Download Case Discussion and Administration Technique

Pearls and Practical Considerations for
Biologic Agents
Scott Vogelgesang, MD
Shane Madsen, PharmD, BCPS
Division of Immunology, Rheumatology and Allergy
University of Iowa
Department of Pharmaceutical Care
University of Iowa Hospitals & Clinics
Disclosure
• Scott Vogelgesang and Shane Madsen report no actual or
potential conflicts of interest associated with this presentation.
Learning Objectives
• Upon successful completion of this activity, participants
should be able to:
• Differentiate between biologic agents
• Identify potential short and long-term adverse events that may
occur with biologic agents
• Develop an appropriate screening and monitoring plan for various
biologic agents
• Discuss pertinent patient counseling points for patients who are
prescribed biologic agents
Outline
• Introduction
• Rheumatoid arthritis
• Systemic Lupus Erythematosus
• belimumab
• tocilizumab
• Screening prior to initiation
• labs
• medical considerations
• vaccines
• tofacitinib
• On treatment considerations
• anakinra
• Pipeline
• TNF antagonists
• abatacept
• rituximab
• Psoriatic arthritis
• ustekinumab
• secukinumab
• apremilast
• Take home points
Introduction
• Therapy of Rheumatoid Arthritis – interesting history
• Gold
• Everyone “knew” RA was caused by infection
• No antibiotics – experimentation with heavy metals as therapy
• Gold – those with arthritis got better
• Hydroxychloroquine – 1940’s antimalarial - those w/ arthritis got better
• First “designer drug” – sulfasalazine
• Everyone “knew” RA was an infection so use an antibiotic (sulfapyradine)
• Everyone knew aspirin helped RA so use salicylate
• Combined the two: sulfasalazine
• Skip ahead to 1990s – Immunologists recognized that TNF and IL-1
were responsible for the inflammatory response in RA – Development
of anti-TNF and anti-IL-1 drugs
• Since: Understand and target pieces of the immune system…
Summary
RHEUMATOID ARTHRITIS
Rheumatoid arthritis is a systemic inflammatory disease which
manifests itself in multiple joints of the body. The inflammatory
process primarily affects the lining of the joints (synovial
membrane), but can also affect other organs. The pathophysiology
involves antibody, B cells, T cells and cytokines.
http://www.cdc.gov/arthritis/basics/rheumatoid.htm
TNF Antagonists
• Inhibits Tumor Necrosis
Factor
• Adverse Effects
• Infections
• Upper respiratory infections
• Urinary tract infections
• Reactivation of TB
• Fungal infections
• Reactivation of hepatitis B
• Demyelinating Disease /
Neuropathies
• Malignancy (Lymphoma)?
• Lupus-like reactions
• Avoid in heart failure
TNF Antagonists
• Etanercept (Enbrel)
• Adalimumab (Humira)
• Soluble TNF receptor
• Humanized TNF antibody
• Subcutaneous
• Subcutaneous
• Short half-life
• Moderate half-life
• Infliximab (Remicade)
• Chimeric TNF antibody
• Golimumab (Simponi &
Simponi Aria)
• Infusion
• Humanized TNF antibody
• Longest half-life
• Subcutaneous & infusion
• Certolizumab (Cimzia)
• Humanized TNF antibody
• Subcutaneous
• Moderate half-life
• Long half-life
Abatacept (Orencia)
• CTLA4 Ig – Blocks T cell
signaling and therefore T cell
activation
• Subcutaneous & infusion
• Side Effects
• Infusion Reactions
• Infection
• ? Increased cancer
(lymphoma) risk
Rituximab (Rituxan)
• Monoclonal antibody directed
against CD20 - Depletes B
cells
• IV infusion
• Side Effects
• Infusion reactions
• Infections?
• PML (progressive multifocal leukoencephalopathy)
• Hepatitis B reactivation
• Hypogammaglobulinemia
• Decreased CD4 counts
Tocilizumab (Actemra)
• Monoclonal antibody - inhibits
IL-6
• Subcutaneous & infusion
• Dose modifications for LFTs,
platelets, and ANC
• Side Effects
• Infection
• Reactivation of TB
• Fungal infections
• Reactivation of Hepatitis B
• Cytopenias
• Increased liver tests
• Increased lipids
• GI perforations
Tofacitinib (Xeljanz)
• Inhibits Janus Kinase – involved
with T cell signaling/ activation/
proliferation
• Oral tablet
• Renal & hepatic dosing
• Dose modifications: neutropenia,
lymphopenia & anemia
• Drug interactions
• Side Effects
• Infection
• Reactivation TB
• Fungal infections
• Cytopenias
• GI symptoms; Liver irritation
• Elevated lipids
• Increased risk for cancer
(Lymphoma)?
