Consumer medicine information

DBL Leucovorin Calcium injection and tablets

Calcium folinate

BRAND INFORMATION

Brand name

DBL Leucovorin Calcium 300 mg/30 mL and 50 mg/5 mL Injection

Active ingredient

Calcium folinate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Leucovorin Calcium injection and tablets.

What is in this leaflet

This leaflet answers some of the common questions that you may have about DBL™ Leucovorin Calcium Injection and DBL™ Leucovorin Calcium Tablets (leucovorin calcium). It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being treated with leucovorin calcium, against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet in a safe place. You may need to read it again.

What DBL™ Leucovorin Calcium is used for

DBL™ Leucovorin Calcium is considered to be a supportive therapy. It is used in two main situations:

  1. When your body does not have enough folic acid.
    This occurs in conditions such as megaloblastic anaemia, where the level of red blood cells and iron in the blood is too low. Megaloblastic anaemia can happen during pregnancy or infancy, or due to liver disease, malnutrition, or a reduced ability to absorb folic acid from the diet.
  2. As an antidote or rescue therapy to the toxic effects of some medications such as methotrexate.

DBL™ Leucovorin calcium is not addictive.

Before you are given DBL™ Leucovorin Calcium

When you must not be given it

You must not be given DBL™ Leucovorin Calcium Injection or DBL™ Leucovorin Calcium Tablets if you have or have had an allergy to leucovorin calcium, folic acid, or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to leucovorin calcium may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

You must not be given DBL™ Leucovorin Calcium Injection or DBL™ Leucovorin Calcium Tablets if you have pernicious anaemia or any other megaloblastic anaemias which are due to a lack of Vitamin B12

You must not be DBL™ Leucovorin Calcium Injection or DBL™ Leucovorin Calcium Tablets after the expiry date (EXP) printed on the pack. If you are given this medicine after the expiry date has passed, it may not work as well.

You must not be given DBL™ Leucovorin Calcium Injection or DBL™ Leucovorin Calcium Tablets if the packaging is torn or shows signs of tampering.

If you are not sure whether you should be given DBL™ Leucovorin Calcium Injection or DBL™ Leucovorin Calcium Tablets, talk to your doctor or pharmacist.

Before you are given it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes.

Tell your doctor or pharmacist if you are breastfeeding or plan to breastfeed. Your doctor or pharmacist will discuss the possible risks and benefits of being given leucovorin calcium when breastfeeding.

Tell your doctor or pharmacist if you have or have had any medical conditions, especially the following:

  • pernicious anaemia
  • Vitamin B12 deficiency
  • fits or convulsions (epilepsy).

If you have not told your doctor or pharmacist about any of the above, tell them before you are given leucovorin calcium.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and leucovorin calcium may interfere with each other. These include:

  • some drugs used to treat epilepsy (fits), including phenytoin, phenobarbitone, succinimides and primidone
  • fluorouracil (5-FU), a medicine used to treat some cancers
  • folic acid antagonists, medicines used to treat some infections (e.g. cotrimoxazole or pyrimethamine)
  • methotrexate, a medicine used to treat rheumatoid arthritis, psoriasis, inflammatory bowel disease or some cancers

These medicines may be affected by leucovorin calcium, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor or pharmacist will advise you.

How DBL™ Leucovorin Calcium is given

How much is given

Your doctor will decide what dose and how long you will receive leucovorin calcium. This depends on the condition you are being treated for.

How it is given

DBL™ Leucovorin Calcium Injection can be given in three ways:

  • as a slow injection into a vein
  • as a continuous infusion (intravenous drip) into a vein
  • as a deep injection into a large muscle.

DBL™ Leucovorin Calcium Injection must only be given by a doctor or nurse.

DBL™ Leucovorin Calcium Tablets should be swallowed with a full glass of water.

DBL™ Leucovorin Calcium Tablets should be taken on an empty stomach, for example, at least half an hour before food or two hours after food.

If you take too much (overdose)

As DBL™ Leucovorin Calcium Injection or DBL™ Leucovorin Calcium Tablets are given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26 in Australia, or call 0800 764 766 in New Zealand) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much DBL™ Leucovorin Calcium Injection or DBL™ Leucovorin Calcium Tablets. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of a leucovorin calcium overdose include the side effects listed below in the 'Side Effects' section, but are usually of a more severe nature.

While you are being given DBL™ Leucovorin Calcium

Things you must do

Tell your doctor, nurse or pharmacist if you have any concerns before, during or after administration of DBL™ Leucovorin Calcium Injection or DBL™ Leucovorin Calcium Tablets.

