Its applications in clinical toxicology are rather more limited to methotrexate overdose, adjunct to methanol poisoning and occasionally massive. Methotrexateinduced pancytopenia oxford academic journals. To be eligible for inclusion, a study had to include hunger et al. Uremia from acute mtx toxicity can stimulate the chemoreceptor trigger. Does folic acid reduce the toxicity of methotrexate. Lowdose methotrexate ldmtx that is administered during rheumatoid arthritis ra treatment has hematological adverse effects such as pancytopenia, although rare. Most individuals eliminate methotrexate predictably, but methotrexate elimination can be prolonged in some individuals, placing them at high risk for severe toxicity andor death if leucovorin rescue therapy is prematurely discontinued. Taking folic acid can help to make up for, or supplement, the folate that your body loses when you take methotrexate. Dermatological handfoot syndrome in combination with fluorouracil i.
Folinic acid rescue is standard therapy following highdose intravenous methotrexate to prevent toxicity. A biochemical perspective of methotrexate neurotoxicity with insight on nonfolate rescue modalities. Leucovorin rescue after methotrexate higher dose regimensoverdose. This includes methotrexate rheumatrex, pyrimethamine daraprim, trimethoprim trimpex, proloprim, and others. Effect of folic or folinic acid supplementation on toxicity and efficacy of methotrexate in rheumatoid arthritis. The editorial suggested that folic acid 1 milligram daily is the most common utilization of the supplement for methotrexate treated patients. Leucovorin versus folic acid in the treatment of methotrexate. Dec 23, 2019 folic acid is the manufactured form of folate.
Acute methotrexate toxicity madke b, singh al indian j drugs. Royal national hospital for rheumatic diseases royal national. Leucovorin calcium rescue is indicated after high dose methotrexate therapy in osteosarcoma. Evaluation, identification, and management of acute methotrexate. In addition, leucovorin rescue is recommended because leucovorin. If patients develop worsening chronic renal failure fbc should be monitored closely and dose reduction considered. The inclusion of folinic acid with methotrexate therapy is so essential that chemotherapy protocols using methotrexate also include detailed recommendations in regards to folinic acid rescue administration.
Methotrexate inhibits nucleic acid synthesis by blocking the activation of folic acid. However, it fails to metabolize the intracellular mtx and hence concomitant folinic acid needs to be administered. While folinic acid is a form of folate that can be found in nature. Oct 29, 2018 methotrexate can also cause side effects, such as nausea, vomiting, and stomach pain. It selectively rescues normal cells from the toxic effects caused by mtxs. Commercially available leucovorin is composed of a 1. Review how long can folinic acid rescue be delayed after. It is best to read this information with our general information about chemotherapy and.
The effect of leucovorin rescue therapy on methotrexateinduced. Jul 23, 2015 the purpose of this study is to assess the impact of folinic acid fa rescue following methotrexate mtx graftversushost disease gvhd prophylaxis on regimen related toxicity and transplantation outcomes after allogeneic hematopoietic cell transplantation allohct in a double blind randomized controlled trial. The effect of leucovorin rescue therapy on methotrexate. Serves as a cofactor supplement to counteract folic acid antagonists such as methotrexate. Trimethoprim toxicity prophylaxis and treatmentleucovorin is indicated as an antidote to the toxic effects of folic acid antagonists such as methotrexate, pyrimethamine, or trimethoprim. Folic and folinic acid whats the differencefolic acid and folinic acid are two different forms of vitamin b9 folate. Displaces methotrexate from intracellular binding sites and restores the folate required for dnarna synthesis. As in sosin and handas patients it has been used for rescue medication in methotrexate overdose or severe side effects in rheumatology and oncology. How long can folinic acid rescue be delayed after high. Folinic acid replenishes intracellular stores of reduced folic acid by competitively inhibiting cellular uptake of methotrexate. Also used in conjunction with methotrexate to reduce its toxicity folinic acid rescue, calcium leucovorin rescue.
