Riva Leucovorin Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

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

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

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 4

1 INDICATIONS ............................................................................................................... 4

1.1 Pediatrics ................................................................................................................ 4

1.2 Geriatrics ................................................................................................................ 4

2 CONTRAINDICATIONS ................................................................................................. 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 4

4 DOSAGE AND ADMINISTRATION ................................................................................. 5

4.2 Recommended Dose and Dosage Adjustment ....................................................... 5

4.4 Administration ........................................................................................................ 6

5 OVERDOSAGE .............................................................................................................. 6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 7

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

7.1 Special Populations................................................................................................. 9

7.1.1 Pregnant Women ............................................................................................. 9

7.1.2 Breast-feeding .................................................................................................. 9

7.1.3 Pediatrics .......................................................................................................... 9

7.1.4 Geriatrics .......................................................................................................... 9

8 ADVERSE REACTIONS ................................................................................................ 10

8.1 Adverse Reaction Overview .................................................................................. 10

8.2 Clinical Trial Adverse Reactions ............................................................................ 10

8.5 Post-Market Adverse Reactions ........................................................................... 11

9 DRUG INTERACTIONS ................................................................................................ 11

9.1 Serious Drug Interactions ..................................................................................... 11

9.2 Drug Interactions Overview .................................................................................. 12

9.3 Drug-Behavioural Interactions .............................................................................. 12

9.4 Drug-Drug Interactions ......................................................................................... 13

9.5 Drug-Food Interactions ......................................................................................... 13

9.6 Drug-Herb Interactions ......................................................................................... 13

9.7 Drug-Laboratory Test Interactions ........................................................................ 13

10 CLINICAL PHARMACOLOGY ....................................................................................... 14

10.1 Mechanism of Action ...................................................................................... 14

10.2 Pharmacodynamics ........................................................................................ 14

10.3 Pharmacokinetics ........................................................................................... 14

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 15

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 15

PART II: SCIENTIFIC INFORMATION ....................................................................................... 16

13 PHARMACEUTICAL INFORMATION ............................................................................ 16

14 CLINICAL TRIALS ........................................................................................................ 17

14.2 Comparative Bioavailability Studies ................................................................ 17

15 MICROBIOLOGY ........................................................................................................ 18

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 18

17 SUPPORTING PRODUCT MONOGRAPHS .................................................................... 18

PATIENT MEDICATION INFORMATION .................................................................................. 19

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

RIVA LEUCOVORIN (leucovorin calcium) is indicated for:

• diminishing the toxicity and counteracting the effect of impaired methotrexate elimination.
• treatment of megaloblastic anemias due to folate deficiency, as in sprue, nutritional deficiency, megaloblastic anemias of pregnancy and infancy.

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 WARNINGS AND PRECAUTIONS, 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

RIVA LEUCOVORIN therapy is contraindicated in patients with:

• Known hypersensitivity to the active substance or to any of the excipients. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• Pernicious anemia or other megaloblastic anemias where Vitamin B₁₂ is deficient. A hematologic remission may occur while neurologic manifestations continue to progress.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.2 Recommended Dose and Dosage Adjustment

Impaired methotrexate Elimination or Accidental Overdosage

RIVA LEUCOVORIN rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion (see 7 WARNINGS AND PRECAUTIONS). As the time interval between the administration of antifolate and RIVA LEUCOVORIN rescue increases, the effectiveness of RIVA LEUCOVORIN in counteracting toxicity decreases.

There are no fixed guidelines regarding the dose of methotrexate that triggers an automatic subsequent leucovorin calcium administration, since tolerance to this folate antagonist depends on various factors. The dose of methotrexate varies, nevertheless folinate rescue is necessary when methotrexate is given at doses exceeding 500 mg/m² and has to be considered with doses of 100 mg - 500 mg/m².

Leucovorin calcium rescue treatment should commence approximately 24 hours after the beginning of methotrexate infusion. Dosage regimens vary depending upon the dose of methotrexate administered. In general, leucovorin calcium should be administered at a dose of 15 mg (approximately 10 mg/m²) every 6 hours for 10 doses, either parenterally by intramuscular injection, bolus intravenous injection, intravenous infusion, or orally using leucovorin calcium tablets.

