Infliximab

PBS
Codes

Compassionate Portal Remicade (Janssen)

Compassionate Portal Remsima (Celltrion)

Patient
Information

Infliximab Drug Information

Pharmacodynamics

Pivotal Studies - UC

Therapeutic Drug Monitoring

Pivotal Studies - Crohns

Adverse Effects

Use in Pregnancy

Infliximab Pharmacodynamics

Infliximab is a chimeric monoclonal antibody that binds to and neutralizes tumor necrosis factor alpha (TNF-α), thereby inhibiting proinflammatory cytokine activity and reducing inflammation in autoimmune conditions.

Mechanism of Action

Primary action: Binds with high affinity to both soluble and transmembrane forms of TNF-α
Neutralizes TNF-α biological activity by preventing receptor binding

Key Pharmacodynamic Effects

Reduces inflammatory cell infiltration
Decreases expression of:
- Adhesion molecules (ICAM-1, VCAM-1)
- Pro-inflammatory cytokines (IL-1, IL-6)
- Acute phase proteins
Reduces angiogenesis factors
Decreases tissue destruction mediators

Clinical Manifestations of PD Effects

Reduced inflammation in affected tissues
Decreased acute phase reactants (CRP, ESR)
Lower inflammatory cytokine levels
Mucosal healing in IBD
Reduced joint destruction in rheumatoid arthritis

Time Course

Onset: Clinical effects typically seen within 1-2 wks
Peak effect: Usually achieved by 8-12 weeks
Duration: Effects can last 6-8 weeks after single dose

Complement-Dependent Cytotoxicity (CDC)

Mechanism:
- Fc portion of infliximab activates complement cascade
- Forms membrane attack complex (MAC)
- Results in lysis of TNF-α expressing cells
Major targets:
- Activated T lymphocytes
- Macrophages
- Other TNF-α producing inflammatory cells

Antibody-Dependent Cell-Mediated Cytotoxicity

Process:
- Infliximab's Fc region binds to Fc receptors on NK cells
- NK cells recognize and destroy TNF-α expressing cells
Target cells:
- TNF-α producing macrophages
- Activated lymphocytes
- Other inflammatory cells expressing membrane TNF-α
Impact:
- Reduces inflammatory cell populations
- Contributes to long-term disease modification

Apoptosis Induction

Mechanisms:
- Direct signaling through membrane TNF-α
- Activation of caspase pathways
Specific effects:
- Programmed cell death of activated T cells
- Reduction in inflammatory cell populations
- Decreased tissue infiltration by immune cells
Clinical importance:
- Critical for sustained remission
- May explain mucosal healing in IBD

Additional Secondary Effects

Immune modulation:
- Altered cytokine production patterns
Tissue remodeling:
- Reduced fibroblast activation
- Decreased matrix metalloproteinase production
- Modified angiogenesis

Infliximab Pharmacokinetics

Infliximab exhibits dose-proportional pharmacokinetics with a long terminal half-life of 7-9.5 days, undergoes proteolytic degradation, and demonstrates increased clearance in patients with high inflammatory burden or developing anti-drug antibodies.

Absorption and Distribution

Administration: Intravenous infusion only
Volume of distribution: 3-4.5 L
Distribution characteristics:
- Primarily in vascular compartment
- Limited extravascular distribution
- Minimal tissue penetration

Pharmacokinetic Parameters

Half-life: 8-9.5 days
Clearance: 11-15 mL/hour
Linear pharmacokinetics at standard dosing
Steady state typically reached by third infusion
Peak serum concentrations: Dose-dependent
- 118 μg/mL for 5 mg/kg dose
- 192 μg/mL for 10 mg/kg dose

Metabolism and Elimination

Primary mechanism: Protein catabolism
No hepatic cytochrome P450 involvement
Sites of catabolism:
- Reticuloendothelial system
- Antigen-presenting cells
No significant renal elimination of intact molecule

Factors Affecting Pharmacokinetics

a) Patient-related:

Body weight
Serum albumin levels
Gender (slightly higher clearance in males)
Development of anti-drug antibodies
Inflammatory burden
Concomitant immunomodulators

b) Disease-specific:

Disease type and severity
Protein loss (e.g., in IBD)
Inflammatory status

Dosing Considerations

Loading dose regimen:
- Weeks 0, 2, and 6
- Achieves steady state more rapidly
Maintenance dosing:
- Every 8 weeks typical
- May require adjustment based on response
Therapeutic drug monitoring recommended

Infliximab Pivotal Studies - Crohns

The ACCENT I and ACCENT II trials demonstrated infliximab's efficacy in inducing and maintaining remission in moderate-to-severe Crohn's disease, while the SONIC study established its superior efficacy when combined with azathioprine versus either agent as monotherapy.

