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Note: This section has health/medical information. It was not written by a health care professional, however, the author has an MS in biochemistry and has a good knowledge of drugs and how they work. The medical references are at the bottom of this page.
Methotrexate is a chemotherapy drug used to treat leukemia, lymphomas, and osteosarcoma. It is also used in the treatment of AIDS and rheumatoid arthritis, which is of interest because you can find information on this drug on the Web at sites relevant to these diseases as well as cancer sites.
How it's administered
Methotrexate is given IV (intravenous), PO (orally), IM (intramuscular), and IT (intrathecal; spinal).
When and how to give oral methotrexate
PO (oral). Oral methotrexate should be given at least an hour after the evening meal; some sources say two hours after a meal. Do not give with milk. Give it just before bed, since your child should not eat for an hour after taking it.
IT (intrathecal; spinal). IT methotrexate is given in the hospital clinic under the doctor's supervision.
IV (intravenous). Some protocols call for high-dose IV methotrexate. This is usually administered in the hospital. Before administration, your child will need to be well-hydrated. Drinking fluids helps, but it's often done IV. During methotrexate administration and just after, your child will be monitored for drug elimination, hydrated, and treated with leucovorin (see below). Some parents report that they asked for or were given the option to do the entire methotrexate IV treatment or at least the hydration part at home, with the child wearing a backpack for the IV containers. If you are comfortable with this, do ask your doctor if you can do it at home. If you are not, don't let them force you to do it at home.
IM (intramuscular). IM methotrexate is given at the hospital clinic. Occasionally, a parent is given the dose to be administered by a non-clinic nurse, for instance, if the family is going on vacation.
Doses in ALL trials: High dose (HD) vs low dose
POG protocols: IV ID methotrexate is1g/m2, HD is 2.5g/m2, as given IV over 4-24 hours, usually with leukovorin rescue. CCG protocols that include "escalating" IV methotrexate administer it 0.10 g/m2 over 10-15 min, then escalate each subsequent dose by 50mg/m2/dose to toxicity. When given PO, methotrexate is 15-20 mg/m2/day in maintenance. POG employs 4 PO doses of mtx, each 25mg/m2, for 100mg/m2/day in intensive continuation.
- Co-trimoxazole. Do not give methotrexate within 24 hours of a dose of this antibiotic (or probably any other; ask your doctor). Co-trimoxazole intensifies the effect of the methotrexate. (See the section on adverse reactions on the antibiotics page.)
- NSAIDs: nonsteroidal anti-inflammatory drugs. These over the counter anti-inflammatories prolong the levels of methotrexate in the blood. NSAIDs include aspirin, ibuprofen, acetaminophen, and naproxen.
- Cisplatin. Since this drug would be administered by your oncologist, they would be aware of methotrexate treatment at the same time.
- Vitamin C. Increases toxicity.
- Phenytoin (an antiepileptic).
Common side effects.
- skin and eye sensitivity to sunlight
- abnormal liver function tests
- hair loss
- skin rashes
- headache, backache, spinal cord irritation (when given IT)
Less common side effects:
- nausea, vomiting, loss of appetite, upset stomach, diarrhea
- mouth sores
- kidney damage
- headache, drowsiness, blurred vision
- liver damage (yellow skin and eyes)
- lung damage (dry cough)
- hair loss
- neurotoxicity which can cause learning disabilities
(All of the adverse effects reverse when the drug is discontinued. The above listing of side effects was taken from hospital obtained instruction sheets, Web sites, as well as Nancy Keene's book, Childhood Leukemia.)
The parents' version of side effects:
In an informal survey of online groups, at least one parent reported observing at least one of the each of the above side effects in their child, with perhaps the exclusion of lung, liver, and kidney damage. (Damage to these organs is monitored by the oncologists and chemo adjusted accordingly; damage can show up long after chemo is discontinued; other chemo agents can also cause damage, so it's hard to pinpoint what caused it. Hair loss and immunosuppression too can be caused by multiple agents. Liver and kidney function is more likely to be affected with IV doses.)
One parent's child in the online discussions had a stroke attributed to methotrexate -- see the discussion the section on parents comments on side effects. There is some concern that seizures can be attributed to IT methotrexate -- see the parent comment under IT methotrexate.
The above side effects differ widely according to the dose and the method of administration. So, I'll break them down according to PO, IT, IV, and IM.
Side effects of oral methotrexate
With oral doses, most parents report nausea and skin and eye sensitivity to sunlight. Here are some additional comments:
- "My daughter gets raised pimple-like bumps on her cheeks. They come and go. Onco docs say it normal and a side effect of the methotrexate. She also gets heat rash-like bumps on her neck where it meets her collarbone, it also comes and goes, it also is a side effect of the methotrexate."