Anakinra (Kineret)
• Inhibits IL-1, decreasing
inflammation
• Daily (perhaps multiple times
daily) subcutaneous injection
• Limited distribution:
• 1 pharmacy
• Side Effects
• Injection site reactions
• Not so much…
Questions?
PSORIATIC ARTHRITIS
Psoriatic arthritis is a type of arthritic inflammation that occurs in
about 15 percent [25%?] of patients who have a skin rash called
psoriasis. This particular arthritis can affect any joint in the body,
and symptoms vary from person to person. The pathophysiology is
not clear (or perhaps not the same for all). Abnormalities are
similar to rheumatoid arthritis (Antibody, B cells, T cells and
cytokines) however there may be similarities to the
spondyloarthropathies (like ankylosing spondylitis).
https://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Psoriatic_Arthritis/
Ustekinumab (Stelara)
• Human antibody against IL-12
and IL-23
• Subcutaneous injection at
week 0, then week 4 then
every 12 weeks
• Side Effects
• URI
• Headache
• Fatigue
• Infection
• TB reactivation
• Seizures
• CNS changes
• Increased cancer risk?
Secukinumab (Cosentyx)
• Monoclonal antibody –
inhibits IL-17A
• Subcutaneous injection
weeks 0,1,2,3 and 4;
then every 4 weeks
• Side effects
• URI
• Diarrhea
• Reactivation of TB
• Worsening of Crohn’s
Disease
Apremilast (Otezla)
• Inhibits phosphodiesterase 4
leading to increased cAMP levels
• Downregulatory signal in immune cells
• Decreased TNF and IL-17
• Oral tablet
• Renal dosing
• Drug interactions
• Side Effects
• Diarrhea, nausea and vomiting
• Upper Respiratory Infection
• Headache
• Worsening depression
SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic Lupus Erythematosus is an autoimmune disease in which
the immune system produces antibodies to cells within the body
leading to widespread inflammation and tissue damage. The
pathophysiology involves antibody predominantly (and plasma
cells and B cells by extension).
http://www.cdc.gov/arthritis/basics/lupus.htm
Belimumab (Benlysta)
• Inhibits B cell activating
factor (BAFF)
• IV infusion
• Side Effects
• Infection
• Urinary tract infection
• Pulmonary infections
• Depression
• Increased risk for cancer
(Lymphoma)?
Questions?
SCREENING PRIOR TO INITIATION
Prior to starting: labs
Hep B
panel
Hep C
TB
SCr
LFTs
CBC
TNFi
x
x
x
x
x
x
abatacept
x
x
x
x
x
x
rituximab
x
x
x
x
x
x
tocilizumab
x
x
x
x
x
x
Medication /
Class
tofacitinib
x
x
x
x
x
CBC
w/ diff
(ANC & Plt)
x
(neutrophils,
lymphocytes,
anemia)
Lipid
panel
x
x
Prior to starting: labs
Medication /
Class
Hep B
panel
Hep C
TB
anakinra
SCr
LFTs
x
x
CBC
ustekinumab
x
x
x
x
x
x
secukinumab
x
x
x
x
x
x
apremilast
x
belimumab
x
x
CBC
w/ diff
x
Lipid
panel
Prior to starting: medical issues
Demyelinating
Heart
nervous
Medication /
Cancer
Failure
system
Class
disease
TNFi
x
abatacept
x
x
x
x
Weight
x
x
x
x
x
Serious
COPD
infections
x
x
x
x
rituximab
x
tocilizumab
tofacitinib
Lupus
Recent
abdominal
surgery / hx
of
diverticulitis
x
Prior to starting: Medical issues
Medication /
Class
Cancer
Serious
infections
anakinra
x
x
ustekinumab
x
x
secukinumab
Depression
x
x
x
Crohn’s
Disease
x
x
apremilast
belimumab
Weight
x
x
Prior to starting: vaccines
American College of Rheumatology Recommendations
Killed vaccines
Pneumococcal
DMARD monotherapy
Combination DMARDs
TNFi biologics
Non-TNF biologics
X
X
X
X
Influenza
X
X
X
X
Hepatitis Ba
Recombinant vaccine
Live attenuated
vaccine
Human Papillomavirusb
Herpes zosterc*
Before initiating therapy
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: disease-modifying antirheumatic drugs (DMARDs); tumor necrosis factor inhibitor (TNFi); Rheumatoid
arthritis (RA)
* Deviates from CDC recommendations
a. Given if known hepatitis B risk factors are present (intravenous drug abuse, multiple sex partners in previous six
months, health care personnel)
b: Human Papillomavirus Vaccine- Given to people who are normally eligible (in individuals 11-26 years old).
c: RA patients > 50 years old should receive herpes zoster vaccine prior to starting biologic therapy. Can start
therapy 2 weeks after vaccine.
