Leucovorin Calcium Injection (Sandoz Canada) Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................. 2

TABLE OF CONTENTS ................................................................................................................ 2

PART 1: HEALTHCARE PROFESSIONAL INFORMATION .............................................................. 5

1 INDICATIONS ................................................................................................................ 5

1.1 Pediatrics ............................................................................................................... 5

1.2 Geriatrics ............................................................................................................... 5

2 CONTRAINDICATIONS ................................................................................................... 5

3 SERIOUS WARNINGS AND PRECAUTIONS BOX .............................................................. 6

4 DOSAGE AND ADMINISTRATION ............................................................................... 6

4.2 Recommended Dose and Dosage Adjustment ....................................................... 6

4.3 Reconstitution ....................................................................................................... 8

4.4 Administration ....................................................................................................... 8

5 OVERDOSE .................................................................................................................... 8

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING .................................. 9

7 WARNINGS AND PRECAUTIONS .................................................................................... 9

General ............................................................................................................................ 10

Gastrointestinal ............................................................................................................... 11

Monitoring and Laboratory Tests .................................................................................... 11

Neurologic ....................................................................................................................... 12

Reproductive Health ........................................................................................................ 12

7.1 Special Populations .............................................................................................. 12

7.1.1 Pregnancy ............................................................................................................ 12

7.1.2 Breast-feeding ..................................................................................................... 12

7.1.3 Pediatrics ............................................................................................................. 12

7.1.4 Geriatrics ............................................................................................................. 13

8 ADVERSE REACTIONS .................................................................................................. 13

8.1 Adverse Reaction Overview ................................................................................. 13

8.2 Clinical Trial Adverse Reactions............................................................................ 14

8.5 Post-Market Adverse Reactions ........................................................................... 15

9 DRUG INTERACTIONS ................................................................................................. 15

9.1 Serious Drug Interactions ..................................................................................... 15

9.4 Drug-Drug Interactions ........................................................................................ 15

9.5 Drug-Food Interactions ........................................................................................ 17

9.6 Drug-Herb Interactions ........................................................................................ 17

9.7 Drug-Laboratory Test Interactions ....................................................................... 17

10 CLINICAL PHARMACOLOGY ......................................................................................... 17

10.1 Mechanism of Action ........................................................................................... 17

10.2 Pharmacodynamics .............................................................................................. 17

10.3 Pharmacokinetics ................................................................................................. 18

11 STORAGE, STABILITY AND DISPOSAL .......................................................................... 19

PART 2 : SCIENTIFIC INFORMATION ....................................................................................... 20

13 PHARMACEUTICAL INFORMATION ............................................................................. 20

14 CLINICAL TRIALS ......................................................................................................... 21

15 MICROBIOLOGY .......................................................................................................... 21

16 NON-CLINICAL TOXICOLOGY ....................................................................................... 21

17 SUPPORTING PRODUCT MONOGRAPH ....................................................................... 22

Patient Medication Information ............................................................................................ 23

PART 1: HEALTHCARE PROFESSIONAL INFORMATION

1 INDICATIONS

LEUCOVORIN CALCIUM INJECTION (leucovorin calcium) is indicated:

• To diminish the toxicity and counteract the effect of impaired methotrexate elimination, and of accidental overdosages of folic acid antagonist
• To treat megaloblastic anemias due to folate deficiency, as in sprue and other nutritional deficiencies; and megaloblastic anemias of pregnancy and infancy (see 2 CONTRAINDICATIONS).
• For pre-treatment followed by fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use (see 7.1.3 Pediatrics).

1.2 Geriatrics

Geriatrics: Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness (see 7 WARNINGS AND

PRECAUTIONS, General and 7.1.4 Geriatrics).

2 CONTRAINDICATIONS

LEUCOVORIN CALCIUM INJECTION is contraindicated for:

• Pernicious anemia therapy or other megaloblastic anemias secondary to a deficiency of vitamin B12. Its use can lead to an apparent response of the hematopoietic system, but neurological damage may occur or progress if already present.
• Known hypersensitivity to this drug or to any ingredient in the formulation or component of the container (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).
• Intrathecal administration.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

4 DOSAGE AND ADMINISTRATION

4.2 Recommended Dose and Dosage Adjustment

Due to calcium content of leucovorin solution, no more than 160 mg of leucovorin should be injected, per minute, intravenously.