ACCENT I Trial (2002)

Design:
- Multicenter, randomized, double-blind
- 573 patients with moderate-severe CD
- Initial responders randomized to maintenance vs placebo
Key findings:
- 58% responded to single induction dose
- Maintenance therapy (5 or 10 mg/kg) superior to episodic
- Sustained remission at week 54:
  - 28.3% (5 mg/kg)
  - 38.4% (10 mg/kg)
  - 13.6% (placebo)
Impact: Established efficacy of maintenance therapy

ACCENT II Trial (2004)

Focus: Fistulizing Crohn's disease
Design:
- 306 patients with draining fistulas
- Responders randomized to maintenance vs placebo
Results:
- Complete fistula closure: 36% vs 19% (placebo)
- Median time to loss of response: 40 vs 14 weeks
Significance: Proved efficacy in fistula healing

SONIC Trial (2010)

Design:
Compared infliximab, azathioprine, and combination
508 biologic-naive patients
30-week primary endpoint
Results:
Corticosteroid-free remission:
46.2% combination therapy
34.9% infliximab monotherapy
24.1% azathioprine alone
Impact: Established superiority of combination therapy

Step-Up/Top-Down Trial (2008)

Design:
- Compared early combined immunosuppression vs conventional management
- 133 treatment-naive patients
Results:
- Higher remission rates with early combined therapy
- Reduced corticosteroid use
- Better mucosal healing
Impact: Supported early aggressive therapy

Infliximab Pivotal Studies - UC

The ACT 1 and ACT 2 trials demonstrated infliximab's efficacy in inducing clinical response, remission, and mucosal healing in patients with moderate-to-severe ulcerative colitis who failed conventional therapy.

ACT 1 and ACT 2 Trials (2005)

Design:
- Randomized, double-blind, placebo-controlled
- ACT 1: 364 patients, 54 weeks
- ACT 2: 364 patients, 30 weeks
- Doses: 5 mg/kg, 10 mg/kg, or placebo
Key Results ACT 1:
- Clinical response week 8:
  - 69% (5 mg/kg)
  - 61% (10 mg/kg)
  - 37% (placebo)
- Clinical remission week 54:
  - 35% (5 mg/kg)
  - 34% (10 mg/kg)
  - 17% (placebo)
Key Results ACT 2:
- Similar week 8 responses
- Sustained through week 30
Impact: Led to FDA approval

UC-SUCCESS (2016)

Type: Randomized, double-blind, controlled trial
Duration: 16 weeks
Population: 231 moderate-to-severe UC patients
Key inclusion criteria:
Mayo score 6-12
Endoscopic subscore ≥2
Biologic-naive patients
Active disease despite steroids/5-ASA

Treatment Arms

Group 1: Infliximab (5mg/kg) + Azathioprine (2.5mg/kg)
Group 2: Infliximab (5mg/kg) monotherapy
Group 3: Azathioprine (2.5mg/kg) monotherapy

Primary Endpoint

Corticosteroid-free remission at week 16
Results:
Combination therapy: 39.7%
Infliximab alone: 22.1%
Azathioprine alone: 23.7%
Statistically significant difference (p=0.017)

Secondary Endpoints

Mucosal healing:
- Combination: 62.8%
- Infliximab: 54.6%
- Azathioprine: 36.8%
Clinical response:
- Combination: 77.1%
- Infliximab: 68.9%
- Azathioprine: 50.0%

Safety Outcomes

Adverse events similar across groups
No new safety signals identified

Key Findings

Superiority of combination therapy
Better endoscopic outcomes
Improved clinical responses
Acceptable safety profile
Support for early aggressive therapy

Clinical Implications

Supports combination therapy in moderate-severe UC
Guides therapeutic decision making
Influences treatment algorithms
Important for biologic-naive patients

Infliximab Head to Head Trials

In the VARSITY trial, adalimumab was inferior to vedolizumab for clinical remission in ulcerative colitis, while the SEAVUE study showed comparable efficacy between ustekinumab and adalimumab in Crohn's disease, with no direct head-to-head trials comparing infliximab to other biologics in IBD.

