METHOTREXATE – FOR USE IN IBD
METHOTREXATE CLINICAL PROTOCOL
FOR INFLAMMATORY BOWEL DISEASE (IBD)
Approved by:
Designation
Consultant
Gastroenterologists
Name
Dr K Kapur
Signature
Dr A Soliman
Dr S Riyaz
Dr E Said
Dr K Mudhi
Chief Pharmacist
Mike V Smith
Lead Pharmacist
Gillian Smith
Specialist IBD
Pharmacist
Fernando Garcia
Fuertes
Written by: Fernando Garcia Fuertes, Specialist IBD Pharmacist Date: May 2014
Approved by Medicines Management Committee Date: July 2014
Review date: May 2018
Date
METHOTREXATE – FOR USE IN IBD
1. Aims
The aims of this protocol are:
- To ensure evidence based care is delivered to patients requiring methotrexate
according to BSG guideline and ECCO guideline.
- To monitor patients initiated on methotrexate, side effects profile, potential
complications and possible drug interactions with methotrexate.
- To support healthcare professionals involve by providing up-to-date guidance for
use of methotrexate.
2. Gastroenterolgist responsibilities
-
To assess the suitability of the patient for treatment
To initiate treatment
To perform baseline tests
To inform patient of side effects and long term monitoring required prior to
inititisiating treatment.
3. Responsibilities for the IBD Pharmacist, IBD Nurse or PIU Nurse
-
To counsel the patient on methotrexate
To initiate the administration of subcuteneous injection
To train patient to self-administer the injection subcutaneously
4. Drug monitoring and discharge by IBD Pharmacists
-
To monitor blood test on behalf of Gastroenterologist until drug stable
To supply methotrexate monitoring booklets once patient is ready to be
transferred to GP
5. Indications for use of Methotrexate in IBD
Methotrexate 25mg weekly (oral, subcutaneous or intramuscular injection –
unlicensed for use in IBD). (A. Dignass, 2010)
Methotrexate is generally reserved for treatment of active or relapsing Crohn’s
disease in those refractory to or intolerant of thiopurines. (AG., 2003)
The evidence base for efficacy of methotrexate in UC is restricted to observational
studies.
Note: Patients should be advised not to become pregnant or attempt to father a child
following 3 months following cessation of treatment.
6. Mechanism of action:
Currently, several pharmacological mechanisms of methotrexate action have been
suggested, including inhibition of purine and pyrimidine synthesis, suppression of
transmethylation reaction with accumulation of polyamines, reduction of antigenWritten by: Fernando Garcia Fuertes, Specialist IBD Pharmacist Date: May 2014
Approved by Medicines Management Committee Date: July 2014
Review date: May 2018
METHOTREXATE – FOR USE IN IBD
dependent T-cell profiferation, and promotion of adenosine release with adenosinemediated suppression of inflammation. (BN., 2005). It is possible that a combination
of these mechanisms is responsible for the antiinflammatory effects of methotrexate.
To date, the adenosine-mediated antiinflammatory effect of methotrexate is best
supported by the in vitro, in vivo, and clinical data.
Anti-inflammatory Effect of Methotrexate is Mediated by Adenosine:
Adenosine is an endogenous purine nucleoside that, following its release into the
extracellular space, binds to specific adensosine receptors expressed on the cell
surface. Adenosine is an important signaling molecule modulating a vast array of
physiological funtions. However, extensive evidence suports the hypothesis that
adenosine, acting on adenosine receptors, is a key mediatro of th antiinflammatory
effect of methotrexate.
7. Base line tests
-
Full Blood Counts (FBC)
Urea & Electrolytes (U&Es)
Liver Function Test (LFTs)
Peptide of type III procollagen (P3NP) assay. If it is raised discuss with
Gastroenterologist before starting treatment.
HBV and HCV screening
Chest Xray and pulmonary function test (if pre-existing lung disease)
eg. asthma, pulmonary fibrosis etc. (Consultant to confirm on referral form).
8. Contraindication (Medac, 2014)
-
Hypersensitivity to the active substance or to any of the excipients listed.
