANA titers during treatment
  • Elevated liver enzymes - in controlled trials, ALT elevations ≥ 3 x ULN occurred in 2% of control-treated patients and 2% of Simponi-treated patients. Concomitant methotrexate may increase the risk.
  • Simponi antibodies - in trials, anti-golimumab antibodies have been detected in up to 38% of patients. Concomitant immunosuppressants lowers the risk of antibody development. A trend toward decreased drug concentrations and efficacy was noted in antibody-positive patients when compared to antibody-negative patients.
  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis have been reported
  • Vaccines - Do not give live or attenuated vaccines. Administration of live vaccines to infants exposed to golimumab in utero is not recommended for 6 months following the mother’s last golimumab infusion during pregnancy. When possible, update immunizations prior to starting golimumab. Golimumab may attenuate the immune response to non-live vaccines.
  • CYP enzyme activity - suppression of inflammatory mediators by TNF inhibitors may increase CYP enzyme activity and decrease blood levels of drugs metabolized by CYP enzymes. Use caution when initiating or stopping TNF inhibitors in patients taking concomitant CYP450 substrates with a narrow therapeutic index (e.g. warfarin, cyclosporine, theophylline). Monitor drug levels and drug effects (e.g. INR) when appropriate.
  • Liver disease - has not been studied
  • Kidney disease - has not been studied

Infliximab | Remicade® | Inflectra® | Renflexis® | Avsola®

Dosage forms

Vial (Remicade®)
  • 100 mg single dose vial
Vial (Inflectra®)
  • 100 mg single dose vial
  • Inflectra is a biosimilar to Remicade
  • Inflectra is infliximab-dyyb
Vial (Renflexis®)
  • 100 mg single dose vial
  • Renflexis is a biosimilar to Remicade
  • Renflexis is infliximab-adba
Vial (Avsola®)
  • 100 mg single dose vial
  • Avsola is a biosimilar to Remicade
  • Avsola is infliximab-axxq

Dosing

Crohn's disease (Adults)
  • Starting: 5 mg/kg at Weeks 0, 2, and 6
  • Maintenance: 5 mg/kg every 8 weeks
  • May increase to 10 mg/kg in patients who respond and then lose their response
  • Target trough concentration in IBD: ≥ 5 mcg/ml [5]
Crohn's disease (≥ 6 years old)
  • Starting: 5 mg/kg at Weeks 0, 2, and 6
  • Maintenance: 5 mg/kg every 8 weeks
Ulcerative colitis (Adults)
  • Starting: 5 mg/kg at Weeks 0, 2, and 6
  • Maintenance: 5 mg/kg every 8 weeks
  • Target trough concentration in IBD: ≥ 5 mcg/ml [5]
Ulcerative colitis (≥ 6 years old)
  • Starting: 5 mg/kg at Weeks 0, 2, and 6
  • Maintenance: 5 mg/kg every 8 weeks
Rheumatoid arthritis
  • Starting: 3 mg/kg at Weeks 0, 2, and 6
  • Maintenance: 3 mg/kg every 8 weeks
  • Should be given with methotrexate
  • May increase dose to 10 mg/kg or shorten dosing interval to 4 weeks in patients with partial response
Ankylosing spondylitis
  • Starting: 5 mg/kg at Weeks 0, 2, and 6
  • Maintenance: 5 mg/kg every 6 weeks
Psoriatic arthritis
  • Starting: 5 mg/kg at Weeks 0, 2, and 6
  • Maintenance: 5 mg/kg every 8 weeks
Plaque Psoriasis
  • Starting: 5 mg/kg at Weeks 0, 2, and 6
  • Maintenance: 5 mg/kg every 8 weeks

Efficacy / Other studies


Other

  • Prior to infusion, may premedicate with antihistamine, acetaminophen, and/or corticosteroids
  • Infuse over a period of not less than 2 hours
  • Keep vials refrigerated
  • Unopened vials may also be stored at temperatures up to a maximum of 30°C (86°F) for a single period of up to 6 months
  • Upon removal from refrigerated storage, Remicade cannot be returned to refrigerated storage

Mechanism of action

  • Tumor Necrosis Factor inhibitor - Remicade is a chimeric IgG1κ monoclonal antibody (composed of human constant and murine variable regions) specific for human tumor necrosis factor-alpha (TNF-alpha). Remicade binds TNF-alpha and prevents it from binding with TNF-alpha receptors.

