Pharm
Methotrexate
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Methotrexate
, Amethopterin, MTX, Methotrexate Toxicity
Pharmacology
Mechanism
Antimetabolite Chemotherapy
(Cell Cycle Specific)
S-Phase toxin (DNA synthesis phase)
Folic Acid
structural analog
Competitively inhibits at Dihydrofolate Reductase
Inhibits de novo
Pyrimidine
synthesis
Decreases
Tetrahydrofolate
production
Effects
Suppresses DNA synthesis (and cell division) in the
Gastrointestinal Tract
, skin and
Bone Marrow
Pharmacokinetics
Oral
Bioavailability
: 60%
Peak blood concentration: 1 to 3 hours
Half-Life
: 8 hours
Well tolerated dose cutoffs
Children <20 mg
Adults <60 mg
Indications
Ectopic Pregnancy
Psoriasis
Rheumatoid Arthritis
(
DMARD
)
Early
Rheumatoid Arthritis
Chronic Late
Rheumatoid Arthritis
Seronegative
Rheumatoid Arthritis
Cancer
Chemotherapy
Acute Myelocytic
Anemia
Head and Neck Cancer
Cervical Cancer
Breast Cancer
Testicular Cancer
Wilms Tumor
Sarcoma
Dosing
Co-administer
Folic Acid
1 mg orally daily (or 5-7 mg once weekly)
Reduces adverse effects (
Vomiting
,
Stomatitis
, hepatotoxicity)
Does not decrease Methotrexate efficacy
Rheumatoid Arthritis
Range: 7.5 - 20 mg/week PO, SQ, IM
Taken one day per week either in one dose or in a split dose, 12 hours apart
Split dosing may be better tolerated (fewer gastrointestinal side effects)
Consider
Parenteral
dosing if oral dosing is not tolerated
Have the patient choose a day of the week for the medication to be taken
Specify that day on the prescription (e.g. Monday)
Initial: 7.5 to 10 mg per week (e.g. 5 mg orally twice daily every Monday)
Lowest effective dose: 7.5 mg orally once daily every Monday AM
Titrate to target dose of at least 15 mg per week over a 4-6 week period
Average dose: 10 mg orally twice daily every Monday (20 mg/week)
Maximum dose: 12.5 mg orally twice daily every Monday (25 mg/week)
Cancer
Chemotherapy
Oral: 2.5 to 5 mg/day
Intrathecal: 10 mg weekly to biweekly
Efficacy
Rheumatoid Arthritis
Very effective (>85% initially)
Response in 4-6 weeks (faster than other
DMARDs
)
Curative in
Choriocarcinoma
Adverse Effects
Oral and Gastrointestinal (most common)
Nausea
or
Vomiting
Oral Ulcer
s
Stomatitis
Diarrhea
Hepatic
Hepatic Fibrosis
Elevated transaminases
Cirrhosis
Pulmonary
Pulmonary fibrosis or infiltrates
Hypersensitivity
Pneumonitis
Presents with dry cough, fever,
Dyspnea
on exertion
Stop Methotrexate and exclude infection
Start high dose
Corticosteroid
s
Consider gallium lung scan
Neuropsychiatric
Dysphoria
Hematologic
Minimal
Immunosuppression
Contrast with
Imuran
, Cytoxan,
Sandimmune
Myelosuppression
Thrombocytopenia
Cost
Very expensive (>$1000 per year)
Monitoring
Baseline screening
Complete Blood Count
with
Platelet Count
Recent
Chest XRay
Liver Function Test
s
Aspartate Aminotransferase
(AST)
Alanine Aminotransferase
(ALT)
Alkaline Phosphatase
Albumin
Consider
Hepatitis B
and
Hepatitis C
serologies
Renal Function
Tests
Creatinine
Follow-up Monitoring: (monthly x3, then every 8 weeks)
Complete Blood Count
with
Platelet Count
Liver Function Test
s
Aspartate Aminotransferase
(AST)
Alkaline Phosphatase
Renal Function
Tests
Creatinine
Liver
Biopsy Indications
Cumulative Methotrexate dose >8 gram
Prior heavy
Alcohol
use
Persistently elevated AST (
SGOT
) 2-3x normal
Psoriatic Arthritis
Contraindications
Absolute
Renal Insufficiency
(
Serum Creatinine
> 1.5)
Pleural Effusion
Ascites
Active
Stomatitis
Diarrhea
Infection
Contraindications
Relative (due to hepatotoxicity)
Alcohol
Use
Pre-existing liver disease
Diabetes Mellitus
Obesity
Age >70 years
Management
Toxicity or
Overdose
Consider
Activated Charcoal
if presents within first hours of ingestion and patient controlling airway
May require multiple doses of
Activated Charcoal
if
Renal Failure
is present
Background
Methotrexate
Overdose
is potentially lethal if not treated
Most common antineoplastic
Overdose
Toxicity occurs with repeated high doses, massive oral ingestions (>1000 mg) or
Renal Failure
Single large dose typically saturates absorption and is less likely to cause toxicity
Labs
See
Unknown Ingestion
Gene
ral approach including other toxicology studies (e.g.
Acetaminophen
level)
Serum Methotrexate level (repeat as needed when administering antidotes)
Comprehensive Panel and
Complete Blood Count
daily in massive ingestion
Optimize
Urine Output
Administer
Intravenous Fluid
s
Alkalinize the urine (IV bicarbonate) to prevent Methotrexate precipitation in renal tubules
Place 150 meq bicarbonate in each liter of fluid
Administer folinic acid or Leucovorin (Citrovorum factor, Leucovorin rescue)
Bypasses the Methotrexate induced blockade of dihydrofolate reductase
Dihydrofolate reductase is an enzyme that typically activate
Folate
Indicated if Methotrexate ingestion >1000 mg or
Renal Failure
Start with Leucovorin 40 mg orally, then
Leucovorin 10 mg/m2 IV over 15 min every 3 hours until Methotrexate level <0.01 umol/L
Glucarpidase
Glucarpidase is an enzyme that breaks down Methotrexate (as well as Leuocovorin)
Glucarpidase is expensive and not widely available
Indicated in intrathecal or massive intravenous dose
Other measures
Hemodialysis
may be indicated in significant
Acute Kidney Injury
Disposition
Observe and treat symptomatic exposures until Methotrexate level <0.01 umol/L
Asymptomatic exposures should be observed 6 hours before discharge
References
Mason and Vohra (2018) in EM:Rap 18(8): 13
Tomaszewski (2022) Crit Dec Emerg Med 36(7): 32
Drug Interactions
Agents that increase Methotrexate levels
Antibiotics (hold Methotrexate dose until antibiotic course completed)
Sulfa antibiotics (e.g.
Trimethoprim Sulfamethoxazole
)
Cephalosporin
s
Penicillin
s
Proton Pump Inhibitor
s
May decrease Methotrexate (and metabolite)
Renal Clearance
and result in toxic levels
Hold
Proton Pump Inhibitor
s for a few days before and after high dose Methotrexate infusions
Consider use of an
H2 Blocker
in place of a
Proton Pump Inhibitor
Exercise
caution in chronic lower dose Methotrexate with
Proton Pump Inhibitor
s
Risk of toxicity increases with concurrent
NSAID
s and
Aspirin
(also decrease methotrexate
Renal Clearance
)
Decrease Methotrexate dose if mild toxicity signs occur
Stop Methotrexate for severe toxicity (e.g.
Bone Marrow
toxicity)
References
(2012) Presc Lett 19(12): 72
References
(2014) Presc Lett 21(10): 56
Furst (1997) Br J Rheumatol 36:1196-204 [PubMed]
Jones (2000) Am Fam Physician 62(7):1607-14 [PubMed]
Matterson (2000) Mayo Clin Proc 75:669-74 [PubMed]
Pincus (1999) Clin Rheumatol 17(6 Suppl 18): S2-S124 [PubMed]
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