Severe liver impairment. Contraindicated if bilirubin values are >5 mg/dl (85.5
μmol/L).
Note: Methotrexate should be administered with great caution, if at all, to patients
with significant current or previous liver disease, especially when caused by
alcohol.
-
Alcohol abuse.
Severe renal impairment (Creatinine clearance less than 20 ml/min)
Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia,
thrombocytopenia, or significant anaemia.
Serious, acute or chronic infections such as tuberculosis and HIV.
Ulcers of the oral cavity and known active gastrointestinal ulcer disease.
-
-
Pregnancy: Methotrexate can cause foetal death, embryotoxicity, abortion or
teratogenic effects when administered to pregnant women. During pregnancy,
especially in the first trimester, cytotoxic drugs must only be given when strictly
indicated, weighing the needs of the mother against the risks to the foetus.
Treatment with methotrexate during the first trimester has resulted in a high risk
of malformations (in particular cranial malformation and malformation of the
extremities).
Breast-feeding: Methotrexate passes into breast milk in quantities such that there
is a risk to the child even at therapeutic doses. Breast feeding must therefore be
discontinued during treatment with methotrexate.
Written by: Fernando Garcia Fuertes, Specialist IBD Pharmacist Date: May 2014
Approved by Medicines Management Committee Date: July 2014
Review date: May 2018
METHOTREXATE – FOR USE IN IBD
-
Concurrent vaccination with live vaccines.
9. Dose
-
-
-
-
The standard induction dose is 25mg subcutaneously ONCE WEEKLY for 16
weeks.
Maintenance dose: 15mg orally ONCE WEEKLY thereafter.
Subcutaneous route is preferable than oral as it shows less changes in variability
in the drug absorption (Kurnik D, 2003)
Treatment should be started by subcutaneous route. A switch to oral
administration may be attempted for maintenance while carefully monitoring the
clinical response.
Subcutaneous route is as effective as intramuscular dosing.
Doses < 15mg/week are ineffective for active Crohn’s disease.
Feagan TRIAL study suggest that many patients who relapse while receiving lowdose maintenance therapy with methotrexate might ultimately be able to
discontinue prednisolone therapy if the dose of methotrexate is increased to
25mg weekly (Feagan B, 2000).
Note: Retreatment with higher dose of methotrexate (25mg), usually in
combination with prednisolone, induced remission in over half the patients who
had relapsed (Feagan B, 2000).
Gastrointestinal side effects from methotrexate can be limited by co-prescribing
folic acid 5mg daily except on the day of methotrexate.
10. Adverse Drug Reaction (Medac, 2014)
-
-
The most frequently reported undesirable effects
Ulcerative stomatitis
Leucopenia
Neutropenia
Trombocytopenia
Nausea and bloating
Lost of appetite
Other frequently reported undesirable effects are:
Headache
Drowsiness
Feeling unwell
Unusual tiredness
Flu-like symptoms
Chills and fever
Dizziness
Reduced resistance to infections
Diarrhoea (especially during the first 24-48 hours after administration of
methotrexate)
Skin rashes – urticaria / pruritis /flushing of the face
Joint pains / arthralgia
Written by: Fernando Garcia Fuertes, Specialist IBD Pharmacist Date: May 2014
Approved by Medicines Management Committee Date: July 2014
Review date: May 2018
METHOTREXATE – FOR USE IN IBD
-
Abdominal pain (pancreatitis)
Pulmonary complications such as pneumonitis followed by interstitial fibrosis. The
latter may be progressive.
-
Mild elevation in serum liver enzymes and, more importanly, with development of
chronic liver injury, progressive fibrosis, cirrhosis and portal hypertension.
Symptoms are usually absent until cirrhosis is present, and liver tests are tipically
normal or minimally and transiently elevated. Dose regimens (5 to 15mg in one
dose weekly with folate supplementation), fibrosis and clinically apparent liver
disease are rare even with long term use. The hepatic fibrosis and cirrhosis due
to methotrexate typically arise after 2 to 10 years of treatment and can present
with ascites, variceal hemorrhage or hepatosplenomegaly. (Medicine, 2014)
11. Folic Acid
Folic acid 5mg orally should be prescribed daily except on the day of methotrexate.