- "My son gets those litte rashy bumps around his mouth."
- "I can always count on my son (17 yo) being very tired the day after he takes his weekly MTX. He'll often take a nap or just lie around most of the day."
- "I have noticed that my son is wired and tired on methotrexate night, and he often has leg pains that night or the day or night after the dose."
- "My daughter had serious problems with rashes during maintenance. the doctors thought that she had developed an allergy to the weekly methotrexate. She often would be covered with rashes which looked like small, red circles with tan, flaky skin inside. They were extremely itchy and unattractive. We spent hundreds of dollars at the dermatologist trying various prescription remedies. None worked. In desperation, I went to our local herbalist and asked if she had anything totally nontoxic, which would help the rash but not affect her chemotherapy. She sold me a small tub of salve made from olive oil, vitamin E oil, and calendula flowers. We checked with her oncologist before using it. It totally cured the rash after two days, and worked each time that the rash reappeared. What a relief!"
- "When my son took his weekly oral methotrexate, he would be sick to his stomach in the night, so we gave 1 - 4 mg zofran 30 minutes before the medication, then gave the methotrexate. Then he went straight to bed. When he woke up in the morning, we gave another 4 mg zofran tablet, then 30 minutes later, let him eat breakfast. If we skipped the zofran, then he would wake up and be nauseated. If he vomited, then he would be drained for the entire day. Sometimes sleep until early afternoon."
- "We have noticed that our daughter isn't as sharp as usual, everything seems to take extra effort.. and extra time to get done, reading something simple, simple math, her art isn't as colorful or detailed. She is just "off"."
- "My daughter had horrible rashes and hives, thought to be an allergic reaction, treated with atarax throughout treatment and reduced methotrexate due to this and low counts. She only had a few "actual total doses."
- "We always give it at night right before she goes to bed. The next day or so she might exhibit any combination of the following, a little extra pale, tiredness (she usually takes a nap), slight decrease in appetite (very slight with the oral). After a couple of days she'd be back to "normal"."
Side effects of IT methotrexate
IT treatment usually results in tiredness, headache, backache, spinal cord irritation. IT methotrexate is often given with other IT drugs or IV drugs; it can be hard to attribute effects to the methotrexate, or even to the anaesthesia used to sedate the child. After spinals, kids usually feel tired, for at least the rest of the day, perhaps into the next as well. Side effects have also been attributed to the rate at which the spinal is administered; a doctor who gives the doses slowly is prized by parents because the kids feel fewer headaches.
- "The interthecal administration of methotrexate seems to have the greatest effect on her physically. The day following a spinal injection she is guaranteed to be tired and take to her bed a couple of times. This will last at least for a couple of days. At the same time she gets this she also gets IV vincristine. She gets the IV vincristine monthly and at 5-7 days after recieving it we can see effects (pale, tired, loss of appetite - which is her way of avoiding being sick) but when combined with the IT methotrexate these seem to be even more noticeable. There is some preliminary evidence that the spinal injection of some chemotherapy drugs causes some neurological damage resulting in learning delays or disabilities. I have noticed some things that could be attributed to this in my daughter, but until I see how she does in school and with speech and language therapy and some therapy for the emotional side of things I'll withhold judgement as to whether there is any permanent damage due to the chemo. Also, there was some concern at one point whether she had had a seizure as a result of an IT methotrexate dose. Be sure that if your child has a siezure closely following an IT that the doctors do another spinal to check for neurotoxicity."
Side effects of IV methotrexate
- "I would have my son drink lots and lots of water before we'd go to the hospital for IV methotrexate. Not only did it seem to shorten our stay there but it also seemed to keep the mouth sores in check. He would get mouth sores - terrible mouth sores. We would give him a mix of benedryl and maalox to swab on the sores. We would also watch for yeast infection which he did get once.We also premed with zofran one hour before and throughout IV methotrexate. He was on the standard regimen arm (A) of POG 9406 and just had the hardest time with the chemo - including mouth sores, fever and neutrapenia with the methotrexate. However, his little friend is on regimen C which had a higher dose of methotrexate along with other drugs - he did sooo well. He did have mouth sores once. He also suffered from neutrapenia. But if you asked the nurses on the floor they all thought my son who received the higher dose because of the effects. Some of these effects seem to be pretty individualized."
- "He got the high dose methotrexate. The thing we didn't really know about after his first infusion was the mouth sores. We knew they could happen but we were no way prepared for the awful sores that covered his mouth. They were so bad that he didn't eat for almost a week. He lost 3 pounds. After that we knew what to expect and did preventative mouthcare with the Peridex."
- "High dose IV methotrexate made my son very, very sick - despite anti-emetics. He also found that the orals made him nauseous, and after relapse made him vomit. I believe it is not one of the drugs that score very high on the vomit scale, but it made him as sick as anything else!"
