Otrexup 10mg/0.4ml Inj, 0.4ml
WARNING: Severe side effects like bone marrow problems, liver problems, lung problems, and infections can happen with this drug. Some side effects may not go away and can be deadly. You must talk with the doctor about the risks of this drug. This drug may cause kidney problems in some patients. Talk with the doctor.Regular blood work and other exams will need to be done to check for side effects. Follow what the doctor has told you. Tell your doctor if you have kidney problems or extra fluid around your stomach area or lungs. The chance of side effects may be raised.Talk with your doctor if you are getting radiation. There may be more chance of harm to tissue and bone.New types of cancer have happened in people taking this drug. If you have questions, talk with the doctor.It is common to have diarrhea, upset stomach, throwing up, or mouth sores with this drug. However, sometimes these may be signs of severe and sometimes deadly stomach or bowel problems. Tell your doctor if you get any new or worsening signs. You may need to stop this drug.Severe skin reactions have happened with this drug. These have included Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and other severe skin reactions. Sometimes these have been deadly. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin; other skin irritation (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.Very bad and sometimes deadly bone marrow problems and stomach or bowel problems have happened when this drug was taken with nonsteroidal anti-inflammatory drug (NSAIDs) like ibuprofen or naproxen.Not all methotrexate products are used to treat cancer. Talk with the doctor.This drug may cause harm to an unborn baby or loss of an unborn baby. A pregnancy test will be done before you start this drug to show that you are NOT pregnant.If you or your sex partner may become pregnant, you must use birth control while taking this drug and for some time after the last dose. Ask your doctor how long to use birth control. If you or your sex partner gets pregnant, call your doctor right away.Do not take if you are pregnant.This drug must only be used when other drugs cannot be used or have not worked. Talk with your doctor to be sure that the benefits of this drug are more than the risks. @ COMMON USES: It is used to treat some types of arthritis.It is used to treat some types of psoriasis.It may be given to you for other reasons. Talk with the doctor.
Drug Class
Antirheumatic, Antineoplastic, Immunosuppressant
Pharmacologic Class
Antimetabolite, Folic acid antagonist
Pregnancy Category
Category X
FDA Approved
Oct 2013
DEA Schedule
Not Controlled
Overview
What is this medicine?
Otrexup is a pre-filled syringe containing methotrexate, a medication used to treat certain types of arthritis (like rheumatoid arthritis and juvenile idiopathic arthritis) and severe psoriasis. It works by reducing inflammation and slowing down the overgrowth of certain cells in the body. It is typically given as a shot under the skin once a week.
How to Use This Medicine
Proper Use of This Medication
To use this medication correctly, follow your doctor's instructions and read all the information provided. This medication is administered via injection into the fatty tissue of the skin, typically on the top of the thigh or in the belly area. If you will be self-administering the injection, your doctor or nurse will provide guidance on the proper technique.
Important Administration Guidelines
Do not inject the medication within 2 inches (5 cm) of the belly button.
Check the solution for cloudiness, leakage, or particles before use. If any of these conditions are present, do not use the medication.
Avoid injecting the medication into skin that is irritated, tender, bruised, red, scaly, hard, scarred, or has stretch marks.
If you are unsure whether a dose was injected correctly or experience difficulty administering the dose, consult your doctor or pharmacist before using another dose.
Safe Disposal of Needles and Supplies
Dispose of used needles in a designated needle/sharp disposal box.
Do not reuse needles or other items.
When the disposal box is full, follow local regulations for proper disposal.
If you have any questions, consult your doctor or pharmacist.
Dosing and Frequency
Your dosage and frequency of administration will be determined by your doctor based on the specific health condition being treated.
Important: This medication should never be taken daily unless prescribed for certain types of cancer. Incorrect use of this medication can lead to serious errors. Ensure you understand your dosage and administration schedule. If you are unsure, consult your doctor.
Monitoring and Adjustments
The way you take this medication may change based on blood work results, side effects, and the medication's effectiveness.
Handle this medication with care, and consult your doctor or pharmacist for guidance on proper handling.
Additional Recommendations
Drink plenty of non-caffeinated liquids, unless your doctor advises you to limit fluid intake.