Folinic acid also known as 5formyl tetrahydrofolic acid or leucovorin is the 5formyl derivative of tetrahydrofolic acid, a necessary cofactor in the body. We searched the cochrane library, medline, embase, and us national institutes of health. Folate supplementation, in the form of folic acid or folinic acid, is often coadministered with mtx to minimize adverse effects eg, stomatitis, gastrointestinal intolerance, bone marrow toxicity. Highdose folinic acid, in addition to standard folinic acid res. Major side effects of lowdose methotrexate uptodate. The effect of folic acid supplementation on the toxicity of lowdose methotrexate in patients with rheumatoid arthritis. Cancer drug manual the manual, 1994, british columbia cancer. Methotrexate toxicitymethotrexate toxicity methotrexate mtx is a chemotherapeutic drug that is structurally similar to folic acid. A person taking the medication for rheumatoid arthritis ra can take a. In methanol toxicity it serves as a tetrahydrofolate source to help the body eliminate the. A person taking the medication for rheumatoid arthritis ra can take a folic acid supplement to help reduce. Royal national hospital for rheumatic diseases brian stables, chairman james scott, chief executive withheld and should be given folinic acid rescue 29 section m1.
Folic acid or folinic acid for reducing side effects of. The focus of this chapter is the use of folic and folinic acids as antidotes. Folate deficiency and mtx toxicity share some similar symp tomatology. Folinic acid, as the calcium salt, is used an antidote to folic acid antagonists such as methotrexate which act by binding to dihydrofolate reductase, the enzyme responsible for conversion to tetrahydrofolate. May 31, 20 folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by mtx, with a 76. Methotrexate can also cause side effects, such as nausea, vomiting, and stomach pain. Cancer drug manual the manual, 1994, british columbia cancer agency bcca.
It metabolizes circulating metho trexate to 2,4diaminon10methylpteroic acid dampa. Methotrexate excretion can be enhanced by hydration with 3 lm 2 per day to maximize urine output. Wolff, md 2 introduction although folic acid antagonists such as methotrexate mtx have been used to treat acute lymphocytic leukemia all for 65 years 1,the preferred dose andschedule of administrationremain. Even though folic and folinic acid work in a similar way, there is a slight difference between them. Ortiz z1, shea b, suarezalmazor me, moher d, wells ga, tugwell p. Leucovorin calcium folinic acid is a reduced form of folic acid. Progression of osteosarcoma after highdose methotrexate.
Jun 03, 20 the amount needed to reverse toxicity is proportional to the methotrexate concentration. Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. Leucovorin may also be used for purposes not listed in this medication guide. Leucovorin is an active metabolite of folic acid and an essential coenzyme for nucleic acid synthesis. After hdmtx infusions, folinic acid rescue therapy leucovorin lv is administered to reduce toxic side effects wennerstrand et al.
All, high grade lymphoma since methotrexate is excreted by the kidneys renal function must be closely monitored before, during and after treatment and doses must be modified if renal function is impaired. To challenge the view that the dose of folinic acid rescue after highdose methotrexate mtx has no significance in the prevention of neurotoxicity and to present the minority view that. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. The results showed that it is possible to safely initiate rescue at 48 by checking serum.
The main toxicities of hdmtx are elevated serum transaminase levels and renal insufficiency, which can delay drug clearance. Methotrexate and oral ulceration british dental journal. Mtx inhibits dihydrofolate reductase, an enzyme that reduces folic acid to tetrahydrofolic acid. Reducing toxicity of methotrexate with folic acid the bmj. Leucovorin calcium is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists. If methotrexate level is 2 x106m increase dose of iv folinic acid as in table 3 if methotrexate level pdf. Folinic acid leucovorin or calcium folinate macmillan. This is sometimes called folinic acid rescue or leucovorin rescue. Review how long can folinic acid rescue be delayed after high. Antidote for unintentional overdosage of methotrexate e. For diminishing toxicity and counteracting the effects of high dose methotrexate, folinic acid is fda approved in both adults and children. Although wellestablished and widely used for hematological adverse effects caused by highdose mtx, leucovorin folinic acid treatment does not have an agreedupon administration for ldmtxinduced pancytopenia. A rapidly fatal case of lowdose methotrexate toxicity ncbi.
