Methotrexate | John Hunter Hospital

Methotrexate Pharmacodynamics

Methotrexate works through multiple molecular mechanisms to exert anti-inflammatory and immunomodulatory effects critical for IBD management, with inhibition of folate metabolism being central but not the only pathway involved.

Primary Mechanism of Action

Dihydrofolate reductase (DHFR) inhibition: Competitively inhibits conversion of dihydrofolate to tetrahydrofolate
Folate antagonism: Disrupts one-carbon transfer reactions essential for purine and pyrimidine synthesis
Thymidylate synthetase: Indirect inhibition reduces DNA synthesis
Cell cycle effects: Primarily affects S-phase (DNA synthesis phase) of cell cycle
Polyglutamated forms: Enhance intracellular retention and potency

Anti-inflammatory Mechanisms

Adenosine pathway: Increases extracellular adenosine release
Adenosine receptors: Activation of A2A and A3 adenosine receptors reduces inflammation
Cytokine inhibition: Reduces production of TNF-α, IL-1β, IL-6, IL-8, and IL-12
NFκB pathway: Inhibits activation of nuclear factor kappa B
JAK/STAT pathway: Modulates signaling through Janus kinase/signal transducer and activator of transcription
Apoptosis: Induces apoptosis in activated T cells

Cellular Effects

T-cell function: Inhibits T-cell activation and proliferation
B-cell function: Reduces antibody production
Neutrophils: Decreases chemotaxis and adhesion molecule expression
Monocytes/macrophages: Reduces cytokine production and phagocytic activity
Dendritic cells: Impairs antigen presentation
Endothelial cells: Decreases adhesion molecule expression

Molecular Targets

AICAR transformylase: Inhibition leads to increased AICAR, which increases adenosine release
S-adenosylmethionine-dependent transmethylations: Reduced methylation affects gene expression
Polyamines: Alters polyamine metabolism involved in cellular proliferation
Reactive oxygen species: Indirectly affects oxidative stress pathways
Leukotriene synthesis: Reduces production of inflammatory leukotrienes
Metalloproteinases: Decreases production and activity of matrix metalloproteinases

Dose-Response Relationship

Low doses (7.5-25 mg weekly): Primarily anti-inflammatory effects
Intermediate doses (>25-50 mg weekly): Combined anti-inflammatory and antiproliferative effects
High doses (>50 mg): Primarily cytotoxic effects, rarely used in IBD
Onset of action: 3-6 weeks for clinical improvement in IBD
Duration of effect: Sustained through weekly dosing due to polyglutamate retention
Threshold effect: Minimal effective dose typically 15 mg weekly in Crohn's disease

Methotrexate Pharmacokinetics

Methotrexate demonstrates complex absorption, distribution, metabolism and excretion properties that impact its clinical use in IBD, with parenteral administration providing more reliable drug levels than oral dosing.

Absorption

Oral bioavailability: 50-90% dose-dependent (decreases at doses >15 mg)
Parenteral routes (SC/IM): Nearly 100% bioavailability
Food: High-fat meals may delay absorption, but minimal effect on total absorption
First-pass metabolism: Minimal, but contributes to variable oral bioavailability
Saturable absorption: Oral absorption becomes saturable at higher doses

Distribution

Volume of distribution: 0.7-1.0 L/kg
Plasma protein binding: 50-70% (primarily to albumin)
Tissue distribution: Concentrates in liver, kidneys, and intestinal epithelium
Blood-brain barrier: Limited penetration at low doses
Synovial fluid: Achieves high concentrations in inflamed tissues
Third-spacing: Accumulates in pleural effusions and ascites

Metabolism

Hepatic metabolism: Limited (approximately 10%)
Major metabolite: 7-hydroxymethotrexate (less active than parent compound)
Polyglutamation: Intracellular conversion to polyglutamate forms
Polyglutamates: Retained inside cells for weeks to months
Enzyme systems: Not significantly metabolized by cytochrome P450 enzymes
First-pass effect: Minimal compared to other oral medications