VARSITY Trial (2019)

Vedolizumab vs Adalimumab in UC
Design:
- First head-to-head biologic trial in UC
- 769 patients with moderate-severe UC
- 52-week trial
Results:
- Clinical remission: Vedolizumab superior (31.3% vs 22.5%)
- Endoscopic improvement: Vedolizumab superior (39.7% vs 27.7%)
- Corticosteroid-free remission: Similar
- Better safety profile with vedolizumab

MOTIVATE (Ongoing)

Comparing ustekinumab vs infliximab in CD

Design:

Randomized, multicenter
Biologic-naive patients
Primary endpoint: Clinical remission at week 52
Status: Results pending

SERENE-CD (2023)

Adalimumab high vs standard dose vs infliximab in CD
Design:
- Three-arm randomized trial
- Moderate-severe CD
Key findings:
- Similar efficacy between optimized adalimumab and infliximab
- Higher adalimumab dose improved outcomes

Singh et al. (2020) - UC Network Meta-analysis

Scope:
- 16 trials (Phase 2/3)
- 4,996 patients
- All approved biologics
Rankings for Induction:
- 1st: Infliximab + azathioprine
- 2nd: Infliximab
- 3rd: Vedolizumab
- 4th: Adalimumab
Maintenance Findings:
- Similar efficacy among agents
- Higher rates of adverse events with anti-TNFs

Hazlewood et al. (2015) - CD Network Meta-analysis

Methodology:
- 39 trials included
- Multiple treatment comparisons
Results:
- Best efficacy: Combination therapy (IFX + AZA)
- Monotherapy rankings:
  - Similar efficacy among anti-TNFs
  - Adalimumab slightly better for fistula
Safety Considerations:
- Serious infections similar
- Lymphoma risk with combination therapy

Burr et al. (2019) - Comparative Efficacy

Focus:
- All biologics and small molecules
- Included emerging therapies
Findings:
- Induction of remission:
  - Anti-TNFs most effective
  - Ustekinumab intermediate
  - Vedolizumab slower onset
- Maintenance:
  - Similar efficacy across classes
  - Better safety with newer agents

Infliximab Adverse Effects

Infliximab can cause serious adverse effects including infusion reactions, increased risk of infections (particularly tuberculosis), reactivation of hepatitis B, demyelinating disorders, heart failure exacerbation, malignancies, and development of anti-drug antibodies.

Serious Adverse Effects:

Infections

Serious infections
Tuberculosis reactivation
Opportunistic infections
Sepsis
Fungal infections (esp. histoplasmosis)

Malignancy

Lymphoma risk (especially in young patients)
Hepatosplenic T-cell lymphoma
Non-melanoma skin cancer
Melanoma

Immunologic

Lupus-like syndrome
Demyelinating disorders
Autoimmune hepatitis
Vasculitis

Cardiac

Heart failure exacerbation
New-onset heart failure
Arrhythmias

Common Adverse Effects:

Infusion Reactions

Acute: during/shortly after infusion
- Fever
- Chills
- Urticaria
- Dyspnea
- Chest pain
Delayed: days after infusion
- Myalgias
- Arthralgias
- Rash
- Fever

General

Upper respiratory infections
Headache
Fatigue
Nausea
Abdominal pain
Diarrhea

Laboratory Abnormalities:

Elevated liver enzymes
Neutropenia
Anti-nuclear antibodies
Anti-drug antibodies
Altered lipid profile

Pregnancy/Fetal Risk:

Category B
Crosses placenta
Third trimester concerns
Live vaccine restrictions in infants

Infliximab Monitoring

Regular monitoring of infliximab therapy includes screening for tuberculosis, hepatitis B, assessment of infliximab trough levels, anti-drug antibodies, complete blood count, liver function tests, and surveillance for infections and adverse effects.

