Leucovorin Calcium

1. Health Canada Product Monograph — Leucovorin Calcium

• Leucovorin is used to reduce the toxicity of folic acid antagonist drugs and to treat their overdose.
• Leucovorin is used to reduce the toxic effects of methotrexate when methotrexate is given as cancer chemotherapy.
• Leucovorin is used to treat megaloblastic anemia caused by folate deficiency, including megaloblastic anemia occurring during pregnancy or infancy.
• Leucovorin is given before fluorouracil to help prolong survival in the palliative treatment of advanced colorectal cancer.

• There are no adequate, well-controlled studies of leucovorin in pregnant women, though leucovorin is itself a naturally occurring intermediate in folic acid metabolism and is actually used to treat folate-deficiency anemia that occurs during pregnancy.

• It is not known whether leucovorin passes into breast milk in clinically important amounts, but leucovorin combined with fluorouracil is not recommended in breastfeeding women, because of the toxicity of fluorouracil.

• Older adults are at greater risk of severe toxicity, including severe diarrhea and dehydration, when leucovorin is combined with fluorouracil, and a reduced starting dose of fluorouracil is recommended in this population.

• Leucovorin has not been authorized for pediatric use in Canada because sufficient data are not available, and it may increase the frequency of seizures in susceptible children.

• For overdose of a folic acid antagonist, leucovorin should be given as soon as possible, since treatment becomes less effective if more than four hours have passed since the overdose.
• For rescue after high-dose methotrexate chemotherapy, leucovorin is generally started 6 to 24 hours after the methotrexate dose, with the amount and duration adjusted based on serum methotrexate and creatinine levels.
• For megaloblastic anemia due to folate deficiency, oral leucovorin is generally preferred over injection, except when severe vomiting prevents oral absorption.
• For advanced colorectal cancer, leucovorin is given by slow intravenous injection before each dose of fluorouracil for five consecutive days, with this cycle repeated roughly every four weeks if the patient has recovered from prior toxicity.
• No more than 160 mg of leucovorin should be injected per minute intravenously, due to its calcium content.
• Leucovorin may be given intramuscularly, by intravenous injection, or diluted for intravenous infusion, but must never be given intrathecally (into the spinal fluid).
• When diluted for intravenous infusion, the solution should be used within 24 hours if stored at room temperature, or within 8 hours if diluted with certain hypertonic solutions.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• Leucovorin has very low toxicity in animal studies, and there is no reported experience with parenteral leucovorin overdose in humans.
• No specific antidote or toxic syndrome is described for leucovorin overdose itself, since it is a naturally occurring form of folate.

• Nausea and vomiting may occur.
• Fever may occur.
• Dizziness may occur.
• Red, swollen lips may occur.
• When combined with fluorouracil, low red blood cell counts (anemia) may occur.
• When combined with fluorouracil, low white blood cell counts (neutropenia or leukopenia) may occur.
• When combined with fluorouracil, low platelet counts (thrombocytopenia) may occur.
• When combined with fluorouracil, redness, swelling, and tenderness of the palms and soles (hand-foot syndrome) may occur.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, can occur.
• Seizures have been reported.
• Fainting (syncope) has been reported.
• Hives (urticaria) can occur.
• Severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, some fatal, have been reported, particularly when leucovorin is combined with other drugs known to cause these reactions.
• When combined with fluorouracil, severe and potentially fatal digestive toxicity, including diarrhea and mucositis (mouth and bowel ulceration), can develop and requires prompt monitoring.
• When combined with fluorouracil, severe suppression of bone marrow function (myelosuppression) can occur and has been fatal in some cases.
• High blood ammonia levels (hyperammonemia), causing confusion or irritability, have been reported.
• Fever occurring together with a severe drop in white blood cells (febrile neutropenia) can signal a serious infection and requires prompt medical evaluation.
• Seek urgent medical attention for severe or persistent diarrhea, painful mouth sores that prevent eating or drinking, signs of infection or bleeding, seizures, or an allergic reaction.

• Use with caution, and only under the supervision of a physician experienced in cancer chemotherapy, when leucovorin is combined with fluorouracil or methotrexate.
• Use with caution in patients with reduced kidney function, dehydration, ascites, pleural effusion, or acidic urine, since these can delay methotrexate clearance and increase toxicity.
• Use with caution and monitor closely for diarrhea and mouth sores when leucovorin and fluorouracil are given together, since these are early warning signs of severe toxicity.
• Use with caution in patients taking anti-epileptic drugs such as phenobarbital, primidone, or phenytoin, since leucovorin may reduce their effectiveness and increase seizure risk.
• Use with caution in elderly or debilitated patients receiving leucovorin with fluorouracil, who are at greater risk of severe or fatal toxicity.
• Avoid excessive leucovorin doses during methotrexate rescue, since this may reduce the antitumour effect of methotrexate, particularly in central nervous system tumours.
• Monitor blood calcium levels when leucovorin is combined with fluorouracil, and provide calcium supplementation if levels are low.
• Be aware that resistance to methotrexate caused by reduced drug transport into cells can also reduce the effectiveness of leucovorin rescue, since both drugs use the same cellular transport system.

• Contraindicated in pernicious anemia or other megaloblastic anemias caused by vitamin B12 deficiency, since leucovorin can mask a worsening of nerve damage in these conditions.
• Contraindicated in patients with known hypersensitivity to leucovorin or any ingredient in the formulation.
• Contraindicated for intrathecal (spinal) administration, since fatalities have been reported after leucovorin was mistakenly injected this way following an intrathecal methotrexate overdose.

• Leucovorin may reduce the effectiveness of anti-epileptic drugs such as phenobarbital, primidone, and phenytoin, increasing the risk of seizures in patients taking these medications.
• Leucovorin can reduce or completely neutralize the effect of folic acid antagonist drugs, including methotrexate, cotrimoxazole, and pyrimethamine.
• Leucovorin may inhibit the antibacterial effect of trimethoprim or co-trimoxazole.
• Leucovorin enhances the toxicity and cell-killing effect of fluorouracil, and the two drugs must never be mixed in the same injection or infusion.
• Leucovorin given at the same time as systemic methotrexate can cancel out the intended anticancer effect of methotrexate, so the two are generally not given simultaneously except in specific rescue protocols.
• Leucovorin has been given at the same time as pyrimethamine without interfering with its antimalarial effect, so this specific combination has not required dose adjustment.

• Not applicable; this formulation of leucovorin is given by injection, so food timing does not apply.

• Leucovorin is timed around the specific treatment protocol it supports, such as a set number of hours after a methotrexate dose or immediately before each dose of fluorouracil, rather than around meals.

• Store refrigerated, between 2°C and 8°C, protected from light and freezing.

• Leucovorin is used to protect healthy cells from the toxic effects of certain chemotherapy drugs, or to treat folate-deficiency anemia.
• If you are receiving leucovorin with fluorouracil, report diarrhea or mouth sores to your healthcare professional right away, since these can be early signs of serious toxicity.
• Tell your healthcare professional about any seizure medications you take, since leucovorin can interact with them.
• Leucovorin must never be given into the spine; it is given only into a muscle or vein.