Storage and Disposal
Store this medication at room temperature, protected from light and moisture. Do not store it in a bathroom.
Missed Dose
* If you miss a dose, contact your doctor to determine the best course of action.
To use this medication correctly, follow your doctor's instructions and read all the information provided. This medication is administered via injection into the fatty tissue of the skin, typically on the top of the thigh or in the belly area. If you will be self-administering the injection, your doctor or nurse will provide guidance on the proper technique.
Important Administration Guidelines
Do not inject the medication within 2 inches (5 cm) of the belly button.
Check the solution for cloudiness, leakage, or particles before use. If any of these conditions are present, do not use the medication.
Avoid injecting the medication into skin that is irritated, tender, bruised, red, scaly, hard, scarred, or has stretch marks.
If you are unsure whether a dose was injected correctly or experience difficulty administering the dose, consult your doctor or pharmacist before using another dose.
Safe Disposal of Needles and Supplies
Dispose of used needles in a designated needle/sharp disposal box.
Do not reuse needles or other items.
When the disposal box is full, follow local regulations for proper disposal.
If you have any questions, consult your doctor or pharmacist.
Dosing and Frequency
Your dosage and frequency of administration will be determined by your doctor based on the specific health condition being treated.
Important: This medication should never be taken daily unless prescribed for certain types of cancer. Incorrect use of this medication can lead to serious errors. Ensure you understand your dosage and administration schedule. If you are unsure, consult your doctor.
Monitoring and Adjustments
The way you take this medication may change based on blood work results, side effects, and the medication's effectiveness.
Handle this medication with care, and consult your doctor or pharmacist for guidance on proper handling.
Additional Recommendations
Drink plenty of non-caffeinated liquids, unless your doctor advises you to limit fluid intake.
Storage and Disposal
Store this medication at room temperature, protected from light and moisture. Do not store it in a bathroom.
Missed Dose
* If you miss a dose, contact your doctor to determine the best course of action.
Lifestyle & Tips
- Take exactly as prescribed, usually once a week. Do NOT take daily.
- Take folic acid supplementation as directed by your doctor to reduce side effects (e.g., mouth sores, nausea).
- Avoid alcohol completely while on methotrexate, as it can increase the risk of liver damage.
- Avoid excessive sun exposure and use sunscreen, as methotrexate can increase sun sensitivity.
- Report any signs of infection (fever, chills, sore throat) immediately.
- Avoid live vaccines (e.g., MMR, varicella, nasal flu vaccine) while on methotrexate.
- Maintain good hydration.
Available Forms & Alternatives
Available Strengths:
- Otrexup 10mg/0.4ml Pf Inj 4 X 0.4ml
- Otrexup 15mg/0.4ml Pf Inj 4 X 0.4ml
- Otrexup 20mg/0.4ml Pf Inj 4 X 0.4ml
- Otrexup 25mg/0.4ml Pf Inj 4 X 0.4ml
- Otrexup 10mg/0.4ml Inj, 0.4ml
- Otrexup 17.5mg/0.4ml Pf Injection
- Otrexup 12.5/0.4ml Inj, 0.4ml
- Otrexup 22.5/0.4ml Inj, 0.4ml
- Otrexup 17.5mg/0.4ml Pf Injection
- Otrexup 22.5/0.4ml Inj, 0.4ml
Dosing & Administration
Adult Dosing
Standard Dose:
For Rheumatoid Arthritis (RA) or Psoriasis: 10 mg to 25 mg once weekly, administered subcutaneously.
Dose Range:
10 - 25 mg
Condition-Specific Dosing:
Rheumatoid Arthritis:
Initial: 7.5 mg once weekly, adjusted to optimal response, typically 10-25 mg once weekly. Max 25 mg/week.
Psoriasis:
Initial: 10-25 mg once weekly as a single dose, or 2.5 mg every 12 hours for 3 doses each week (total 7.5 mg/week). Max 25 mg/week.
Pediatric Dosing
Neonatal:
Not established
Infant:
Not established
Child:
For Polyarticular Juvenile Idiopathic Arthritis (pJIA): Initial 10 mg/m² once weekly, adjusted to optimal response, typically 10-30 mg/m² once weekly. Max 25 mg/week.