Chart adapted by Emily Prinz, Pharm.D., from Figure 8, 2015 American College of Rheumatology Guidelines for the Treatment of Rheumatoid
Arthritis.
Prior to Starting: other considerations
• Pregnancy
• Have a discussion: risks vs benefits
• RA often improves during pregnancy
• Insurance formulary
• Ability to self administer injections
ON TREATMENT CONSIDERATIONS
On treatment: Vaccines
American College of Rheumatology Recommendations
Killed vaccines
Pneumococcal
Influenza
Hepatitis Ba
Recombinant vaccine
Live attenuated
vaccine
Human Papillomavirusb
Herpes zosterc*
While already taking therapy
DMARD monotherapy
X
X
X
X
X
Combination DMARDs
X
X
X
X
X
TNFi biologicsd
X
X
X
X
X
X
X
X
Non-TNFi
biologicsd
Abbreviations: disease-modifying antirheumatic drugs (DMARDs); tumor necrosis factor inhibitor (TNFi); Rheumatoid
arthritis (RA)
* Deviates from CDC recommendations
a. Given if known hepatitis B risk factors are present (intravenous drug abuse, multiple sex partners in previous six
months, health care personnel)
b: Human Papillomavirus Vaccine- Given to people who are normally eligible (in individuals 11-26 years old).
c: RA patients > 50 years old should receive herpes zoster vaccine prior to starting biologic therapy. Can received
therapy 2 weeks after vaccine.
d: RA patients currently receiving biologics should not receive live attenuated vaccines
Chart adapted by Emily Prinz, Pharm.D., from Figure 8, 2015 American College of Rheumatology Guidelines for the Treatment of Rheumatoid
Arthritis.
On treatment: labs
• Laboratory monitoring
• Mostly without recommendations / guidelines
• Primarily with clinical suspicion
• Tofacitinib:
• 4-8 weeks post initiation: CBC w/ diff, LFTs, and lipids
• Q3 months: CBC w/ diff, LFTs
• Tocilizumab:
• 4-8 weeks post initiation: CBC w/ diff, LFTs, and lipids
• Q3 months: CBC w/ diff, LFTs
• Q6 months: lipids
On treatment
• Hold the medication for a week (or perhaps two) when
fever is present; Patient looks sick
• NOT necessary for apremilast
• Injection site reactions
• Lasts 2-7 days
• Usually worse with 2nd and 3rd injection
• Usually minimize by 6 weeks
• Ensure allowing to warm up prior to administration (30-45 minutes)
• Cold pack – before and / or after
• Antihistamines
• Topical steroids
• Rule out skin infection – good hygiene practices for injection
On treatment
• Perioperative Management
•
Most recent guidance
etanercept
adalimumab
infliximab
golimumab
certolizumab
tocilizumab subcut
tociluzmab IV
abatacept subcut
abatacept IV
rituximab
hold 2 weeks
hold 3 weeks
hold 6 weeks
hold 6 weeks
hold 6 weeks
hold 3 weeks
hold 4 weeks
hold 2 weeks
hold 4 weeks
no recommendation to hold
Goodman, S. Rheumatoid Arthritis: Perioperative Management of Biologics and
DMARDS. Sem Arth and Rheum 2015;44:627-632
Pipeline for rheumatology
• Biosimilars:
• infliximab, etanercept, & adalimumab – approved by FDA
• rituximab – application submitted to FDA
• IL-17 inhibitors: brodalumab, ixekizumab (both currently approved for
•
•
•
•
•
•
•
•
•
psoriasis)
JAK inhibitors: baricitinib, filgotinib
IL-6 inhibitors: sarilumab, sirukumab
CD20 inhibitor: obinutuzumab
CD22 inhibitor: epratuzumab
Anti-interferon-α: anifrolumab, sifalimumab
BAFF/Blys inhibitor: blisibimod
Blys & APRIL inhibitor: atacicept
Synthetic cannabinoid: ajulemic acid
FCX-013 gene therapy
Summary
Take Home Points
• Infection risk is likely higher in general for biologic agents
• Hold the medication for a week (or perhaps two) when
• Fever is present
• Patient looks sick
• Vaccinations are critical to minimize preventable infections
• Assess vaccination status at PCP or pharmacy visits
• Avoid live-virus vaccines:
• No biologic combinations
Zoster, Varicella, Measles, Mumps, Rubella, Nasal influenza
Questions?