Comprehensive Guide to Methotrexate: Uses, Dosage, Side Effects, and More

What is Methotrexate?

Overview of Methotrexate

Generic Name: Methotrexate

Brand Name: Trexall, Rheumatrex, generics

Drug Group: Antimetabolite (antifolate, chemotherapeutic, immunosuppressant)

Commonly Used For

• Treat certain cancers like leukemia and lymphoma.
• Manage rheumatoid arthritis (RA).
• Control severe psoriasis.

Key Characteristics

Form: Oral tablets (2.5 mg, 5 mg, 7.5 mg, 10 mg), injectable solution (25 mg/mL, 50 mg/2 mL), or IV infusion (detailed in Dosage section).

Mechanism: Inhibits folate metabolism, arresting rapidly dividing cells.

Approval: FDA-approved (1953) and EMA-approved for oncology and rheumatology.

Indications and Uses of Methotrexate

Methotrexate is indicated for a wide range of oncologic, rheumatologic, and dermatologic conditions, leveraging its antiproliferative and immunosuppressive effects:

Acute Lymphoblastic Leukemia (ALL): Induces remission in children and adults, per oncology guidelines, supported by clinical trials showing 80–90% initial response rates.

Non-Hodgkin Lymphoma (NHL): Manages aggressive lymphomas, improving survival, recommended in hematology protocols.

Rheumatoid Arthritis (RA): Reduces joint inflammation and slows disease progression, with rheumatology evidence of ACR20 response in 60–70% of patients.

Psoriasis (Severe): Controls plaque psoriasis unresponsive to topical therapies, with dermatology data showing 75% improvement in PASI scores.

Psoriatic Arthritis: Treats joint and skin symptoms, supported by rheumatologic-dermatologic studies.

Crohn’s Disease: Investigated off-label to induce remission in steroid-dependent cases, with gastroenterology evidence.

Systemic Lupus Erythematosus (SLE): Managed off-label to control lupus nephritis, with rheumatology research.

Ectopic Pregnancy: Used off-label for medical termination, with obstetrics-gynecology data.

Osteosarcoma: Applied off-label in adjuvant therapy, with orthopedic-oncology studies.

Juvenile Idiopathic Arthritis (JIA): Initiated off-label in children, with pediatric rheumatology evidence.

Dosage of Methotrexate

Dosage for Adults

Acute Lymphoblastic Leukemia (ALL):

• IV: 3.3 mg/m² every 12 hours for 4 doses on days 1, 8, 15, and 22, with leucovorin rescue.

Non-Hodgkin Lymphoma (NHL):

• IV: 200–1000 mg/m² as a single dose or infusion, followed by leucovorin rescue, every 2–3 weeks.

Rheumatoid Arthritis (RA):

• Oral/Subcutaneous: 7.5–15 mg once weekly, titrated up to 20–25 mg based on response and tolerance.

Psoriasis (Severe):

• Oral: 10–25 mg once weekly, adjusted based on skin clearance and toxicity.

Dosage for Children

Juvenile Idiopathic Arthritis (JIA):

• Oral/Subcutaneous: 10–15 mg/m² once weekly, maximum 20 mg, under pediatric rheumatology supervision.

ALL:

• IV: 1–12 g/m² high-dose therapy with leucovorin rescue, tailored to protocol.

Dosage for Pregnant Women

Pregnancy Category X: Contraindicated due to teratogenic risk; consult an obstetrician for alternative therapies.

Dosage Adjustments

Renal Impairment: Mild (CrCl 50–80 mL/min): Reduce by 25%; moderate (CrCl 30–50 mL/min): Reduce by 50%; severe (CrCl <30 mL/min): Avoid.

Hepatic Impairment: Mild to moderate (Child-Pugh A or B): Use cautiously with reduced dose; severe (Child-Pugh C): Contraindicated.

Concomitant Medications: Adjust if combined with NSAIDs or trimethoprim, increasing toxicity; monitor liver function.

Elderly: Start with lower doses (e.g., 5–7.5 mg weekly); monitor renal and hepatic function.

Folate Deficiency: Supplement with folic acid (1 mg daily) to mitigate side effects.

Additional Considerations

• Administer this active ingredient once weekly, with oral doses taken as a single dose or split (e.g., 2.5 mg every 12 hours for 3 doses).
• Take on an empty stomach or with food to reduce nausea, but avoid alcohol.
• Use injectable forms under medical supervision for high-dose regimens.