Adolescent:
For Polyarticular Juvenile Idiopathic Arthritis (pJIA): Initial 10 mg/m² once weekly, adjusted to optimal response, typically 10-30 mg/m² once weekly. Max 25 mg/week.
Dose Adjustments
Renal Impairment:
Mild:
CrCl 51-80 mL/min: Consider 25% dose reduction or close monitoring.
Moderate:
CrCl 10-50 mL/min: Consider 50% dose reduction or avoid use. Methotrexate elimination is significantly impaired.
Severe:
CrCl <10 mL/min: Contraindicated.
Dialysis:
Methotrexate is poorly dialyzable. Contraindicated in patients requiring dialysis due to prolonged elimination and increased toxicity risk.
Hepatic Impairment:
Mild:
Use with caution. Monitor liver function closely.
Moderate:
Avoid or use with extreme caution. Significant risk of hepatotoxicity.
Severe:
Contraindicated in patients with severe hepatic impairment (e.g., cirrhosis, ascites, significant elevation of liver enzymes).
Pharmacology
Mechanism of Action
Methotrexate is an antimetabolite that inhibits dihydrofolate reductase (DHFR), an enzyme essential for DNA synthesis, repair, and cellular replication. By inhibiting DHFR, methotrexate prevents the reduction of dihydrofolate to tetrahydrofolate, a critical cofactor for purine and pyrimidine synthesis. This leads to inhibition of DNA, RNA, and protein synthesis. In rheumatologic and dermatologic conditions, its anti-inflammatory and immunosuppressive effects are thought to be due to inhibition of lymphocyte proliferation, induction of adenosine release, and inhibition of polymorphonuclear leukocyte chemotaxis.
Pharmacokinetics
Absorption:
Bioavailability:
Subcutaneous: Approximately 80-90% (compared to IV). Oral bioavailability is variable and dose-dependent (e.g., 30-50% at doses >30 mg/m²).
Tmax:
Subcutaneous: 1-2 hours.
FoodEffect:
Not significant for subcutaneous administration. Oral absorption may be delayed by food.
Distribution:
Vd:
0.4-0.8 L/kg (initial distribution phase); higher in ascites or pleural effusions.
ProteinBinding:
Approximately 50% (primarily to albumin).
CnssPenetration:
Limited (poorly crosses the blood-brain barrier at conventional doses; higher doses or intrathecal administration are needed for therapeutic CNS concentrations).
Elimination:
HalfLife:
Terminal half-life: 3-10 hours (low dose); 8-15 hours (high dose). Prolonged in renal impairment or third-space fluid accumulation.
Clearance:
Primarily renal clearance via glomerular filtration and active tubular secretion.
ExcretionRoute:
Mainly renal (50-90% unchanged within 24 hours); small amount via biliary excretion (5-10%).
Unchanged:
50-90%
Pharmacodynamics
OnsetOfAction:
Rheumatoid Arthritis/Psoriasis: Clinical improvement typically seen within 3-6 weeks, with full effect potentially taking 12 weeks or longer.
PeakEffect:
Not directly applicable as a single peak effect for chronic conditions; refers to maximal therapeutic benefit over time.
DurationOfAction:
Effects persist as long as weekly dosing is maintained. Elimination half-life dictates dosing frequency.
Safety & Warnings
BLACK BOX WARNING
Methotrexate has several Black Box Warnings:
1. **Bone Marrow Suppression:** May occur abruptly and lead to severe myelosuppression, aplastic anemia, and pancytopenia. Monitor CBCs frequently.
2. **Hepatotoxicity:** Can cause acute and chronic liver toxicity, including fibrosis and cirrhosis. Monitor LFTs frequently. Avoid alcohol.
3. **Nephrotoxicity:** Renal impairment can lead to accumulation and increased toxicity. Monitor renal function.
4. **Pulmonary Toxicity:** Acute or chronic interstitial pneumonitis can occur at any time during therapy and may be fatal. Symptoms include dry cough, fever, dyspnea.
5. **Gastrointestinal Toxicity:** Diarrhea, stomatitis, and mucositis can be severe and require interruption of therapy. Hemorrhagic enteritis and intestinal perforation may occur.