Can folic acid help reduce methotrexate side effects. This rescue regimen replenishes intracellular stores of reduced folate and attenuates. Methotrexateinduced leukoencephalopathy reversed by. Folinic acid rescue at 48hours after highdose mtx without toxicity in an early bfm allrez 2002 study 22, children with relapsed all were treated with a 36hour infusion of mtx 1gm2 and folinic acid 15mgm2 at 48 and 54hours. Leucovorin also is indicated as a rescue after highdose methotrexate therapy in osteosarcoma and as a part of chemotherapeutic treatment programs in the. Leucovorin rescue was discontinued as mtx levels were now 0. Management of methotrexate toxicity is aimed towards giving folinic acid rescue and enhancing methotrexate elimination. Eleven patients were taking folic acid and one folinic acid. The efficacy of folic acid and folinic acid in reducing. This inhibition interferes with dna synthesis and cell reproduction. Royal national hospital for rheumatic diseases royal. Folinic acid is more expensive than folic acid, it can bypass the effect of methotrexate on dihydrofolate reductase and replete the intracellular supply of reduced folate. Jul 29, 2019 leucovorin is used to reduce the side effects of large doses or accidental overdose of medications that can reduce the effects of folic acid in the body.
Methotrexate concentration monitoring is a standard component of highdose methotrexate treatment. Leucovorin versus folic acid in the treatment of methotrexate toxicity. Methotrexate is a medication that is used for treating severe rheumatoid arthritis and psoriasis. Aug 22, 2016 medical toxicologists use folic and folinic acid in the treatment of druginduced toxicity due to folic acid antagonists and methanol. By mouth, or by intravenous infusion, or by intravenous injection. Both are commonly taken for reducing the side effects of the medication methotrexate. To determine the optimal time of folinic acid rescue after methotrexate mtx. Methotrexate toxicity methotrexate toxicity maryland poison center. Essentials of glucarpidase rescue glucarpidase is a methotrexate antidote that was approved by the us food and drug administration on january 17, 2012. Successful rescue by leucovorin depends on rapid elimination of mtx by the kidneys, which requires aggressive pretreatment as well as posttreatment hydration and urinary alkalinization. Folic acid and folinic acid for reducing the side effects. A rapidly fatal case of lowdose methotrexate toxicity. Already in use during the 1970s and 1980s as rescue treatment for cancer patients experiencing unacceptable toxicity with the anticancer agent methotrexate, folic acid took on a much higher profile and, ultimately, landmark status, when it was conclusively shown to reduce neural tube defects ntds in 1991.
Folinic acid is the antidote of choice for treating mtx toxicity. It is mainly used with higher doses of methotrexate to help reduce the side effects. For that reason, folinic acid is often considered a better option than folic acid. For patients supplemented with any form of exogenous folate either folic or folinic acid whilst on mtx therapy for rheumatoid arthritis, a 26% relative 9% absolute risk reduction was seen for the incidence of gi side effects such as nausea, vomiting or abdominal pain rr 0. Medical toxicologists use folic and folinic acid in the treatment of druginduced toxicity due to folic acid antagonists and methanol.
It is routinely used for folinic acid rescue therapy following administration of highdoses of parenteral methotrexate in oncologic practice. Folic acid and folinic acid for reducing side effects in. Leucovorin folinic acid is the reduced and active form of folic acid. Folinic acid is also sometimes given with methotrexate, which is used to treat different types of cancer. Folic acid and folinic acid for reducing the side effects of. Leucovorin calcium is also indicated to diminish the toxicity and. How long can folinic acid rescue be delayed after highdose. High leucovorin doses during highdose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. The effect of folinic acid rescue following mtx gvhd.