How to Use Methotrexate

Administration:

• Oral: Swallow tablets whole with water, taken once weekly on a consistent day.
• Subcutaneous/IM: Inject into the thigh or abdomen using a prefilled syringe, rotating sites.
• IV: Administer as an infusion over 30–60 minutes by a healthcare professional.

Timing: Schedule weekly doses (e.g., every Monday) to maintain consistency; high-dose therapy follows protocol schedules.

Monitoring: Watch for mouth sores, fatigue, or signs of infection (e.g., fever); report changes immediately.

Additional Tips:

• Store at 20–25°C (68–77°F), protecting from light and moisture; keep out of reach of children.
• Avoid live vaccines during therapy due to immunosuppression risk.
• Use sunscreen and protective clothing to prevent photosensitivity reactions.
• Schedule regular blood tests (e.g., CBC, liver enzymes) every 1–2 weeks initially, then monthly.
• Educate patients on recognizing early signs of toxicity (e.g., yellowing skin, severe diarrhea).

Contraindications for Methotrexate

Hypersensitivity: Patients with a known allergy to Methotrexate or its components.

Severe Renal Impairment: Contraindicated in CrCl <30 mL/min due to accumulation risk.

Severe Hepatic Disease: Avoid in Child-Pugh Class C due to hepatotoxicity risk.

Pregnancy and Breastfeeding: Contraindicated (Category X) due to teratogenic and fetal harm potential.

Active Infections: Avoid in untreated bacterial, viral, or fungal infections due to immunosuppression.

Alcoholism: Contraindicated due to increased liver damage risk.

Bone Marrow Suppression: Avoid in severe anemia, leukopenia, or thrombocytopenia.

Peptic Ulcer Disease: Contraindicated in active ulcers due to gastrointestinal bleeding risk.

Side Effects of Methotrexate

Common Side Effects

• Nausea (20–30%, managed with antiemetics or food)
• Fatigue (15–25%, improves with rest)
• Mouth Sores (10–20%, relieved with oral rinses)
• Hair Loss (5–15%, reversible post-therapy)
• Rash (5–10%, treated with moisturizers)

These effects may subside with adaptation or dose adjustment.

Serious Side Effects

Additional Notes

Regular monitoring with CBC, liver function tests (LFTs), and creatinine every 1–2 weeks is essential to detect toxicity early.

Patients with pre-existing liver conditions should undergo liver biopsies if therapy exceeds 2 years.

Report any unusual symptoms (e.g., persistent cough, yellowing skin) immediately to a healthcare provider.

Folic acid supplementation (1 mg daily, except on dosing day) can reduce mucosal and hematologic side effects.

Long-term use (>5 years) requires periodic pulmonary function tests to assess for fibrosis.

Warnings & Precautions for Methotrexate

General Warnings

Bone Marrow Suppression: Risk of pancytopenia; monitor CBC weekly during initiation.

Hepatotoxicity: Risk of fibrosis or cirrhosis with long-term use; check liver enzymes monthly.

Pulmonary Toxicity: Risk of interstitial pneumonitis; assess for dyspnea or cough.

Renal Impairment: Risk of toxicity accumulation; monitor CrCl regularly.

Gastrointestinal Ulceration: Risk of bleeding or perforation; avoid in active ulcers.

Additional Warnings

Neurotoxicity: Rare leukoencephalopathy; monitor for confusion or seizures.

Skin Reactions: Risk of severe dermatitis or Stevens-Johnson syndrome; discontinue if rash worsens.

Lymphoproliferative Disorders: Risk with immunosuppression; evaluate lymph nodes.

Photosensitivity: Increased sunburn risk; use sun protection.

Hypersensitivity Reactions: Rare anaphylaxis; stop if severe.

Use in Specific Populations

Pregnancy: Category X; avoid due to teratogenicity.

Breastfeeding: Contraindicated; discontinue nursing.

Elderly: Higher toxicity risk; adjust dose and monitor closely.

Children: Safe for JIA or ALL with oversight.

Renal/Hepatic Impairment: Contraindicated or adjusted based on severity.

Additional Precautions

• Inform your doctor about liver disease, kidney issues, or recent infections before starting this medication.
• Avoid alcohol and NSAIDs to reduce hepatotoxicity and bleeding risk.
• Use contraception during and for 3 months after therapy due to teratogenic effects.

