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Managing A Side Effect
Acute Methotrexate Toxicity
Bhushan Madke, Adarsh Lata Singh
Department of Dermatology, Venereology and Leprosy, Jawaharlal Nehru Medical College, AVBR Hospital, Wardha, Maharashtra,
India
Address for correspondence: Department of Dermatology, Venereology and Leprosy, Jawaharlal Nehru Medical College and AVBR Hospital,
Sawangi, Wardha - 442 001, India. E-mail: drbhushan81@gmail.com
ETIOPATHOGENESIS
Methotrexate (MTX) inhibits mitosis of the cells by
antagonizing folic acid required for deoxyribonucleic acid
(DNA) synthesis of cells. Once in the cell, MTX inhibits
dihydrofolate (DHF) reductase, an enzyme responsible
for the conversion of DHF to tetrahydrofolate (THF).
Consequently, there is a reduction in thymidylate and purine
biosynthesis. DNA synthesis eventually halts and cells can
no longer divide. Polyglutamination of MTX prolongs its
intracellular presence. Hence, cells with the capability of
effective polyglutamination such as leukemic myeloblasts,
synovial macrophages, lymphoblasts, and epithelia are
more susceptible to the action of MTX.[1] Acute MTX
toxicity presents as pancytopenia, gastrointestinal (GI)
mucositis, hepatotoxicity, pulmonary toxicity, and acute
renal failure.[2,3]
The most common cause of acute MTX toxicity is an
accidental overdose of MTX tablets by the patient or
physicians prescription error. MTX is prescribed by
many physicians as three consecutive dosages of 2.5mg
at an interval of 12 h. Folic acid tablets are prescribed on
other non-MTX days. In India, many of our patients may
make an error to distinguish between MTX and folic acid
tablets and thus may land up with acute MTX toxicity.
Predisposing factors for developing MTX toxicity include
acute renal failure, hypoalbuminemia, and concurrent
use of drugs known to interact with MTX. Salicylates
and nonsteroidal anti-inflammatory drugs (NSAIDs) can
decrease the renal elimination and the tubular secretion
of MTX while trimethoprim/sulfamethoxazole (Septran)
can enhance the cytotoxic effects of MTX as trimethoprim
is an antifolate reductase inhibitor.[4] Concomitant use of
MTX and NSAIDs, increase the risk of MTX toxicity as
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NSAIDs inhibits MTX clearance and displace MTX from
protein binding sites.
CLINICAL FEATURES
MTX toxicity targets vital organs and structures of the
body namely skin, GI mucosa, kidney, liver, and bone
marrow. Major toxic effects of MTX, such as hepatic,
renal, pulmonary, and bone marrow disorders, occur
less frequently than the minor effects but may be life-
threatening. Signs and symptoms of acute MTX toxicity are
based on extent and severity of organ involvement.
Common case scenario of acute MTX toxicity in psoriasis
is a patient having long standing history of chronic plaque
psoriasis presenting with sudden onset of erosions or ulcers
in psoriatic plaques [Figure1] and sudden onset of severe
mucosal ulceration in the oral cavity. Apatient may present
with fever secondary to infection. Paradoxically, the patient
may have hypothermia due to the development of sepsis.
Many-a-times, scaly psoriatic plaque may not be visible
due to profound effects of MTX toxicity. Careful history
from the patient or patients relative should be obtained
with regard to psoriasis and MTX use.
Most of these patients are admitted to critical care setup or
hospital; critical care physician needs to make a complete
assessment of the patient to assess underlying sepsis or
systemic disease. Average and approximate days for the
development of various side effects are summarized in the
following Table1.
Investigations
Laboratory investigations reveal signs of myelosuppression,
that is, pancytopenia. Kidney function tests and liver
function tests may reveal organ affection.
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How to cite this article: Madke B, Singh AL. Acute methotrexate toxicity.
Indian J Drugs Dermatol 2015;1:46-9.
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Madke and Singh: Managing methotrexate toxicity
Figure 1: Trunk showing eroded psoriatic plaques (Image contributed
by Dr. Yashpal Manchanda, Consultant Dermatologist, Department of
Dermatology, Farwaniya Hospital, Kuwait).
TREATMENT
Ideally, the patient presenting with suspected signs and
symptoms of MTX toxicity should be admitted in an
intensive care setting, and reverse barrier nursing should
be observed by treating staff.
Three broad targets are involved in managing acute MTX
toxicity: Folinic acid rescue, elimination of MTX from the
body, and organ specific care
Folinic acid rescue
Folinic acid is the antidote of choice for treating MTX
toxicity. This rescue regimen replenishes intracellular stores
of reduced folate and attenuates the MTX toxicity. Ideally,
the serum levels of MTX should be estimated in all cases
of acute MTX toxicity, however; the facility for serum
MTX measurement is not widely available, and most cases
are managed on clinical grounds. Serum MTX levels give
guiding schedule for folinic acid rescue therapy. The dose
of IV folinic acid should be adjusted according to the MTX
levels as shown in Table2.
Serum MTX levels should be measured every 24 h until
the levels fall below 0.2 mol/L. However, there is no
rationale for MTX therapeutic drug monitoring in the setting
of low-dose toxicity arising from weekly MTX dosing
(525mg/week).
Elimination of methotrexate from the body
Hydration
The vast majority of MTX is cleared by the kidneys (more
than 90%). Asatisfactory diuresis must be established
(approximately 600ml urine over 6 h, or 200ml urine over 2 h)
and fluid input should be approximately 3 L/m2/day until MTX
Indian Journal of Drugs in Dermatology July-December 2015 Volume 1 Issue 1
levels are 0.2 mol/L or below, to maintain urine output and
facilitate MTX excretion. Fluid balance should be monitored
carefully to prevent renal toxicity and fluid overload. Aim for
a urine output of approximately 2L/m2/day until the MTX
level has fallen to 0.2 mol/L.
Alkalinization of urine
MTX and its metabolites (2, 4-diamino-N(10)-methylpteroic
acid [DAMPA]) are poorly soluble at acidic pH levels. An
increase in urine pH from 6.0 to 7.0 increases the solubility
of MTX and its metabolites by 5-to 8-fold and prevents
crystal deposition. Urinary alkalinization with 4050 mEq
of sodium bicarbonate per liter of IV fluid reduces the risk
of intratubular crystal formation. MTX and its metabolite
7-OH-MTX, which is seen predominantly with high-dose
MTX therapy, show, respectively, 20-and 12-fold increased
solubility when pH increases from 5.0 to 7.0. Urine pH
must be >7 to promote MTX excretion and prevent MTX
crystallization. It should be maintained at this throughout the
treatment period and until levels are 0.2 mol/L or below.[5]
Managing delayed methotrexate excretion
Glomerular filtration, tubular secretion, and tubular
reabsorption all play a role in the renal clearance of
MTX. Paradoxically, toxic levels of MTX pose a grave
danger to renal tubules thereby leading to decreased renal
clearance. MTX-induced nephrotoxicity mainly arises by
two mechanisms: Crystal nephropathy and direct tubular
toxicity.[6,7]
Glucarpidase (carboxypeptidase, CPDG2 enzyme) was
approved by the United States Food and Drug Administration
in the treatment of plasma MTX concentrations
(>1 mol/L) in patients with delayed MTX clearance due to
impaired kidney function.[8] Glucarpidase is a recombinant
form of the CPDG2 enzyme, produced via modified
Escherichia coli. It is a homodimeric protein composed
of 390 amino acids. The molecular weight is 83 kDa. The
enzyme works by rapidly metabolizing circulating (not
intracellular) MTX to two inactive metabolites: Glutamate
and 2,4-diamino-N-10-methylpteroic acid (DAMPA).
Use of CPDG2 enzyme should be considered if serum
MTX concentration 10 mol/L and rise in creatinine of
100% or more after the last dose of MTX. Treatment with
glucarpidase reduces serum MTX levels by 97% or more
within 15min. However, treatment with glucarpidase does
not affect the intracellular MTX concentration and hence
high dose folinic acid should be continued.
The drug is sold as a sterile, preservative-free white
lyophilized powder with 1000 units per single-use vial. Each
vial also contains lactose monohydrate (10mg), Tris-HCl
(0.6mg), and zinc acetate dihydrate (0.002mg). Each vial
should be reconstituted (immediately prior to use) with 1ml
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Madke and Singh: Managing methotrexate toxicity

