methotrexate (Rheumatrex, MTX)

Indications

• treatment of malignancies
  • breast cancer
  • head & neck cancer
  • bladder cancer bladder
  • acute lymphoblastic leukemia
    • including intrathecal methotrexate for meningeal leukemia
  • lymphomas (Hodgkin's disease & non-Hodgkin's lymphoma)
  • osteogenic sarcoma
  • gestational trophoblastic carcinoma
• treatment of autoimmune disease
  • rheumatoid arthritis {improves long-term survival}
  • psoriasis & psoriatic arthritis
  • Reiter's syndrome
  • polymyositis, dermatomyositis
  • systemic lupus erythematosus
  • Wegener's granulomatosis
  • vasculitis
• treatment of tubal ectopic pregnancy

Contraindications

• severe renal insufficiency
• severe hepatic impairment
• severe bone marrow suppression
• preganacy or lactation
  • discontinue 3 months prior to conception
• regular alcohol consumption

* abortifacient

* discontinue >= 3 months prior to pregnancy

pregnancy category = x

safety in lactation = -

Dosage

• solid tumors: 20-40 mg/m2 IV/PO every 1-3 weeks
• leukemias: 200-500 mg/m2 IV every 2-4 weeks
• intrathecal 10-15 mg liquid preserve free, 2-4 mL volume
• rheumatoid arthritis:
  • start 7.5 mg PO/IM/SC weekly
  • max 50 mg weekly
  • ideal dose is as high as 25 mg/week, assuming normal renal function
  • adjunctive therapy with folic acid 1 mg QD
  • subcutaneous methotrexate is more effective than once-weekly oral dosing & should be tried before resorting to a biologic agent
• psoriasis: 12.5-50 mg IM/PO weekly-monthly
• tubal ectopic pregnancy: 50 mg/m2 IM single dose

Injection: 25 & 50 mg/mL (2 mL, 10 mL).

Powder for injection: 20 mg, 1000 mg.

SC syringe 2.5-3 mL, needle 25 g, 5/8 inch (VA)

IM syringe 2.5-3 mL, needle 22 g, 1.5 inch (VA)

Tabs: 2.5 mg.

Pharmacokinetics

• dose-dependent oral absorption
  • impaired absorption with oral doses > 15 mg
• well distributed to body water
• undergoes polyglutamation in cell,
  • product inhibits AICAR transformylase of purine synthesis
  • results in increased release of adenosine
• 10% metabolized to a potentially nephrotoxic metabolite
• 90% eliminated in the urine
• elimination 1/2life is 3 hours
• onset of action is 3-6 weeks {RA}

elimination via kidney

elimination via liver

1/2life = 8-15 hours

protein binding = 65 %

elimination by hemodialysis = +

elimination by hemoperfusion = +

elimination by peritoneal dialysis = -

Monitor

• CBC, serum creatinine, LFT's
  • baseline & monthly for 1st 3 months after initating or increasing dose
  • then every 3 months
  • use with leflunomide requires monthly serum AST, serum ALT, serum albumin
  • hold for serum ALT, serum AST 2x upper limit of normal
• baseline chest x-ray
• liver biopsy after 1.5-2 or 3-4 grams (cumulative); not done much at VAMC
• SLCO1B1 genotyping
  • allelic SNP variants associated with SLCO1B1 are associated with GI toxicity