Impaired Methotrexate Elimination or Inadvertent Overdosage

For the treatment of accidental overdosage of folic acid antagonists, it is generally given in

Serious Warnings and Precautions

• LEUCOVORIN CALCIUM INJECTION should only be given by intramuscular or intravenous injection and must not be administered intrathecally (see 2 CONTRAINDICATIONS and 4 DOSAGE AND ADMINISTRATION). Death has been reported when folinic acid has been administered intrathecally following intrathecal overdose of methotrexate.
• LEUCOVORIN CALCIUM INJECTION should only be used with 5-fluorouracil under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.
• Patients receiving any combination therapy regimen involving leucovorin and fluorouracil should be carefully monitored for diarrhea and/or stomatitis/mucositis as these are the first indications that severe and potentially life-threatening toxicity could develop (see 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS).
• Fatalities have occurred as a result of gastrointestinal toxicity (predominantly mucositis and diarrhea) (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS).
• Fatalities have occurred as a result of myelosuppression (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS).
• Cases of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some fatal, have been reported in patients receiving leucovorin in combination therapy (see 8 ADVERSE REACTIONS).
• Leucovorin may diminish the effect of anti-epileptic substances such as phenobarbital, primidone and phenytoin. During leucovorin administration in epileptic patients treated with these substances, there is a risk to increase the frequency of seizures due to a decrease of plasma concentrations of anti-epileptic drugs (see 9 DRUG INTERACTIONS).

amounts equal to the weight of the antagonist used.

Rescue with LEUCOVORIN CALCIUM INJECTION should begin as soon as possible after an inadvertent overdosage and within 24-36 hours of methotrexate administration when there is delayed excretion. LEUCOVORIN CALCIUM INJECTION 10 mg/m² should be administered intravenously, or intramuscularly every 6 hours until the serum methotrexate level is less than 5 x 10^-8 M. In the presence of gastrointestinal toxicity, nausea or vomiting due to methotrexate, LEUCOVORIN CALCIUM INJECTION should be administered. Because absorption is saturable, doses greater than 25 mg should be given intravenously.

Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10^-6 M or the 48 hour level is greater than 9 x 10^-7 M, the dose of LEUCOVORIN CALCIUM INJECTION should be increased to 100 mg/m² intravenously every 3 hours until the methotrexate level is less than 5 x 10^-8 M.

Hydration (3 L/day) and urinary alkalinization with NaHCO₃ should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

Treatment of Megaloblastic Anemia:

For treatment of megaloblastic anemia due to folate deficiency, the dose should not exceed 1 mg daily. There is no evidence that doses greater than 1 mg daily have greater efficacy than those of 1 mg. The loss of folates in the urine becomes roughly logarithmic when the amount administered exceeds 1 mg.

Treatment of Advanced Colorectal Cancer:

Leucovorin is administered at 200 mg/m² by slow intravenous injection prior to dosing with 370 mg/m² fluorouracil by slow intravenous injection, for 5 consecutive days.

This 5-day treatment course may be repeated at 4-week (28 days) intervals, provided that the patient has completely recovered from the toxic effects of the prior treatment course.

In subsequent treatment courses, the dosage of fluorouracil should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity. For patients who did not experience toxicity in the prior treatment course, fluorouracil dosage may be increased by 10% . Leucovorin dosages are not adjusted for toxicity.

4.3 Reconstitution

Parenteral Products:

Dilution for Intravenous Infusion: LEUCOVORIN CALCIUM INJECTION, 10 mg/mL, may be further diluted for intravenous infusion to concentrations of 0.06 mg/mL to 1.0 mg/mL with one of the following solutions:

Dextrose 5% in water

Dextrose 10% in water

Dextrose 10% in saline

Ringer’s Injection

Lactated Ringer’s Injection

Physiological saline (0.9% sodium chloride)

The vial contents diluted with Ringer’s Injection, Lactated Ringer’s injection, and Physiological saline are stable for up to 24 hours at room temperature. The vial contents diluted with Dextrose 5% in water are stable for up to 12 hours at room temperature. The vial contents diluted with Dextrose 10% in water and Dextrose 10% in saline are stable for up to 6 hours at room temperature. Due to the possibility of antimicrobial contamination, unused solution should be discarded after that time.