MONITORING REQUIREMENTS:

Pre-treatment Screening:

Essential Tests:

Tuberculosis screening:
- Quantiferon Gold
- Chest X-ray
Hepatitis B serology
Full Blood Count
Liver function tests
Baseline inflammatory markers

Additional Considerations:

HIV testing
Pregnancy test if applicable
Vaccination status review
Cancer screening as appropriate

Target Levels:

Induction Phase:
Week 6: >20-30 μg/mL

Higher targets for:

Fistulizing disease
Acute severe colitis
Perianal disease

Maintenance Phase:

Trough levels: 3-7 μg/mL (IBD)
Higher targets (7-10 μg/mL) for:
- Perianal disease
- Deep ulcers
- Previous surgery

Monitoring Schedule:

Proactive Monitoring:

End of induction (week 14)
Every 6-12 months if stable
Before stopping therapy
After dose changes

Reactive Monitoring:

Loss of response
Partial response
Infusion reactions
Before restarting after holiday

Clinical Algorithms:

Low Levels (<3 μg/mL):

Without antibodies:
- Dose intensification
- Interval shortening
- Add immunomodulator
With antibodies:
- Switch within class
- Switch mechanism

Therapeutic Levels:

Good response: continue
Poor response:
- Switch mechanism
- Evaluate complications

Factors Affecting Levels:

Patient-related:

Body weight
Albumin
Disease severity
Inflammatory burden

Treatment-related:

Dosing interval
Immunomodulator use
Anti-drug antibodies

Infliximab Drug Interactions

Infliximab should not be co-administered with other TNF inhibitors due to increased infection risk, may reduce the effectiveness of live vaccines, and concomitant immunosuppressants can increase risk of infections while potentially reducing immunogenicity.

Live Vaccines - Critical Interaction

Mechanism: Compromised immune response + risk of vaccine-induced infection
- MMR (measles, mumps, rubella)
- Varicella
- Yellow fever
- Oral polio
- BCG
- Rotavirus
- Smallpox
Timing considerations:
- Wait 3-6 months after last infliximab dose before live vaccines
- Complete all needed live vaccines at least 4 weeks before starting infliximab
Inactivated vaccines are generally safe but may have reduced efficacy

Immunosuppressive Medications

a) Methotrexate:

Often co-prescribed intentionally
Benefits: Can reduce antibody formation against infliximab
Risks:
- Increased immunosuppression
- Higher infection risk
- Need for closer monitoring

Monitoring:
- CBC every 4-8 weeks
- Liver function tests
- Watch for opportunistic infections

b) Corticosteroids:

Increased risk of:
- Serious infections
- Opportunistic infections
- Tuberculosis reactivation
Recommendation: Use lowest effective dose
Extra monitoring needed for:
- Blood glucose
- Blood pressure
- Bone density

c) Azathioprine/6-mercaptopurine:

Similar to methotrexate interaction
Benefits: May improve efficacy
Risks:
- Increased immunosuppression
- Hepatotoxicity
- Bone marrow suppression
Need regular monitoring of:
- Complete blood count
- Liver function
- TPMT levels before initiation

Biologic Medications

Absolute contraindication with:
- Other TNF inhibitors (adalimumab, etanercept)
- IL-1 inhibitors (anakinra)
- IL-12/23 inhibitors (ustekinumab)
- JAK inhibitors (tofacitinib)
Risks:
- Severe infections
- Malignancy
- Autoimmune reactions

Antibiotics

No direct interactions
May need more frequent use due to infection risk
Monitor for:
- Opportunistic infections
- TB reactivation
- Fungal infections

Cardiovascular Medications

Warfarin:
- Monitor INR more frequently
- Watch for bleeding risk
Antihypertensives:
- No significant direct interaction
- Monitor BP regularly

Infliximab in Pregnancy

Infliximab is categorized as pregnancy category B, crosses the placenta after the first trimester, and is generally considered low-risk during pregnancy, though it should be discontinued in the third trimester to minimize neonatal immunosuppression.