Overdose and Management of Methotrexate

Overdose Symptoms

• Nausea, vomiting, or stomatitis as early signs.
• Severe cases: Bone marrow suppression, renal failure, or seizures.
• Mucosal ulcers, hematemesis, or jaundice with high doses.
• Coma or profound pancytopenia with extremely high exposure.

Immediate Actions

Contact the Medical Team: Seek immediate medical help if overdose is suspected.

Supportive Care: Administer IV fluids, monitor renal function, and transfuse blood products if needed.

Specific Treatment: Use leucovorin (folinic acid) rescue (10–25 mg/m² every 6 hours) until Methotrexate levels fall below 0.05–0.1 µmol/L; consider glucarpidase in severe cases.

Monitor: Check CBC, liver enzymes, and Methotrexate levels every 12–24 hours for 48–72 hours.

Patient Education: Advise against doubling doses and to store securely.

Additional Notes

• Overdose risk is high with dosing errors; use calibrated devices for oral doses.
• Report persistent symptoms (e.g., severe fatigue, black stools) promptly.

Drug Interactions with Methotrexate

This active ingredient may interact with:

• NSAIDs: Increases toxicity (e.g., ibuprofen); avoid or monitor.
• Penicillins: Enhances levels (e.g., amoxicillin); adjust dose.
• Probenecid: Raises Methotrexate concentration; use cautiously.
• Trimethoprim: Potentiates myelosuppression; avoid combination.
• Phenytoin: Reduces Methotrexate efficacy; monitor levels.

Action: Provide your healthcare provider with a complete list of medications.

Patient Education or Lifestyle

Pharmacokinetics of Methotrexate

Absorption: Oral, peak at 1–2 hours; bioavailability 60–80% (reduced by food).

Distribution: Volume of distribution ~0.4–0.8 L/kg; 50–70% protein-bound.

Metabolism: Hepatic to 7-hydroxymethotrexate; polyglutamated in cells.

Excretion: Primarily renal (80–90% unchanged); half-life 3–15 hours (prolonged in renal impairment).

Half-Life: 3–15 hours, with high-dose therapy extending to 24–48 hours.

Pharmacodynamics of Methotrexate

This drug exerts its effects by:

• Inhibiting dihydrofolate reductase, depleting tetrahydrofolate needed for DNA synthesis.
• Suppressing immune responses in RA and psoriasis via adenosine release.
• Exhibiting dose-dependent risks of myelosuppression and hepatotoxicity.

Storage of Methotrexate

Temperature: Store at 20–25°C (68–77°F); protect from light and moisture.

Protection: Keep in original container, away from heat and humidity.

Safety: Store in a secure location out of reach of children and pets due to toxicity risk.

Disposal: Dispose of unused tablets or syringes per local regulations or consult a pharmacist.

Frequently Asked Questions (FAQs)

Q: What does Methotrexate treat?
A: This medication treats cancer, arthritis, and psoriasis.

Q: Can this active ingredient cause nausea?
A: Yes, nausea is common; take with food if needed.

Q: Is Methotrexate safe for children?
A: Yes, for JIA or ALL with supervision.

Q: How is this drug taken?
A: Orally or by injection, once weekly.

Q: How long is Methotrexate treatment?
A: Weeks to months, depending on condition.

Q: Can I use Methotrexate if pregnant?
A: No, it’s contraindicated; consult a doctor.

Regulatory Information

This medication is approved by:

U.S. Food and Drug Administration (FDA): Approved in 1953 for cancer and later for RA and psoriasis.

European Medicines Agency (EMA): Approved for oncology, rheumatology, and dermatology.

Other Agencies: Approved globally for various indications; consult local guidelines.

References

1. U.S. Food and Drug Administration (FDA). (2023). Trexall (Methotrexate) Prescribing Information.
   • Official FDA documentation detailing the drug’s approved uses, dosage, and safety.
2. European Medicines Agency (EMA). (2023). Methotrexate Summary of Product Characteristics.
   • EMA’s comprehensive information on the medication’s indications and precautions in Europe.
3. National Institutes of Health (NIH). (2023). Methotrexate: MedlinePlus Drug Information.
   • NIH resource providing detailed information on the drug’s uses, side effects, and precautions.
4. World Health Organization (WHO). (2023). WHO Model List of Essential Medicines: Methotrexate.
   • WHO’s inclusion of Methotrexate for cancer and autoimmune diseases.
5. Arthritis & Rheumatology. (2022). Methotrexate in RA.
   • Peer-reviewed article on Methotrexate efficacy (note: access may require a subscription).