Tofacitinib

PBS Codes

Patient Information

Tofacitinib Drug Information

Pharmacodynamics

Adverse Effects and Monitoring

Tofacitinib Pharmacodynamics

Tofacitinib selectively inhibits Janus kinase (JAK) enzymes, particularly JAK1 and JAK3, thereby blocking cytokine signaling and downregulating inflammatory pathways implicated in autoimmune conditions.

Core Mechanism:

JAK Inhibition

Tofacitinib is a small molecule JAK inhibitor
Primarily inhibits JAK1 and JAK3, with less activity against JAK2
Blocks intracellular signaling of multiple cytokines including:
- IL-2, IL-4, IL-6, IL-7, IL-9, IL-15, IL-21
- Type I and II interferons

Key Effects in IBD:

Immune Cell Regulation

Reduces T cell proliferation and activation
Decreases production of proinflammatory cytokines
Impacts both innate and adaptive immune responses

2. Mucosal Healing

Promotes intestinal barrier repair
Reduces epithelial cell apoptosis
Enhances mucosal healing through decreased inflammation

3. Clinical Impact

Rapid onset of action (within 2-4 weeks)
Reduces disease activity scores
Improves endoscopic appearance of mucosa
Achieves clinical remission in many patients

Cellular Effects:

T Cells

Decreases Th1 and Th17 cell activity
Reduces production of inflammatory cytokines
Impacts T cell differentiation and survival

B Cells

Reduces B cell activation and proliferation
Decreases antibody production
Impacts B cell development

Innate Immune Cells

Reduces neutrophil recruitment
Decreases macrophage activation
Impacts dendritic cell function

Tofacitinib Pharmacokinetics

Tofacitinib exhibits rapid oral absorption with 74% bioavailability, reaches peak plasma levels within 0.5-1 hours, is metabolized primarily via CYP3A4, and has a half-life of approximately 3 hours with elimination occurring mainly through renal excretion.

Absorption:

Oral Bioavailability

~74% bioavailability
Rapid absorption (Tmax ~0.5-1 hour)
Food does not significantly affect absorption
Peak plasma concentrations achieved within 24-48 hours of starting therapy

Formulation

Available as immediate-release tablets
Standard dosing: 5mg or 10mg BID for IBD
Extended-release formulation exists but not typically used in IBD

Distribution:

Volume of Distribution

~87L at steady state
~70% bound to plasma proteins
Distributes well into tissues
Crosses blood-brain barrier minimally

Metabolism:

Primary Pathways

~70% hepatic metabolism
CYP3A4 is primary metabolizing enzyme
CYP2C19 plays minor role
Produces multiple metabolites, most inactive

Drug Interactions

Strong CYP3A4 inhibitors increase exposure
Dose adjustment needed with:
- Ketoconazole
- Other strong CYP3A4 inhibitors
- Combined CYP3A4/CYP2C19 inhibitors

Elimination:

Half-life

Terminal t½ ~3 hours
Steady state reached within 24-48 hours
No significant accumulation with BID dosing

Excretion Routes

~30% renal excretion (unchanged drug)
~70% hepatic metabolism and biliary excretion
Small amount in feces as unchanged drug

Special Populations:

Renal Impairment

Mild: No dose adjustment needed
Moderate: Consider dose reduction
Severe: Use with caution, reduced dose recommended

Hepatic Impairment

Mild (Child-Pugh A): No adjustment needed
Moderate (Child-Pugh B): Dose reduction recommended
Severe: Not recommended

Other Considerations

Age and gender: No significant impact
Body weight: Minor impact on exposure
Race: No clinically significant differences

Tofacitinib Pivotal Studies

Tofacitinib demonstrated efficacy in ulcerative colitis in the OCTAVE Induction 1 and 2 trials and OCTAVE Sustain maintenance study, showing significantly higher rates of clinical remission and mucosal healing compared to placebo, though its efficacy in Crohn's disease has been less compelling in clinical trials.

ULCERATIVE COLITIS

OCTAVE Program:

OCTAVE Induction 1 & 2:

Sandborn WJ et al. NEJM 2017;376:1723-36
Design: Two identical Phase 3 RCTs
Dose: 10mg BID induction
Primary endpoint: Remission at week 8
Key findings:
- Remission rates: 18.5% vs 8.2% (placebo)
- Mucosal healing: 31.3% vs 15.6%

OCTAVE Sustain:

Same NEJM publication
52-week maintenance
Doses: 5mg or 10mg BID
Results:
- Remission (5mg): 34.3%
- Remission (10mg): 40.6%
- Placebo: 11.1%

OCTAVE Open (Extension):

