Leucovorin Calcium (leucovorin calcium)

Dosage of leucovorin calcium is expressed in terms of leucovorin.

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There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Folic Acid/Pafolacianine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Folate, folic acid, and folate-containing supplements may reduce binding of pafolacianine to folate receptors expressed on ovarian cancer cells.

CLINICAL EFFECTS: Folate, folic acid, and folate-containing supplements could reduce the detection of malignant lesions with pafolacianine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid administration of folate, folic acid, or folate-containing supplements within 48 hours before administration of pafolacianine.

DISCUSSION: Folate, folic acid, and folate-containing supplements may reduce binding of pafolacianine to folate receptors expressed on cancer cells, which could result in reduced detection of malignant lesions with pafolacianine.

Folic Acid; Pyrimethamine/Hydantoins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown, but probably involves altered metabolism of the hydantoin.

CLINICAL EFFECTS: May observe decreased effectiveness of hydantoin, resulting in loss of seizure control.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If both drugs are administered, monitor both the hydantoin plasma levels as well as the seizure control of the patient. Adjust the dose of hydantoin accordingly.

DISCUSSION: The effects of an interaction are not expected to occur in the majority of patients. Discontinuation of folic acid has caused phenytoin levels to increase in patients who experienced a decrease in phenytoin levels when folic acid was started. Monitor these patients for hydantoin toxicity. Signs and symptoms of hydantoin toxicity include ataxia, nystagmus and involuntary movements.

Leucovorin/Fluorouracil & Fluorouracil Prodrugs

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Leucovorin has been shown to enhance both the therapeutic and toxic effects of fluoropyrimidines, such as 5-fluorouracil (5-FU).(1)

CLINICAL EFFECTS: Leucovorin, when used concurrently with 5-FU, has been shown to increase side effects of 5-FU.(1)

PREDISPOSING FACTORS: Patients who are intermediate or poor dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no DPYD function. Since DPYD is the rate-limiting enzyme involved in fluoropyrimidine metabolism, these patients may be more susceptible to the effects of this interaction.(3)

PATIENT MANAGEMENT: When leucovorin is added to 5-FU therapy, the dose of 5-FU must be reduced from that of the normally administered dose. Patients should be closely monitored for appearance and severity of side effects to determine whether it is appropriate to alter the dose of 5-FU.(1)

DISCUSSION: A retrospective study reviewed all patients over the age of 18 years treated with combination fluorouracil and leucovorin either as adjuvant or palliative treatment. A total of 122 patients (60% male) were included in the study. Ninety-four patients received fluorouracil (425 mg/m2, IV) and leucovorin (20 mg/m2, IV) daily for five days and repeated every four weeks. Twenty-eight patients received fluorouracil (400 mg/m2, IV) and leucovorin (80 mg/m2, IV) once per week for six weeks of an eight week course. All patients were treated for up to six months. Forty-eight patients (39%) experienced toxicity including fatigue (21%), mucositis (17%), diarrhea (11%), and nausea (11%).(2) A study involving 35 patients evaluated a combination of cisplatin (20 mg/m2) on Day 1 through Day 3, leucovorin (200 mg/m2) on Day 1 through Day 5, and 5-fluorouracil (500 mg/m2) on Day 1 through Day 5. If patients tolerated the low dose of 5-fluorouracil, the dose was increased to a maximum of 750 mg/m2/day during the remaining courses. Grade I mucositis occurred in three patients, Grade II in 16 patients, and Grade III in 13 patients. The dose of 5-fluorouracil was decreased in patients with Grade II and Grade III mucositis, which helped to decrease symptoms.(3) A randomized trial in advanced colorectal carcinoma patients compared fluorouracil (500 mg/m2 on Days 1-5) every four weeks with escalation as tolerated with high-dose leucovorin (500mg/m2) with fluorouracil (600 mg/m2) given weekly for six weeks with a two-week rest period and with low-dose leucovorin (25 mg/m2) with fluorouracil (600 mg/m2) given weekly for six weeks with a two-week rest period. Severe or worse diarrhea was reported in 25% and 13% of patients receiving high-dose leucovorin and low-dose leucovorin with fluorouracil, respectively. Nine elderly patients experienced fatal toxicity during the initial treatment cycle with combination therapy.(4) A study in five patients with metastatic colorectal carcinoma examined the effects of high dose leucovorin (500 mg/m2) on fluorouracil pharmacokinetics. Subjects received a single dose of fluorouracil (600 mg/m2) with leucovorin and, one week later, without leucovorin. With concurrent leucovorin, the time of distribution of fluorouracil increased 44% (p<0.0005) and fluorouracil volume of distribution increased 84% (p<0.03). There were no changes in fluorouracil plasma clearance or AUC. Although fluorouracil anabolite levels were lower at two minutes and five minutes post-dose when administered following leucovorin, levels were similar thereafter.(5)

