1. Methotrexate is a disease-modifying drug used to treat rheumatoid arthritis and psoriasis. It works by inhibiting DNA synthesis and causing bone marrow suppression. 2. The patient was incorrectly prescribed a combination drug of methotrexate and folic acid instead of methotrexate alone, resulting in toxicity and bone marrow suppression leading to death. 3. Pharmacist intervention is needed to prevent prescribing errors and monitor for methotrexate toxicity through bloodwork and clinical exams. Supportive care like blood transfusions and growth factors may be required to treat methotrexate induced bone marrow suppression.

1. METHOTREXATE
INDUCED BONE
MARROW SUPPRESSION
BY,
REIMA ELIZABETH JACOB
5TH PHARM-D
ROLL NO.22

2. • Methotrexate is a disease-modifying drug indicated in the treatment of
severe, active, classical or definite rheumatoid arthritis, including juvenile
arthritis, and severe recalcitrant psoriasis which is unresponsive to
conventional therapy.
• Rheumatoid arthritis
Adult: 7.5 mg once weekly, adjust by response. Not more than 20 mg once
weekly.
• For neoplastic disease-daily dosing orally or intramuscularly

3. • Methotrexate is a folic acid antagonist that inhibits DNA synthesis.
• It irreversibly binds to dihydrofolate reductase, inhibiting the formation of
reduced folates, and thymidylate synthetase, resulting in inhibition of
purine and thymidylic acid synthesis.
• Given for moderate to severe rheumatoid arthritis.

4. • MTX enters the cells where it is polyglutamated and the latter form may be
responsible for its therapeutic effects.
• The most common side effects are those involving GIT (nausea, vomiting),
hepatic, CNS (headache, dizziness), haematological and rarely respiratory.
• Most of these can be reduced by supplemented folic acid /folinic acid
without interfering with the efficacy of the drug.

6. • It is teratogenic and thus its use is contraindicated during pregnancy and
lactation (Pregnancy category- X)
• Methotrexate probably induces liver toxicity by intracellular accumulation
of MTX polyglutamates.
• MTX-induced nodulosis is more common in RF-negative
patients.Adenosine-A1 receptors have been implicated in the development
of the nodulosis.

7. • Full blood counts, renal and liver function tests, and chest x-rays are
required before treatment commences and blood tests repeated regularly (2-
4 weekly) until therapy is stabilised.

8. 1. Bone marrow suppression
• It can occur abruptly
• Mechanism- acquired stem cell injury, hypo proliferation and maturation
defects of hemapoietic cells occur
• Direct or indirect effects of the drug on DNA synthesis
• Pancytopenia is the most common manifestation
• Clinically significant drop in WBC or platelet count and elevation of
MCV calls for immediate withdrawal of MTX and introduction of
supportive therapy.
TOXIC EFFECTS

10. • Folic acid supplementation 1 mg daily.
• Moderate to severe bone marrow suppression usually needs folinic acid
(leucovorin)- Administered as calcium folinate by IV injection or IV
infusion (at max. rate of 160mg/min), initial dose equal to or exceeding
dose of MTX- for suspected MTX overdose
• Blood transfusions , platelet transfusions
• Pancytopenia has been seen after accidental methotrexate overdose in
patients with hypoalbuminemia.

12. 2. Liver toxicity:
• Liver cirrhosis reported. Abnormalities can return to normal within 2
weeks after which treatment may be recommended if judged
appropriately.
3. Pulmonary Toxicity:
• Discontinue the drug if pneumonitis is suspected

13. 4. Nephrotoxicity:
• Methotrexate concentrates in the kidneys, gallbladder and spleen as well as
in the liver.
• Renal excretion eliminates 60 to 95 percent of a dose.
• Methotrexate is contraindicated in any patient with a creatinine clearance of
less than 50 mL per minute
5. Patients should be warned of the possible development of malignant
hematologic diseases such as non-Hodgkin's lymphoma during therapy.

