This presentation is on the review of the drug Methotrexate in Dermatology. It was made by Dr. Jerriton, 1st year PG resident in dermatology.

2. INTRODUCTION
• Old name: Amethopterin
• Biochemical name: 4-amino N10 methyl pteroylglutamic acid
• Antimetabolite
• FDA Approval:
- Psoriasis – 1971
- RA – Late 1980s
• Irreversible inhibitor of DHFR
• Competitive antagonist of Folic acid

3. CHEMICAL STRUCTURE
• Structurally similar to FA; differs in 2 positions –

4. ROUTES & FORMULATIONS
ROUTES
• Oral
• Parenteral
1. Intramuscular
2. Intravenous
3. Intraarterial
4. Intrathecal
5. Subcutaneous
6. Intramatricial

5. ROUTES & FORMULATIONS
FORMULATIONS
• Tablets – 2.5 mg, 5 mg, 7.5 mg, 10 mg & 15 mg
• Injections – 2.5 mg/ml, 15 mg/ml & 25 mg/ml
PRICE IN SVMCH
• 2.5 mg tablet costs Rs. 5/-
• 5 mg tablet costs Rs. 8/-
• 7.5 mg tablet costs Rs. 11/-
• 2 ml vial (15 mg/ml) costs Rs. 46/-

6. ABSORPTION & DISTRIBUTION
• Rapidly absorbed through GIT
• Concurrent food intake (particularly milk-based) reduces
bioavailability in children, but not in adults
• Peak level (oral route) occurs in 1 hour
• Distributed throughout body
• Has poor penetration to CNS

7. METABOLISM & EXCRETION
• After absorption, undergoes triphasic reduction in body –
1. 1st Phase: Takes 0.75 hours and represents distribution in body
2. 2nd Phase: Takes 2-4 hours and represents renal excretion
3. 3rd Phase: Takes 10-27 hours and represents terminal half-life
• 50 % is bound to plasma proteins
• Metabolized intracellularly (including in liver) to polyglutamated forms
• These metabolites are also inhibitors of DHFR (hence adds to toxicity)

8. MECHANISM OF ACTION
1. Inhibits DNA synthesis during S phase of cell cycle and thereby inhibits
cell division
2. Suppresses T cell proliferation and blocks migration of activated T cells
to certain tissues
3. Suppresses B cell antibody production
4. Increases adenosine production which exerts anti-inflammatory effects

9. MECHANISM OF ACTION

10. MECHANISM OF ACTION

11. MECHANISM OF ACTION

12. DRUG INTERACTIONS

13. DRUG INTERACTIONS

14. DRUG INDICATIONS & CONTRAINDICATIONS

15. SELECTION OF PATIENTS IN PSORIASIS

16. SELECTION OF PATIENTS IN PSORIASIS
1. Psoriasis as debilitating disease
2. Uncontrolled by conventional therapies
3. Not likely to respond to conventional therapies
4. Practicality issue (job related, nearby hospital with phototherapy units)
5. Affordability
6. Women of child bearing age, pregnancy & lactation
7. Other relative contradictions

17. THERAPEUTIC GUIDELINES
• Once plan is made to start MTX, dose and route have to be considered
• Oral weekly doses are well tolerated
• If not tolerating, parenteral (IM) route can be tried

18. THERAPEUTIC GUIDELINES
WEEKLY DOSE SCHEDULE
1. Single weekly dose
2. Three divided doses in 24 hours (0, 12, 24 hr)

19. THERAPEUTIC GUIDELINES
INITIAL DOSE
• Start with 5-10 mg ‘test’ dose
• Escalate to 2.5 – 5 mg / week to a maximum of 30 mg / week
• Taper by 2.5 mg / week to lowest possible dose that controls disease

20. MONITORING

21. MONITORING
LAB MONITORING (FOLLOW UP)
1. Done within 1–2 weeks after beginning therapy or escalating the dose
and is continued for 4 weeks
2. If WBC is < 3500/mm3, PLT is <100 000/mm3, or there is an increase over
twice the upper normal value for liver transaminase levels, discontinue
or reduce the dosage of MTX
3. If the laboratory abnormality has resolved the drug may be restarted at
a lower dose after a 2–3-week rest.
4. After the first month of therapy this laboratory monitoring can be
gradually reduced in frequency to a range of every 3–4 months.

22. MONITORING
LIVER BIOPSY CONSIDERATIONS
The choice to monitor with liver biopsy depends on:
1. The state of the disease
2. Presence of concomitant disease affecting risk
3. Patient behavioral characteristics (alcohol consumption, etc.)
4. Patient choice

23. MONITORING
GRADING OF LIVER BIOPSY FINDINGS

24. MONITORING
LIVER BIOPSY (INITIAL)
• It is either done as pre-treatment biopsy or delayed baseline biopsy
• Pre-treatment liver biopsy is needed when:
1. Family history of liver disease
2. History of consumption of alcohol / IV drugs
3. Obese patients (risk factor for liver toxicity and NASH)
4. Diabetic patients (risk factor for liver toxicity)
5. Pre-MTX workup showed liver or serological abnormality
• Delayed baseline liver biopsy is done between 3rd and 6th month of
starting therapy in otherwise healthy patients or when the cumulative
dose is 1.5 gm