Leucovorin/Trimethoprim-Sulfamethoxazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Leucovorin may protect Pneumocystis jirovecii from the effects of trimethoprim-sulfamethoxazole by providing a source of folate.(1,2)

CLINICAL EFFECTS: Concurrent use of leucovorin in patients undergoing prophylaxis against or being treated for Pneumocystis jiroveci pneumonia (formerly called Pneumocystic carinii) with trimethoprim-sulfamethoxazole has been associated with treatment failure and increased mortality.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of leucovorin and trimethoprim-sulfamethoxazole should be avoided in patients undergoing prophylaxis against or being treated for Pneumocystis jiroveci (formerly carinii) pneumonia.(1-4) The Australian manufacturer of leucovorin states simultaneous administration of folinic acid and folic acid antagonists (e.g. trimethoprim-sulfamethoxazole, pyrimethamine) is contraindicated because the folinic acid can completely negate the effect of the folic acid antagonist.(5) Leucovorin is an effective treatment for trimethoprim-sulfamethoxazole induced bone marrow suppression.(3)

DISCUSSION: In a prospective, double-blind study in 92 AIDS patients with Pneumocystis jiroveci (formerly carinii) pneumonia, concurrent use of leucovorin with trimethoprim-sulfamethoxazole resulted in an increase in treatment failure (15% versus 0) and death (11% versus 0). Leucovorin was also associated with a shorter time to therapeutic failure. Patients receiving leucovorin did have a lower incidence of neutropenia; however, there was no difference in the time to occurrence of neutropenia.(4) In a study in 12 AIDS/ARC patients, leucovorin had no effect on trimethoprim-sulfamethoxazole induced cytopenia.(6) In a study in HIV patients with no history of Pneumocystis jiroveci pneumonia, administration of leucovorin had no effect on patient tolerance to trimethoprim-sulfamethoxazole.(7) In a case report, two renal transplant patients with Pneumocystis jiroveci pneumonia failed to respond to treatment with trimethoprim-sulfamethoxazole until concurrent leucovorin was discontinued.(1) In a case report, an AIDS patient developed Pneumocystis jiroveci pneumonia despite a regimen of concurrent trimethoprim-sulfamethoxazole and leucovorin.(2)

Levoleucovorin; Leucovorin/Glucarpidase

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Glucarpidase hydrolyzes the carboxyl-terminal glutamate residue from folates such as leucovorin, rendering them inactive.(1)

CLINICAL EFFECTS: A leucovorin dose given near the time of glucarpidase administration may not be effective.

PREDISPOSING FACTORS: Leucovorin dose given within two hours of glucarpidase administration.

PATIENT MANAGEMENT: The combination of glucarpidase and leucovorin are used to treat toxic concentrations of methotrexate. Patients with potentially life threatening methotrexate serum levels or toxicity must receive both drugs. However, in addition to inactivating methotrexate, glucarpidase also inactivates leucovorin. To help decrease leucovorin inactivation, stagger leucovorin administration so it is not given within two hours of glucarpidase dose. Continue leucovorin treatment based upon pre-glucarpidase methotrexate blood levels.(1) Note that depending upon the laboratory assay used, glucarpidase administration may cause erroneous methotrexate measurements for 48 hours post dose.(1)

DISCUSSION: In a study of cancer patients treated with a high dose methotrexate and leucovorin rescue regimen, glucarpidase given two hours before leucovorin reduced the area-under-curve (AUC) of the active leucovorin metabolite, 5-methyltetrahydrofolate, by 92 per cent.(1)

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• Pernicious anemia
• Vitamin b12 deficiency

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

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Rare or Very Rare

• Anaphylaxis
• Dyspnea
• Hypersensitivity drug reaction
• Seizure disorder
• Stevens-johnson syndrome
• Toxic epidermal necrolysis
• Urticaria

Rare or Very Rare

• Chills
• Pruritus of skin
• Skin rash
• Syncope

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Animal reproduction studies have not been performed with leucovorin. It is also not known whether leucovorin can cause fetal harm when administered to pregnant women. Leucovorin should be used during pregnancy only when clearly needed.

Since it is not known if leucovorin is distributed into milk, the drug should be used with caution in nursing women.

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