4.4 Administration

LEUCOVORIN CALCIUM INJECTION may be administered as received by intramuscular injection or intravenous injection, or it may be diluted for intravenous infusion (see 4.3 Reconstitution, Dilution for Intravenous Infusion).

Warning: As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used.

5 OVERDOSE

Folic acid has low acute and chronic toxicity in man. No adverse effects have been noted in adults after the ingestion of 400 mg/day for 5 months or 10 mg/day for 5 years.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, and composition

LEUCOVORIN CALCIUM INJECTION is available as a 10 mg/mL sterile, unpreserved, isotonic solution of folinic acid as the calcium salt, in single use Pharmacy Bulk Vials for IV administration only in the following doses and volumes:

• 500 mg/ 50 mL supplied in amber vials of 50 mL
• 1000 mg/ 100 mL supplied in amber vials of 100 mL

The Pharmacy Bulk Vial is supplied to hospitals with a recognized intravenous admixture program only.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Since leucovorin may enhance the toxicity of fluorouracil, combination therapy consisting of leucovorin and fluorouracil for advanced colorectal cancer should be administered under the supervision of a physician experienced in the use of antimetabolite cancer chemotherapy. Particular care should be taken in the treatment of elderly or debilitated colorectal cancer patients, as these patients may be at increased risk of severe toxicity. Death from severe enterocolitis, diarrhea and dehydration has been reported in elderly patients receiving leucovorin and fluorouracil. Concomitant granulocytopenia and fever were present in some but not all of the patients.

In cases of overdosage of folic acid antagonists, prompt administration of leucovorin calcium is essential. As the time interval between antifolate administration [e.g., Methotrexate (MTX)] and LEUCOVORIN CALCIUM INJECTION increases, the effectiveness of leucovorin in counteracting the toxicity decreases.

Monitoring of the serum methotrexate concentration is essential in determining the optimal dose of leucovorin to give and duration of therapy. Delayed methotrexate excretion may be an indication of a third space fluid accumulation (i.e., ascites, pleural effusion), renal insufficiency, low pH of urine or inadequate hydration. Higher doses of leucovorin or prolonged administration may be indicated in such cases. Leucovorin has no apparent effect on pre-existing methotrexate nephrotoxicity.

Excessive leucovorin doses must be avoided since this might impair the antitumour activity of methotrexate, especially in CNS tumours where leucovorin accumulates after repeated courses.

Resistance to methotrexate as a result of decreased membrane transport also implies resistance to folinic acid rescue as both medicinal products share the same transport system.

In case of co-administration of leucovorin and fluorouracil, diarrhea and/or stomatitis/mucositis are the first indications that severe and potentially life-threatening toxicity could develop. Patients who experience these symptoms while receiving any combination therapy regimen involving leucovorin and fluorouracil should be carefully monitored. Further therapy should be withheld until these symptoms resolve. Treatment-related deaths have been sporadically reported in patients receiving leucovorin/fluorouracil combination therapy.

Leucovorin enhances the toxicity of fluorouracil. When these drugs are administered concurrently in the palliative therapy of advanced colorectal cancer, the dosage of fluorouracil must be reduced. Although the toxicities observed in patients treated with the combination of leucovorin and fluorouracil are qualitatively similar to those observed in patients treated with fluorouracil alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be more severe in patients receiving the combination therapy.

Leucovorin should be used with caution after methotrexate chemotherapy, when the following medical problems exist:

• Aciduria (urine pH less than 7)
• Ascites
• Dehydration (Note: Inadequate hydration including that secondary to vomiting may also result in increased methotrexate toxicity.)
• Gastrointestinal obstruction
• Pleural or peritoneal effusions
• Renal function impairment (Note: Risk of methotrexate toxicity is increased because elimination of methotrexate may be impaired and accumulation may occur; even small doses of methotrexate may lead to severe myelosuppression and mucositis; larger doses and/or increased duration of leucovorin treatment may be necessary.)

