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Rheumatrex Dose Pack Side Effects

Generic Name: methotrexate

Note: This page contains side effects data for the generic drug methotrexate. It is possible that some of the dosage forms included below may not apply to the brand name Rheumatrex Dose Pack.

In Summary

Common side effects of Rheumatrex Dose Pack include: increased liver enzymes. See below for a comprehensive list of adverse effects.

For the Consumer

Applies to methotrexate: oral tablet

As well as its needed effects, methotrexate (the active ingredient contained in Rheumatrex Dose Pack) may cause unwanted side effects that require medical attention.

Major Side Effects

If any of the following side effects occur while taking methotrexate, check with your doctor immediately:

More common:
  • Black, tarry stools
  • blood in the urine or stools
  • bloody vomit
  • diarrhea
  • joint pain
  • reddening of the skin
  • sores in the mouth or lips
  • stomach pain
  • swelling of the feet or lower legs
Less common:
  • Back pain
  • blurred vision
  • confusion
  • convulsions (seizures)
  • cough or hoarseness
  • dark urine
  • dizziness
  • drowsiness
  • fever or chills
  • headache
  • lower back or side pain
  • painful or difficult urination
  • pinpoint red spots on the skin
  • shortness of breath
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • yellow eyes or skin

Minor Side Effects

Some methotrexate side effects may not need any medical attention. As your body gets used to the medicine these side effects may disappear. Your health care professional may be able to help you prevent or reduce these side effects, but do check with them if any of the following side effects continue, or if you are concerned about them:

More common:
  • Hair loss, temporary
  • loss of appetite
  • nausea or vomiting
Less common:
  • Acne
  • boils on skin
  • pale skin
  • skin rash or itching

For Healthcare Professionals

Applies to methotrexate: compounding powder, injectable powder for injection, injectable solution, oral tablet, subcutaneous solution


Uncommon (0.1% to 1%): Vasculitis
Rare (less than 0.1%): Pericarditis, pericardial effusion, pericardial tamponade, hypotension, thromboembolic events (e.g., arterial thrombosis, cerebral thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein thrombosis, pulmonary embolism), myocardial ischemia
Frequency not reported: Cerebral edema[Ref]


Common (1% to 10%): Exanthema, erythema, itching
Uncommon (0.1% to 1%): Urticaria, photosensitivity, depigmentation or hyperpigmentation of the skin, alopecia, increase of rheumatic nodules, painful lesions of psoriatic plaque, herpetiform eruption of the skin, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome)
Rare (0.01% to 0.1%): Increased pigmentary changes of nails, acne, petechiae, ecchymoses, erythema multiforme, cutaneous erythematous eruptions
Very rare (less than 0.01%): Furunculosis, telangiectasia
Frequency not reported: Exfoliative dermatitis, skin necrosis, skin ulceration, folliculitis, hidradenitis, allergic vasculitis[Ref]


Uncommon (0.1% to 1%): Inflammation and ulceration of the vagina
Very rare (less than 0.01%): Loss of libido (males and females), impotence, impaired menstruation, vaginal discharge, infertility, abortion, fetal death, fetal defects, gynecomastia, defective oogenesis or spermatogenesis, transient oligospermia, vaginal bleeding[Ref]


Very common (10% or more): Anorexia, nausea, vomiting, abdominal pain, inflammation, ulcerations of the mucous membrane of mouth and throat (especially during the first 24 to 48 hours after administration), stomatitis, dyspepsia, dehydration
Common (1% to 10%): Diarrhea (especially during the first 24 to 48 hours after administration)
Uncommon (0.1% to 1%): GI bleeding and ulcers, pancreatitis
Rare (0.01% to 0.1%): Gingivitis, enteritis, melena, malabsorption
Very rare (less than 0.01%): Hematemesis, toxic megacolon
Frequency not reported: Glossitis[Ref]


Generally, the incidence and severity of acute side effects are related to dose and frequency of administration. The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, abdominal distress, malaise, undue fatigue, chills and fever, dizziness, and decreased resistance to infection.[Ref]


Uncommon (0.1% to 1%): Dysuria
Rare (0.01% to 0.1%): Oliguria, anuria, azotemia
Very rare (less than 0.01%): Proteinuria
Frequency not reported: Cystitis, hematuria[Ref]


Common (1% to 10%): Leukocytopenia, thrombocytopenia, anemia
Uncommon (0.1% to 1%): Pancytopenia, agranulocytosis, hematopoietic disorders
Rare (0.01% to 0.1%): Megaloblastic anemia
Very rare (less than 0.01%): Severe bone marrow depression, aplastic anemia, lymphadenopathy, lymphoproliferative disorders (partly reversible), eosinophilia, neutropenia
Frequency not reported: Hemorrhage, hematoma, myelosuppression[Ref]

Preexisting myelosuppression or low hematologic cell counts are contraindications to the use of this drug, particularly in patients with rheumatoid arthritis or psoriasis. Close monitoring of the CBC is mandatory. Profound count nadirs may require therapy discontinuation, at least temporarily. Folate therapy and/or leucovorin rescue may be preventive or palliative. Treated patients who become febrile should be assumed to have neutropenia until proven otherwise.