- "I would add that with the high dose methotrexate, many kids must be on TPN due to the terrible digestive tract sores. Magic Mouthwash and Peridex for the mouth, and just "time" to let the stomach sores heal. We also had heard of the mouth sores, but had no idea how bad they could be. A dry mouth and red gums signals the beginning of the sores. The inside of his mouth just peeled off in sheets, under his tongue, his throat, he vomitted and couldn't eat for a week either...did the TPN and LOTS of IV hydration. Oh, and I almost forgot: the mtx rash (from toxicity) -- a sunburn-like rash that eventually peels -- the treatment he got for this was hydrocortisone cream and Eucerin cream. Itstarted as a "pink belly" and spread over this entire body. Some kids also run a fever during this time."
- "We were told not only to drink a lot at home before the hydration, but either to suck on ice chips as much as possible or drink lots and lots of water during the time to prevent mouth sores."
- "My son, 18 yo, had no problems with the high dose (24 hr IV) methotrexate during induction except that it wiped him out. He did not get sick, (dry heaves once) but more so than this it knocked him out. He was very tired for days. He is a very laid back kid, does not get excited about anything, even good things, very quiet. I think this helped him. He was very relaxed and had his metho and waited. He had to wait a couple extra days to get out of hospital because it took hinm longer to lower his levels than normal.. That was the only problem. Now he gets it once a week and once again, not sick, just wiped out tired!"
- "Our oncodoc gave us a med called Carafate for sores he might have in his throat and stomach. We didn't have to use it very often. It can't be taken with dairy."
- "My daughter was also given Carafate after every IV methotrexate as she had horrible mouth sore and no ANC."
Side effects of IM methotrexate
Most of the complaints about IM methotrexate stem from the shot itself:
- "It's just "routine" to put her EMLA on her thigh muscle, go to the office and get her shot. When she has her spinal the dosage of her IM is reduced by half. That's about it. She's had no problems with the IM's at all."
- "My son doesn't like the shots at all. He says they burn. He's worked on relaxing during the shot and he also uses emla cream (1 - 2 hours prior to the shot). He dosn't seem to have any after effects from these."
- "We had a nurse who told us to have her sit on the edge of the table and turn both of her feet in as that kept everything relaxed and the space open."
- "It's hard to tell what side effects might have been attributed to the IM shot of methotrexate since she was also getting so many other chemo drugs at the time. She definitely didn't like the shot part."
Rare but documented side effects include seizures and strokes. A stroke happened to a two year old boy being treated with methotrexate for lymphoma. His mom wrote the following:
"The things I would like parents to know:
- Strokes are very rare side effects, particularly when they appear without any other indication of methotrexate toxicity. All types of brain damage caused by methotrexate is more common if the child also has had radiation.
- If your child shows signs that he could have suffered neurological damage, don't let the docs discount stroke without an MRI or proof of a different cause. Strokes can manifest themselves in a variety of ways, depending upon where the stroke occurs and the type of stroke. In our case, our son's symptoms grew worse during the first five days because the stroke (aka, infarct, insult, edema, injury) was swelling and growing, thereby impacting more areas. The worsening symptoms confused our doctors, who thought that a stroke was a single event.
- If your child has a stroke, be sure to rule out methotrexate as a cause before continuing with chemotherapy. On very rare occasions, a stroke can occur without other indication that methotrexate was the cause.
- If your child has a stroke, insist on physical and speech therapy immediately. Children have remarkable powers to recover, but they need help. Care must be taken to ensure that their muscles do not deteriorate before they recover use on their own. Skilled pediatric physical and occupational therapists will be the most helpful professionals around after a child has a stroke.
- Remember that strokes can effect different systems depending on where they are located. A child can be experiencing nerve pain and can lose vision or hearing, in addition to the obvious loss of movement or speech."
Three references pulled from MEDLINE concerning seizures/strokes:
- Neurology 1991 Nov;41(11):1847-1848. Stroke-like syndrome, mineralizing microangiopathy, and neuroaxonal dystrophy following intrathecal methotrexate therapy. Phanthumchinda K, Intragumtornchai T, Kasantikul V
- Pediatr Hematol Oncol 1994 Jul;11(4):445-449. Interference of high-dose methotrexate in the metabolism of valproate? Schroder H, Ostergaard JR. A case of tonic-clonic seizure was observed in a child with acute lymphoblastic leukemia a few hours after a 24-hour infusion of high-dose methotrexate (MTX; 5 g/m2). Because of former epileptic symptoms, <snip>.