Sandborn WJ et al. Aliment Pharmacol Ther 2019;50:435-47
Long-term safety/efficacy
Up to 3 years follow-up

POST-MARKETING/SAFETY

Safety Analysis:

Cohen SB et al. RMD Open 2020;6:e001395
Integrated safety analysis
Identified key risks:
- VTE
- Herpes zoster
- Malignancy

RIVETING Study:

Real-world effectiveness
Post-marketing surveillance
Clinical practice outcomes

SPECIFIC POPULATIONS

Bio-naive vs Bio-experienced:

Subgroup analyses from OCTAVE
Different response rates
Predictive factors

Asian Population:

Motoya S et al. J Gastroenterol 2018;53:1024-35
Specific subgroup analysis
Similar efficacy/safety

META-ANALYSES

Singh S et al. Clin Gastro Hepatol 2020

Network meta-analysis
Comparative efficacy
Treatment positioning

Regulatory Reviews:

FDA Advisory Committee
EMA Assessment Report
Post-marketing requirements

KEY FINDINGS

Efficacy:

Rapid onset of action
Oral administration advantage
Effective in bio-experienced
Similar rates bio-naive/experienced

Safety Considerations:

VTE risk (FDA boxed warning)
Herpes zoster risk
Lipid monitoring
Laboratory monitoring requirements

Tofacitinib Adverse Effects and Monitoring

Tofacitinib's adverse effects include increased risk of serious infections, herpes zoster, venous thromboembolism, major adverse cardiovascular events, malignancies (particularly lymphoma), gastrointestinal perforations, elevated lipid levels, and liver enzyme abnormalities.

MAJOR SAFETY CONCERNS

Thromboembolic Risk:

Increased VTE/PE risk
Higher with 10mg BID
Risk factors:
- Age >50, Prior VTE, Obesity, Smoking, OCPs/HRT

Infections:

Serious Infections:

Bacterial pneumonia
UTIs
Cellulitis
Sepsis risk

Opportunistic:

Herpes zoster (key risk)
TB reactivation
Fungal infections
PJP pneumonia

Viral:

HSV reactivation
CMV reactivation
EBV monitoring
Hepatitis B reactivation

LABORATORY ABNORMALITIES

Hematologic:

Lymphopenia
Neutropenia
Anemia
ALC monitoring thresholds

Metabolic:

Lipid elevation
LDL/HDL changes
Triglycerides
Monitoring frequency
CPK elevation

Hepatic:

Transaminitis
Drug-induced liver injury
Monitoring frequency

MONITORING PROTOCOL

Pre-treatment:

Screening:

FBC/CMP, Lipid panel
TB testing (QFT/PPD)
Hepatitis B/C, HIV
VZV serology
Pregnancy test

Vaccinations:

Zoster vaccine
Pneumococcal
Influenza
COVID-19
Update all inactive vaccines

Ongoing Monitoring:

First 3 months:

FBC/CMP monthly
Lipids at 4-8 weeks
TB risk assessment
Infection surveillance

Maintenance:

CBC/CMP q3months
Lipids q6months
Annual TB screening
Skin cancer screening

DOSE MODIFICATIONS

Laboratory Thresholds:

ALC <500: Interrupt
ANC <1000: Interrupt
Hb decrease >2g: Interrupt
LFT >3x ULN: Modify

Tofacitinib Drug Interactions

Tofacitinib exposure is significantly increased when co-administered with strong CYP3A4 inhibitors (ketoconazole) or when used with other CYP3A4 substrates, requiring dose adjustment, while its immunosuppressive effects can be enhanced when combined with biologics, corticosteroids, or other immunosuppressants, increasing infection risk.

MAJOR INTERACTION CATEGORIES

CYP3A4 Inhibitors:

Strong Inhibitors (Avoid/Reduce dose):

Ketoconazole
Itraconazole
Clarithromycin
Ritonavir
Grapefruit juice

Moderate Inhibitors (Caution):

Fluconazole
Erythromycin
Diltiazem
Verapamil

CYP2C19 Interactions:

Omeprazole
Esomeprazole
Cimetidine

IMMUNOSUPPRESSIVE INTERACTIONS

Biologics (Contraindicated):

Anti-TNF agents
Vedolizumab
Ustekinumab
IL-12/23 inhibitors

Other Immunosuppressants:

Avoid combination with:
- Azathioprine
- 6-MP
- Methotrexate
- Cyclosporine
- Tacrolimus

COMMON IBD MEDICATIONS

Safe Combinations:

5-ASA compounds
Topical steroids
Antibiotics (most)
Probiotics
Antidiarrheals

Requiring Monitoring:

Corticosteroids:

Increased infection risk
Careful tapering
VTE risk assessment

Iron supplements:

Spacing administration
Absorption effects

CARDIOVASCULAR MEDICATIONS

Antithrombotics:

Warfarin monitoring
DOAC interactions
Antiplatelet agents
VTE prophylaxis

Antihypertensives:

Generally safe
Monitor BP
CCB interactions noted above

Lab Monitoring:

Enhanced when using:
CYP inhibitors
Multiple immunosuppressants
High-risk combinations

Clinical Monitoring:

Infection signs
Therapeutic efficacy
Adverse effects
Drug levels when applicable

Tofacitinib Use in Pregnancy

Tofacitinib is not recommended during pregnancy due to limited human data, with animal studies showing reproductive toxicity, and should be used only if potential benefits outweigh risks, with adequate contraception advised during treatment and for at least 4 weeks after discontinuation.

PREGNANCY CATEGORIZATION

FDA Pregnancy Category: C
EMA: Contraindicated
Australian Category: D
Recommendation: Avoid in pregnancy

PRECONCEPTION COUNSELING

For Women:

Planning:

Stop tofacitinib 8-12 weeks before conception
Switch to pregnancy-compatible therapy
Consider alternative IBD treatments:
- Certolizumab
- Infliximab
- Adalimumab

Contraception:

Required during treatment
Continue 4-8 weeks after stopping
Reliable method needed
Consider drug interactions

For Men:

Limited data on sperm effects
No clear contraindication
Can continue during partner's pregnancy
Monitor partner's pregnancy outcomes

PREGNANCY REGISTRY DATA

Pregnancy Outcomes:

OCTAVE data limited
Rheumatology registry data:
- Spontaneous abortions
- Congenital anomalies
- Live birth rates

Tofacitinib Pregnancy Registry:

Ongoing collection
Voluntary reporting
Limited numbers currently
Need for more data

ACCIDENTAL EXPOSURE

First Trimester:

Stop medication immediately
Document exposure timing
Enhanced monitoring
Fetal assessment

Management:

Risk assessment
Alternative therapy initiation
Close monitoring
Detailed documentation

Tofacitinib General References

PIVOTAL CLINICAL TRIALS

OCTAVE Program:

Primary Publication:

Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2017;376(18):1723-1736.

Long-term Extension:

Sandborn WJ, Panés J, D'Haens GR, et al. Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of Data From Global Clinical Trials. Clin Gastroenterol Hepatol. 2019;17(8):1541-1550.

SAFETY/ADVERSE EVENTS

Integrated Safety Analysis:

Cohen SB, Tanaka Y, Mariette X, et al. Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis. RMD Open. 2020;6(3):e001395.

Specific Safety Concerns:

Mahadevan U, Dubinsky MC, Su C, et al. Outcomes of Pregnancies With Maternal/Paternal Exposure in the Tofacitinib Safety Databases for Ulcerative Colitis. Inflamm Bowel Dis. 2018;24(12):2494-2500.

REAL-WORLD EVIDENCE

Clinical Practice:

Weisshof R, Aharoni Golan M, Sossenheimer PH, et al. Real-World Experience with Tofacitinib in IBD at a Tertiary Center. Dig Dis Sci. 2019;64(7):1945-1951.

Post-marketing:

Paschou S, Albarran YCA, et al. Tofacitinib for the treatment of ulcerative colitis: an update on the clinical evidence. Ther Adv Gastroenterol. 2022;15:17562848221075259.

META-ANALYSES

Comparative Efficacy:

Singh S, Murad MH, Fumery M, et al. First- and Second-line Pharmacotherapies for Patients With Moderate to Severely Active Ulcerative Colitis: An Updated Network Meta-analysis. Clin Gastroenterol Hepatol. 2020;18(10):2179-2191.

Safety Review:

Olivera PA, Lasa JS, Bonovas S, et al. Safety of Janus Kinase Inhibitors in Patients With Inflammatory Bowel Diseases or Other Immune-mediated Diseases: A Systematic Review and Meta-Analysis. Gastroenterology. 2020;158(6):1554-1573.

SPECIFIC POPULATIONS

Asian Population:

Motoya S, Watanabe M, Kim HJ, et al. Tofacitinib induction and maintenance therapy in East Asian patients with active ulcerative colitis: subgroup analyses from three phase 3 multinational studies. Intest Res. 2018;16(2):233-245.

Elderly Patients:

Curtis JR, Schulze-Koops H, Takiya L, et al. Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis. Clin Exp Rheumatol. 2017;35(3):390-400.

GUIDELINES/CONSENSUS

ACG Guidelines:

Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol. 2019;114(3):384-413.

ECCO Guidelines:

Raine T, Bonovas S, Burisch J, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohns Colitis. 2022;16(1):2-17.