sodium chloride 0.9% and administered over 5min by bolus
IV injection. Acaution should be borne that both folinic
acid and its active metabolite, 5-methyl THF (5-mTHF) are
substrates for glucarpidase and may reduce folate levels.
Therefore, to minimize a clinically significant drug-drug
interaction, patients should receive folinic acid 2 h before
or after a dose of glucarpidase.[9]
Organ specific care
Methotrexate induced myelosuppression
All cases of MTX toxicity should be presumed to have
neutropenia unless proved otherwise and ideally should be
managed under Intensive Care Unit. At the cost of repetition,
it is emphasized that all patients of MTX toxicity should
be isolated, and reverse barrier nursing protocol should
Table1: Chronology of events in MTX toxicity
Acute toxicity Number of days after MTX use
Mucositis
Maculopapular rash
Hepatitis
Myelosuppression
Renal toxicity
Ocular irritation
MTX: Methotrexate
be scrupulously followed by health care staff. Apatient of
MTX toxicity having neutropenia and febrile episodes have
a high risk of developing bacterial sepsis and portends a poor
prognosis. Abroad spectrum parenteral nonnephrotoxic
antibiotic preferably a third generation cephalosporin should
be instituted for neutropenic fever. Pending the results of
leucovorin rescue, patients can be transfused with packed
red blood cells and platelets. Alternately, recombinant
granulocyte colony-stimulating factors (G-CSFs) therapy
reduces the severity and duration of neutropenia and the
consequent risk of febrile neutropenia. Recombinant human
G-CSF acts on hematopoietic cells to stimulate production,
maturation, and activation of neutrophils.[10]
Oral care
Patient education is important and forms a crucial part in the
management of mucositis. Acustomized patient instruction
should be followed to reduce the pain and discomfort of
mucositis.
Patients are encouraged to sit upright at a 90 angle and
3-5
lean their head slightly forward
1-5
Eat slowly, food should be cut into small pieces and
1-10
7-10
chewed completely
1-3 Eat small frequent meals instead of heavy meals
1-3 Food taken should be warm, or at room temperature.
Hot food and drinks should be avoided