Monitoring of the serum methotrexate (MTX) concentration is essential in determining the optimal dose and duration of therapy. If serum creatinine increases after methotrexate therapy or if methotrexate plasma concentrations are above certain threshold (see Table 1), the dose of leucovorin calcium should be increased according to the plasma methotrexate concentrations as soon as the risk is recognized. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin calcium should be administered parenterally. In the case of intravenous administration, no more than 160 mg of leucovorin calcium should be injected per minute due to the calcium content of the solution. Further, oral administration of doses greater than 25 mg is not recommended since the digestive absorption of leucovorin calcium is saturable; these doses should be administered parenterally.

In addition to leucovorin calcium administration, measures to ensure the prompt excretion of methotrexate are an integral part of the leucovorin calcium rescue treatment. These measures include:

1. a) Maintenance of urine output above 2,500 mL/24 hr in adults by increased oral or intravenous fluids 12 hours before and for 36 hours after the end of methotrexate infusion.
2. b) Alkalinisation of urine so that the urinary pH is greater than 7.0 before methotrexate infusion. Foods, drinks and drugs that may increase urinary acidity should be avoided during the therapy.
3. c) Plasma methotrexate concentration and serum creatinine should be measured at least 24, 48, and 72 hours after the initiation of the methotrexate infusion. These measurements must be continued until the plasma methotrexate level is less than 5 x 10^-8 molar (0.05 μm).

Delayed methotrexate excretion may be seen in some patients. This may be caused by a third space accumulation (as seen in ascites or pleural effusion for example), renal insufficiency or inadequate hydration (see 7 WARNINGS AND PRECAUTIONS). Under such circumstances, higher doses of leucovorin calcium and/or prolonged administration may be indicated. Some dosage and administration guidelines are given in Table 1.

Table 1 – Dosage and Administration Guidelines for Leucovorin Calcium Rescue

Hydration (3 L/d) and urinary alkalinization with NaHC0₃ should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

Megaloblastic Anemia Due to Folic Acid Deficiency

Doses up to 15 mg daily have been suggested.

Health Canada has not authorized an indication for pediatric use.

4.4 Administration

Tablets are administered orally.

5 OVERDOSAGE

Folic acid is a water-soluble vitamin converted in the body by the action of folate reductase to folinic acid (leucovorin calcium), which is rapidly eliminated in the urine.

Folic acid has low acute and chronic toxicity in humans. There have been no reported sequelae in patients who have received significantly more leucovorin calcium than the recommended dosage. However, excessive amounts of leucovorin calcium may nullify the chemotherapeutic effect of folic acid antagonists. 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.

Should overdosage of the combination of 5-fluorouracil and leucovorin calcium occur, the overdosage instructions for 5-FU should be followed.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 2 – Dosage Forms, Strengths, Composition and Packaging

RIVA LEUCOVORIN 5 mg tablets are supplied as white to off white, round convex tablets, engraved “IT” above bisect and “54” below bisect on one side, other side is plain.

Availability:

Bottles of 24 tablets

Bottles of 100 tablets

7 WARNINGS AND PRECAUTIONS

General

Since leucovorin calcium may enhance the toxicity of fluorouracil, leucovorin calcium/fluorouracil combination therapy 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 (see 9 DRUG INTERACTIONS and 7.1.4 Geriatrics).

Leucovorin calcium should only be used with 5-fluorouracil or methotrexate under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.

Treatment-related deaths have been sporadically reported in patients treated with RIVA LEUCOVORIN plus fluorouracil combination therapy regimens. In general, diarrhea 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 incorporating RIVA LEUCOVORIN plus fluorouracil should be carefully followed and further therapy should be withheld until these symptoms resolve.

Gastrointestinal

Gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be more severe in patients receiving leucovorin calcium plus fluorouracil combination (see 9 DRUG INTERACTIONS, 9.2 Drug Interactions Overview).

Therapy with RIVA 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 monitored with particular care 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 receiving this therapy.