Patient monitoring is recommended when leucovorin is administered as part of methotrexate chemotherapy programs. Monitoring may include creatinine clearance determinations prior to therapy; plasma or serum methotrexate determinations to detect developing renal function impairment (an increase of greater than 50% within 24 hours is associated with severe renal toxicity); urine pH determination (recommended every 6 hours to ensure that the pH remains greater than 7.0 to minimize the risk of methotrexate nephropathy). Leucovorin has no apparent effect on pre-existing methotrexate nephrotoxicity.

Gastrointestinal

Therapy with leucovorin /fluorouracil must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity, until those symptoms have resolved. Patients with diarrhea must be closely monitored until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur. Elderly or debilitated patients are at greater risk for severe toxicity when receiving this therapy. In elderly patients, it is recommended to begin with a reduced dosage of fluorouracil.

Monitoring and Laboratory Tests

Calcium levels should be monitored in patients receiving combined leucovorin /5-fluorouracil treatment and calcium supplementation should be provided if calcium levels are low. Complete blood count (CBC) with differential and platelets: prior to each treatment; weekly during the first two courses; at time of anticipated white blood cell (WBC) nadir in all courses thereafter. Electrolytes and liver function tests: prior to each treatment for the first three courses and prior to every other course thereafter.

Neurologic

Seizures and/or syncope have been reported rarely in cancer patients receiving leucovorin, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases or other predisposing factors, however, a causal relationship has not been established.

Reproductive Health

• Fertility:

Calcium folinate is an intermediate product in the metabolism of folic acid and occurs naturally in the body. No fertility studies have been conducted with calcium folinate in animals.

7.1 Special Populations

7.1.1 Pregnancy

Leucovorin is an intermediate product in the metabolism of folic acid and occurs naturally in the body.

There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women.

7.1.2 Breast-feeding

There has been evidence that folinic acid is excreted in human breast milk, therefore, caution should be exercised when administering leucovorin to nursing mothers. Calcium folinate in combination with 5-fluorouracil is not recommended for use in woman who are breast-feeding.

7.1.3 Pediatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. Leucovorin may increase the frequency of seizures in susceptible children.

7.1.4 Geriatrics

No information is available regarding the use of leucovorin in geriatrics. Elderly patients are at greater risk of developing severe toxicity when treated with the combination of leucovorin plus fluorouracil for the palliative treatment of colorectal cancer.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Table 2: Adverse Drug Reactions during Leucovorin Calcium Monotherapy

Generally, the safety profile depends on the applied regimen of 5-fluorouracil due to enhancement of the 5-fluorouracil induced toxicities. Additional undesirable effects, when used in combination with 5-fluorouracil, are presented in Table 3.

Table 3: Adverse Drug Reactions during Leucovorin Calcium Combination Therapy with 5-fluorouracil

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Allergic reactions, wheezing, skin rash, hives or itching occur rarely. In combination regimens, the toxicity of fluorouracil is enhanced by leucovorin. The most common manifestations are mucositis, stomatitis, leukopenia and/or diarrhea which may be dose limiting. In clinical trials with this drug combination, these toxicities were found to be controllable by appropriately reducing the dose of fluorouracil.

8.5 Post-Market Adverse Reactions

Cases of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some fatal, have been reported in patients receiving leucovorin in combination with other agents known to be associated with these disorders. A contributory role of leucovorin in these occurrences of SJS/TEN cannot be excluded.

Fatalities have occurred as a result of gastrointestinal toxicity (predominantly mucositis and diarrhea) and myelosuppression. In patients with diarrhea, rapid clinical deterioration leading to death can occur.