6. **Opportunistic Infections:** Increased risk of serious, sometimes fatal, opportunistic infections, including Pneumocystis jirovecii pneumonia.
7. **Tumor Lysis Syndrome:** May occur in patients with rapidly growing tumors.
8. **Dermatologic Reactions:** Severe, potentially fatal, dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) have been reported.
9. **Secondary Malignancy:** Lymphoma and other malignancies have been reported.
10. **Concomitant Use with NSAIDs:** Concomitant administration of NSAIDs with high-dose methotrexate has been reported to elevate and prolong serum methotrexate levels, resulting in severe and fatal toxicities. Caution should be used when NSAIDs are administered concomitantly with low-dose methotrexate.
1. **Bone Marrow Suppression:** May occur abruptly and lead to severe myelosuppression, aplastic anemia, and pancytopenia. Monitor CBCs frequently.
2. **Hepatotoxicity:** Can cause acute and chronic liver toxicity, including fibrosis and cirrhosis. Monitor LFTs frequently. Avoid alcohol.
3. **Nephrotoxicity:** Renal impairment can lead to accumulation and increased toxicity. Monitor renal function.
4. **Pulmonary Toxicity:** Acute or chronic interstitial pneumonitis can occur at any time during therapy and may be fatal. Symptoms include dry cough, fever, dyspnea.
5. **Gastrointestinal Toxicity:** Diarrhea, stomatitis, and mucositis can be severe and require interruption of therapy. Hemorrhagic enteritis and intestinal perforation may occur.
6. **Opportunistic Infections:** Increased risk of serious, sometimes fatal, opportunistic infections, including Pneumocystis jirovecii pneumonia.
7. **Tumor Lysis Syndrome:** May occur in patients with rapidly growing tumors.
8. **Dermatologic Reactions:** Severe, potentially fatal, dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) have been reported.
9. **Secondary Malignancy:** Lymphoma and other malignancies have been reported.
10. **Concomitant Use with NSAIDs:** Concomitant administration of NSAIDs with high-dose methotrexate has been reported to elevate and prolong serum methotrexate levels, resulting in severe and fatal toxicities. Caution should be used when NSAIDs are administered concomitantly with low-dose methotrexate.
Side Effects
Urgent Side Effects: Seek Medical Help Right Away
Although rare, some people may experience severe and potentially life-threatening side effects while taking this medication. If you notice any of the following symptoms, contact your doctor immediately or seek emergency medical attention:
Allergic Reaction: Rash, hives, itching, redness, swelling, blistering, or peeling skin (with or without fever), wheezing, tightness in the chest or throat, difficulty breathing, swallowing, or talking, unusual hoarseness, or swelling of the mouth, face, lips, tongue, or throat.
Infection: Fever, chills, severe sore throat, ear or sinus pain, cough, increased or discolored sputum, painful urination, mouth sores, or a wound that won't heal.
Bleeding: Vomiting or coughing up blood, coffee ground-like vomit, blood in the urine, black, red, or tarry stools, gum bleeding, abnormal vaginal bleeding, unexplained bruises or bruising that worsens, or uncontrollable bleeding.
Pancreatitis: Severe stomach pain, severe back pain, or severe nausea and vomiting.
Kidney Problems: Inability to urinate, changes in urine output, blood in the urine, or sudden weight gain.
Liver Problems: Dark urine, fatigue, decreased appetite, nausea or stomach pain, light-colored stools, vomiting, or yellowing of the skin or eyes.
Lung or Breathing Problems: Shortness of breath, difficulty breathing, cough, or fever.
Nerve Problems: Abnormal burning, numbness, or tingling sensations; weakness; or paralysis (inability to move a body part).
Other Severe Symptoms: Pinpoint red spots on the skin, severe dizziness or fainting, seizures, confusion, excessive sleepiness, changes in vision, bone pain, swelling, warmth, numbness, color changes, or pain in a leg or arm, weakness on one side of the body, speech or thinking difficulties, balance problems, drooping on one side of the face, or blurred vision, headache, or neck stiffness.