- Pediatr Hematol Oncol 1992 Apr;9(2):157-165. Transient encephalopathy following a single exposure of high-dose methotrexate in a child with acute lymphoblastic leukemia. Kubo M, Azuma E, Arai S, Komada Y, Ito M, Sakurai M An episode of transient encephalopathy after the first course of intravenous high-dose methotrexate (HD-MTX; 1000 mg/m2) was observed in a 4-year-old girl with acute lymphoblastic leukemia.
Special precautions to take while your child is taking methotrexate
Your child must wear sunscreen while outside. And, don't forget sunglasses! The eyes are more sensitive to the damaging rays of the sun when methotrexate is being given.
If you are giving your child vitamins, find some without added folic acid. Here are some suggestions from the online groups:
- Hexavitamin. (Bought over the counter at the Stanford pharmacy. It's coated so some of the little kids might not like it.)
- Children's Multi-Vitamins, Jamieson Natural Sources, C.E. Jamieson & Company Limited, Toronto-Vancouver-Montreal, Toronto, Ontario, Canada, M4V 1L5
To stave off the ill effects, your child should drink at least 2 quarts of high calorie fluids such as juices and nectars per day.
Avoid use of over-the-counter drugs without first consulting with your doctor or pharmacist.
Methotrexate: How it works
A section by the editor, playing chemist.
Here is the structure of methotrexate:
The CA name for methotrexate is: N[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid. The CA registry number is 59-05-2. Common synonyms: Mexate, Methylaminopterin, Emtexate, Metatrexan, Methopterin, MTX dihydrate, Folex, Folex PFS, Amethopetrin.
Methotrexate is an antineoplastic, an antirheumatic, a nucleic acid anti-metabolite (like 6-MP,above), and a "folic acid antagonist".
Hmm, folic acid, a necessary nutrient. Let's see, here's folic acid, let's compare:
You can see that the nitrogen group has a CH3 on it and there is an OH group in the double ring instead of an NH2 group. Enough to make a difference in a biosynthesis scheme!
At two stages in the biosynthesis of purines (adenine and guanine) and at one stage in the synthesis of pyrimidines (thymine, cytosine, and uracil), one-carbon transfer reactions occur which require specific coenzymes.These coenzymes are synthesized in the cell from tetrahydrofolic acid. Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it thinking that it is folic acid. In fact, methotrexate looks so good to the enzyme that it binds to it quite strongly. All the folic acid reductase enzymes in the cell bind merrily to the methotrexate and ignore any folic acid they might see. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Again, without DNA, no cell division.
Most of the parents of cancer kids have been told not to give folic acid supplements during chemo since it interferes with the action of the methotrexate.
Methotrexate has a general toxicity because it affects all rapidly dividing cells, such as those in the intestonal mucosa and prevents the production of tetrahydrofolate from folic acid in all tissues. Tetrahydrofolate is a necessary compound in many biosynthetic pathways, not just the synthesis of DNA. One of these is the synthesis of L-glutamate. One parent told us that her oncodoc recommended glutamic acid supplements, and that they helped her child immensely. Makes sense.
Also listed by the hospital: the possible adverse effects of this drug are mouth lesions in the form of painful patches on the lips, gums and mucosa of the mouth. These clear rapidly with stopping the drug. Along with mouth ulcers, there can also occur ulceration of other parts of the digestive tract with abdominal pain, vomiting and diarrhea. This drug can depress the bone marrow, which leads to a depression of white blood cells, platelets, and red blood cells.
Which means that they will be monitoring your child's CBC. With high doses of methotrexate, they will monitor fluid intake and urine output closely. Leucovorin is a medicine that may be prescribed. Leucovorin is an antianemic and an antidote for folic acid antagonists. Leucovorin is the active form of the B complex vitamin, folate. Another name for Leucovorin is folinic acid: the very name I found in a biochem text - it said that it could help alleviate the effects of methotrexate! "Leucovorin is used as an antidote to drugs that decrease levels of folic acid. Folic acid helps red and white blood cell formulation and the synthesis of hemoglobin. Some treatments require what is called leucovorin rescue, because the drug used to treat the cancer or other infection has had an adverse effect on folic acid levels. Leucovorin is used to reduce anemia in people taking dapsone, a preventive treatment for PCP. Leucovorin is also used in combination with chemotherapy such as methotrexate." (The words in "" are from the link on Leucovorin given above.)
Biochemistry/oncology texts. Web sites accessed 2011. I also refered to our COG protocol (1961) and the drug sheets we received with the drug.
- Clinical Oncology, 3rd ed., Abeloff et al., 2004
- Biochemistry, McGilvery, 1970
- Childhood Leukemia: A Guide for Families, Friends, and Caregivers, 4th ed., by Nancy Keene, 2010.
- MedlinePlus (U.S. National Library of Medicine)