Tell all the doctors, dentists and pharmacists who are treating you that you are being given leucovorin calcium.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being given Leucovorin Calcium.

Things you must not do

Do not give leucovorin calcium to anyone else, even if they have the same condition as you.

Do not take leucovorin calcium to treat any other complaints unless your doctor or pharmacist tells you to.

Do not stop taking leucovorin calcium, or lower the dosage, without checking with your doctor or pharmacist.

Side effects

Tell your doctor, nurse, or pharmacist as soon as possible if you do not feel well while you are being given leucovorin calcium.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • fever
  • nausea, vomiting
  • diarrhoea
  • sore mouth / mouth ulcers or cold sores
  • irritability or trouble sleeping

These side effects are usually mild.

Tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital if you notice any of the following:

  • signs of an allergic reaction, such as those listed at the start of this leaflet.
  • fits or convulsions.
  • Stomach pain

These are serious side effects. You may need urgent medical attention or hospitalisation.

Other side effects not listed above may occur in some patients.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Do not be alarmed by this list of side effects. You may not experience any of them.

Even after you have finished being treated with DBL™ Leucovorin Calcium, you should tell your doctor if you notice any side effects listed in this section.

After being given leucovorin calcium

Storage

DBL™ Leucovorin Calcium Injection will be stored in the pharmacy or on the ward.

The injections should be kept in a refrigerator where the temperature stays between 2 - 8 degrees C, and protected from light.

DBL™ Leucovorin Calcium Tablets should be kept in a cool dry place where the temperature stays below 25 degrees C.

Do not store DBL™ Leucovorin Calcium Tablets or any other medicine in the bathroom or near a sink.

Do not leave them in the car on hot days or on window sills.

Heat and dampness can destroy some medicines.

Keep DBL™ Leucovorin Calcium Tablets where children cannot reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop using DBL™ Leucovorin Calcium Injection or DBL™ Leucovorin Calcium Tablets or they have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

DBL™ Leucovorin Calcium Injection

What it looks like

DBL™ Leucovorin Calcium Injection is a clear, straw-coloured solution.

Ingredients

Active ingredient:

  • calcium folinate

Other ingredients:

  • sodium chloride
  • water for injection

DBL™ Leucovorin Calcium Tablets

What they look like

DBL™ Leucovorin Calcium tablets are yellowish-white, round, flat tablets. They are scored and engraved with the letters CF.

Ingredients

Active ingredient:

  • calcium folinate, equivalent to 15 mg folinic acid

Other ingredients:

  • lactose
  • microcrystalline cellulose
  • magnesium stearate

DBL™ Leucovorin Calcium Tablets do not contain sucrose, gluten, tartrazine, or any other azo dyes.

Sponsor

DBL™ Leucovorin Calcium Injection and DBL™ Leucovorin Calcium Tablets are supplied by:

Australian Sponsor

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

Australian Registration Numbers:

DBL™ Leucovorin Calcium Injection

  • 15 mg/2 mL AUST R 16351

DBL™ Leucovorin Calcium Tablets

  • 15 mg AUST R 16364

Date of leaflet update: December 2019.

Published by MIMS March 2020

BRAND INFORMATION

Brand name

DBL Leucovorin Calcium 300 mg/30 mL and 50 mg/5 mL Injection

Active ingredient

Calcium folinate

Schedule

S4

 

1 Name of Medicine

Calcium folinate.

2 Qualitative and Quantitative Composition

DBL Leucovorin Calcium Injection presentations: 50 mg/ 5 mL and 300 mg/30 mL contain calcium folinate equivalent to 50 mg and 300 mg folinic acid respectively.
DBL Leucovorin Calcium Injection vial 50 mg/5 mL contains 10 mg of folinic acid per mL.
DBL Leucovorin Calcium Injection vial 300 mg/30 mL contains 10 mg of folinic acid per mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

DBL Leucovorin Calcium Injection is a clear straw to pale yellow coloured sterile solution of folinic acid in water for injection free from visible particular matter.

4 Clinical Particulars

4.1 Therapeutic Indications

Folinic acid has shown good results in the treatment of certain megaloblastic anaemias resulting from folic acid deficiency. This mainly occurs in infants, during pregnancy, in malabsorption syndromes, liver diseases, sprue and malnutrition. It is not more effective than folic acid for these conditions.
Folinic acid has also shown good results in reducing the toxicity and circumventing the effect of folic acid antagonists, if therapeutically desired.