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

Serious Drug Interactions

• Patients receiving any combination therapy regimen involving leucovorin and fluorouracil should be carefully monitored for diarrhea and/or stomatitis/mucositis as these are the first indications that severe and potentially life-threatening toxicity could develop (see 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS).
• Leucovorin may diminish the effect of anti-epileptic substances such as phenobarbital, primidone and phenytoin. During leucovorin administration in epileptic patients treated with these substances, there is a risk to increase the frequency of seizures due to a decrease of plasma concentrations of anti-epileptic drugs (see 9 DRUG INTERACTIONS).
• Leucovorin enhances the cytotoxicity and toxicity of fluorouracil. Leucovorin must not be mixed with fluorouracil in the same intravenous injection or infusion (see 9 DRUG INTERACTIONS).

9.4 Drug-Drug Interactions

The following drugs or combinations containing these drugs may interact with leucovorin with clinical significance:

• Anticonvulsants, barbiturate
• Anticonvulsant, hydantoin
• Primidone

Large doses of leucovorin may counteract the anticonvulsant effects of these medications.

Leucovorin has been administered simultaneously with pyrimethamine without interfering with its anti-malarial therapy.

Table 4 – Established or Potential Drug-Drug Interactions

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Leucovorin is a reduced form of folic acid, which is readily converted to other reduced folic acid derivatives (e.g., tetrahydrofolate). Because it does not require reduction by dihydrofolate reductase as does folic acid, leucovorin is not affected by blockages of this enzyme by folic acid antagonists (dihydrofolate reductase inhibitors). This allows purine and thymidine synthesis, and thus DNA, RNA and protein synthesis to occur. Leucovorin may limit methotrexate action on normal cells by competing with methotrexate for the same transport processes into the cell. .

Leucovorin enhances the cytotoxicity of fluoropirimidines such as fluorouracil by their metabolites, methylene tetrahydrofolate and fluorodeoxyuridine monophosphate, forming a stable ternary complex with thymidylate synthase and thereby decreasing intracellular levels of that enzyme and the product thymidylate. The cell then dies as a result of thymine starvation.

10.2 Pharmacodynamics

A folic acid deficiency is produced during therapy with the folic acid antagonists aminopterin and amethopterin (Methotrexate) used as antineoplastic agents and with the chemotherapeutic agent pyrimethamine. These agents competitively inhibit the conversion of folic acid to folinic acid. Their affinity for folate reductase is so much greater than that of folic acid that not even large doses of folic acid will correct the drug-induced deficiency. In the event of a severe toxic reaction, the already reduced form, folinic acid, can be given, since it can be used directly to form new coenzyme.

10.3 Pharmacokinetics

The pharmacokinetics of leucovorin was evaluated after intravenous, intramuscular and oral administration of a 25 mg dose of leucovorin to healthy male subjects in a randomized crossover study.

Serum total reduced folates (as measured by Lactobacillus casei assay) reached a mean peak of 1259 ng/mL (range-1625) at 10 minutes and 436 ng/mL (range 240-725) at 52 minutes after intravenous and intramuscular administration respectively. This initial rise in total reduced folates was primarily due to the parent compound 5-formyl-tetrahydrofolate (measured by Streptococcus faecalis assay) which rose to 1206 ng/mL at 10 minutes and 360 ng/mL at 28 minutes after intravenous and intramuscular administration, respectively. A sharp drop in parent compound followed and coincided with the appearance of the metabolite (also active) 5-methyl-tetrahydrofolate which became the predominant circulating form of the drug (intravenous administration). The mean peak of 5-methyl tetrahydrofolate was 258 ng/mL and occurred at 1.3 hours. The level of the metabolite 5-methyl-tetrahydrofolate increased subsequently over time until at 1.5 hours it represented 50% of the circulating total folates (intramuscular administration). The terminal half-life of total reduced folates was 6.2 hours with parenteral administration. There was no statistically significant difference between i.m. and i.v. administration in the AUC for total reduced folates, 5-formyl-tetrahydrofolate, or 5-methyl-tetrahydrofolate.

Leucovorin distributes to all tissues, readily penetrates the blood brain barrier and actively concentrates in the cerebrospinal fluid. Leucovorin (5-formyl-tetrahydrofolate) is rapidly and extensively metabolized to other tetrahydrofolate derivatives, the major metabolite being 5-methyl-tetrahydrofolate. Approximately 80-90% of the dose is excreted in the urine. Elimination half-lives of parent drug and active metabolite are 32 and 227 minutes respectively.