Cytopenia occurs in 5% to 25% of patients with rheumatoid arthritis (RA) who receive long-term therapy. Risk factors include renal dysfunction, preexisting folate deficiency, increased mean corpuscular volume value, advanced age, concomitant use of other anti-folate medications (such as trimethoprim-sulfamethoxazole), and possibly hypoalbuminemia, concomitant infection, history of bone marrow injury, surgery, and concurrent use of NSAIDs or probenecid. Pancytopenia is rarely observed in patients with rheumatoid arthritis. Bone marrow recovery typically occurs within two weeks after the withdrawal of MTX.[Ref]


Very common (10% or more): Increase in liver related enzymes (ALAT, ASAT, alkaline phosphatase, bilirubin, and LDH levels) is commonly reported but usually resolves within one month after cessation of therapy
Uncommon (0.1% to 1%): Development of liver fattening, fibrosis and cirrhosis (occurs frequently despite regularly monitored, normal values of liver enzymes), drop of serum albumin
Rare (0.01% to 0.1%): Acute hepatitis, hepatotoxicity
Very rare (less than 0.01%): Reactivation of chronic hepatitis, acute liver degeneration, liver insufficiency, liver failure, liver atrophy, necrosis[Ref]

Methotrexate can cause acute elevations of liver function tests (elevated serum transaminases in 15% of patients with rheumatoid arthritis (RA) on low-dose therapy) or chronic hepatotoxicity (fibrosis and cirrhosis). The incidence of liver fibrosis and cirrhosis in patients with RA (low doses) averages 3% to 7% and 0.1%, respectively. Meta-analysis has revealed the incidence of progression of liver disease (worsening of 1 grade on the histologic classification of Roenigk) in patients with RA or psoriatic arthritis averages 27%, or 7% per gram of MTX (total dose) given. Chronic hepatotoxicity typically develops only after chronic use of higher doses (2 years or more of total doses of 1.5 grams or more), is more likely in patients who ingest ethanol, who are aged, who are obese, who have chronic renal insufficiency, or who have diabetes.

In general, the following serve as guidelines for patients with non-oncologic conditions:

1) Screen all patients to be treated with complete liver blood tests (transaminases, albumin, alkaline phosphatase, bilirubin), hepatitis B and C serologic studies (some experts recommend viral serology's only in patients with abnormal liver function tests), baseline serum creatinine and complete blood count (CBC);
2) Baseline liver biopsy if the patient has preexisting liver disease, persistently abnormal baseline AST (aspartate aminotransferase), history of excessive alcohol consumption (greater than 3 drinks/day), or chronic hepatitis B or C infection;
3) Monitor hepatic enzymes every 4 to 8 weeks (with the understanding that they are not necessarily predictive of fibrosis/cirrhosis), discontinuing MTX if serum transaminase levels meet or exceed 2 to 3x baseline (some guidelines recommend withholding MTX for 1 to 2 weeks if significant abnormalities persist);
4) Liver biopsy should be considered if significant hepatic enzyme abnormalities persist for 2 to 3 months. Liver biopsy should be performed if 6 of 12 monthly AST levels are above the upper limit of normal or serum albumin levels are less than normal in the setting of well controlled disease;
5) If liver biopsy shows Roenigk grade I, II, or IIIA (mild fibrosis), MTX may be resumed with monitoring as described above; if liver biopsy show Roenigk grade IIIB (moderate fibrosis) or IV (cirrhosis), MTX should be discontinued;
6) MTX should be discontinued in patients with significant liver abnormalities, as described above, who refuse liver biopsy;
7) It is still debated whether post-therapy biopsy should be performed every 2 to 3 years or after each 1.5 to 2.0 grams cumulative dose given, regardless of liver chemistries.