14. Hypothetical Case

15. SUBJECTIVE
• Name: X
• Age: 31 years
• Sex: Female
• DOA-29/12
• Ward: Dermatology ward
• Chief complaints: C/O back pain and joint pain. No H/O fever
• Provisional Diagnosis: Sero-negative arthritis and vitamin D insufficiency

16. OBJECTIVE
• Temperature: 98.4oF
• PR-84/mt
• RR-22/mt
• BP-120/80mmHg
• Lungs: clear
• P/A- soft
• CNS-NFND +
• CVS-NAD

17. • History of present illness : K/C/O sero-negative arthritis for 9 years
• Family History: Nil
• Allergies: Nil

18. Treatment Given
• Day 1:
1. T.HCQS 200mg PO BD
2. T.Megabid 75mg PO 0-0-1
3. C.Evion 400mg PO BD
4. T.Defcort PO 6mg 1-0-0 on alternate day
5. T.Mext 7.5 F 1-0-0
6. T.Shel HD PO 1 OD
7. T.Rabium DSR PO 0-0-1

19. • Day 2
1. D.Rise PO 1 BD
2. T.HCQS 200mg PO BD
3. T.Megabid 75mg PO 0-0-1
4. C.Evion 400mg PO BD
5. T.Mext 7.5 F 1-0-0
6. T.Shel HD PO 1 OD
7. T.Rabium DSR PO 0-0-1

20. Patient was discharged and was prescribed
• Mext 7.5F for 1 week
• Folic acid 1mg for 1 week on alternate days
• Patient death happened at home

21. Abnormal lab parameters on 30/12
• Vitamin D- 29 ng/ml ( 30- 100 ng/ml)
• Peripheral smear-Normochromic normocytic anemia, fragmented RBC’s
seen suggestive of hemolysis.
• Hb-10.6 g/dl ( Low)
• WBC count is decreased-3800 cu/mm, shift to left is seen in neutrophillic
series
• Platelets are adequate on smear
• N- 51% (low), L-48%, E-5% (high)
• ESR-61 mm/hr (High)

22. • Serum albumin- 3.2 g/dl (3.5-4.8 g/dl)
• Mean blood glucose – 71 mg/dl ( high)
• Serum potassium- 3.4 mm mol/L (3.5-5.3 mm mol/L)
• Rheumatoid factor ( RA/RF), serum- 6.12 IU/ml ( 0-20 IU/ml)-RF negative
• CRP-4.17 mg/L (0-10 mg/L)
• Iron, total, serum-50.1 ug/dl ( 60-180 ug/dl) (low)

23. ASSESSMENT
• She was diagnosed with sero negative arthritis with Vitamin D insufficiency
• Seronegative patients have negative RF titer with higher levels of
inflammations and it include a group of disorders called sero negative
spondyloarthropathy (ankylosing spondylitis, psoriatic arthritis and reactive
arthritis)
• They are less aggressive than typical RA with same treatment modalities.
• Background- Systemic Lupus Erythematous (Immune pancytopenias i.e,
refractory anemia in systemic lupus erythematosus)

24. PHARMACIST INTERVENTION
• The patient was prescribed with T. Mext 7.5F which is a combination of
MTX 7.5mg along with folic acid 1mg which should be administered like
M+F+F+M+F+F+F (for 1 week orally).
• Instead of T. Mext 7.5F the drug intended was T.Mext 7.5mg which
contains MTX alone
• For arthritis, the recommended dose of MTX is 7.5mg orally twice weekly.
• This error resulted in toxicity, initial stages of bone marrow suppression and
gradually death of the patient.

25. NORMAL BONE MARROW BONE MARROW SUPPRESSION

27. PRESCRIBING
ERROR!!!
DISPENSING
ERROR!!!
ADMINISTERING
ERROR!!!

29. • MTX treatment should be discontinued
• Blood transfusions should be done for severe myelosuppression.
• Drug Interactions:
1.Deflazacort Methotrexate (Moderate )
Synergestic immuno-suppressive effect
2. Methotrexate Rabeprezole (Major)
Caution advised, consider stopping proton pump inhibitor during high-
dose methotrexate tx: combo may increase methotrexate and metabolite
levels, risk of toxicity

30. • Bedside pharmacist intervention is required- check whether the right drug is
being administered at the right time.
• Proper screening of the drugs prescribed required.
• Educate the nursing professionals
• Inform doctor that such a drug combination is not available in the hospital
formulary.

31. • A pre-methotrexate evaluation is important to ensure proper patient
selection for this effective but potentially toxic drug.