FDA-approved indications

  • Crohn's disease (adult and pediatric)
  • Rheumatoid arthritis (in combination with methotrexate)
  • Psoriatic Arthritis
  • Ankylosing Spondylitis
  • Ulcerative colitis (adult and pediatric)
  • Plaque Psoriasis

Side effects


Side effect Infliximab Placebo
Upper respiratory tract infection 32% 25%
Headache 18% 14%
Sinusitis 14% 8%
Pharyngitis 12% 8%
Coughing 12% 8%
Abdominal pain 12% 8%
Rash 10% 5%
Dyspepsia 10% 7%
Fatigue 9% 7%
Urinary tract infection 8% 6%
Hypertension 7% 5%
Fever 7% 4%
Itching 7% 2%
Yeast infection 5% 3%
Other
  • Infusion reactions - up to 18% of patients; serious reactions are rare


Drug interactions

  • Abatacept - DO NOT COMBINE. Combination increases risk of serious infection with no added benefit.
  • Anakinra - DO NOT COMBINE. Combination increases risk of serious infection with no added benefit.
  • Tocilizumab - DO NOT COMBINE. Combination increases risk of serious infection.
  • Immunosuppressants - in trials, infliximab was combined with other immunosuppressants including methotrexate, NSAIDs, corticosteroids, azathioprine, 6-MP, and aminosalicylates. Concomitant immunosuppressants, particularly methotrexate, may reduce the incidence of hypersensitivity reactions and the production of anti-infliximab antibodies.
  • CYP enzyme activity - suppression of inflammatory mediators by TNF inhibitors may increase CYP enzyme activity and decrease blood levels of drugs metabolized by CYP enzymes. Use caution when initiating or stopping TNF inhibitors in patients taking concomitant CYP450 substrates with a narrow therapeutic index (e.g. warfarin, cyclosporine, theophylline). Monitor drug levels and drug effects (e.g. INR) when appropriate.

Contraindications / Precautions

  • Heart failure - infliximab may cause new-onset heart failure or worsen existing heart failure. Infliximab at doses > 5 mg/kg should not be given to patients with moderate to severe (NYHA class III and IV) heart failure. There have been post-marketing reports of new-onset heart failure in infliximab-treated patients younger than 50 years old. If infliximab (≤ 5 mg/kg) is to be used in patients with any degree of heart failure, caution should be used.
  • Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). The American College of Rheumatology recommends treating latent TB for at least one month before starting a TNF inhibitor. Active TB should be treated completely before starting a TNF inhibitor. [2]
  • Serious infections - TNF inhibitors may increase the risk of serious infections including tuberculosis, invasive fungal infections, bacterial infections, viral infections, and others. In RA patients treated for 1 year, 5.3% of Remicade-treated patients developed serious infections as compared to 3.4% of placebo-treated patients.
  • Elevated liver enzymes - in controlled trials, ALT elevations between 1 - 3 X ULN occurred in up to 51% of Remicade-treated patients. ALT elevations ≥ 3 X ULN occurred in up to 10% of Remicade-treated patients. Mild-to-moderate elevations typically decreased or resolved with either continuation or discontinuation of Remicade, or modification of concomitant medications. Discontinue Remicade if LFTs reach ≥ 5 X ULN.
  • Hepatitis B - patients infected with hepatitis B may have reactivation of disease while taking TNF inhibitors. Test patients before initiating therapy. Monitor infected patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Malignancies - TNF inhibitors may increase the risk for certain cancers, particularly lymphoma. Concomitant immunosuppressants may increase the risk.
  • Cervical cancer - In an observational study, the risk for invasive cervical cancer was increased in women receiving infliximab for RA. The risk was particularly high in women > 60 years old. Cervical cancer screening should continue in women receiving infliximab.
  • Vascular events during infusion - vascular events including stroke, MI, hypo/hypertension, transient vision loss, and arrhythmias have been reported during and within 24 hours of infliximab infusions. Discontinue infusion if events occur.
  • Neurologic reactions - TNF inhibitors have been associated with CNS manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Use caution when prescribing to patients with neurologic disorders.
  • Blood dyscrasias - blood dyscrasias including aplastic anemia have been reported
  • Drug-induced lupus - TNF inhibitors have been associated with drug-induced lupus in a small number of patients
  • Autoantibodies - in controlled trials, 50% of Remicade-treated patients and 20% of placebo-treated patients developed positive ANA titers during treatment. Anti-dsDNA antibodies developed in 20% of Remicade-treated patients compared to 0% of placebo-treated patients.
  • Infliximab antibodies - in trials, anti-inflixamab antibodies were detected in up to 51% of patients. In some studies, antibody development was associated with reduced efficacy and an increased rate of infusion reactions.
  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis have been reported. Most reactions occurred during or within 2 hours of infliximab infusion. Cases of a serum sickness-like reaction have been reported in patients who develop infliximab antibodies. Serum sickness may present with fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema, and/or dysphagia. The risk of hypersensitivity reactions is increased in patients who restart infliximab after a period of being off the drug.
  • Vaccines - infliximab may attenuate the response to vaccines. When possible, vaccinations should be updated before starting therapy. Do not give live or attenuated vaccines during therapy. Infliximab crosses the placenta and has been detected in infants exposed in utero for up to 6 months following birth. Wait at least six months before giving live or attenuated vaccines to exposed infants.
  • Therapeutic infectious agents (e.g. BCG vaccine) - therapeutic infectious agents such as live attenuated bacteria (e.g. BCG bladder instillation for the treatment of cancer) should not be given to patients on infliximab because clinical infections could occur
  • Liver disease - has not been studied
  • Kidney disease - has not been studied