Placental Transfer:

Active transport across placenta starting week 20
Highest transfer during third trimester
Detectable levels in infant up to 6-12 months after birth
Higher cord blood than maternal levels at delivery

Pregnancy Outcomes:

No significant increase in:
- Spontaneous abortion rates
- Congenital malformations
- Preterm delivery
- Low birth weight

Timing Considerations:

Pre-conception:

Generally safe to continue
Disease control important before conception
Individual risk-benefit assessment needed

During Pregnancy: First Trimester:

Limited placental transfer
Can continue if needed for disease control

Second Trimester:

Beginning of active transport
Consider risk/benefit of continuing

Third Trimester:

High placental transfer
Consider stopping around week 32-34 if disease stable
Continue if active disease requires control

In a post marketing study, 1850 maternally IFX-exposed pregnancies with known outcomes were identified

Of the 1850 pregnancies (mean age 29.7 years), 1526 (82.5%) resulted in live births. Crohn’s disease (67.7%)

ulcerative colitis (18.4%)

82.8% of live births were exposed to IFX in the first trimester.

Outcomes :

Spontaneous abortion/intrauterine death/ectopic pregnancy/molar pregnancy (12.1%),
preterm births (9.2%),
low birth weight infants (3.6%),
congenital anomalies (2.0%)
infant infections (1.2%)

Frequencies of congenital anomalies and other adverse outcomes were similar in women exposed to IFX in the first trimester and those exposed in the third trimester.

More preterm births (13–18.8%) and infant complications (8.7–12.5%) were reported with concomitant immunosuppressant use.

Ref : Geldhof, A., Slater, J., Clark, M. et al. Exposure to Infliximab During Pregnancy: Post-Marketing Experience. Drug Saf 43, 147–161 (2020). https://doi.org/10.1007/s40264-019-00881-8

Infliximab Reference

Meta-analyses:

Singh et al. Clinical Gastro Hepatol 2016

Network meta-analysis biologics
Comparative efficacy

Stidham et al. Gut 2014;63:935-45

Anti-TNF comparative effectiveness
Indirect comparison method

Real-world Cohorts:

TREAT Registry

Lichtenstein et al. Am J Gastro 2012;107:1409-22
Long-term safety data
Risk-benefit assessment

ENCORE Registry

European observational cohort
Real-world effectiveness

Recent Biosimilar Data:

NOR-SWITCH

Jørgensen et al. Lancet 2017;389:2304-16
Non-inferiority of CT-P13

PROSIT-BIO

Armuzzi et al. IBD 2019;25:568-75
Real-world biosimilar switch

ULCERATIVE COLITIS

Pivotal Trials:

ACT 1 & ACT 2

Rutgeerts et al. NEJM 2005;353:2462-76
Established efficacy in moderate-severe UC
5mg/kg at 0,2,6 then q8 weeks
Primary endpoints: clinical response week 8
ACT 1: 54 weeks
ACT 2: 30 weeks

ACCENT 1 (Maintenance)

Hanauer et al. Lancet 2002;359:1541-49
Established maintenance efficacy
Scheduled vs episodic therapy

SONIC (Combination Therapy)

Colombel et al. NEJM 2010;362:1383-95
IFX + AZA superior to monotherapy
Higher steroid-free remission
Better mucosal healing

CROHN'S DISEASE

Early Pivotal Studies:

Targan et al. NEJM 1997;337:1029-35

First RCT in CD
Single dose induction
Established clinical efficacy

Present et al. NEJM 1999;340:1398-1405

Fistulizing CD
Established efficacy in fistula closure

Long-term/Comparative:

ACCENT 2

Sands et al. NEJM 2004;350:876-85
Maintenance in fistulizing disease

COMMIT Trial

Feagan et al. Gastro 2014;146:681-88
IFX + MTX vs IFX alone

TDM Studies:

TAXIT

Vande Casteele et al. Gastro 2015;148:1320-29
Concentration-based dosing
Target trough levels

TAILORIX

D'Haens et al. Gastro 2018;154:1343-51
Intensive TDM-based dosing