Other Possible Side Effects
Most medications can cause side effects, but many people experience none or only mild symptoms. If you're concerned about any of the following side effects or if they persist, contact your doctor:
Decreased appetite
Hair loss
Dizziness, fatigue, or weakness
Stomach pain
Common cold symptoms
This is not an exhaustive list of potential side effects. If you have questions or concerns, consult your doctor. You can also report side effects to the FDA at 1-800-332-1088 or online at https://www.fda.gov/medwatch.
Although rare, some people may experience severe and potentially life-threatening side effects while taking this medication. If you notice any of the following symptoms, contact your doctor immediately or seek emergency medical attention:
Allergic Reaction: Rash, hives, itching, redness, swelling, blistering, or peeling skin (with or without fever), wheezing, tightness in the chest or throat, difficulty breathing, swallowing, or talking, unusual hoarseness, or swelling of the mouth, face, lips, tongue, or throat.
Infection: Fever, chills, severe sore throat, ear or sinus pain, cough, increased or discolored sputum, painful urination, mouth sores, or a wound that won't heal.
Bleeding: Vomiting or coughing up blood, coffee ground-like vomit, blood in the urine, black, red, or tarry stools, gum bleeding, abnormal vaginal bleeding, unexplained bruises or bruising that worsens, or uncontrollable bleeding.
Pancreatitis: Severe stomach pain, severe back pain, or severe nausea and vomiting.
Kidney Problems: Inability to urinate, changes in urine output, blood in the urine, or sudden weight gain.
Liver Problems: Dark urine, fatigue, decreased appetite, nausea or stomach pain, light-colored stools, vomiting, or yellowing of the skin or eyes.
Lung or Breathing Problems: Shortness of breath, difficulty breathing, cough, or fever.
Nerve Problems: Abnormal burning, numbness, or tingling sensations; weakness; or paralysis (inability to move a body part).
Other Severe Symptoms: Pinpoint red spots on the skin, severe dizziness or fainting, seizures, confusion, excessive sleepiness, changes in vision, bone pain, swelling, warmth, numbness, color changes, or pain in a leg or arm, weakness on one side of the body, speech or thinking difficulties, balance problems, drooping on one side of the face, or blurred vision, headache, or neck stiffness.
Other Possible Side Effects
Most medications can cause side effects, but many people experience none or only mild symptoms. If you're concerned about any of the following side effects or if they persist, contact your doctor:
Decreased appetite
Hair loss
Dizziness, fatigue, or weakness
Stomach pain
Common cold symptoms
This is not an exhaustive list of potential side effects. If you have questions or concerns, consult your doctor. You can also report side effects to the FDA at 1-800-332-1088 or online at https://www.fda.gov/medwatch.
Seek Immediate Medical Attention If You Experience:
- Severe nausea, vomiting, or diarrhea
- Mouth sores or ulcers
- Unusual bleeding or bruising
- Signs of infection (fever, chills, persistent sore throat)
- Yellowing of skin or eyes (jaundice)
- Dark urine
- Shortness of breath, persistent dry cough
- Severe skin rash, blistering, or peeling
- Swelling in ankles or feet
- Severe fatigue or weakness
Before Using This Medicine
Before Taking This Medication: Important Information to Share with Your Doctor
It is essential to inform your doctor about the following:
Any allergies you have, including allergies to this medication, its components, or other substances, such as foods or drugs. Be sure to describe the symptoms you experienced.
Certain health conditions, including:
+ Alcohol use disorder
+ Bone marrow disease, such as low white blood cell count, low platelet count, or anemia
+ Kidney disease
+ Liver disease
+ A weak immune system
If you are breast-feeding, please note that you should not breast-feed while taking this medication. Additionally, you may need to avoid breast-feeding for a period after your last dose. Consult your doctor to determine the necessary duration.
This list is not exhaustive, and it is crucial to discuss all your medications (prescription, over-the-counter, natural products, and vitamins) and health problems with your doctor and pharmacist. This will help ensure your safety while taking this medication. Never start, stop, or change the dose of any medication without first consulting your doctor.
It is essential to inform your doctor about the following:
Any allergies you have, including allergies to this medication, its components, or other substances, such as foods or drugs. Be sure to describe the symptoms you experienced.