Abatacept (Orencia®)

Dosage forms

Prefilled syringe
  • 50 mg/0.4 ml
  • 87.5 mg/0.7 ml
  • 125 mg/ml
  • Comes in package of 4 syringes
Single-use vials
  • Comes in 250 mg vial

Dosing

Rheumatoid arthritis and Psoriatic arthritis
  • Prefilled syringe (subcutaneous)
    • Dosing: 125 mg subcutaneously once weekly
    • Loading dose: In rheumatoid arthritis patients, may give IV loading dose per guidelines below. Loading dose is not recommended for psoriatic arthritis. If IV loading dose is given, initiate first subcutaneous dose within a day of IV loading dose.
    • If transitioning from IV therapy to subcutaneous, administer the first subcutaneous dose instead of the next scheduled intravenous dose
  • Intravenous
    • Starting: weight-based dose at Week 0, 2, and 4
    • Maintenance: weight-based dose every 4 weeks

Body weight (kg) Dose # of vials
< 60 kg 500 mg 2
60 - 100 kg 750 mg 3
> 100 kg 1000 mg 4
Juvenile idiopathic arthritis
  • Prefilled syringe - subcutaneous (≥ 2 years old)

Body weight (kg) Dose (once weekly)
10 to less than 25 kg 50 mg
25 to less than 50 kg 87.5 mg
≥ 50 kg 125 mg

  • Intravenous (≥ 6 years old)
    • Starting: 10 mg/kg at Week 0, 2, and 4
    • Maintenance: 10 mg/kg dose every 4 weeks
    • If weight is ≥ 75 kg, use adult dosing

Efficacy


Other

Prefilled syringe
  • Keep refrigerated
  • Solution should be clear and colorless to pale yellow
  • Let syringe warm to room temperature for 30 - 60 minutes before injecting
  • Inject subcutaneously in the thigh, abdomen, or outer upper arms. Rotate injection sites.
Intravenous infusion
  • Orencia is infused over 30 minutes

Mechanism of action

  • T-cell inhibitor - Orencia is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc portion of human immunoglobulin G1 (IgG1). Orencia inhibits T-lymphocyte activation by binding to CD80 and CD86, thereby blocking interaction with CD28. CD28 interaction is necessary for full activation of T-lymphocytes.

FDA-approved indications

  • Rheumatoid arthritis - as monotherapy or concomitantly with DMARDs other than TNF inhibitors
  • Psoriatic arthritis - with or without non-biologic DMARDs
  • Juvenile idiopathic arthritis - in patients ≥ 2 years old as monotherapy or with methotrexate

Side effects


Side effect Abatacept Placebo
Headache 18% 13%
Nasopharyngitis 12% 9%
Dizziness 9% 7%
Hypertension 7% 4%
Dyspepsia 6% 4%
Other
  • Injection site reactions - 2.6% of patients; reactions include hematoma, pruritus, and erythema
  • Infusion reactions - 9% of patients; most common reactions include dizziness, headache, and hypertension


Drug interactions

  • TNF inhibitors - DO NOT COMBINE. The addition of Orencia to TNF inhibitors in adults with RA increased the risk of infections (63% vs 43%) and serious infections (4.4% vs 0.8%) when compared to TNF inhibitor monotherapy.
  • Other biologic therapies - there is insufficient evidence to assess the safety of combining Orencia with other biologic therapies; therefore, the use of Orencia with other biologics is not recommended
  • Janus kinase inhibitors - there is insufficient evidence to assess the safety of combining Orencia with janus kinase inhibitors; therefore, the use of Orencia with janus kinase inhibitors is not recommended.

Lab interactions

  • Blood glucose testing - intravenous Orencia contains maltose which can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinoline quinone (e.g. ACCU-CHEK, FreeStyle, TRUEtest, CoZmonitor). Falsely elevated readings may occur on the day of infusion. Use an alternative method for checking blood sugars on infusion days. Orencia for subcutaneous injection does not contain maltose.