Hematologic

RIVA LEUCOVORIN (leucovorin calcium) treatment may mask pernicious anemia and other megaloblastic anemias resulting from vitamin B₁₂ deficiency.

RIVA LEUCOVORIN should not be used for the treatment of macrocytosis caused by direct or indirect DNA synthesis inhibitors (e.g. hydroxycarbamide, cytarabine, mercaptopurine, thioguanine).

Monitoring and Laboratory Tests

The following provides general advice for monitoring patients; however, specific monitoring recommendations may vary with local medical practice.

5-fluorouracil/leucovorin calcium therapy

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.

Methotrexate/leucovorin calcium therapy

Serum creatinine levels and serum methotrexate levels: at least once daily.

Urine pH: in cases of methotrexate overdose or delayed excretion, monitor as appropriate, to ensure maintenance of pH ≥7.0.

Neurologic

Seizures and/or syncope have been reported rarely in cancer patients receiving leucovorin calcium, usually in association with fluoropyrimidine and anti-epileptic drugs such as phenobarbital, phenytoin, primidone, and succinimides administration (see 9 DRUG INTERACTIONS).

In epileptic patients treated with phenobarbital, phenytoin, primidone, and succinimides there is a risk to increase the frequency of seizures due to a decrease of plasma concentrations of anti-epileptic drugs. Clinical monitoring, possibly monitoring of the plasma concentrations and, if necessary, dose adaptation of the anti-epileptic drug during leucovorin calcium administration and after discontinuation is recommended.

Reproductive Health: Female and Male Potential

• Fertility

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

Skin

Cases of Stevens - Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some fatal, have been reported in patients receiving leucovorin calcium 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 (see 3 SERIOUS WARNINGS AND PRECAUTIONS).

7.1 Special Populations

7.1.1 Pregnant Women

There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women. Animal studies do not indicate reproductive toxicity (see 16 NON-CLINICAL TOXICOLOGY). There are no indications that folic acid induces harmful effects if administered during pregnancy. During pregnancy, 5-fluorouracil and methotrexate should only be administered on strict indications, where the benefits of the drug to the mother should be weighed against possible hazards to the foetus. Should treatment with methotrexate or other folate antagonists take place despite pregnancy or lactation, there are no limitations as to the use of RIVA LEUCOVORIN (leucovorin calcium) to diminish toxicity or counteract the effects.

5-fluorouracil use is generally contraindicated during pregnancy and contraindicated during breast-feeding; this applies also to the combined use of RIVA LEUCOVORIN (leucovorin calcium) with 5-fluorouracil.

Please refer also to the health-care professional label for methotrexate, other folate antagonists and 5-fluorouracil-containing medicinal products.

7.1.2 Breast-feeding

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RIVA LEUCOVORIN is administered to a nursing mother.

7.1.3 Pediatrics

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

7.1.4 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). Deaths from severe enterocolitis, diarrhea and dehydration have been reported in elderly patients receiving leucovorin and fluorouracil. Concomitant granulocytopenia and fever were present in some but not all of the patients.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Allergic sensitization, including anaphylactoid/anaphylactic reactions (including shock) and urticaria, has been reported following administration of leucovorin calcium.

Table 3 –Adverse Reactions associated with Leucovorin Calcium

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.

Leucovorin calcium in Combination with 5-fluorouracil (5-FU)

In combination regimens, the toxicity profile of 5-FU is enhanced by leucovorin calcium. 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 reversible with appropriate modification of 5-FU administration.

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:

Table 4 –Adverse Reactions associated with Leucovorin Calcium in Combination with 5-FU

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 calcium 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

9.2 Drug Interactions Overview

Leucovorin calcium may diminish the effect of anti-epileptic substances: phenobarbital, primidone, phenytoin and succinimides, and may increase the frequency of seizures (a decrease of plasma levels of enzymatic inductor anticonvulsant drugs may be observed because the hepatic metabolism is increased as folates are one of the cofactors). 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.

