Comprehensive Guide on Methotrexate, Calcium Folinate, and Related Considerations

A summary table to recap the essential points about Methotrexate, its interactions, and Calcium Folinate:

Category	Details
Methotrexate
Class	Antimetabolite, Folic Acid Antagonist
Mechanism of Action	Inhibits dihydrofolate reductase, blocking DNA, RNA, and protein synthesis in rapidly dividing cells
Indications	Cancer (e.g., ALL, breast cancer), Rheumatoid arthritis, Psoriasis, Ectopic pregnancy
Dosage (example)	RA: 7.5 mg orally once weekly; Cancer: 20 mg/m² IV weekly
Adverse Effects	Common: Nausea, vomiting, stomatitis, mucositis, fatigue; Serious: Myelosuppression, hepatotoxicity
Monitoring	Liver function tests, renal function tests, CBC, chest X-ray
Contraindications	Pregnancy, severe hepatic/renal impairment, blood dyscrasias
Interactions	PPIs, Penicillins, PCP prophylaxis drugs (TMP-SMX), NSAIDs, Probenecid

Calcium Folinate
Class	Chemoprotectant, Antidote
Mechanism of Action	Bypasses methotrexate inhibition of dihydrofolate reductase, protecting normal cells
Indications	Methotrexate rescue, Megaloblastic anemia, Methotrexate overdose
Dosage (example)	15 mg/m² every 6 hours after methotrexate
Adverse Effects	Common: Nausea, vomiting, diarrhea, rash; Serious: Allergic reactions
Monitoring	Serum methotrexate levels, renal function
Interactions	Methotrexate (counteracts toxicity), 5-Fluorouracil (enhances effects), Sulfonamides

Drugs to Avoid with Methotrexate	Examples	Reason
Proton Pump Inhibitors (PPIs)	Omeprazole, Pantoprazole	Decreases methotrexate renal clearance, increases toxicity
Penicillins	Amoxicillin, Penicillin V	Reduces methotrexate renal clearance, increases toxicity
PCP Prophylaxis Drugs	Trimethoprim-sulfamethoxazole (TMP-SMX)	Increases toxicity by inhibiting methotrexate excretion
NSAIDs	Ibuprofen, Naproxen	Inhibits methotrexate renal clearance, increases toxicity
Probenecid		Inhibits renal secretion of methotrexate, increases toxicity

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Generic Name: MethotrexateTrade Names: Trexall, Rheumatrex, Otrexup, Rasuvo

Class: Antimetabolite, Folic Acid Antagonist

Mechanism of Action: Methotrexate inhibits dihydrofolate reductase, an enzyme involved in the synthesis of tetrahydrofolate, which is necessary for DNA synthesis and cell replication. This leads to inhibition of DNA, RNA, and protein synthesis, affecting rapidly dividing cells such as cancer cells, immune cells, and epithelial cells.

Indications:

• Oncological Uses: Acute lymphoblastic leukemia (ALL), breast cancer, choriocarcinoma, head and neck cancers, non-Hodgkin lymphoma, osteosarcoma.

• Non-Oncological Uses: Rheumatoid arthritis, psoriasis, Crohn's disease, ectopic pregnancy.
  

Dosage and Administration:

• For Cancer:

  • Acute Lymphoblastic Leukemia (ALL): Induction phase, 20 mg/m² IV weekly.

  • Breast Cancer: 40 mg/m² IV on days 1 and 8 of a 28-day cycle.

  • Choriocarcinoma: 15-30 mg/dose IM or IV for 5 days, repeat every 12-14 days.

  • Non-Hodgkin Lymphoma: 200-500 mg/m² IV every 3-4 weeks.

• For Rheumatoid Arthritis:

  • Initial dose: 7.5 mg orally once weekly or 2.5 mg every 12 hours for 3 doses once weekly.

  • Maintenance dose: 7.5-25 mg weekly.

• For Psoriasis:

  • 10-25 mg orally or IM once weekly.

• For Ectopic Pregnancy:

  • 50 mg/m² IM as a single dose.
    

Adjustments:

• Renal Impairment:

  • CrCl 60-80 ml/min: Administer 65% of dose.

  • CrCl 30-59 ml/min: Administer 50% of dose.

  • CrCl <30 ml/min: Contraindicated.

Adverse Effects:

• Common: Nausea, vomiting, stomatitis, mucositis, abdominal pain, fatigue, dizziness.

• Serious: Myelosuppression, hepatotoxicity, pulmonary fibrosis, nephrotoxicity, neurotoxicity.

Monitoring:

• Baseline and periodic liver function tests, renal function tests, complete blood count (CBC)

• Chest X-ray for pulmonary toxicity

Contraindications:

• Pregnancy, breastfeeding, severe hepatic or renal impairment, pre-existing blood dyscrasias (e.g., bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia).
  

Interactions:

1. Proton Pump Inhibitors (PPIs):

   • Examples: Omeprazole, Esomeprazole, Pantoprazole

   • Reason: PPIs can decrease the renal clearance of methotrexate, leading to increased levels of methotrexate and its metabolites, which can result in toxicity.

2. Penicillins:

   • Examples: Amoxicillin, Penicillin V, Ampicillin

   • Reason: Penicillins can reduce the renal clearance of methotrexate, increasing its levels and risk of toxicity.

3. Pneumocystis Carinii Pneumonia (PCP) Prophylaxis Drugs:

   • Examples: Trimethoprim-Sulfamethoxazole (TMP-SMX)

   • Reason: Trimethoprim can increase methotrexate toxicity by inhibiting its renal excretion and can also act as a folate antagonist, which can compound the effects of methotrexate.

4. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):

   • Examples: Ibuprofen, Naproxen, Diclofenac

   • Reason: NSAIDs can inhibit renal clearance of methotrexate, increasing the risk of methotrexate toxicity.

5. Probenecid:

   • Reason: Probenecid inhibits the renal tubular secretion of methotrexate, leading to increased levels and risk of toxicity.
     

Calcium Folinate Overview

Generic Name: Calcium Folinate Trade Names: Leucovorin, Folinic Acid

Class: Chemoprotectant, Antidote

Mechanism of Action: Calcium folinate is a form of folic acid that acts as an antidote to folic acid antagonists like methotrexate. It works by bypassing the dihydrofolate reductase inhibition caused by methotrexate, allowing for the normal synthesis of DNA, RNA, and protein in healthy cells. This helps to protect normal cells from the toxic effects of methotrexate without interfering with its anti-cancer activity.

Indications:

• Methotrexate Rescue: To reduce the toxic effects of high-dose methotrexate therapy in cancer treatment.

• Megaloblastic Anemia: Due to folic acid deficiency when oral folic acid therapy is inadequate or inappropriate.

• Overdose Treatment: For inadvertent methotrexate overdose or impaired methotrexate elimination.

Dosage and Administration:

• Methotrexate Rescue:

  • High-Dose Methotrexate Therapy:

    • Typical Dose: 15 mg/m² IV, IM, or oral every 6 hours until methotrexate levels fall below 5 x 10⁻⁸ M.

    • Adjust dose based on serum methotrexate concentration and renal function.

• Megaloblastic Anemia:

  • Adults and Children: 1 mg to 5 mg IV, IM, or oral daily.

• Methotrexate Overdose:

  • Initial Dose: 15 mg/m² IV every 6 hours until methotrexate levels are below toxic levels.

  • Subsequent Doses: Based on methotrexate plasma levels and patient response.

Adjustments:

• Dosage may need to be adjusted based on the patient’s renal function and methotrexate clearance.

Adverse Effects:

• Common: Nausea, vomiting, diarrhea, rash.

• Serious: Allergic reactions, including anaphylaxis.

Monitoring:

• Serum Methotrexate Levels: To guide the dosage and duration of calcium folinate therapy.

• Renal Function Tests: Regular monitoring is necessary to adjust the dosage.

Contraindications:

• Pernicious anemia or other megaloblastic anemias secondary to vitamin B12 deficiency.

Interactions:

• Methotrexate: Calcium folinate is used to counteract methotrexate toxicity.

• 5-Fluorouracil: Enhances the effects and toxicity of 5-FU; used together in some cancer treatments.

• Sulfonamides: May antagonize the effects of folinic acid.
  

Patient Education:

• Adherence: Take methotrexate and calcium folinate exactly as prescribed.

• Report Side Effects: Notify the healthcare provider of any signs of infection, unusual bleeding or bruising, persistent cough, or shortness of breath.

• Follow Monitoring Instructions: Regular blood tests are essential to monitor methotrexate levels and adjust calcium folinate dosage accordingly.

• Avoid Alcohol: Avoid alcohol and other hepatotoxic substances while on methotrexate therapy.
  

Summary:

Methotrexate is a versatile drug used in various oncological and non-oncological conditions due to its antimetabolite properties. Appropriate dosage adjustments, monitoring, and patient education are crucial to ensure its efficacy and safety. Calcium folinate is used to protect normal cells from the toxic effects of methotrexate, ensuring the continuation of normal DNA synthesis. Avoid using methotrexate with Proton Pump Inhibitors (PPIs), Penicillins, PCP prophylaxis drugs (such as TMP-SMX), NSAIDs, and Probenecid to minimize the risk of increased methotrexate levels and subsequent toxicity. Proper dosage, careful monitoring, and patient education are vital to ensure the effectiveness and safety of these treatments.