25. MONITORING
LIVER BIOPSY (FOLLOW UP)
• If 2 or more consecutive liver biopsies (repeated after every 1.5 gm total
dose) show Grade I or II changes alone, then further follow up with liver
biopsy can be done after a cumulative dose of every 3 gm, with non-
invasive tests for liver fibrosis done in between.
• The non-invasive tests include:
1. Radionuclide scan
2. Aminopyrine breath test
3. PIIINP (Type III Procollagen Peptide)
4. Ultrasound
• For Grade IIIA change, liver biopsy is repeated every 6 months
• For Grade IIIB & IV, Methotrexate is discontinued

26. SIDE EFFECTS & TOXICITY
Risk factors:
1. Obesity
2. Steatohepatitis
3. Cumilative dose > 1.5 gm
4. Alcohol intake
HEPATOTOXICITY

27. SIDE EFFECTS & TOXICITY
PULMONARY TOXICITY
• Idiosyncratic
• Presents as acute pneumonitis or chronic fibrosis
• Chest X-ray is done if symptoms occur

28. SIDE EFFECTS & TOXICITY
HAEMATOLOGIC EFFECTS
• Causes myelosupression leading to pancytopenia
• Risk factors:
• Daily folate supplementation (1 – 5 mg) significantly reduces risk

29. SIDE EFFECTS & TOXICITY
GASTROINTESTINAL EFFECTS
• Nausea, vomiting, diarrhoea & ulcerative stomatitis
• Presence of ulcerative stomatitis warrants discontinuation of MTX
• Folate reduces GI toxicity

30. SIDE EFFECTS & TOXICITY
RENAL EFFECTS
• Seen only in high doses (50 – 250 mg / m2 IV)
• Risk is more with reduced renal function

31. SIDE EFFECTS & TOXICITY
MALIGNANCY
• Rare
• Lymphoma

32. SIDE EFFECTS & TOXICITY
REPRODUCTIVE EFFECTS
• Pregnancy category X
• Potent teratogen causing skeletal and neurological defects

33. SIDE EFFECTS & TOXICITY
CUTANEOUS EFFECTS
• MTX-Induced Accelerated Rheumatoid Nodulosis (MIARN)
• MTX-induced papular eruptions (Paradoxical Drug Reaction)
• Generalized brownish hyperpigmentation on sun exposed areas
• Flag sign: hyperpigmented bands on hair, alternating with normal colored
hair

34. ACUTE TOXICITY
CLINICAL PRESENTATION
• Happens with accidental daily dosing of MTX
• Presents with fever, arthralgia, vasculitic rashes, occular irritation, ulcer
over psoriatic plaques and extensive stomatitis and mucositis

35. ACUTE TOXICITY
MANAGEMENT
1. Stop drug
2. Folinic acid rescue
3. Elimination of MTX from body
4. Organ specific care

36. FOLINIC ACID RESCUE DOSE CALCULATION

37. ELIMINATION OF MTX FROM BODY
1. HYDRATION
A satisfactory diuresis must be established (approximately 600 ml urine
over 6 h, or 200 ml urine over 2 h) and fluid input should be approximately 3
L/m 2/day until MTX levels are 0.2 µmol/L or below

38. ELIMINATION OF MTX FROM BODY
1. HYDRATION
A satisfactory diuresis must be established (approximately 600 ml urine
over 6 h, or 200 ml urine over 2 h) and fluid input should be approximately 3
L/m 2/day until MTX levels are 0.2 µmol/L or below
2. ALKALINIZATION
• An increase in urine pH from 6.0 to 7.0 increases the solubility of MTX
and its metabolites
• Urinary alkalinization with 40–50 mEq of sodium bicarbonate per liter of
IV fluid

39. ELIMINATION OF MTX FROM BODY
1. HYDRATION
A satisfactory diuresis must be established (approximately 600 ml urine
over 6 h, or 200 ml urine over 2 h) and fluid input should be approximately 3
L/m 2/day until MTX levels are 0.2 µmol/L or below
2. ALKALINIZATION
• An increase in urine pH from 6.0 to 7.0 increases the solubility of MTX
and its metabolites
• Urinary alkalinization with 40–50 mEq of sodium bicarbonate per liter of
IV fluid
3. MANAGING DELAYED EXCRETION
Glucarpidase is a recombinant form of the CPDG2 enzyme rapidly
metabolized MTX into inactive metabolites

40. ORGAN SPECIFIC CARE
• Managed in ICUs
• broad spectrum parenteral nonnephrotoxic antibiotic
• Blood and blood products transfusion
• Oral care

41. REFERENCES
1. Wolverton, Comprehensive Dermatologic Drug Therapy, 3rd Edition
2. IADVL’s Textbook on Cutaneous Adverse Drug Reactions, 1st Edition
3. Madke B, Singh AL. Acute methotrexate toxicity. Indian J Drugs Dermatol
2015;1:46-9.