In epileptic patients treated with phenobarbital, phenytoin, primidone, and succinimides there is a risk to increase the frequency of seizures due to a decrease of plasma concentrations of anti-epileptic drugs. Clinical monitoring, possibly monitoring of the plasma concentrations and, if necessary, dose adaptation of the anti-epileptic drug during RIVA LEUCOVORIN administration and after discontinuation is recommended.

When leucovorin calcium is given in conjunction with a folic acid antagonist (eg, cotrimoxazole, pyrimethamine, methotrexate, antibiotic with antifolic effect) the efficacy of the folic acid antagonist may either be reduced or completely neutralised.

Preliminary animal and human studies have shown that small quantities of systemically administered leucovorin calcium enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin calcium may reduce the efficacy of intrathecally administered methotrexate.

Leucovorin calcium may enhance the toxicity of fluorouracil (see 7 WARNINGS AND PRECAUTIONS). 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 calcium plus 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 (see 7 WARNINGS AND PRECAUTIONS).

9.3 Drug-Behavioural Interactions

Interactions with behaviour have not been established.

9.4 Drug-Drug Interactions

Table 5 - Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

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 calcium, the calcium salt of folinic acid (citrovorum factor), is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid. The biologically active component of the mixture is the (-)-L-isomer. It is a metabolite of folic acid and an essential coenzyme for nucleic acid synthesis used in cytotoxic therapy.

10.2 Pharmacodynamics

Leucovorin calcium 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 calcium is not affected by blockage 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 calcium may limit methotrexate action on normal cells by competing with methotrexate for the same transport processes into the cell. Leucovorin calcium rescues bone marrow and gastrointestinal cells from methotrexate but has no apparent effect on pre-existing methotrexate nephrotoxicity.

Leucovorin calcium is extensively converted to 5-methyltetrahydrofolate in the intestine prior to absorption. In this form, it is a major component of the total active human serum folate. Oral absorption is saturable at doses above 25 mg.

Leucovorin calcium enhances the cytotoxicity of fluoropyrimidines such as 5-fluorouracil (5FU) 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.

10.3 Pharmacokinetics

The pharmacokinetics after intravenous, intramuscular and oral administration of a 25 mg dose of leucovorin calcium were studied in male volunteers.

After intravenous administration, serum total reduced folates (as measured by Lactobacillus casei assay) reached a mean peak of 1259 ng/mL (range 897-1625). The mean time to peak was 10 minutes. This initial rise in total reduced folates was primarily due to the parent compound 5-formyl-THF (measured by Streptococcus faecalis assay), which rose to 1206 ng/mL at 10 minutes. A sharp drop in parent compound followed and coincided with the appearance of the metabolite (also active), 5-methyl-THF, which became the predominant circulating form of the drug. The mean peak of 5-methyl-THF was 258 ng/mL and occurred at 1.3 hours. The terminal half-life for total reduced folates was 6.2 hours.

After intramuscular injection, the mean peak of serum total reduced folates was 436 ng/mL (range 240- 725) and occurred at 52 minutes. Similar to IV administration, the initial sharp rise was due to the parent compound. The mean peak of 5-formyl-THF was 360 ng/mL and occurred at 28 minutes. The level of the metabolite 5-methyl-THF increased subsequently over time until at 1.5 hours it represented 50% of the circulating total folates. The mean peak of 5-methyl-THF was 226 ng/mL at 2.8 hours. The terminal half-life of total reduced folates was 6.2 hours. There was no difference of statistical significance between IM and IV administration in the AUC for total reduced folates, 5-formyl-THF or 5-methyl-THF.

After oral administration of leucovorin calcium reconstituted with the aromatic elixir, the mean peak concentration of serum total reduced folates was 393 ng/mL (range 160-550). The mean time to peak was 2.3 hours and the terminal half-life was 5.7 hours. The major component was the metabolite 5-methyltetrahydrofolate to which leucovorin calcium is partially converted in the intestinal mucosa. The mean peak of 5-methyl-THF was 367 ng/mL at 2.4 hours. The peak level of the parent compound was 51 ng/mL at 1.2 hours. The AUC of total reduced folates after oral administration of the 25 mg dose was 92% of the AUC after intravenous administration.

