Methotrexate - A Comprehensive Drug Review in Dermatology

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

1. INTRODUCTION Old name: Amethopterin Biochemical name: 4-amino N 10 methyl pteroylglutamic acid Antimetabolite FDA Approval: - Psoriasis – 1971 - RA – Late 1980s Irreversible inhibitor of DHFR Competitive antagonist of Folic acid

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

3. ROUTES & FORMULATIONS ROUTES Oral Parenteral Intramuscular Intravenous Intraarterial Intrathecal Subcutaneous Intramatricial

4. 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/-

5. 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

6. METABOLISM & EXCRETION After absorption, undergoes triphasic reduction in body – 1 st Phase: Takes 0.75 hours and represents distribution in body 2 nd Phase: Takes 2-4 hours and represents renal excretion 3 rd 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)

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

8. MECHANISM OF ACTION

9. MECHANISM OF ACTION

10. MECHANISM OF ACTION

11. DRUG INTERACTIONS

12. DRUG INTERACTIONS

13. DRUG INDICATIONS & CONTRAINDICATIONS

14. SELECTION OF PATIENTS IN PSORIASIS

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

16. 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

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 WEEKLY DOSE SCHEDULE Single weekly dose Three divided doses in 24 hours (0, 12, 24 hr )

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

19. MONITORING

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

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

22. MONITORING GRADING OF LIVER BIOPSY FINDINGS

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

24. 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: Radionuclide scan Aminopyrine breath test PIIINP (Type III Procollagen Peptide) Ultrasound For Grade IIIA change, liver biopsy is repeated every 6 months For Grade IIIB & IV, Methotrexate is discontinued

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

26. SIDE EFFECTS & TOXICITY Risk factors: 1. Obesity 2. Steatohepatitis 3. Cumilative dose > 1.5 gm 4. Alcohol intake HEPATOTOXICITY PULMONARY TOXICITY Idiosyncratic Presents as acute pneumonitis or chronic fibrosis Chest X-ray is done if symptoms occur

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

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

29. SIDE EFFECTS & TOXICITY GASTROINTESTINAL EFFECTS Nausea, vomiting, diarrhoea & ulcerative stomatitis Presence of ulcerative stomatitis warrants discontinuation of MTX Folate reduces GI toxicity RENAL EFFECTS Seen only in high doses (50 – 250 mg / m 2 IV) Risk is more with reduced renal function

30. SIDE EFFECTS & TOXICITY GASTROINTESTINAL EFFECTS Nausea, vomiting, diarrhoea & ulcerative stomatitis Presence of ulcerative stomatitis warrants discontinuation of MTX Folate reduces GI toxicity RENAL EFFECTS Seen only in high doses (50 – 250 mg / m 2 IV) Risk is more with reduced renal function MALIGNANCY Rare Lymphoma

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

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

33. 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

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 MANAGEMENT Stop drug Folinic acid rescue Elimination of MTX from body Organ specific care

35. FOLINIC ACID RESCUE DOSE CALCULATION

36. ELIMINATION OF MTX FROM BODY 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 µ mol /L or below

37. ELIMINATION OF MTX FROM BODY 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 µ mol /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

38. ELIMINATION OF MTX FROM BODY 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 µ mol /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 MANAGING DELAYED EXCRETION Glucarpidase is a recombinant form of the CPDG2 enzyme rapidly metabolized MTX into inactive metabolites

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

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