Certain health conditions, including:
+ Alcohol use disorder
+ Bone marrow disease, such as low white blood cell count, low platelet count, or anemia
+ Kidney disease
+ Liver disease
+ A weak immune system
If you are breast-feeding, please note that you should not breast-feed while taking this medication. Additionally, you may need to avoid breast-feeding for a period after your last dose. Consult your doctor to determine the necessary duration.
This list is not exhaustive, and it is crucial to discuss all your medications (prescription, over-the-counter, natural products, and vitamins) and health problems with your doctor and pharmacist. This will help ensure your safety while taking this medication. Never start, stop, or change the dose of any medication without first consulting your doctor.
Precautions & Cautions
It is essential to inform all your healthcare providers, including doctors, nurses, pharmacists, and dentists, that you are taking this medication.
When starting this medication, avoid driving and other activities that require alertness until you understand how it affects you. You may be more susceptible to infections, so it's crucial to practice good hygiene by washing your hands frequently and avoiding close contact with people who have infections, colds, or flu.
Be aware that this medication may increase your risk of bleeding easily. To minimize this risk, be cautious and avoid injuries. Use a soft-bristled toothbrush and an electric razor for shaving.
Before receiving any vaccinations, consult your doctor, as some vaccines may not be effective or may increase the risk of infection when taken with this medication. Additionally, discuss your alcohol consumption with your doctor.
You may be more prone to sunburn while taking this medication. To protect yourself, avoid direct sunlight, sunlamps, and tanning beds. Use sunscreen and wear protective clothing and eyewear when going outside. Continue to take these precautions for as long as your doctor advises.
If you experience excessive fluid loss, unusual sweating, vomiting, diarrhea, decreased appetite, or unusual thirst, notify your doctor promptly. This medication can cause severe nervous system problems, which may be temporary or long-lasting and can worsen over time. In some cases, these problems may not improve and can be life-threatening. If you have concerns, discuss them with your doctor.
If you have undergone radiation therapy, inform your doctor. Elderly patients (65 years and older) should use this medication with caution, as they may be more susceptible to side effects.
This medication may affect fertility, potentially leading to difficulty getting pregnant or fathering a child. It is unclear whether fertility will return to normal if this occurs. If you miss a menstrual period, have unprotected sex, or suspect that your birth control has failed, contact your doctor immediately.
When starting this medication, avoid driving and other activities that require alertness until you understand how it affects you. You may be more susceptible to infections, so it's crucial to practice good hygiene by washing your hands frequently and avoiding close contact with people who have infections, colds, or flu.
Be aware that this medication may increase your risk of bleeding easily. To minimize this risk, be cautious and avoid injuries. Use a soft-bristled toothbrush and an electric razor for shaving.
Before receiving any vaccinations, consult your doctor, as some vaccines may not be effective or may increase the risk of infection when taken with this medication. Additionally, discuss your alcohol consumption with your doctor.
You may be more prone to sunburn while taking this medication. To protect yourself, avoid direct sunlight, sunlamps, and tanning beds. Use sunscreen and wear protective clothing and eyewear when going outside. Continue to take these precautions for as long as your doctor advises.
If you experience excessive fluid loss, unusual sweating, vomiting, diarrhea, decreased appetite, or unusual thirst, notify your doctor promptly. This medication can cause severe nervous system problems, which may be temporary or long-lasting and can worsen over time. In some cases, these problems may not improve and can be life-threatening. If you have concerns, discuss them with your doctor.
If you have undergone radiation therapy, inform your doctor. Elderly patients (65 years and older) should use this medication with caution, as they may be more susceptible to side effects.
This medication may affect fertility, potentially leading to difficulty getting pregnant or fathering a child. It is unclear whether fertility will return to normal if this occurs. If you miss a menstrual period, have unprotected sex, or suspect that your birth control has failed, contact your doctor immediately.
Overdose Information
Overdose Symptoms:
- Severe myelosuppression (low white blood cells, red blood cells, platelets)
- Severe mucositis (mouth sores, GI inflammation)
- Acute renal failure
- Hepatotoxicity
What to Do:
Call 1-800-222-1222 (Poison Control Center) immediately. Leucovorin rescue is the primary antidote for methotrexate overdose, administered as soon as possible. Glucarpidase may be used in cases of delayed methotrexate elimination due to impaired renal function.