4.2 Dose and Method of Administration

Dosage.

In the treatment of accidental overdosage of folic acid antagonists, e.g. methotrexate, DBL Leucovorin Calcium should be administered as promptly as possible. As the time interval between antifolate administration and DBL Leucovorin Calcium rescue increases, DBL Leucovorin Calcium's effectiveness in counteracting toxicity diminishes.
Monitoring of serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with DBL Leucovorin Calcium. Delayed methotrexate excretion may be caused by a third space fluid accumulation (i.e. ascites, pleural effusion), renal insufficiency or inadequate hydration. Under such circumstances, higher doses of DBL Leucovorin Calcium or prolonged administration may be indicated.

DBL Leucovorin Calcium rescue after methotrexate therapy.

The recommendations for DBL Leucovorin Calcium rescue are based on a methotrexate dose of 12 to 15 g/m2 administered by intravenous infusion over four hours (see product information for methotrexate). DBL Leucovorin Calcium rescue at a dose of 15 mg (approximately 10 mg/m2) every six hours for ten doses starts 24 hours after the beginning of the methotrexate infusion. In the presence of gastrointestinal toxicity, nausea or vomiting, DBL Leucovorin Calcium should be administered parenterally. Serum creatinine and methotrexate levels should be determined at least once daily. DBL Leucovorin Calcium Injection administration, hydration and urinary alkalinisation (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). Foods, drinks and drugs that may increase urinary acidity should be avoided during the therapy. The DBL Leucovorin Calcium dose should be adjusted or folinic acid rescue extended based on the following guidelines shown in Table 1.
Patients who experience delayed methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate DBL Leucovorin Calcium therapy, these patients require continuing hydration and urinary alkalinisation and close monitoring of fluid and electrolyte status until the serum methotrexate level has fallen to below 0.05 microM and the renal failure has resolved.
Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration which are significant but less severe than the abnormalities described above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, DBL Leucovorin Calcium rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g. medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

Note.

The above dosage recommendations do not necessarily apply to experimental high dose methotrexate therapy. High dose methotrexate therapy should only be administered by qualified specialists and in hospitals where the necessary facilities are available. Recent published literature should be consulted for details at all times.

Impaired methotrexate elimination or inadvertent overdosage.

DBL Leucovorin Calcium rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. DBL Leucovorin Calcium 10 mg/m2 should be administered intravenously, intramuscular every six hours until the serum methotrexate level is less than 0.01 microM. In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin calcium should be administered parenterally. Serum creatinine and methotrexate levels should be determined at intervals of 24 hours. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 microM or the 48 hour level is greater than 0.9 microM, the dose of leucovorin calcium should be increased to 100 mg/m2 intravenously every three hours until the methotrexate level is less than 0.01 microM.
Hydration (3 L/day) and urinary alkalinisation with sodium bicarbonate solution should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

Treatment of megaloblastic anaemias.

Parenteral administration.

Up to 1 mg daily. There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.

Treatment of pyrimethamine overdosage.

The dosage of pyrimethamine in treating toxoplasmosis is 10 to 20 times its dosage for malaria and approaches the toxic level. Since DBL Leucovorin Calcium is not utilised by protozoa, it can be given simultaneously without impairing the effectiveness of therapy. The usual dosage is 3 to 9 mg/day by intramuscular injection for three days or until the platelet and leucocyte counts have reached safe levels.

Method of administration.

Folinic acid may be given parenterally by intramuscular injection, intravenous injection or intravenous infusion. Folinic acid should not be administered intrathecally.
For Hospital Use Only.
DBL Leucovorin Calcium Injection contains no antimicrobial agent. This product is for single use in one patient only.
When required for intravenous infusion, DBL Leucovorin Calcium Injection may be diluted in 1 litre of 5% w/v glucose in water for injections or normal saline. Such solutions are stable for 24 hours when stored between 2 to 8°C. However, to avoid microbial contamination hazards, infusion should be commenced as soon as practicable after preparation of the solution. Infusion should be completed within 24 hours and any residue discarded.
Admixed solutions for parenteral administration should be visually inspected for particulate matter and discolouration prior to administration where solution and container permit. Do not use if solution is cloudy or precipitated.

Laboratory tests.

Patients being treated with DBL Leucovorin Calcium following methotrexate therapy, including inadvertent overdose, or patients with impaired methotrexate elimination, should have serum creatinine and methotrexate levels determined at intervals of 24 hours. Leucovorin Calcium dosage should be adjusted on the basis of laboratory test results.