Adverse effects

• stomatitis (2%)
• elevated serum transaminases (24%)
• hepatic cirrhosis (liver biopsy recommended at cumulative doses > 1.5-2 grams, 3-4 grams on another account)
• myelosuppression, leukopenia (7%), macrocytic anemia
• opportunistic infection (10%)
• pneumonitis (3-7%, < 5%)
  • most serious complication
    • increased risk of death due to lung disease (RR 1.53)
  • may follow upper respiratory tract infection
  • no clear dose-response relationship
  • chest X-ray: diffuse reticular & ground-glass opacities
  • prognosis generally good after stopping methotrexate
  • glucocorticoids may be of benefit
• gastrointestinal intolerance
  • nausea, mild (< 100 mg)
  • diarrhea
• teratogenic & may cause permanent sterility
  • discontinue 3 months prior to conception
• acute renal failure
  • precipitates in renal tubules (hyperuricemia)
  • alkaline diuresis may be helpful
• skin disorders
  • pruritus, skin desquamation, erythema, vasculitis, alopecia, depigmentation or hyperpigmentation, photosensitivity
  • methotrexate increases frequency of rheumatoid nodules & may lead to occurrence of nodules at unusual places such as fingertip pads
  • hand & foot syndrome
  • skin cancer
• conjunctivitis
• cystitis
• arthralgia
• CNS toxicity:
  • encephalopathy
  • seizures
  • fever/chills
  • dizziness
• CNS toxicity with intrathecal administration:
  • arachnoiditis
  • subacute toxicity
  • demyelinating encephalopathy (months to years later)
• has been associated with rapid progression of HIV1 infection
• low dose (up to 20 mg weekly) 2.2% vs 1.1% for placebo
  • gastrointestinal distress, pulmonary complications, infections
  • hematologic adverse events
  • skin cancer
  • osteoporotic fractures of the distal tibia
• more adverse effects in patients with psoriatic arthritis than rheumatoid arthritis
• folic acid deficiency: ensure compliance

*Toxicity: glucarpidase (Voraxaze) FDA-approved for treatment of methotrexate toxicity due to renal failure

* adverse effects including alopecia, myelosuppression, liver-function test abnormalities, & gastrointestinal symptoms may be responsive to folic acid

Drug interactions

• leucovorin
  • antagonizes early effects of methotrexate
  • used as rescue
• Septra/Bactrim & other trimethoprim-containing agents increase risk of myelosuppression
• NSAIDs & probenecid increase methotrexate serum levels & toxicity
• alcohol in combination may increase risk of hepatic injury
  • 1 drink (14 g of ethanol)/day does not appear to increase serum transaminases
  • > 1 drink/day increases risk of alcholic hepatitis
• cholesterol binding resins & fiber decrease absorption of methotrexate
• live virus vaccines
• pyrimethamine
• phenytoin
• 5-fluorouracil
• caffeine may reduce effectiveness of methotrexate

• drug interaction(s) of methotrexate with influenza virus vaccine
• drug interaction(s) of methotrexate with biological response modifier
• drug interaction(s) of methotrexate with proton pump inhibitors
• drug interaction(s) of methotrexate with caffeine

Test interactions

increases serum K+

Laboratory

• specimen:
  • serum, plasma (heparin, EDTA)
  • cerebrospinal fluid (CSF)
  • centrifuge & remove cells as soon as possible
  • stable at 4 degrees for 24 hours
  • stable at -20 degrees for 1 month
  • collect specimen at 30 minutes after low dose IV
  • collect specimen at 2 hours after low dose oral
  • collect specimen at 24, 48 & 72 after high dose IV
  • protect from light
• methods: HPLC, RIA, REA, enzyme inhibition, EIA, FPIA
• interferences:
  • RIA: hyperbilirubinemia, lipemia, methemoglobinemia, & methotrexate metabolites may interfere
• labs with Loincs
  • methotrexate in erythrocytes
  • methotrexate in body fluid
    • methotrexate in serum/plasma
      • methotrexate free in serum/plasma
    • methotrexate in CSF
    • methotrexate in urine

Mechanism of action

• folic acid analog
• binds to dihydrofolate reductase inhibiting thymidine formation
• diminishes inflammation by increasing adenosine levels
  • increases release of adenosine from cells
• may also diminish inflammation by inhibition of polyamines
• high activity during S phase 6 Mechanism of drug resistance:
  • defective transport via folate transporter
  • decreased activity of folyl-polyglutamate synthetase
  • increased activity of target enzyme dihydrofolate reductase

More general terms

• aminopterin
• folate antagonist; folic acid analog; folic acid antagonist
• disease-modifying antirheumatic agent (DMARD)

Additional terms

• dihydrofolate reductase (DHFR, tetrahydrofolate dehydrogenase)
• folate transporter
• folylpolyglutamate synthase, mitochondrial; folylpoly-gamma-glutamate synthetase; FPGS; tetrahydrofolylpolyglutamate synthase; tetrahydrofolate synthase (FPGS)
• methotrexate in serum/plasma

Component of

• cyclophosphamide/methotrexate/5-fluorouracil (CMF)

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=126941
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=72440
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4112
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=61796