32. Premethotrexate Evaluation
• Complete blood count with differential
• Platelet count
• Serum creatinine
• Blood urea nitrogen
• Urinalysis
• Liver function tests
• Serum bilirubin
• Serum albumin
• Hepatitis A, B, and C serologies
• HIV risk assessment/testing, if appropriate Chest radiograph

33. My plan
• The patient should be supplemented with folic acid 1 mg daily. Studies
show that low-dose folate does not interfere with the efficacy of
methotrexate and avoid taking the folate dose on the same day as the
methotrexate dose.
• Require close monitoring through clinical assessments and laboratory
testing.
• Patient with bone marrow suppression should be treated with Leucovorin
rescue: after 24 hours of mod-high doses of MTX to rescue normal cells.
• TDM of MTX

34. Methotrexate Monitoring form

35. • Infections that arise are managed depending on the pathogen and on
available therapy.
• After blood is drawn and other cultures are taken, broad-spectrum
antibiotics should be started empirically in the presence of febrile
neutropenia.
• The addition of antifungal agents should be considered in the presence of
persistent fever despite adequate antibacterial coverage.
• The patient should receive immunizations for influenza and pneumococcal
pneumonia to prevent respiratory infections (live vaccine should be
avoided)

36. • Vit B12 supplementation should be done ( 1000 mcg as IM for achieving
hematologic and neurologic responses).
• Blood ( to improve oxygen delivery)and platelet transfusion( for bleeding)
• If irreversible damage has occurred bone marrow transplantation can be
done.

37. Newer treatment options
• Hematopoietic growth factors, such as granulocyte colony-stimulating
factor (G-CSF) and granulocyte-macrophage colony-stimulating factor
(GM-CSF), may be useful in patients with neutropenia who have infections,
without requiring a white blood cell transfusion.
• For immune mediated bone marrow suppression-Patients with severe
aplastic anemia who receive antithymocyte globulin (ATG) or
antilymphocyte globulin (ALG) but do not receive BMT have a 41%
response rate and a 1-year survival rate of 55%. The addition of androgens
increases response rates to 70%, with a 1-year survival rate of 76%
(Danazol).ATG or ALG should be given with corticosteroids to prevent
serum sickness.

38. Other drugs for RA in this patient are
• Leflunomide
• Non-Biologic combination or anti-TNF
• Non-biologic DMARD except sulfasalazine
Or no response to these give
• Anti-TNF:Etanrcept,Infliximab
• Rituximab
• Abatacept

39. MONITORING PARAMETERS
• CBC with differential and platelets, prior to therapy initiation, every month
during therapy, more frequently at dose changes and initiation, when there
is an increased MTX blood levels
• AST, albumin
• Infections due to MTX therapy
• Fluid overload due to blood transfusions.
• Monitoring serum ferritin levels and measuring total iron urinary excretion
can determine the effectiveness of therapy- to avoid iron overload.

40. REGARDING DRUGS
• Educate the patient to never accept MTX more than once a week.
• Emphasize the weekly dose and warn patients that daily dosing of this drug
is fatal. If an accidental overdose occurs, an antidote can be used
(leucovorin rescue).
• Stay away from people with infections.
• For mouth irritations or sores use soft tooth brush or cotton swab and rinse
mouth with non-alcoholic mouth rinses.

41. • Tell patients to avoid alcohol including beer, wine and hard liquor because
of the increased risk of liver disease.
• Discuss potential drug interactions, especially salicylates, over-the-counter
NSAIDs and TMP SMX
• Tell patients to call immediately if they develop signs of infection
(immuno-suppression), coughing or shortness of breath (pulmonary
toxicity) or unusual bleeding (liver or bone marrow suppression).

42. • Both women and men of reproductive age should use birth control during
MTX therapy ( for 3 months)
• MTX can cause sun sensitivity- use sunscreen and avoid tanning beds.
• Other effects include alopecia, headache, sore throat, diarrhea or kidney
failure. Potentially Fatal: interstitial lung disease, leukoencephalopathy,
paresis, demyelination with intrathecal use; foetal deaths.

43. REGARDING LIFESTYLE MODIFICATION
• Maintain adequate hydration during therapy
• Follow balanced diet
• Maintain weight- weight reduction alleviate stress on inflamed joints
• Maintain hygienic environment.
• Do not eat raw fish, seafood, meat or eggs.

44. REFERENCES
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