Drug Interactions
Contraindicated Interactions
- Live vaccines (increased risk of infection)
- Pemetrexed (severe myelosuppression)
- Probenecid (decreased methotrexate clearance)
- Trimethoprim/Sulfamethoxazole (increased methotrexate toxicity)
Major Interactions
- NSAIDs (e.g., ibuprofen, naproxen, diclofenac): Increased and prolonged methotrexate levels, leading to severe toxicity (myelosuppression, nephrotoxicity). Use with extreme caution, especially with high-dose methotrexate.
- Salicylates (e.g., aspirin): Increased methotrexate levels and toxicity.
- Proton Pump Inhibitors (PPIs) (e.g., omeprazole, pantoprazole): May increase and prolong methotrexate serum levels, particularly at high doses.
- Folic acid antagonists (e.g., pyrimethamine, trimetrexate): Additive toxicity.
- Nitrous oxide: May potentiate methotrexate toxicity by inhibiting methionine synthase.
- Retinoids (e.g., acitretin, etretinate): Increased risk of hepatotoxicity.
- Phenytoin: Decreased phenytoin levels, increased methotrexate toxicity.
- Sulfonamides (e.g., sulfasalazine): Increased methotrexate toxicity due to displacement from protein binding and/or reduced renal clearance.
- Tetracyclines, Chloramphenicol: May interfere with enterohepatic recirculation, increasing methotrexate levels.
Moderate Interactions
- Oral antibiotics (e.g., neomycin, penicillin, tetracycline): May alter gut flora, affecting methotrexate absorption/metabolism.
- Theophylline: Methotrexate may decrease theophylline clearance.
- Caffeine: High caffeine intake may reduce methotrexate efficacy in RA (theoretical, not consistently proven clinically significant).
Minor Interactions
- Not available
Monitoring
Baseline Monitoring
Complete Blood Count (CBC) with differential and platelets
Rationale: To establish baseline hematologic status and detect pre-existing myelosuppression.
Timing: Prior to initiation of therapy.
Liver Function Tests (LFTs) including AST, ALT, albumin, bilirubin
Rationale: To establish baseline liver function and detect pre-existing hepatic impairment.
Timing: Prior to initiation of therapy.
Renal Function Tests (Serum Creatinine, eGFR, BUN)
Rationale: To establish baseline renal function, as methotrexate is primarily renally cleared.
Timing: Prior to initiation of therapy.
Chest X-ray (CXR)
Rationale: To rule out pre-existing pulmonary disease, especially if pulmonary symptoms are present, due to risk of methotrexate pneumonitis.
Timing: Prior to initiation of therapy (optional, based on clinical judgment).
Hepatitis B and C serology
Rationale: To screen for chronic viral hepatitis, which can be exacerbated by immunosuppression.
Timing: Prior to initiation of therapy.
Routine Monitoring
Complete Blood Count (CBC) with differential and platelets
Frequency: Every 2-4 weeks for the first 3-6 months, then every 1-2 months.
Target: Maintain WBC >3,000/mm³, ANC >1,500/mm³, Platelets >100,000/mm³.
Action Threshold: Hold dose for significant drops (e.g., WBC <3,000, ANC <1,500, Platelets <100,000); consider dose reduction or discontinuation.
Liver Function Tests (AST, ALT, albumin)
Frequency: Every 2-4 weeks for the first 3-6 months, then every 1-2 months.
Target: AST/ALT <2x ULN (Upper Limit of Normal).
Action Threshold: Hold dose for persistent AST/ALT elevation >2x ULN; consider liver biopsy for persistent elevations or if cumulative dose is high.
Renal Function Tests (Serum Creatinine, eGFR)
Frequency: Every 2-4 weeks for the first 3-6 months, then every 1-2 months.
Target: Stable creatinine, eGFR within normal limits for age.
Action Threshold: Hold dose or reduce dose for significant increase in creatinine or decrease in eGFR.