Leucovorin has an onset of action of 20-30 minutes with peak levels occurring at 1.7 hours. Similar serum levels are produced after oral and intravenous administration, approximately 12% greater than after intramuscular use. Onset of action is 10-20 minutes after intramuscular administration with peak levels occurring at 0.7 hours. Leucovorin has a 3-6 hour duration of action. Absorption from the deltoid is 8% higher than from the gluteal muscle after intramuscular injection.

The serum half-life of leucovorin (or 5-formyl-tetrahydrofolate) was 35-45 minutes following both oral and intramuscular administration. The serum half-life of 5-methyl-tetrahydrofolate was about 2 1 /4 hours. 5-methyl-tetrahydrofolate was excreted via the kidneys in a manner proportional to its serum concentration.

Methotrexate did not seem to affect the absorption of folate.

11 STORAGE, STABILITY AND DISPOSAL

Vials of 10 mg/mL should be stored at refrigerated temperatures (2-8°C). LEUCOVORIN CALCIUM INJECTION is light sensitive and should be protected from light. The liquid formulation should be used immediately once removed from refrigeration. Discard any unused portion.

PART 2 : SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Leucovorin calcium (folic acid derivative)

This drug substance is also known as calcium folinate, citrovorum factor, or the calcium salt of 5-formyl-5,6,7,8-tetrahydrofolic acid.

Chemical name: (R,S)-N-{4-[[2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amino]-benzoyl}-L-glutamate, calcium salt

Molecular formula and molecular mass: C₂₀H₂₁CaN₇O_7, 511.5 g/mol (salt)

471.5 g/mol (base)

Structural formula:

Physicochemical properties:

Calcium folinate is a yellowish white or yellow, odourless, powder. It is very soluble in water and practically insoluble in alcohol. It decomposes above 250°C.

14 CLINICAL TRIALS

The clinical trial data on which the original indication was authorized are not available.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General toxicology

In mice, the LD50 was 991 mg/kg intravenously. Toxic symptoms included body tremors, marked ataxia, clonic convulsions and deaths within 10 minutes in CD-1 male mice. The single-dose oral LD50 could not be determined because, at doses as high as 20,000 mg/kg, no toxicity was observed in CD-1 and Long-Evans male rats. Doses higher than this could not be given because of the limitations of dose volume and viscosity.

In subchronic studies, oral doses of leucovorin at 0, 75, 225 or 675 mg/kg daily for over 30 days to rats and beagle dogs produced no drug-related toxic effects on body weight, food consumption, hematology, blood chemistry, urinalysis or pathology. No alteration in ECG in dogs occurred. Ophthalmoscopic examinations of rats and dogs revealed no drug-induced toxic effects.

Genotoxicity

No studies have been performed to evaluate the genotoxic potential of leucovorin calcium.

Carcinogenicity

Carcinogenicity studies have not been performed with leucovorin calcium.

Reproductive and developmental toxicology

Embryo-fetal reproduction toxicity studies have been performed in rats and rabbits. Rats were dosed up to 1800 mg/m2 which is 9 times the maximum recommended human dose, and rabbits were dosed up to 3300 mg/m2 which is 16 times the maximum recommended human dose. There was no embryo-fetal toxicity noted in rabbits. At the maximum dose in rats, there was a slight increase in early embryonic resorptions and no other adverse effects on embryo-fetal development. No resorptions were noted in dose groups at 5 times the maximum recommended human dose.

No dedicated animal fertility studies have been performed for leucovorin calcium.

17 SUPPORTING PRODUCT MONOGRAPH

1. 1. LEUCOVORIN CALCIUM INJECTION USP, Solution, 10 mg/mL, submission Control : 058177, Product Monograph, Novopharm Limited Canada, December 21, 1998
2. 2. LEUCOVORIN CALCIUM INJECTION, Solution, 10 mg/mL, submission Control: 294459, Product Monograph, Teva Canada Limited, May 13, 2025