Contraindications / Precautions

  • TNF inhibitors - DO NOT COMBINE. May increase risk of serious infection.
  • Infusion reactions - rare cases of anaphylaxis have been reported with Orencia infusion. Administer under medical supervision.
  • Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). The American College of Rheumatology recommends treating latent TB for at least one month before starting abatacept. Active TB should be treated completely before starting abatacept. [2]
  • Hepatitis B - patients infected with hepatitis B may have reactivation of disease while taking Orencia. Test patients before initiating therapy. Monitor infected patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Vaccines - patients may receive non-live vaccines. Do not give live or attenuated vaccines concurrently with Orencia or within 3 months of discontinuation.
  • COPD - patients with COPD had a greater number of adverse events (COPD exacerbations, cough, rhonchi, dyspnea) while using Orencia. Use caution in this population.
  • Serious infections - Orencia may increase the risk of serious infections including tuberculosis, invasive fungal infections, bacterial infections, viral infections, and others. In trials, the incidence of serious infections in Orencia-treated patients was 3% compared to 1.9% in placebo-treated patients. The most common serious infections were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis.
  • Malignancies - Orencia may increase the risk for certain cancers, particularly lymphoma, lung cancer, and skin cancers. Periodic skin cancer screening is recommended in all patients.
  • Immunosuppression - Orencia suppress T-cell activation which may increase the risk of infections and malignancies
  • Orencia antibodies - in trials, anti-Orencia antibodies were detected in up to 10% of patients. It's unclear if antibody development is associated with reduced efficacy and/or an increase in hypersensitivity reactions.
  • Blood glucose test strips (infusion) - maltose in the Orencia infusion may cause falsely elevated blood glucose readings on the day of infusion with certain test strips and monitors.
  • Liver disease - has not been studied
  • Kidney disease - has not been studied

Natalizumab (Tysabri®)

Dosage forms

Single-use vials
  • Comes in 300 mg vial

Dosing

Crohn's disease
  • Dosing: 300 mg every 4 weeks
  • If benefit is not seen by 12 weeks, discontinue
  • For patients using steroids, begin tapering steroids as soon as benefit from Tysabri is seen. If steroids cannot be tapered within 6 months, discontinue Tysabri.
  • Tysabri is given by IV infusion over 1 hour
  • Because of the risk of PML, providers must be enrolled in the Tysabri CD TOUCH program in order to prescribe Tysabri
Multiple sclerosis

Efficacy


Mechanism of action

  • T-cell inhibitor - Tysabri is a recombinant humanized IgG4ϰ monoclonal antibody that binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the α4-mediated adhesion of leukocytes to their counter-receptor(s). Inhibiting this interaction prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue

FDA-approved indications

  • Crohn's disease
  • Multiple sclerosis

Side effects


Side effect Natalizumab
(N=983)
Placebo
(N=431)
Headache 32% 23%
Upper respiratory infection 22% 16%
Nausea 17% 15%
Fatigue 10% 8%
Arthralgia 8% 6%
Throat pain 6% 4%
Rash 6% 4%
Dyspepsia 5% 3%
Constipation 4% 2%
Vaginal infections 4% 2%
Urinary tract infections 3% 1%
Cough 3% <1%
Other
  • Infusion reactions - in Crohn's trials, up to 11% of patients; most common reactions include headache, nausea, urticaria, pruritus, and flushing


Contraindications / Precautions

  • TNF inhibitors - DO NOT COMBINE. May increase risk of PML.
  • Immunosuppressants - DO NOT COMBINE. May increase risk of PML.
  • Corticosteroids - taper corticosteroids when starting Tysabri
  • Progressive multifocal leukoencephalopathy (PML) - Tysabri increases the risk of PML which has a mortality rate of > 20%. Symptoms of PML progress over days to weeks and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. Risk is increased by longer duration of therapy (especially > 2 years), prior treatment with immunosuppressants, and the presence of anti-JCV antibodies. Risk of PML by JC antibody index and length of therapy are presented in the tables below. Providers must be enrolled in the Tysabri CD TOUCH program in order to prescribe Tysabri.