Symptom Monitoring
- Signs of infection (fever, chills, sore throat)
- Unusual bleeding or bruising (petechiae, purpura)
- Fatigue, weakness, pallor (anemia)
- Shortness of breath, cough (pneumonitis)
- Nausea, vomiting, diarrhea, oral ulcers (GI toxicity, mucositis)
- Yellowing of skin or eyes, dark urine (hepatotoxicity)
- Skin rash, itching, peeling skin (dermatologic reactions)
- Headache, dizziness, confusion (CNS effects, rare at low doses)
Special Patient Groups
Pregnancy
Contraindicated in pregnancy for non-oncologic indications (e.g., RA, psoriasis) due to significant risk of fetal death and severe birth defects. Women of childbearing potential must use effective contraception during and for at least 6 months after therapy. Men should use effective contraception during and for at least 3 months after therapy.
Trimester-Specific Risks:
First Trimester:
High risk of major congenital malformations (e.g., craniofacial, limb, CNS abnormalities) and fetal death.
Second Trimester:
Risk of fetal toxicity, growth restriction, and potential for malformations.
Third Trimester:
Risk of fetal toxicity and adverse pregnancy outcomes.
Lactation
Contraindicated during breastfeeding. Methotrexate is excreted into breast milk and can cause serious adverse reactions in a breastfed infant, including myelosuppression.
Infant Risk:
High risk of myelosuppression, immunosuppression, and other toxicities.
Pediatric Use
Approved for polyarticular juvenile idiopathic arthritis (pJIA). Dosing is weight/body surface area-based. Close monitoring for toxicity is essential, similar to adults. Risk of hepatotoxicity and myelosuppression is present.
Geriatric Use
Use with caution due to increased likelihood of decreased renal and hepatic function, and concomitant diseases or other drug therapy. Dose adjustments may be necessary based on renal function. Increased susceptibility to toxicity (e.g., myelosuppression, hepatotoxicity).
Clinical Information
Clinical Pearls
- Methotrexate is a once-weekly medication. Emphasize this to patients to prevent accidental daily dosing, which can be fatal.
- Folic acid supplementation (typically 1-5 mg once weekly, 24-48 hours after methotrexate dose) is crucial to reduce common side effects like mucositis, nausea, and myelosuppression, without significantly impacting efficacy.
- Strict avoidance of alcohol is paramount due to the risk of hepatotoxicity.
- Patients should be educated on signs of infection, bleeding, and pulmonary symptoms, and to report them immediately.
- Renal function is a key determinant of methotrexate clearance; monitor closely and adjust dose as needed.
- Otrexup is a pre-filled syringe designed for ease of subcutaneous administration, which can improve adherence and reduce GI side effects compared to oral formulations.
Alternative Therapies
- Other conventional synthetic DMARDs (csDMARDs): Hydroxychloroquine, Sulfasalazine, Leflunomide
- Biologic DMARDs (bDMARDs): TNF inhibitors (e.g., Adalimumab, Etanercept, Infliximab), IL-6 inhibitors (e.g., Tocilizumab), T-cell costimulation modulators (e.g., Abatacept), B-cell depleting agents (e.g., Rituximab)
- Targeted Synthetic DMARDs (tsDMARDs): JAK inhibitors (e.g., Tofacitinib, Baricitinib, Upadacitinib)
- For Psoriasis: Phototherapy, other systemic agents (e.g., Cyclosporine, Apremilast), biologics (e.g., Ustekinumab, Secukinumab, Ixekizumab)
Cost & Coverage
Average Cost:
Varies significantly by strength and pharmacy. For Otrexup 10mg/0.4ml, typically $500-$1000+ per 4 prefilled syringes
Generic Available:
Yes
Insurance Coverage:
Tier 2 or 3 (Specialty drug). Often requires prior authorization.
General Drug Facts
If your symptoms or health issues persist or worsen, it's essential to contact your doctor for further guidance. To ensure your safety, never share your medication with others or take someone else's medication. Some medications may come with an additional patient information leaflet, so be sure to check with your pharmacist for more information. If you have any questions or concerns about your medication, don't hesitate to reach out to your doctor, nurse, pharmacist, or other healthcare provider. In the event of a suspected overdose, immediately call your local poison control center or seek medical attention. When seeking help, be prepared to provide details about the medication, including the amount taken and the time it happened, to ensure you receive the best possible care.