4.3 Contraindications

Folinic acid is improper therapy for pernicious anaemia and other megaloblastic anaemias secondary to the lack of Vitamin B12. When treating these conditions with folinic acid, haematological remission may occur, but neurological manifestations are likely to progress.
Known hypersensitivity to the active substance(s) or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Folinic acid should be administered only by intramuscular or intravenous injection and must not be administered intrathecally. When folinic acid has been administered intrathecally following intrathecal overdose of methotrexate, death has been reported.
Folinic acid should only be used with folic acid antagonists, e.g. methotrexate, or fluoropyrimidines, e.g. fluorouracil, under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.
Because of the calcium ion content of the Calcium folinate injections, no more than 160 mg (16 mL of the 50 mg/5 mL or 300 mg/30 mL formulation) should be injected intravenously per minute.
Folinic acid may enhance the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhoea and dehydration have been reported in elderly patients receiving folinic acid and fluorouracil. Concomitant granulocytopenia and fever were present in some, but not all, of the patients.
Seizures and/or syncope have been reported rarely in cancer patients receiving folinic acid, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases.
Since three patients had recurrent neurological symptoms on rechallenge with folinic acid, further treatment with folinic acid is not recommended in these circumstances.
Simultaneous therapy with a folic acid antagonist and folinic acid is not recommended because the effect of the folic acid antagonist is either reduced or completely inhibited.
Folinic acid has no effect on nonhaematological toxicities of methotrexate, such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.
Many cytotoxic medicinal products - direct or indirect DNA synthesis inhibitors - lead to macrocytosis (hydrocarbamide, cytarabine, mercaptopurine, thioguanine). Such macrocytosis should not be treated with folinic acid.
In epileptic patients treated with phenobarbital, phenytoine, 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 calcium folinate administration and after discontinuation is recommended. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)
Folinic acid is not suitable for the treatment if pernicious anaemias and other anaemias resulting from lack of vitamin B12. Haematological remissions may occur, while the neurological manifestations remain progressive.

Folinic acid/ methotrexate.

Calcium folinate must not be administered intrathecally (see Section 4.2 Dose and Method of Administration).
An accidental overdose with a folate antagonist, such as methotrexate, should be treated quickly as a medical emergency. As the time interval between methotrexate administration and folinic acid rescues increases, folinic acid effectiveness in counteracting toxicity decreases.
Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure and all toxicities associated with methotrexate (please see the health-care professional labeling for methotrexate). The presence of pre-existing or methotrexate-induced renal insufficiency is potentially associated with delayed excretion of methotrexate and may increase the need for higher doses or more prolonged use of folinic acid. Folinic acid has no effect on non-haematological toxicities of methotrexate, such as nephrotoxicity resulting from drug methotrexate and/or metabolite precipitation in the kidney.
Excessive folinic acid doses must be avoided since this might impair the antitumour activity of methotrexate, especially in CNS tumours where folinic acid accumulates after repeated courses.
Resistance to methotrexate as a result of decreased membrane transport implies resistance to folinic acid rescue as both medicinal products share the same transport system.

Folinic acid/ fluorouracil.

Folinic acid must not be mixed with fluorouracil in the same IV injection or infusion. Folinic acid may enhance the toxicity profile of fluorouracil, particularly in elderly or debilitated patients. The most common manifestations are leucopenia, mucositis, stomatitis and/or diarrhoea, which may be dose limiting. In addition, hematological adverse reactions have been observed. Deaths from severe enterocolitis, diarrhoea and dehydration have been reported in elderly patients receiving fluorouracil and folinic acid. Concomitant granulocytopenia and fever were present in some but not all patients. When folinic acid and fluorouracil are used in combination, in cases of toxicity the fluorouracil dosage has to be reduced more than when fluorouracil is used alone.
Combined folinic acid/ fluorouracil treatment should not be initiated or maintained in patients with symptoms of gastrointestinal (GI) toxicity, regardless of the severity, until all of these symptoms have completely disappeared. Because diarrhoea may be a sign of GI toxicity, patients presenting with diarrhoea must be carefully monitored until the symptoms have disappeared completely, since rapid clinical deterioration leading to death can occur. If diarrhoea and/or stomatitis occur, it is advisable to reduce the dose of fluorouracil until symptoms have fully disappeared. Especially the elderly and patients with a low physical performance due to their illness are prone to these toxicities.
In elderly patients and patients who have undergone preliminary radiotherapy, it is recommended to begin with a reduced dosage of fluorouracil.
Seizures and/or syncope have been reported rarely in cancer patients receiving folinic acid, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases.
Calcium levels should be monitored in patients receiving combined folinic acid /fluorouracil treatment and calcium supplementation should be provided if calcium levels are low.
Under circumstances leading to delayed methotrexate elimination, treatment with folinic acid may need to be prolonged.