This helps reduce nausea and hepatotoxicity. (See PGD for folic acid).
12. Routine testing
U&E, FBC and LFTs:
Fortnightly for 2 months ( 0-2 months)
Monthly for 4 months
( 2-6 months)
Then 3 monthly
(if bloods are stable)
Peptide of type III procollagen (P3NP) assay for detection of liver fibrosis induced by
methotrexate (Chalmers RJ, (Chalmers RJ, 2005) (Maurice PD, 2005) first 6 month
since started therapy then every 12 moths.
13. Monitoring guidelines
This section is for guidance only. Each decision should be based on the situations own
merits, and discretion used at all times.
The patient should be referred back to the Gastroenterologists if:
Either
WCC < 3.7 x 109/L
or
9
Platelets < 150 x 10 /L or
Neutrophils <1.7 x 109/L
AST or ALT
> 3 times the upper limit
Patients with neutropenia on blood results and signs or symptoms of an infection will be
referred urgently to a Gastroenterologist, who will assess whether admission is
necessary.
Written by: Fernando Garcia Fuertes, Specialist IBD Pharmacist Date: May 2014
Approved by Medicines Management Committee Date: July 2014
Review date: May 2018
METHOTREXATE – FOR USE IN IBD
14. Treatments of overdose (NPIS, 2011)
a. Contact Gastroenterologist
b. Check full blood count, urea, electrolytes and liver function tests. The full blood
count may be normal initially but pancytopenia may develop over the next 7 - 12
days. Repeat blood tests at weekly intervals, if asymptomatic, for 4 weeks after
the overdose.
c. Measure the methotrexate concentration no earlier than 4 - 6 hours after last
ingestion. Discuss with the biochemistry laboratory.
i.
Give folinic acid rescue (leucovorin) without waiting for the result of a
methotrexate assay in those ingesting more than 3 mg/kg in less than 24
hours or those with reduced elimination (renal failure).
ii.
If the methotrexate concentration is unknown, give folinic acid 100 mg/m2
body surface area IV 6 hourly until the methotrexate concentration is
known.
iii.
If methotrexate concentration is known see table below for doses.
Methotrexate drug level
(Molar)
Folinic acid dose
More than 50 micromol/L (more
than 5 x 10-5M)
1000 mg/m2 6 hourly IV (give same dose 3 hourly if
the patient has renal impairment)
5 - 50 micromol/L (5 x 10-5M to 5
x 10-6M)
100 mg/m2 3 hourly IV
0.5 - 5 micromol/L (5 x 10-6M to
5 x 10-7M)
30 mg/m2 6 hourly IV/PO
Less than 0.5 micromol/L (less
than 5 x 10-7M)
10 mg/m2 6 hourly PO/IV
Continue treatment until methotrexate concentration is less than 5 x 10-8M (less than
0.05 micromol/L).
NB - Folic acid cannot be used as a substitute for folinic acid in patients with
methotrexate toxicity because the biological availability of folic acid depends
upon the action of dihydrofolate reductase, which is inhibited by methotrexate.
Folinic acid does not require activation by dihydrofolate reductase so its function
is not affected by the presence of methotrexate.
Written by: Fernando Garcia Fuertes, Specialist IBD Pharmacist Date: May 2014
Approved by Medicines Management Committee Date: July 2014
Review date: May 2018
METHOTREXATE – FOR USE IN IBD
15. Drug interactions (BNF, 2014)
Acetazolamide
Acitretin
Aspirin
Ciclosporin
Ciprofloxacin
Dexamethasone
Digoxin
Doxycycline
Leflunomide
NSAIDs
Neomycin
Penicillins
Phenytoin
Probenecid
Proton Pump
Inhibitors
Pyrimethamine
Sulfamethoxazole
Sulfonamides
Tetracycline
Theophylline
Trimethoprim
excretion of methotrexate increased by alkaline urine due to
acetazolamide
plasma concentration of methotrexate increased by acitretin (also
increased risk of hepatotoxicity)—avoid concomitant use
excretion of methotrexate reduced by aspirin (increased risk of
toxicity)
risk of toxicity when methotrexate given with ciclosporin
excretion of methotrexate possibly reduced by ciprofloxacin
(increased risk of toxicity)
possible increased risk of hepatoxicity when high-dose
methotrexate given with dexamethasone
methotrexate possibly reduces absorption of digoxin tablets
increased risk of methotrexate toxicity when given with doxycycline
risk of toxicity when methotrexate given with leflunomide
excretion of methotrexate probably reduced by NSAIDs (increased
risk of toxicity)—but for concomitant use in rheumatic disease
absorption of methotrexate possibly reduced by neomycin
excretion of methotrexate reduced by penicillins (increased risk of
toxicity)
antifolate effect of methotrexate increased by phenytoin
excretion of methotrexate reduced by probenecid (increased risk of
toxicity)
excretion of methotrexate possibly reduced by proton pump
inhibitors (increased risk of toxicity)
antifolate effect of methotrexate increased by pyrimethamine
increased risk of haematological toxicity when methotrexate given
with sulfamethoxazole (as co-trimoxazole)
increased risk of methotrexate toxicity when given with
sulfonamides
increased risk of methotrexate toxicity when given with tetracycline
methotrexate possibly increases plasma concentration of
theophylline
increased risk of haematological toxicity when methotrexate given
with trimethoprim (also with co-trimoxazole)
Written by: Fernando Garcia Fuertes, Specialist IBD Pharmacist Date: May 2014
Approved by Medicines Management Committee Date: July 2014
Review date: May 2018
METHOTREXATE – FOR USE IN IBD
16. Bibliography
A. Dignass, G. V. (2010). The second European evidence-based Consensus on the diagnosis and
management of Crohn's disease: current management (ECCO). Journal of Crohn's and Colitis,
28-62.
AG., F. (2003). Methotrexate : first or second-line immunomodulator? . European Journal
Gastroenterology and Hepatology, 15:225-31.
BN., C. (2005). Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis.
Pharmacology Review 57 (2), 163-72.
BNF. (2014, March). British National Formulary. Retrieved May 19, 2014, from Medicines Complete:
http://www.medicinescomplete.com/mc/bnf/current/bnf_int511-methotrexate.htm
Chalmers RJ, K. B. (2005). Replacement of routine liver biopsy by procollagen III aminopeptide for
monitoring patients with psoriasi receiving long-term methotrexate: a multicentre audit and
health economic analysis. . The British Journal of Dermatology, 152 (3):444-50.
Feagan B, F. R. (2000). A comparison of methotrexate with placebo for the maintenance of remission
in crohn's disease. The New England Journal of Medicine, 342; 22:1627-1632.
Kurnik D, L. R. (2003). Bioavailability of oral vs subutaneous low-dose methotrexate in patients with
Crohn's disease. Aliment Pharmacology Therapy, 18:57-63.
Maurice PD, M. A. (2005). Monitoring patients on methotrexate: hepatic fibrosis not seen in patients
with normal serum assays of aminoterminal peptide of type III procollagen. The British
Journal of Dermetalogy, 152(3):451-8.
Medac. (2014, 04 23). Medicines Compendium. Retrieved 05 19, 2014, from EMC:
https://www.medicines.org.uk/emc/medicine/22145/SPC/Metoject+50+mg+ml+solution+fo
r+injection/#PHARMACOKINETIC_PROPS
Medicine, U. N. (2014, 5 7). Livertox NIDDK. Retrieved 5 25, 2014, from Livertox:
http://livertox.nlm.nih.gov/Methotrexate.htm
NPIS, U. (2011, 11). TOXBASE. Retrieved 05 19, 2014, from TOXBASE:
http://www.toxbase.org/Poisons-Index-A-Z/M-Products/Methotrexate/
Written by: Fernando Garcia Fuertes, Specialist IBD Pharmacist Date: May 2014
Approved by Medicines Management Committee Date: July 2014
Review date: May 2018