*Pre-biopsy coagulation studies and withholding of aspirin and other NSAIDs are recommended.[Ref]


Uncommon (0.1% to 1%): Allergic vasculitis, severe allergic reactions progressing to anaphylactic shock[Ref]


Common (1% to 10%): Disseminated herpes zoster, pneumocystis carinii pneumonia
Very rare (less than 0.01%): Immunosuppression, hypogammaglobulinemia, sepsis, opportunistic infections (may be fatal in some cases), infections caused by the cytomegalic virus, acute paronychia
Frequency not reported: Nocardiosis, cryptococcus mycosis, disseminated herpes simplex, listeria meningitis, mycobacterium avium, intracellular pneumonia, systemic fungal infections (e.g., cryptococcosis, nocardiosis, aspergillosis, histoplasmosis), sepsis, decreased resistance to infection, pneumocystis jiroveci, pneumonia (most common infection), respiratory tract infection, cutaneous bacterial infections, pneumonia, reactivation of hepatitis B infection, worsening of hepatitis C infection[Ref]

New and/or opportunistic infection can arise during or after therapy with methotrexate due to drug-induced immune suppression. Infections during MTX therapy may occur in up to 58% of patients during low-dose therapy (as in RA). Patients are at great risk after high-dose therapy.

MTX should be held prior to and during elective surgery to minimize the risk of infectious complications.

Limited data have shown that the use of low-dose MTX for patients with rheumatoid arthritis is associated with decreased CD8 and naive CD4 T lymphocytes after only 8 weeks of therapy.

Methotrexate is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes. Immunization may be ineffective when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving methotrexate therapy.[Ref]


Uncommon (0.1% to 1%): Osteoporosis, arthralgia, myalgia
Rare (0.01% to 0.1%): Stress fracture, nodulosis
Very rare (less than 0.01%): Pain, muscular asthenia or paresthesia of the extremities
Frequency not reported: Osteoporosis, osteonecrosis (aseptic necrosis of the femoral head), soft tissue necrosis, abnormal tissue cell changes, arthralgia/myalgia, back pain[Ref]

Nervous system

Common (1% to 10%): Headache, fatigue, drowsiness
Uncommon (0.1% to 1%): Vertigo, confusion, seizures, convulsion, encephalopathy
Very rare (less than 0.01%): Paresis, effect on speech including dysarthria and aphasia, myelopathy, changes in sense of taste (metallic taste), meningism, acute aseptic meningitis[Ref]


Rare (0.01% to 0.1%): Severely impaired vision, visual disturbances, blurred vision
Very rare (less than 0.01%): Conjunctivitis, retinopathy, transient blindness/loss of vision, periorbital edema, blepharitis, epiphora, photophobia, eye discomfort[Ref]


Frequency not reported: Lymphomas and leukemias have been associated with this drug[Ref]


Very rare (less than 0.01%): Fever, impaired wound healing
Frequency not reported: Fetal death, fetal damage, abortion, tinnitus, chills, malaise, fatigue[Ref]


Uncommon (0.1% to 1%): Inflammation and ulceration of the urinary bladder (possibly with hematuria)
Rare (0.01% to 0.1%): Renal failure, elevated serum creatinine and urea level
Frequency not reported: Renal insufficiency (usually with high doses), severe nephropathy[Ref]


Common (1% to 10%): Pulmonary complications due to interstitial alveolitis pneumonitis (e.g., general illness, dry/nonproductive cough, shortness of breath progressing to rest dyspnea, chest pain, fever)
Uncommon (0.1% to 1%): Pulmonary fibrosis
Rare (0.01% to 0.1%): Pharyngitis, apnea, bronchial asthma
Very rare (less than 0.01%): Pneumocystis carinii pneumonia, chronic obstructive pulmonary disease, pleural effusion
Frequency not reported: Acute pulmonary edema, pleurisy, hypoxia, respiratory failure[Ref]


Rare (0.01% to 0.1%): Diabetes mellitus, hyperuricemia
Frequency not reported: Metabolic disorder, tumor lysis syndrome[Ref]


Rare (0.01% to 0.1%): Mood alterations
Very rare (less than 0.01%): Insomnia, cognitive dysfunction
Frequency not reported: Psychosis, depression, confusion, irritability[Ref]


1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

2. Pharmaceutical Society of Australia "APPGuide online. Australian prescription products guide online. Available from: URL:" ([2006]):

3. "Product Information. Methotrexate and Methotrexate LPF (methotrexate)." Lederle Laboratories, Wayne, NJ.

It is possible that some side effects of Rheumatrex Dose Pack may not have been reported. These can be reported to the FDA here. Always consult a healthcare professional for medical advice.

Disclaimer: Every effort has been made to ensure that the information provided is accurate, up-to-date and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This material does not endorse drugs, diagnose patients, or recommend therapy. This information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill , knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate safety, effectiveness, or appropriateness for any given patient. does not assume any responsibility for any aspect of healthcare administered with the aid of materials provided. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the substances you are taking, check with your doctor, nurse, or pharmacist.