Use in the elderly.

Elderly patients are at increased risk of severe toxicity when receiving combination therapy of folinic acid and fluorouracil. Particular care should be taken when treating these patients.

Paediatric use.

There are no data available on use in children.

Effects on laboratory tests.

5-FU/calcium folinate 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/calcium folinate 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Folic acid in large amounts may counteract the antiepileptic effect of phenobarbitone, phenytoin, primidone and succinimides, and increase the frequency of seizures in susceptible children and 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 (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)). Clinical monitoring, possibly monitoring of the plasma concentrations and, if necessary, dose adaptation of the anti-epileptic drug during folinic acid administration and after discontinuation.
High intravenous or intramuscular doses of folinic acid may reduce the efficacy of intrathecally administered methotrexate.
Folinic acid may enhance the toxicity of fluorouracil. When folinic acid is given in conjunction with a folic acid antagonist (e.g. cotrimoxazole, pyrimethamine, methotrexate, antibiotic with antifolic effect) the efficacy of the folic acid antagonist may either be reduced or completely neutralized.
Concurrent administration of chloramphenicol and folic acid in folate deficient patients may result in antagonism of haematopoietic response to folic acid. Calcium folinate may enhance the toxicity of fluorouracil (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category A)
Category A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without proven increase in frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.
There are no adequate and well-controlled clinical studies conducted in pregnant or breastfeeding woman. No formal animal reproductive toxicity studies with folinic acid have been conducted. There are no indications that folic acid induces harmful effects if administered during pregnancy. During pregnancy, 5-flurouracil 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 fetus. Should treatment with methotrexate or other folate antagonists take place despite pregnancy or lactation, there are no limitations as to the use of calcium folinate to diminish toxicity or counteract the effects.
Fluorouracil use is generally contraindicated during pregnancy and contraindicated during breastfeeding; this applies also to the combined use of folinic acid with fluorouracil.
 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 folinic acid is administered to a breastfeeding mother.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Allergic sensitisation, including anaphylactoid reactions and urticaria, has been reported following parenteral administration of folic acid. Nausea and vomiting with very high doses of folinic acid have been reported.
In addition, haematological adverse reactions, such as leucocytopenia, neutropenia, anaemia and thrombocytopenia, may occur. These adverse reactions are dose dependent and their occurrence can usually be decreased by reducing the dosage of cytotoxic drugs. To control these adverse reactions, haematological values e.g. blood leucocyte and thrombocyte levels, and serum electrolyte (e.g. Na, K, Ca) and creatinine levels should be closely monitored.

Immune system disorders.

Frequency undetermined: allergic reactions, urticaria. Very rare: Anaphylactoid/anaphylactic reactions.

Psychiatric disorders.

Insomnia, agitation and depression after high doses.

Nervous system disorders.

Increase in the frequency of attacks in epileptics. Rare: Seizures and/or syncope.

Gastrointestinal disorders.

Gastrointestinal disorders after high disorders, abdominal pain.

General disorders and administrations site conditions.

Frequency undetermined: Fever after administration of folinic acid as solution for injection.
Cases of Stevens - Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some fatal, have been reported in patients receiving folinic acid in combination with other agents known to be associated with these disorders. A contributory role of folinic acid in these occurrences of SJS/TEN cannot be excluded.

Folinic acid in combination with fluorouracil.

Generally the safety profile of folinic acid depends on the applied regimen of fluorouracil due to enhancement of fluorouracil-induced toxicities.
The most common dose-limiting adverse reaction occurring in patients receiving combination of folinic acid and fluorouracil are stomatitis and diarrhoea. Fatalities have occurred as a result of gastrointestinal toxicity (predominantly mucositis and diarrhoea) and myelosuppression. In patients with diarrhoea, rapid clinical deterioration leading to death can occur (see Section 4.4 Special Warnings and Precautions for Use).
Seizures and/or syncope have been reported rarely in cancer patients receiving folinic acid, usually in association with fluoropyrimidine administration (see Section 4.4 Special Warnings and Precautions for Use).
Additional undesirable effects of folinic acid when used in combination with fluorouracil are listed below:

Hepatobiliary disorders.