  • Estimates are for patients with no prior immunosuppressant use
  • Reference [9]
Risk of PML in patients using natalizumab for 25 - 36 months
anti-JCV index PML risk
< 0.9 0.2/1000
0.9 - 1.5 0.3/1000
> 1.5 3/1000
  • Imm = immunosuppressants
  • Examples of immunosuppressants include mitoxantrone, azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil
  • Reference [Manufacturer's PI]
Risk of PML in patients who are anti-JCV antibody positive
Length of Tysabri exposure No prior Imm Prior Imm use
1 - 24 months < 1/1000 1/1000
25 - 48 months 3/1000 12/1000
49 - 72 months 6/1000 13/1000
  • Herpes infections - Tysabri increases the risk of herpes encephalitis, meningitis, and retinitis. The duration of treatment with Tysabri prior to onset ranged from a few months to several years. Monitor patients receiving Tysabri for signs and symptoms of meningitis, encephalitis, and retinitis. Retinitis may present with decreased visual acuity, eye pain, and/or redness.
  • Hepatotoxicity - cases of acute hepatitis and liver failure have occurred
  • Hypersensitivity reactions - hypersensitivity reactions including urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, chest pain, and anaphylaxis have occurred. Reactions typically occur within 2 hours of starting an infusion. Reactions are more common in patients who develop natalizumab antibodies. Check for natalizumab antibodies in patients who have infusion reactions or experience decreased efficacy. Natalizumab should be discontinued in patients with persistent antibodies.
  • Tysabri antibodies - in Crohn's trials, anti-Tysabri antibodies were detected in up to 10% of patients. Antibody development was associated with reduced efficacy and an increase in hypersensitivity reactions. Patients who receive 1 - 2 infusions of Tysabri followed by an extended period without exposure are at greater risk of developing antibodies and experiencing hypersensitivity reactions. Before restarting therapy, antibody testing may be appropriate.
  • Serious infections - Tysabri may increase the risk of serious infections including invasive fungal infections, bacterial infections, viral infections, and others. In Crohn's trials, the incidence of serious infections in Tysabri-treated patients was 3.3% compared to 2.8% in placebo-treated patients.
  • Increase in blood counts - Tysabri increases circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Levels return to normal when Tysabri is discontinued.
  • Decrease in hemoglobin - Tysabri induces mild decreases in hemoglobin levels (mean decrease of 0.6 g/dl) that are frequently transient
  • Thrombocytopenia - cases of thrombocytopenia, including immune thrombocytopenic (ITP), have been reported in the postmarketing setting. If symptoms of thrombocytopenia develop (e.g. bleeding, easy bruising), a platelet count should be checked promptly.
  • Vaccines - patients may receive non-live vaccines. Do not give live or attenuated vaccines.
  • Liver disease - has not been studied
  • Kidney disease - has not been studied

Vedolizumab (Entyvio®)

Dosage forms

Single-use vials
  • 300 mg vial

Dosing

Crohn's disease
  • Starting: 300 mg IV at Weeks 0, 2, and 6
  • Maintenance: 300 mg IV every 8 weeks
  • Entyvio is given by IV infusion over 30 minutes
  • Discontinue if no effect seen after Week 14
Ulcerative colitis
  • Starting: 300 mg IV at Weeks 0, 2, and 6
  • Maintenance: 300 mg IV every 8 weeks
  • Entyvio is given by IV infusion over 30 minutes
  • Discontinue if no effect seen after Week 14

Efficacy


Mechanism of action

  • T-cell inhibitor - Vedolizumab is a humanized monoclonal antibody that specifically binds to the α4β7 integrin and blocks the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue

FDA-approved indications

  • Crohn's disease - treatment of active disease in patients who did not respond to or tolerate tumor necrosis factor inhibitors, immunosuppressants, or corticosteroids
  • Ulcerative colitis - treatment of active disease and maintenance of remission in patients who did not respond to or tolerate tumor necrosis factor inhibitors, immunosuppressants, or corticosteroids

Side effects


Side effect Vedolizumab
(N=1434)
Placebo
(N=297)
Nasopharyngitis 13% 7%
Arthralgia 12% 10%
Fever 9% 7%
Fatigue 6% 3%
Cough 5% 3%
Influenza 4% 2%
Itching 3% 1%
Sinusitis 3% 1%
Oropharyngeal pain 3% 1%
Pain in extremities 3% 1%
Other
  • Infusion reactions - up to 4% of patients; most common reactions include nausea, headache, pruritus, dizziness, fatigue, pyrexia, urticaria, and vomiting


Contraindications / Precautions

  • Natalizumab (Tysabri) - DO NOT COMBINE. May increase risk of PML.
  • TNF inhibitors - DO NOT COMBINE. May increase risk of serious infection.
  • Hypersensitivity reactions - hypersensitivity reactions anaphylaxis, dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have occurred. Reactions have occurred with the first and subsequent infusions and may vary in their time of onset from during infusion or up to several hours post-infusion. In trials, 1 patient out of 1434 had an anaphylactic reaction during Entyvio infusion.
  • Serious infections - Entyvio may increase the risk for serious infections. In trials, the rate of serious infections was 0.07 per patient-year in Entyvio-treated patients compared to 0.06 per patient-year in placebo-treated patients. Serious infections were more frequent in Crohn's disease patients than ulcerative colitis patients. Anal abscesses were the most frequently reported serious infection in Crohn's patients.
  • Progressive Multifocal Leukoencephalopathy (PML) - one case of PML in an Entyvio-treated patient with multiple contributory factors (e.g. HIV infection with a CD4 count of 300 cells/mm3 and prior and concomitant immunosuppression) has been reported in the postmarketing setting. An association between Entyvio and PML may exist. Consider PML diagnosis in patients with new-onset or deteriorating neurological signs and symptoms.
  • Hepatotoxicity - in rare cases, hepatotoxicity has occurred with Entyvio. In controlled trials, AST and ALT elevations ≥ 3 X ULN occurred in < 2% of patients.
  • Vaccines - patients may receive non-live vaccines. The risks of administering live or attenuated vaccines with Entyvio therapy are unknown. Ideally, all vaccines should be brought up to date before initiating Entyvio.
  • Malignancies - Entyvio may increase the risk of malignancy
  • Vedolizumab antibodies - in trials lasting 52 weeks, anti-vedolizumab antibodies were detected in 6% of patients. Of these patients, 65% had neutralizing antibodies. The persistent presence of anti-vedolizumab antibodies was associated with a substantial reduction in vedolizumab levels. It is unknown if antibody development increases the risk of adverse events.
  • Liver disease - has not been studied
  • Kidney disease - has not been studied





Periprocedural studies
Risk of Infection after Knee or Hip Replacement in Patients Taking Biologics or Glucocorticoids, Ann Intern Med (2019) [PubMed abstract]
  • Design: Retrospective cohort study (N=9911 | length - 12 months)
  • Exposure: Receiving abatacept, adalimumab, etanercept, infliximab, rituximab, or tocilizumab before surgery
  • Primary outcome: Comparative risks for hospitalized infection within 30 days and prosthetic joint infection (PJI) within 1 year after surgery
  • Findings: Risks for hospitalized infection, PJI, and readmission after arthroplasty were similar across biologics. In contrast, glucocorticoid use, especially with dosages above 10 mg/d, was associated with greater risk for adverse outcomes.

Perioperative Timing of Infliximab and the Risk of Serious Infection After Elective Hip and Knee Arthroplasty, Arthritis Care Res (Hoboken) (2017) [PubMed abstract]
  • Design: Retrospective cohort study (N=4288 | length - 12 months)
  • Exposure: Timing of infliximab dosing before elective hip or knee replacement
  • Primary outcome: Association of infliximab stop timing with hospitalized infection within 30 days or prosthetic joint infection (PJI) within 1 year
  • Findings: Administering infliximab within 4 weeks of elective knee or hip arthroplasty was not associated with a higher risk of short- or long-term serious infection compared to withholding infliximab for longer time periods. Glucocorticoid use, especially > 10 mg/day, was associated with an increased infection risk.



Pregnancy safety studies

Pregnancy Outcomes After Exposure to Certolizumab Pegol, Arthritis Rheumatol (2018) [PubMed abstract]
  • Design: Prospective cohort study (N=538, length - pregnancy and birth) in women exposed to certolizumab during pregnancy
  • Exposure: Certolizumab exposure during pregnancy
  • Primary outcome: Pregnancy outcomes including miscarriages, stillbirths, and congenital malformations
  • Findings: This analysis represents the largest cohort of pregnant women exposed to an anti-TNF agent for management of chronic inflammatory diseases. Analysis of pregnancy outcomes does not indicate a teratogenic effect of certolizumab, compared to the general population, nor an increased risk of fetal death. The data are reassuring for women of childbearing age considering treatment with certolizumab.

Continuous Anti-TNFα Use Throughout Pregnancy: Possible Complications For the Mother But Not for the Fetus, Am J Gastroenterol (2018) [PubMed abstract]
  • Design: Retrospective cohort study (N=8726, length - pregnancy through 1 year postpartum) in women with IBD
  • Exposure: TNF inhibitor exposure during pregnancy
  • Primary outcome: Composite of disease-, treatment- and pregnancy-related complications during pregnancy for the mother, and infections during the first year of life for children
  • Findings: Anti-TNFα treatment during pregnancy increased the risk of maternal complications compared to unexposed; however, discontinuation before week 24 increased the risk of disease flare. There was no increased risk for children exposed to anti-TNFα up to 1 year of life.

Use of Biologic Therapy by Pregnant Women With Inflammatory Bowel Disease Does Not Affect Infant Response to Vaccines, Clin Gastroenterol Hepatol (2018) [PubMed abstract]
  • Design: Registry cohort study (N=179, length - 7 months)
  • Exposure: Biologic therapy during pregnancy
  • Primary outcome: Protective antibody titers to Hib tetanus toxoid
  • Findings: Vaccination of infants against HiB and tetanus toxin, based on antibody titers measured when infants were at least 7 months old, does not appear to be affected by in utero exposure to biologic therapy

Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection, Gastroenterology (2016) [PubMed abstract]
  • Design: Prospective cohort study (N=80, length - 12 months)
  • Exposure: Adalimumab, infliximab, and/or thiopurine during pregnancy
  • Primary outcome: Rates of clearance of adalimumab and infliximab in newborns after birth and risk of infection during the first year of life
  • Findings: In a prospective study of infants born to mothers who received anti-TNF agents during pregnancy, we detected the drugs until 12 months of age. There was an inverse correlation between the time from last exposure during pregnancy and drug concentration in the umbilical cord. Infliximab was cleared more slowly than adalimumab from the infants. The combination of an anti-TNF agent and thiopurine therapy during pregnancy increased the relative risk for infant infections almost 3-fold compared with anti-TNF monotherapy. Live vaccines therefore should be avoided for up to 1 year unless drug clearance is documented, and pregnant women should be educated on the risks of anti-TNF use.

Cancer risk with TNF inhibitors

Vedolizumab or TNF-antagonist use and risk of new or recurrent cancer in patients with inflammatory bowel disease with prior malignancy, Clin Gastroenterol Hepatol (2020) [PubMed abstract]
  • Design: Retrospective cohort study (N=463 | length = 6.2 years) in patients with current or prior malignancy who were treated with a TNF inhibitor or vedolizumab
  • Exposure: Vedolizumab (N=96) or TNF inhibitor (N=184) vs No immunosuppressive therapy (N=183)
  • Primary outcome: Occurrence of a new primary cancer or recurrent cancer
  • Results:
    • Primary outcome: In a multivariable Cox-model, after adjusting for confounders, there was no increase in the risk of new or recurrent cancer with vedolizumab (HR 1.38 95% CI 0.38 - 1.36) or anti-TNF therapy (HR 1.03, 95% CI 0.65 - 1.64), when compared to no immunosuppressive therapy
  • Findings: Neither Vedolizumab nor TNF-antagonists were associated with increased risk of new or recurrent cancers in patients with prior malignancy

Tumor Necrosis Factor Inhibitors and Cancer Recurrence in Swedish Patients With Rheumatoid Arthritis, Ann Intern Med (2018) [PubMed abstract]
  • Design: Prospective registry cohort study (N=2631, length - 7.9 years) among patients with RA who started TNF inhibitor after being diagnosed with cancer
  • Exposure: Treatment with TNF inhibitors
  • Primary outcome: First recurrence of cancer
  • Findings: The findings suggest that TNF inhibitor treatment is not associated with increased risk for cancer recurrence in patients with RA, although meaningful risk increases could not be ruled out completely.

Malignant Neoplasms in Patients With RA Treated With TNF Inhibitors, Tocilizumab, Abatacept, or Rituximab, JAMA Intern Med (2017) [PubMed abstract]
  • Design: Prospective registry cohort study (N=100,000+, length - 9 years)
  • Exposure: Treatment with tocilizumab, abatacept, rituximab, or TNF inhibitors
  • Primary outcome: First invasive solid or hematologic malignant neoplasm, or skin cancer
  • Findings: The overall risk of cancer among patients with RA initiating TNFi as first or second bDMARD, tocilizumab, abatacept, or rituximab does not differ substantially from that of biologic drug-naive, csDMARD-treated patients with RA, although altered risks for specific cancer types, or those with longer latency, cannot be excluded.

Association Between Use of Thiopurines or TNF Inhibitors Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease, JAMA (2017) [PubMed abstract]
  • Design: Retrospective registry cohort study (N=189,289, length - 6 years)
  • Exposure: Thiopurine monotherapy, anti-TNF monotherapy, or combination therapy, or being unexposed
  • Primary outcome: Incidence of lymphoma
  • Findings: Among adults with IBD, the use of thiopurine monotherapy or anti-TNF monotherapy was associated with a small but statistically significant increased risk of lymphoma compared with exposure to neither medication, and this risk was higher with combination therapy than with each of these treatments used alone. These findings may inform decisions regarding the benefits and risks of treatment.

Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease, JAMA (2014) [PubMed abstract]
  • Design: Retrospective registry cohort study (N=56,146; length = 3.7 years)
  • Exposure:TNF inhibitors vs None in patients with IBD
  • Primary outcome: Rate ratios (RRs) for incident cancer (overall and site-specific)
  • Findings: In this Danish nationwide study, exposure to TNF-α antagonists among patients with IBD was not associated with an increased risk of cancer over a median follow-up of 3.7 years among those exposed. An increased risk associated with longer-term accumulated doses and follow-up cannot be excluded.

Cancer risk with Vedolizumab

Vedolizumab or TNF-antagonist use and risk of new or recurrent cancer in patients with inflammatory bowel disease with prior malignancy, Clin Gastroenterol Hepatol (2020) [PubMed abstract]
  • Design: Retrospective cohort study (N=463 | length = 6.2 years) in patients with current or prior malignancy who were treated with a TNF inhibitor or vedolizumab
  • Exposure: Vedolizumab (N=96) or TNF inhibitor (N=184) vs No immunosuppressive therapy (N=183)
  • Primary outcome: Occurrence of a new primary cancer or recurrent cancer
  • Results:
    • Primary outcome: In a multivariable Cox-model, after adjusting for confounders, there was no increase in the risk of new or recurrent cancer with vedolizumab (HR 1.38 95% CI 0.38 - 1.36) or anti-TNF therapy (HR 1.03, 95% CI 0.65 - 1.64), when compared to no immunosuppressive therapy
  • Findings: Neither Vedolizumab nor TNF-antagonists were associated with increased risk of new or recurrent cancers in patients with prior malignancy

Infliximab biosimilar studies

Infliximab vs CT-P13 (infliximab biosimilar) for Crohn's Disease, Lancet (2019) [PubMed abstract]
  • Design: Randomized controlled trial (N=220, length - 30 weeks)
  • Treatment: Infliximab (Remicade) vs CT-P13 (infliximab biosimilar)
  • Primary outcome: Proportion of patients with a decrease of 70 points or more in Crohn’s Disease Activity Index (CDAI) from baseline to week 6
  • Results:
    • Primary outcome (week 6): Infliximab - 74.3%, CT-P13 - 69.4% (diff –4.9%, 95%CI [–16.9 to 7.3])
    • Primary outcome (week 30): Infliximab - 75.2%, CT-P13 - 76.6% (diff 1.3%, 95%CI [–10.3 to 12.9])
  • Findings: This study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn’s disease. Biosimilar CT-P13 could be a new option for the treatment of active Crohn’s disease

Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH), Lancet (2017) [PubMed abstract]
  • Design: Randomized controlled trial (N=482, length - 52 weeks)
  • Treatment: Brand Remicade (infliximab originator) vs Biosimilar (CT-P13)
  • Primary outcome: Disease worsening during 52-week follow-up
  • Findings: The NOR-SWITCH trial showed that switching from infliximab originator to CT-P13 was not inferior to continued treatment with infliximab originator according to a prespecified non-inferiority margin of 15%. The study was not powered to show non-inferiority in individual diseases.

Outcomes of Patients With Inflammatory Bowel Diseases Switched from a Biosimilar to Remicade, Clin Gastroenterol Hepatol (2019) [PubMed abstract]
  • Design: Cohort study (N=174, length = 24 weeks) in patients with UC or Crohn's disease (CD) who were switched from a biosimilar(CT-P13) to Remicade
  • Primary outcome: Clinical remission and serum drug trough levels and anti-drug antibodies
  • Findings: We collected data from a real-life cohort of patients with CD or UC who were switched from maintenance therapy with a biosimilar to Remicade or were treated with only Remicade. No significant changes were observed in remission, trough levels, or antidrug antibodies in patients switched from the biosimilar to Remicade. No new safety signals were detected.




Patient Assistance Programs for Tumor Necrosis Factor Inhibitors
Drug Manufacturer Ships to FPL limit PAP info Application
Adalimumab (Humira®) Abbvie Patient or doctor < 600% Link Link (online and pdf)
Certolizumab (Cimzia®) UHC Patient < 500% Link Link (online)
Etanercept (Enbrel®) Amgen Patient < 500% Link Link (pdf)
Golimumab (Simponi®) Janssen Pharmacy < 400% Link Link (pdf)
Infliximab (Remicade®) Janssen IV infusion
Doctor's office
< 400% Link Link (pdf)

Patient Assistance Programs for IL-17, IL-23, and IL-12/23 Inhibitors
Drug Manufacturer Ships to FPL limit PAP info Application
Brodalumab (Siliq®) Ortho Patient < 400% Link Link (pdf)
Ixekizumab (Taltz®) Lilly Patient or Doctor < 500% Link Link (online and pdf)
Secukinumab (Cosentyx®) Novartis Patient < 570% Link Link (pdf)
Guselkumab (Tremfya®) Janssen Pharmacy < 400% Link Link (pdf)
Risankizumab (Skyrizi®) Abbvie Patient or Doctor < 600% Link Link (online and pdf)
Tildrakizumab (Ilumya™) Sun Pharma Doctor < 400% Link Link (pdf)
Ustekinumab (Stelara®) Janssen Pharmacy < 400% Link Link (pdf)