Following oral administration, leucovorin calcium is rapidly absorbed and enters the general body pool of reduced folates. Folate is concentrated in the liver and cerebrospinal fluid although distribution occurs to all body tissues. Folates are mainly excreted in the urine, with small amounts in the faeces. Parenteral administration of leucovorin calcium gives higher peak plasma levels than oral administration, but the total plasma folate pool of folinic acid plus its metabolite (N⁵methyl—H₄-folate) remains unchanged. Oral absorption of leucovorin calcium is saturable at doses above 25 mg. The apparent bioavailability of leucovorin calcium was 97% for 25 mg, 75% for 50 mg and 37% for 100 mg.

Leucovorin calcium is the calcium salt of 5-formyl tetrahydrofolic acid. It is an active metabolite of folinic acid and an essential coenzyme of nucleic acid synthesis in cytotoxic chemotherapy. Leucovorin calcium is frequently used to diminish the toxicity and counteract the action of folate antagonists, such as methotrexate. Leucovorin calcium and folate antagonists share the same membrane transport carrier and compete for transport into cells, stimulating folate antagonist efflux. It also protects cells from the effect of folate antagonists by repletion of the reduced folate pool. Leucovorin calcium serves as a pre- reduced source of H4 folate: it can therefore bypass folate antagonist blockage and provide a source for the various coenzyme forms of folic acid. Leucovorin calcium is also frequently used in the biochemical modulation of fluoropyridine (5-FU) to enhance its cytotoxic activity. 5-FU inhibits thymidylate synthase (TS), a key enzyme involved in pyrimidine biosynthesis, and leucovorin calcium enhances TS inhibition by increasing the intracellular folate pool, thus stabilizing the 5-FU-TS complex and increasing 5-FU activity. 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.

11 STORAGE, STABILITY AND DISPOSAL

RIVA LEUCOVORIN Tablets 5 mg:

Tablets should be stored at 15-30°C. Protect from light. Keep out of reach and sight of children.

12 SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions for this drug product.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Leucovorin Calcium (USP) also known as Leucovorin calcium hydrate in Ph. Eur.

Chemical name: Calcium (2S)-2-[4-[[[(6RS)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydropteridin-6-yl]methyl]amino]benzamido]pentanedioate hydrate.

Molecular formula and molecular mass: C₂₀H₂₁CaN₇O₇ x H₂0, 511.5 g/mol (calculated on the anhydrous basis)

Structural formula:

Physicochemical properties: Leucovorin Calcium occurs as a white to light yellow, crystalline powder. There is 0.004 mEq of calcium per mg of leucovorin in each tablet.

Solubility: Leucovorin Calcium is very soluble in water and practically insoluble in ethanol and acetone.

pH: 6.8-8.0

pKa: 3.1 – 4.8 – 10.4

Melting Point: The substance does not have a melting point. It decomposes above 250°C.

Hygroscopicity: The substance is hygroscopic.

14 CLINICAL TRIALS

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

14.2 Comparative Bioavailability Studies

A randomized, blinded, two-treatment, two-period, two-sequence, single-dose, crossover comparative bioavailability study of ^PrRIVA LEUCOVORIN 5 mg tablets (Laboratoire Riva Inc.) with ^PrLEDERLE LEUCOVORIN® 5 mg tablets (Pfizer Canada Inc.) was conducted in healthy, adult, male subjects under fasting conditions. Comparative bioavailability data from 26 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^{1 Pr}RIVA LEUCOVORIN (leucovorin as leucovorin calcium) tablets, 5 mg (Laboratoire Riva Inc.)

^{2 Pr}LEDERLE LEUCOVORIN® (leucovorin as leucovorin calcium) tablets, 5 mg (Pfizer Canada Inc.)

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV%) only

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Genotoxicity, carcinogenicity, and fertility studies have not been conducted with leucovorin calcium.

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.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. LEDERLE LEUCOVORIN (Tablets, 5 mg), submission control 263375, Product Monograph, Pfizer Canada ULC. (OCT 04, 2022)