Table2: Dosages of Folinic Acid and MTX Plasma Concentration(mol/L)

Timing after last MTX dose MTX plasma concentration
and dose of folinic acid
<0.2 mol/L 0.2-0.7 mol/L 0.71-2 mol/L 0.21-19.9 mol/L 20-100 mol/L >100 mol/L*
24 h None 15 mg/m2 15 mg/m2 15 mg/m2 60 mg/m2 See below
6 hourly 6 hourly 6 hourly 6 hourly footnote
48 h None 15 mg/m2 15 mg/m2 150 mg/m2 300 mg/m2 See below
6 hourly 6 hourly 6 hourly 3 hourly footnote
72 h None 30 mg/m2 150 mg/m2 750 mg/m2 3000 mg/m2 See below
6 hourly 6 hourly 3 hourly 3 hourly footnote
MTX: Methotrexate
*If serum MTX levels are more than 100 mol/L, the dose of folinic acid can be calculated using the formula below:
Upper limit of serum methotrexate:
At 24h is 20 mol/L
At 48h is 2 mol/L
At 72h is 0.2 mol/L.

Total daily dose of folinic acid

Patients actual serum methotrexate
standard daily dose of folinic acid
=
Upper limit of serum methotrexate
for the actual day and time

Example
If the 48h methotrexate level was 40 mol/L, and patient has a body surface area of 1.8 m2, the folinic acid dose should be adjusted to:
40 mol / L 60 mg / m 2
Total daily dose of folinic acid =
2 mol / L
= 1200 mg / m 2 / 24 h

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Madke and Singh: Managing methotrexate toxicity
Soft food is always encouraged. Finely chopped cooked
meat, fruits, and vegetables should be taken. Milkshakes
that have very high proteins can also be tried
Usage of straw will not only make drinking easy but
will also avoid direct contact with the affected portion
Do not talk while food is in the mouth
Acidic foods such as tomatoes, grapes, apple fruits or
juices, alcohol and tobacco, and spicy foods should be
avoided
To relieve discomfort of dry mouth, patients are asked
to rinse mouth with water before and after every meal
Symptomatic treatment should be offered for mucositis
Chlorhexidine mouthwash rinse10ml qid (efficacy is
not proven)
Folinic acid mouthwash 15 mg QDS (15 mg/2 ml
injection diluted to10ml with water)
Syrup viscous lignocaine two teaspoon to be swished
and spit 10min before meals
Oral saline rinses.
Topical coating agents: Sucralfate suspension to be kept
in the mouth for 510min to allow sufficient contact time
before each meal.
Pandyas formula: Mix 5ml each of syrup prednisolone
(5mg/5ml), syrup Gelusil and syrup Benadryl. This mixture
should be softly rinsed in the mouth for 2min and then spitted out.
Local care of eroded psoriatic plaques
Treatment of cutaneous erosions is mostly supportive
because cutaneous erosions tend to heal quickly within
12weeks.
Indian Journal of Drugs in Dermatology July-December 2015 Volume 1 Issue 1
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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