Elimination

Primary route: Renal excretion (80-90% unchanged drug)
Secondary route: Biliary excretion (10-20%)
Elimination half-life: 3-10 hours for parent compound
Polyglutamate half-life: Days to weeks (contributes to prolonged effect)
Renal clearance: Filtration and active tubular secretion
Impact of renal impairment: Significant prolongation of half-life
Enterohepatic recirculation: Present, but limited clinical significance

Special Considerations

Renal impairment: Requires dose reduction (contraindicated in severe impairment)
Hepatic impairment: Requires cautious use due to risk of accumulation
Third-spacing conditions: Can alter distribution and elimination
Drug interactions: NSAIDs, penicillins, and probenecid can decrease elimination
Dosing schedule: Weekly administration based on half-life of polyglutamates
Therapeutic levels: Not routinely monitored in IBD practice

Methotrexate Pivotal Studies

The evidence base for methotrexate in IBD demonstrates clear efficacy in Crohn's disease while showing limited benefit in ulcerative colitis, with several landmark trials establishing its role in induction and maintenance therapy.

Crohn's Disease Induction Studies

Feagan et al. (1995, NEJM):

Design: Double-blind, placebo-controlled RCT
Population: 141 patients with chronically active, steroid-dependent Crohn's disease
Intervention: IM MTX 25 mg weekly vs placebo for 16 weeks
Primary outcome: Clinical remission without prednisone
Results: 39.4% MTX vs 19.1% placebo (p=0.025)
NNT: 5 for clinical remission

Oren et al. (1997):

Design: Double-blind RCT
Population: 84 patients with active Crohn's disease
Intervention: Oral MTX 12.5 mg weekly vs placebo for 9 months
Results: No significant difference in remission rates
Conclusion: Lower oral doses may be ineffective

METEOR Trial (Carbonnel et al., 2016):

Design: Double-blind RCT
Population: 199 patients with early Crohn's disease (<6 months)
Intervention: SC MTX 15 mg weekly + prednisolone vs placebo + prednisolone
Primary outcome: Steroid-free remission at week 12
Results: No significant benefit of MTX (30.6% vs 25.5%, p=0.64)
Conclusion: MTX may not be effective for very early disease

Crohn's Disease Maintenance Studies

Feagan et al. (2000, NEJM):

Design: Double-blind, placebo-controlled RCT
Population: 76 patients with Crohn's disease in remission after MTX induction
Intervention: IM MTX 15 mg weekly vs placebo for 40 weeks
Primary outcome: Maintenance of remission
Results: 65% MTX vs 39% placebo (p=0.04)
NNT: 4 for maintained remission

Lémann et al. (2000):

Design: Randomized, double-blind, multicenter trial
Population: 49 steroid-dependent Crohn's disease patients in remission
Intervention: Oral MTX 15 mg weekly vs placebo for 1 year
Results: No significant difference in relapse rates
Conclusion: Questions efficacy of oral MTX for maintenance

Combination Therapy Studies

COMMIT Trial (Feagan et al., 2014):

Design: Double-blind, placebo-controlled RCT
Population: 126 patients with active Crohn's disease
Intervention: Infliximab + MTX 10 mg weekly vs infliximab + placebo
Primary outcome: Time to treatment failure through 50 weeks
Results: No significant benefit of combination therapy (HR 0.78, p=0.34)
Secondary findings: Higher infliximab trough levels in combination group

Combination with Adalimumab (Matsumoto et al., 2016):

Design: Retrospective cohort study
Population: 68 patients with Crohn's disease on adalimumab
Intervention: Adalimumab + MTX vs adalimumab monotherapy
Results: Higher remission rates with combination therapy
Limitations: Non-randomized design, potential bias

Ulcerative Colitis Studies

METEOR UC Study (Carbonnel et al., 2015):

Design: Double-blind, placebo-controlled RCT
Population: 111 patients with steroid-dependent ulcerative colitis
Intervention: SC MTX 25 mg weekly vs placebo
Primary outcome: Steroid-free remission at week 16
Results: No significant difference (MTX 31.7% vs placebo 19.6%, p=0.15)
Conclusion: MTX not superior to placebo

MERIT-UC Trial (Herfarth et al., 2018):

Design: Double-blind, placebo-controlled RCT
Population: 84 patients with UC responding to MTX induction
Intervention: SC MTX 25 mg weekly vs placebo for maintenance
Primary outcome: Maintenance of clinical remission at week 48
Results: No significant difference (MTX 27.0% vs placebo 30.0%, p=0.86)
Conclusion: MTX ineffective for maintaining UC remission

Meta-analyses

McDonald et al. (2014, Cochrane Review):

Analysis: 7 studies in Crohn's disease
Conclusion: MTX effective for induction (RR 1.67) and maintenance (RR 1.67)
Quality of evidence: Moderate

Wang et al. (2015):

Analysis: 6 studies in ulcerative colitis
Conclusion: Limited evidence for efficacy in UC
Quality of evidence: Low

Chande et al. (2014, Cochrane Review):

Analysis: 3 studies in ulcerative colitis
Conclusion: Insufficient evidence to recommend MTX for UC
Quality of evidence: Low to moderate

Methotrexate Adverse Effects

Methotrexate has a well-characterized adverse effect profile that requires careful monitoring and proactive management, with gastrointestinal, hepatic, and hematologic toxicities being most common in IBD patients.

Gastrointestinal Adverse Effects

Nausea: 60-70% of patients (dose-dependent, typically within 24-48 hours of administration)
Vomiting: 15-25% (more common with oral administration)
Stomatitis/mucositis: 10-15% (oral ulcers, gingivitis)
Diarrhea: 10-20% (can be difficult to distinguish from IBD flare)
Anorexia: 20-30% (may contribute to weight loss)
Abdominal discomfort: 10-25% (nonspecific abdominal pain)
Dyspepsia: 15-20% (heartburn, indigestion)
Management strategies:
- Folic acid supplementation (1-5 mg daily, except day of MTX)
- Anti-emetics (ondansetron, metoclopramide) before MTX dose
- Switch from oral to parenteral administration
- Evening administration to allow sleep through side effects
- Split dosing (controversial, limited evidence)

Hepatotoxicity

Transient transaminitis: 50-70% (typically mild, self-limited)
Persistent liver enzyme elevation: 10-15%
Fatty liver disease: 5-10% (more common with long-term use)
Fibrosis: 1-5% (risk increases with cumulative dose)
Cirrhosis: <1% (rare with weekly low-dose regimens)
Risk factors:
- Alcohol consumption
- Obesity (BMI >30)
- Type 2 diabetes
- Pre-existing liver disease
- Daily (vs weekly) administration
- Cumulative dose >1.5-2 g
- Age >50 years
Monitoring recommendations:
- ALT/AST every 2-4 weeks initially, then every 1-3 months
- Fibroscan or other non-invasive fibrosis assessment annually if available
- Consider liver biopsy for persistent elevation >2x ULN despite dose reduction
- Psoriasis guidelines more stringent than IBD guidelines

Hematologic Toxicity

Leukopenia: 10-25% (typically mild, WBC >3000/mm³)
Thrombocytopenia: 5-10%
Anemia: 2-10% (macrocytic pattern)
Pancytopenia: <1% (rare but serious)
Risk factors:
- Renal impairment
- Advanced age
- Folate deficiency
- Drug interactions (TMP-SMX, NSAIDs)
- MTHFR gene polymorphisms
Monitoring:
- CBC with differential every 2-4 weeks initially, then every 1-3 months
- More frequent monitoring with dose changes or new medications
- Hold MTX if WBC <3000/mm³ or platelets <75,000/mm³

Pulmonary Toxicity

Acute pneumonitis: 0.3-0.7% (hypersensitivity reaction)
Chronic interstitial pneumonitis: <0.5%
Pulmonary fibrosis: Rare but serious
Risk factors:
- Pre-existing lung disease
- Diabetes mellitus
- Rheumatoid arthritis (higher risk than IBD)
- Advanced age
- Daily (vs weekly) administration
Clinical presentation:
- Dry cough, dyspnea, fever
- Hypoxemia, diffuse infiltrates on imaging
- Often occurs within first year of treatment
Management:
- Immediate discontinuation of MTX
- Corticosteroids for hypersensitivity pneumonitis
- Supportive care

Dermatologic Effects

Photosensitivity: 5-10%
Alopecia: 1-5% (typically mild, reversible)
Skin ulceration (reactivation of previous inflammatory sites): 1-3%
Acral erythema/palmar-plantar erythrodysesthesia: <1%
Skin hyperpigmentation: <1%
Radiation recall dermatitis: Rare

Renal Effects

Acute renal injury: Rare at low doses used in IBD
Crystalluria: Can occur with high doses or dehydration
Risk increased with:
- Pre-existing renal impairment
- Concurrent nephrotoxic medications
- Dehydration
- NSAIDs co-administration

Neurologic Effects

Headache: 10-15%
Fatigue/malaise: 20-40% (typically 24-48 hours post-dose)
Mood disturbances: 5-10% (irritability, depression)
Cognitive impairment ("MTX fog"): 5-10%
Dizziness/vertigo: 5-8%
Seizures: Extremely rare at IBD doses

Infectious Complications

Overall infection risk: Moderate increase (RR 1.3-1.5)
Common infections:
- Respiratory tract infections
- Herpes zoster reactivation
- Oral candidiasis
Opportunistic infections: Rare at IBD doses
Vaccination considerations:
- Live vaccines contraindicated
- Reduced response to some vaccines
- Annual influenza vaccination recommended
- Pneumococcal vaccination recommended

Miscellaneous Effects

Hyperuricemia: 5-10% (typically asymptomatic)
Osteoporosis: Controversial, limited evidence in IBD
Lymphoproliferative disorders: No clear increased risk at IBD doses
Fertility effects: Reversible oligospermia in men
Teratogenicity: Major concern (addressed in pregnancy section)

Strategies to Reduce Adverse Effects

Folic acid supplementation: 1-5 mg daily (except day of MTX)
Correct vitamin B12 deficiency if present
Parenteral administration for GI intolerance
Split dosing for some patients (limited evidence)
Dose reduction when possible while maintaining efficacy
Avoid alcohol consumption
Maintain adequate hydration
Avoid concurrent nephrotoxic drugs when possibl

Methotrexate Monitoring

Comprehensive laboratory and clinical monitoring is essential for methotrexate therapy in IBD to minimize toxicity risk while maintaining treatment efficacy, with monitoring frequency determined by individual risk factors and treatment duration.

Pre-treatment Assessment

Laboratory tests:

Complete blood count (CBC) with differential
Comprehensive metabolic panel (CMP) including:
- Liver function tests (ALT, AST, alkaline phosphatase, bilirubin)
- Renal function tests (creatinine, BUN, eGFR)
- Albumin
- Electrolytes
Hepatitis B serology (HBsAg, HBcAb, HBsAb)
Hepatitis C antibody
HIV testing (recommended but optional)
Varicella zoster virus (VZV) serology if unknown status
Pregnancy test for women of childbearing potential
Consider TPMT genotyping if concurrent thiopurine planned

Imaging and other tests:

Chest X-ray (baseline assessment)
Pulmonary function tests (if history of lung disease)
Tuberculosis screening (interferon-gamma release assay or PPD)
Fibroscan or other non-invasive liver fibrosis assessment (if available)
Consider MTHFR genetic testing in select cases

Risk assessment:

Alcohol consumption history
BMI calculation (obesity increases hepatotoxicity risk)
Diabetes screening
Medication review for potential interactions
Assessment of vaccination status

Initial Monitoring Phase (First 3 Months)

CBC, liver enzymes, creatinine:
- Every 2 weeks for first month
- Every 2-4 weeks for months 2-3
- More frequent if abnormalities detected
Clinical monitoring:
- Assessment for GI symptoms (nausea, vomiting, abdominal pain)
- Evaluation for mucositis/stomatitis
- Screening for respiratory symptoms
- Skin examination for rash or other dermatologic effects
Dose adjustment based on:
- Clinical response
- Laboratory abnormalities
- Side effect profile
- Weight changes

Maintenance Monitoring Phase

Laboratory monitoring frequency:
- Every 4-8 weeks for months 3-6
- Every 8-12 weeks thereafter if stable
- Return to more frequent monitoring with:
  - Dose changes
  - Addition of potentially interacting medications
  - Development of intercurrent illness
  - Abnormal results
Follow-up assessments:
- CBC with differential
- Liver function tests
- Renal function tests
- Clinical assessment for symptoms of toxicity
- Annual chest X-ray (controversial, practice varies)

Specific Monitoring Parameters

Hematologic monitoring:
- WBC <4,000/mm³: Increase monitoring frequency
- WBC <3,000/mm³: Consider dose reduction
- WBC <1,500/mm³: Hold medication and evaluate
- Platelets <100,000/mm³: Increase monitoring frequency
- Platelets <75,000/mm³: Consider dose reduction
- Platelets <50,000/mm³: Hold medication and evaluate
Hepatic monitoring:
- AST/ALT 1-2× ULN: Continue current dose with increased monitoring
- AST/ALT 2-3× ULN: Consider dose reduction by 25-50%
- AST/ALT >3× ULN: Hold medication until <2× ULN
- Persistent elevation: Consider liver biopsy or alternative therapy
- Monitoring thresholds may vary by guideline
Renal monitoring:
- 25% increase in creatinine: Increase monitoring frequency
- 50% increase in creatinine: Consider dose reduction
- eGFR <30 mL/min: Consider alternative therapy
- Dose adjustment for renal impairment:
  - eGFR 60-80 mL/min: No adjustment typically needed
  - eGFR 30-59 mL/min: 50% dose reduction
  - eGFR <30 mL/min: Avoid if possible

Special Monitoring Situations

Elderly patients (>65 years):
- More frequent monitoring (every 4-6 weeks long-term)
- Lower threshold for dose reduction
- Increased vigilance for drug interactions
Patients with risk factors:
- Obesity: More frequent liver monitoring
- Diabetes: More frequent liver and renal monitoring
- Alcohol use: More stringent liver monitoring
- Polypharmacy: Increased attention to drug interactions
Combination therapy:
- With biologics: Standard monitoring protocol
- With thiopurines: More vigilant hematologic monitoring
- With corticosteroids: Increased attention to infection risk

Therapeutic Drug Monitoring

Methotrexate levels:
- Not routinely recommended in IBD practice
- May be useful in cases of:
  - Suspected toxicity
  - Treatment failure despite adequate dosing
  - Concern for medication nonadherence
  - Significant renal impairment
Polyglutamate monitoring:
- Emerging area but not standard practice
- May predict response/toxicity better than serum levels
- Limited availability outside research settings

Long-term Monitoring Considerations

Cumulative dose monitoring:
- Document lifetime cumulative dose
- Consider fibroscan or other non-invasive fibrosis assessment annually after 1.5-2g cumulative dose
- Liver biopsy considerations:
  - No longer routinely recommended based on cumulative dose alone
  - Consider for persistent enzyme elevation or clinical concerns
Cancer screening:
- Age-appropriate cancer screening per general guidelines
- No additional cancer screening specifically required for MTX
Bone health:
- Consider DEXA scan if other risk factors for osteoporosis
- Not routinely indicated based on MTX use alone
Pulmonary assessment:
- Low threshold for evaluation of new respiratory symptoms
- Annual chest X-ray (controversial, not uniformly recommended)
- PFTs if baseline abnormal or new symptoms develop

Methotrexate Drug Interactions

Methotrexate interacts with numerous medications through various mechanisms that can increase toxicity or reduce efficacy, requiring careful consideration when prescribing for IBD patients.

Decreased Methotrexate Elimination

NSAIDs:

Reduce renal MTX clearance via competition for tubular secretion
Decrease protein binding, increasing free MTX concentration
Highest risk: ketoprofen, indomethacin, naproxen
Lower risk: selective COX-2 inhibitors
Greatest risk with high-dose MTX or chronic NSAID use

Penicillins:

Compete for renal tubular secretion
Amoxicillin, piperacillin, and benzylpenicillin show strongest effect
May increase MTX levels by 30-50%
Risk increases with high-dose or concurrent renal impairment

Probenecid:

Potent inhibitor of renal tubular secretion
Can increase MTX half-life by 50-100%
Contraindicated with MTX unless intentional rescue therapy

Salicylates (high-dose):

Displace MTX from protein binding
Compete for renal excretion
Low-dose aspirin (<100mg daily) typically acceptable

Proton Pump Inhibitors (PPIs):

Reduce renal elimination of MTX
Delay MTX clearance, particularly esomeprazole and pantoprazole
Effect more significant at higher MTX doses

Ciprofloxacin and other fluoroquinolones:

Inhibit renal tubular secretion
Increase MTX serum concentration
Higher risk with impaired renal function

Increased Methotrexate Absorption

Probiotics:

May increase intestinal absorption
Clinical significance uncertain
Consider monitoring if started concurrently

Bile acid sequestrants:

Cholestyramine and colestipol decrease absorption
Can be used therapeutically to enhance elimination after overdose
Separate administration by at least 4 hours

Altered Methotrexate Distribution

Highly protein-bound drugs:

Displace MTX from albumin binding
Examples: sulfonamides, phenytoin, tetracyclines
Increases free (active) MTX concentration

Retinoids:

Compete for plasma protein binding
Potential for increased free MTX fraction
Avoid concurrent use if possible

Pharmacodynamic Interactions

Increased Hematologic Toxicity

Trimethoprim-sulfamethoxazole (TMP-SMX):

Synergistic folate antagonism
Significantly increases risk of bone marrow suppression
Avoid concurrent use; if necessary, increase folate supplementation and monitoring

Pyrimethamine:

Additive antifolate effects
Dramatically increases risk of pancytopenia
Contraindicated combination

Sulfonamide antibiotics:

Additive folate antagonism
Increased risk of myelosuppression
Consider alternative antibiotics when possible

Azathioprine/6-Mercaptopurine:

Potential for additive myelosuppression
Combination used therapeutically but requires close monitoring
More frequent CBC monitoring recommended

Increased Hepatotoxicity

Alcohol:

Synergistic hepatotoxicity
Increases risk of fibrosis and elevated liver enzymes
Recommend abstinence or strict limitation

Leflunomide:

Additive hepatotoxicity
High risk for liver injury, contraindicated combination
Extended washout required if transitioning between therapies

Retinoids (acitretin, isotretinoin):

Combined hepatotoxic effects
Avoid concurrent use
If necessary, require more frequent liver function monitoring

Tetracyclines:

Increased risk of hepatotoxicity
Doxycycline shows stronger interaction than others
Consider alternative antibiotics in long-term therapy

Statins:

Potential additive hepatotoxicity
Monitor LFTs more frequently if co-administered
Pravastatin may have lower interaction potential

Increased Nephrotoxicity

Cyclosporine:

Bidirectional interaction (each increases levels of the other)
Significantly increases risk of nephrotoxicity
Requires dose adjustment and careful monitoring

Cisplatin and other nephrotoxic chemotherapy:

Additive nephrotoxicity
Reduced MTX clearance
Generally avoided in combination

Aminoglycoside antibiotics:

Combined nephrotoxic potential
Increased risk of acute kidney injury
Consider alternative antibiotics when possible

Reduced Efficacy

Folic acid (high dose):

Potentially reduces therapeutic efficacy if dosed inappropriately
Give 24-48 hours after MTX dose
Optimal dose: 1-5mg daily (except day of MTX)

Antibiotics affecting gut flora:

May reduce enterohepatic recirculation
Potential for reduced efficacy (theoretical)
Clinical significance uncertain

Specific Medication Classes

Biologics

Anti-TNF agents (infliximab, adalimumab, certolizumab):

Generally safe combination
May enhance efficacy in Crohn's disease
No significant PK/PD interactions
Monitor for increased infection risk

Anti-integrin therapies (vedolizumab):

No significant PK interactions
Safe to combine with appropriate monitoring
Limited data on efficacy of combination

Anti-IL-12/23 agents (ustekinumab):

No significant PK interactions
Limited data on combination therapy
Theoretical increased immunosuppression

Vaccines

Live vaccines:

Contraindicated during MTX therapy
Increased risk of vaccine-strain infection
Examples: MMR, varicella, yellow fever, oral typhoid
Wait at least 3 months after MTX discontinuation

Inactivated vaccines:

Safe to administer but may have reduced efficacy
Consider checking post-vaccination titers for critical vaccines
Schedule important vaccines before starting MTX when possible

Supplements and Herbals

Folate-containing supplements:
- May reduce MTX efficacy if taken concurrently
- Separate administration by 24-48 hours
St. John's Wort:
- Potential induction of hepatic metabolism
- May reduce MTX efficacy
- Discourage concurrent use
Echinacea:
- Potential hepatotoxicity when combined with MTX
- Discourage concurrent use
Fish oil (high dose):
- May affect platelet function
- Theoretical increased bleeding risk with MTX-induced thrombocytopenia
- Monitor if using high doses

Risk Management Strategies

Clinical Monitoring

Increase monitoring frequency when starting interacting medications
Check CBC and LFTs 1-2 weeks after adding high-risk medications
Lower threshold for dose adjustment with concurrent interacting drugs
Monitor renal function more frequently with nephrotoxic combinations

Practical Recommendations

Schedule MTX 24 hours away from interacting medications when possible
Consider temporary MTX dose reduction when adding high-risk medications
Increase folic acid dose when using other antifolate medications
Document review of medication interactions at each visit
Educate patients to report all new medications, including OTC and supplements

High-Risk Combinations to Avoid

MTX + probenecid
MTX + TMP-SMX
MTX + high-dose salicylates
MTX + leflunomide
MTX + pyrimethamine
MTX with significant alcohol intake
MTX + live vaccines

Laboratory Monitoring for Interactions

With NSAID combination: Monitor creatinine and MTX levels if available
With hepatotoxic medications: Monitor LFTs every 2-4 weeks initially
With myelosuppressive combinations: CBC weekly for first month
With nephrotoxic combinations: Monitor creatinine, electrolytes every 2 weeks initially

Methotrexate Use in Pregnancy

Methotrexate is strictly contraindicated during pregnancy and breastfeeding due to its well-established teratogenic effects, requiring careful planning for both men and women of reproductive potential who are considering therapy.

Teratogenic Effects

FDA pregnancy category: X (contraindicated)
Embryopathic effects:
- Neural tube defects
- Cranial dysplasia
- Hydrocephalus
- Microcephaly
- Limb abnormalities
- Cardiovascular defects
- Growth retardation
Risk periods:
- Highest risk: Weeks 6-8 of gestation (organogenesis)
- First trimester: Greatest risk for major malformations
- Second/third trimesters: Growth restriction, functional deficits
Miscarriage risk:
- Spontaneous abortion rate: 20-40% with exposure
- Higher than background population risk
Dose considerations:
- No truly "safe" dose established
- Risk present even at low weekly doses used in IBD

Preconception Planning - Women

Discontinuation timing:
- Minimum: 1 menstrual cycle (historically recommended)
- Current recommendation: 3-6 months before conception attempt
- Based on elimination of polyglutamate forms
Folic acid supplementation:
- High-dose (5 mg daily) during washout period
- Continue through pregnancy
Contraception requirements:
- Two effective forms recommended during treatment
- Continue for 6 months after discontinuation
- Document negative pregnancy test before initiation
Alternative IBD treatments:
- Transition to pregnancy-compatible treatments:
  - 5-ASA compounds (if effective)
  - Certain biologics (infliximab, adalimumab, certolizumab)
  - Consider pregnancy-compatible immunomodulators if necessary
- Plan transition 3-6 months before conception attempt
Documentation:
- Informed consent regarding teratogenic risks
- Documentation of contraception plan
- Pregnancy test results before and during therapy

Preconception Planning - Men

Spermatogenesis effects:
- Oligospermia (reversible)
- Potential for chromosomal damage to sperm
Discontinuation timing:
- Historical recommendation: 3 months before conception attempt
- Current evidence: Mixed, with some studies showing minimal risk
- Most conservative approach: 3-month washout
Contraception requirements:
- Effective contraception during treatment
- Continue for 3 months after discontinuation
Alternative treatments:
- As for women, transition to pregnancy-compatible treatments
- Consider sperm banking before treatment if future fertility desired
Documentation:
- Informed consent regarding potential effects on sperm
- Documentation of contraception plan

Accidental Exposure During Pregnancy

Immediate actions:
- Discontinue MTX immediately
- High-dose folic acid (5 mg daily)
- Urgent maternal-fetal medicine consultation
Risk assessment:
- Timing of exposure relative to gestation
- Duration of exposure
- Dose of exposure
Counseling:
- Detailed discussion of potential risks
- Options including continuation vs. termination
- Without value judgment or direction
Monitoring if pregnancy continued:
- High-resolution ultrasound
- Serial growth assessments
- Specialized fetal echocardiography
- Amniocentesis consideration
- Multidisciplinary approach with MFM specialist

Breastfeeding

MTX excretion in breast milk:
- Detectable levels in milk
- Milk ratio approximately 0.08
- Potential for accumulation in infant
Recommendations:
- Contraindicated during breastfeeding
- No "safe" minimal dose established
- Do not breastfeed while on MTX
- Wait at least 1 week after last dose before breastfeeding
Alternative options:
- Consider pump and discard until safe to resume
- Transition to breastfeeding-compatible medications if possible

Registry Data and Real-world Evidence

OTIS/MotherToBaby registry:
- Ongoing collection of exposure data
- Confirms significant risk with first-trimester exposure
European registry data:
- Confirms teratogenic risk
- Documents successful pregnancies after appropriate washout
Case reports:
- Numerous reports of malformations with exposure
- Few reports of normal outcomes despite exposure
- Publication bias may exist (adverse outcomes more likely reported)

Fertility Considerations

Effects on female fertility:
- Generally reversible after discontinuation
- Possible temporary effect on ovarian function
- No clear impact on long-term fertility at IBD doses
Effects on male fertility:
- Reversible oligospermia
- Recovery typically within 3 months of discontinuation
- No evidence of permanent fertility impairment at IBD doses
Fertility preservation options:
- Sperm banking for men before treatment
- No specific recommendations for women at IBD doses

Methotrexate General References

Upadacitinib exhibits dose-proportional pharmacokinetics with rapid absorption, high bioavailability, moderate protein binding, metabolism primarily via CYP3A4, and a half-life of approximately 9-14 hours allowing for once-daily dosing.

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