Frequency undetermined: Hyperammonaemia.

General disorders and administration site condition.

Frequency undetermined: Mucositis, stomatitis, cheilitis.

Skin and subcutaneous tissue disorders.

Frequency undetermined: Palmar-Palmar Erythrodysaesthesia syndrome (hand-foot syndrome).

Gastrointestinal disorders.

Very common: Nausea and vomiting, diarrhoea.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Folinic acid is an intermediate in the metabolism of folinic acid and can therefore be considered as a naturally occurring substance. Large doses have been administered with no apparent adverse effects. Such doses suggest that administration of this drug is relatively safe. Signs of excessive dosing, if they occur, should be treated symptomatically.
Excessive amounts of folinic acid nullify the chemotherapeutic effect of folic acid antagonists.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Folinic acid is the formyl derivative of tetrahydrofolic acid which is a metabolite and active form of folic acid. Folinic acid as a co-factor participates in many metabolic reactions including purine synthesis, pyrimidine synthesis and amino acid conversion. It is effective in the treatment of megaloblastic anaemia caused by folic acid deficiency and is a potent antidote for both the haematopoietic and reticuloendothelial toxic effects of folic acid antagonists, e.g. methotrexate, pyrimethamine, trimethoprim.
Folinic acid is used in cytotoxic therapy as an antidote to folic acid antagonists which block conversion of folic acid to tetrahydrofolate by binding enzyme dihydrofolate reductase. In some cancers, folinic acid enters and 'rescues' normal cells, in preference to tumor cells, from the toxic effects of folic acid antagonists, due to a difference in membrane transport mechanism. This principle is applied in high-dose methotrexate therapy with 'folinic acid rescue'.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Distribution.

Following administration, folinic acid enters the general body pool of reduced folates. It has been reported that, following intravenous, intramuscular administration, peak serum level of total reduced folates are achieved within a mean time of 10 minutes, 52 minutes and 1.7 hours, respectively. Peak levels of 5-formyl THF appear at 10 minutes and 28 minutes following intravenous and intramuscular administration respectively. Folate is concentrated in the cerebrospinal fluid and liver although distribution occurs to all body tissues.

Metabolism.

Calcium folinate is rapidly and extensively converted to 5-methyl tetrahydrofolate (an active metabolite) in vivo, with less extensive conversion resulting from parenteral administration.
Reduction in the levels of parent compound coincides with the appearance of the active metabolite 5-methyl THF, which becomes the major circulating form of the drug. Peak levels are observed at 1.5 and 2.8 hours following intravenous and intramuscular administration respectively. The terminal halflife for total reduced folates is reported as 6.2 hours. Tetrahydrofolic acid and its derivatives are distributed to all body tissues, being concentrated in the liver and found in moderate amounts in the CSF.

Excretion.

Folinic acid is eliminated mainly as 10-formyl tetrahydrofolate and 5, 10-methyl tetrahydrofolate. The metabolites are mainly excreted via the urine (80-90%), with elimination being logarithmic in doses exceeding 1 mg.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, Water for injection.

6.2 Incompatibilities

Folinic acid has been reported to be incompatible with injectable forms of methotrexate, fluorouracil droperidol, fosacarnet and phosphonosulphate.
For more information see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2 to 8°C. (Refrigerate. Do not freeze). Protect from light.

6.5 Nature and Contents of Container

DBL Leucovorin Calcium Injection vial 50 mg/5 mL is filled in a 5 mL Type I clear glass vial with a chlorobutyl rubber stopper - single vial per pack.
DBL Leucovorin Calcium Injection vial 300 mg/30 mL is filled in a 30 mL Type 1 clear glass vial with a chlorobutyl rubber stopper - single vial per pack.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Calcium folinate is a white to light yellow, amorphous or crystalline hygroscopic powder. Sodium chloride is included for isotonicity. Sodium hydroxide or hydrochloric acid is used to adjust pH. The vial presentations (50 mg/5 mL and 300 mg/ 30 mL) do not contain a bactericide.
Chemical name: Calcium (2S)-2-[[4-[[[(6RS)-2-amino- 5-formyl-4-oxo-1,4,5,6,7,8-hexahydropteridin-6-yl]methyl] amino]benzoyl]amino]pentanedioate. Chemical Formula: C20H21CaN7O7.xH2O. M.W. = 511.5 (Anhydrous).

Chemical structure.

The chemical structure of calcium folinate is shown below:

CAS number.

1492-18-8.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes