Consumer medicine information

DBL Leucovorin Calcium

Folinic acid

BRAND INFORMATION

Brand name

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

Active ingredient

Folinic acid

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

SUMMARY CMI

DBL™ Leucovorin Calcium

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using DBL Leucovorin Calcium?

DBL Leucovirin Calcium Tablet contains the active ingredient calcium folinate hydrate and DBL Leucovorin Calcium Injection contains the active ingredient calcium folinate. It is a type of Vitamin B used to treat some types of anaemia when they occur during pregnancy and infancy or caused by liver disease, inadequate food intake or poor food absorption. It may also be used to treat the toxic effects of some medicines.

For more information, see Section 1. Why am I using DBL Leucovorin Calcium? in the full CMI.

2. What should I know before treatment with DBL Leucovorin Calcium?

Do not use if you have ever had an allergic reaction to calcium folinate or any of the ingredients listed at the end of the CMI or if you have a type of anaemia caused by too little vitamin B12.

Talk to your doctor if you have any other medical conditions, have problems with your kidneys or have diarrhoea; if you take any other medicines or are pregnant or plan to become pregnant or are breastfeeding.

Discuss the need for any restrictions with food and drink with your doctor.

For more information, see Section 2. What should I know before treatment with DBL Leucovorin Calcium? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with DBL Leucovorin Calcium and affect how it works. It is especially important to tell your doctor if you are taking medicine to treat epilepsy.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use DBL Leucovorin Calcium?

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

More instructions can be found in Section 4. How do I use DBL Leucovorin Calcium? in the full CMI.

5. What should I know while using DBL Leucovorin Calcium?

Things you should do

Ensure tablets are taken on an empty stomach.

Tell your doctor if you are pregnant, trying to become pregnant or are breast-feeding.

Tell any doctor you visit that you are taking DBL Leucovorin Calcium.

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

Things you should not doDo not stop taking this medicine or change the dose unless instructed by your doctor.
Drinking alcoholNo information available.
Looking after your medicine

Injection: This medicine is stored in a hospital at 2 - 8°C.

Tablet: Store below 25°C.

For more information, see Section 5. What should I know while using DBL Leucovorin Calcium in the full CMI.

6. Are there any side effects?

Side effects of this medicine include allergic reactions; lack of control of epilepsy, fits, convulsions or fainting; serious gastrointestinal problems; dehydration; sore mouth; symptoms of severe infection; abnormal bleeding; skin conditions with severe redness, blisters, peeling and bleeding; fever, fatigue, chills, feeling unwell; shortness of breath, dizziness, pale skin, cold hands and feet; rashes; nausea, vomiting, diarrhoea; depression, agitation or trouble sleeping.

For more information on these side effects, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

DBL™ Leucovorin Calcium (loo-koe-VOR-in)

Active ingredient(s): calcium folinate hydrate (tablet) and calcium folinate (injection)

Consumer Medicine Information (CMI)

This leaflet provides important information about using DBL Leucovorin Calcium. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using DBL Leucovorin Calcium.

Where to find information in this leaflet:

1. Why am I using DBL Leucovorin Calcium?
2. What should I know before treatment with DBL Leucovorin Calcium?
3. What if I am taking other medicines?
4. How do I use DBL Leucovorin Calcium?
5. What should I know while using DBL Leucovorin Calcium?
6. Are there any side effects?
7. Product details

1. Why am I using DBL Leucovorin Calcium?

DBL Leucovorin Calcium is a type of Vitamin B and is used to treat:

  • Some types of anaemia when they occur during pregnancy and infancy or caused by liver disease, inadequate food intake or poor food absorption.
  • The toxic effects of some medicines such as methotrexate, fluorouracil and pyrimethamine.

2. What should I know before treatment with DBL Leucovorin Calcium?

Warnings

Do not use DBL Leucovorin Calcium if:

  • you are allergic to calcium folinate, or any of the ingredients listed at the end of this leaflet.
  • you have anaemia caused by low levels of red blood cells or genetically defective red blood cells due to a lack of Vitamin B12.

Check with your doctor if you:

  • have problems with your kidneys
  • have diarrhoea
  • require food and drinks that have low acidity while being treated with DBL Leucovorin Calcium
  • are taking epilepsy medication.

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

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

DBL Leucovorin Calcium may be given to you for the purpose of treating the toxic effects of certain other medications such as:

  • Methotrexate, a medicine used to treat rheumatoid arthritis, psoriasis, inflammatory bowel disease or some cancers
  • 5-fluorouracil (5-FU), a medicine used to treat some cancers
  • Cotrimoxazole or pyrimethamine, medicines used to treat some infections

If you are being treated with any of these medicines and your doctor is not aware, it is critical that you tell them.

Some medicines and DBL Leucovorin Calcium may interfere with each other. These include:

  • medicines used to treat epilepsy such as phenytoin, phenobarbitone, succinimides and primidone
  • chloramphenicol, an antibiotic used to treat bacterial infections

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect DBL Leucovorin Calcium.

4. How do I use DBL Leucovorin Calcium?

How much to take

Your doctor will decide what dose and how long you will receive DBL Leucovorin Calcium Injection and Tablet. This depends on the condition you are being treated for.

DBL Leucovorin Calcium Injection will be given to you by a doctor or nurse.

When to take DBL Leucovorin Calcium Tablet

DBL Leucovorin Calcium Tablet should be swallowed with a full glass of water. It should be taken on an empty stomach, for example, at least half an hour before food or two hours after food. The tablet should be taken whole and not chewed or crushed.

If you forget to take DBL Leucovorin Calcium Tablet

DBL Leucovorin Calcium Tablet should be taken regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you can, but do not take a double dose to make up for forgotten tablet.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you use too much DBL Leucovorin Calcium

If you think that you have used too much DBL Leucovorin Calcium, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using DBL Leucovorin Calcium?

Things you should do

Tell your doctor if you are pregnant, trying to become pregnant or breast-feeding.

Tell any doctor or any healthcare professional you visit that you are using DBL Leucovorin Calcium.

Things you should not do

  • Do not stop taking this medicine or change the dosage unless instructed by your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how DBL Leucovorin Calcium affects you.

Drinking alcohol

No information available.

Looking after your medicine

DBL Leucovorin Calcium Solution for Injection

Stored at the hospital, refrigerated at 2 - 8°C. Do not freeze.

DBL Leucovorin Calcium Tablet

Store below 25°C.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Do not use this medicine after the expiry date.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Side effects

Side effectsWhat to do
  • Fever
  • Nausea
  • Vomiting
  • Sore lips
  • Depression, agitation or trouble sleeping
  • Rashes
Speak to your doctor or nurse if you have any of these side effects and they worry you.
Side effectsWhat to do
  • Signs of an allergic reaction including 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
  • Lack of control of epilepsy
  • Fits or convulsions, and/or fainting
  • Gastrointestinal problems which may include diarrhoea, constipation, ulcers around the anus, blood in faeces (stools), stomach or gut pain/cramps, bloating
  • Problems with your mouth including pus, ulcers, blisters, peeling or swelling, a burning feeling and trouble swallowing or talking
  • Fatigue with shortness of breath and dizziness
  • Pale skin with cold hands and feet
  • Symptoms of severe infection indicated by fever, cough, rash, swelling, diarrhoea, discomfort while urinating
  • Abnormal bleeding such as bruising easily, nose bleeds, bleeding gums, abnormal menstrual bleeding and severe fatigue
  • Skin condition with severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Side effects

Side effectsWhat to do
  • Areas of skin that are red and painful, blister and peel, accompanied by fever, chills and feeling unwell
  • Redness, swelling or peeling of the palms or the soles of the feet.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor, nurse or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side-effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What DBL Leucovorin Calcium Injection contains

Active ingredient
(main ingredient)		calcium folinate
Other ingredients
(inactive ingredients)		sodium chloride, water for injections

DBL Leucovorin Calcium Injection 15 mg/2 mL contains 8.1 mg/mL of sodium chloride.

DBL Leucovorin Calcium Injection 50 mg/5 mL and 300 mg/30 mL contains 8.5 mg/mL of sodium chloride.

What DBL Leucovorin Calcium Tablet contains

Active ingredient
(main ingredient)		calcium folinate hydrate
Other ingredients
(inactive ingredients)		lactose, microcrystalline cellulose, magnesium stearate

Each DBL Leucovorin Calcium Tablet contains 141.4 mg of lactose monohydrate.

Do not take this medicine if you are allergic to any of these ingredients.

What DBL Leucovorin Calcium looks like

DBL Leucovorin Calcium Injection is a clear, straw to pale yellow coloured solution free from visible particulate matter.

DBL Leucovorin Calcium Tablet is light yellow, round, flat with a line and engraved with the letters CF.

Australian Registration Number

DBL Leucovorin Calcium Injection 15 mg/2 mL, AUST R 16351.

DBL Leucovorin Calcium Injection 50 mg/ 5 mL, AUST R 42148.

DBL Leucovorin Calcium Injection 300 mg/ 30 mL, AUST R 116688.

DBL Leucovorin Calcium Tablet 15 mg, AUST R 16364.

Who distributes DBL Leucovorin Calcium

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

This leaflet was prepared in April 2022.

Published by MIMS June 2022

BRAND INFORMATION

Brand name

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

Active ingredient

Folinic acid

Schedule

S4

 

1 Name of Medicine

Folinic acid (as calcium folinate hydrate) - tablets.
Folinic acid (as calcium folinate) - injections.

2 Qualitative and Quantitative Composition

Tablets.

Each DBL Leucovorin Calcium tablet contains 15 mg folinic acid (as calcium folinate hydrate).

Solution for injections.

Each 2 mL DBL Leucovorin Calcium injection 15 mg/2 mL contains 15 mg folinic acid (as calcium folinate).
Each 5 mL DBL Leucovorin Calcium injection 50 mg/5 mL contains 50 mg folinic acid (as calcium folinate).
Each 30 mL DBL Leucovorin Calcium injection 300 mg/30 mL contains 300 mg folinic acid (as calcium folinate).

Excipients with known effects.

Tablets.

Contains sugars as lactose. Each DBL Leucovorin Calcium tablet contains 141.4 mg of lactose monohydrate.

Solution for injection.

DBL Leucovorin Calcium injection 15 mg/2 mL contains 8.1 mg/mL of sodium chloride.
DBL Leucovorin Calcium injection 50 mg/5 mL and 300 mg/30 mL contains 8.5 mg/mL of sodium chloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets.

DBL Leucovorin Calcium tablets are light yellow, round, flat, scored, uncoated tablets, engraved with CF.

Solution for injection.

DBL Leucovorin Calcium injection is a clear straw-to pale yellow coloured sterile, isotonic solution free from visible particular matter. The solution does not contain a bactericide.

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.

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 micromolar 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. 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. Because absorption is saturable, oral administration of doses greater than 25 mg is not recommended. Doses higher than those recommended for oral use must be given intravenously.
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 micromolar.
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 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 micromolar or the 48 hour level is greater than 0.9 micromolar, 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 micromolar.
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.

Tablets.

Daily doses of 5 to 15 mg.

Solution for injection.

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 orally, or parenterally by intramuscular injection, intravenous injection or intravenous infusion. Folinic acid should not be administered intrathecally.

Tablets.

Oral doses should be taken on an empty stomach or in the fasting state since studies of bioavailability of oral tablets have been done with fasting patients only.

Solution for injection.

DBL Leucovorin Calcium injection may be given parenterally by intramuscular injection, intravenous injection or intravenous infusion. DBL Leucovorin Calcium injection should not be administered intrathecally. When DBL Leucovorin Calcium injection has been administered intrathecally following intrathecal overdose of methotrexate, death has been reported (see Section 4.4 Special Warnings and Precautions for Use).
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.
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 solution or 0.9% sodium chloride solution. The diluted 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 unused solution should be 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.

Patient monitoring laboratory tests.

Methotrexate/folinic acid therapy.

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. In cases of methotrexate overdose or delayed excretion, monitor urine pH as appropriate, to ensure maintenance of pH ≥ 7.0.
DBL Leucovorin Calcium dosage should be adjusted on the basis of laboratory test results.

5-Fluorouracil/folinic acid 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.

4.3 Contraindications

DBL Leucovorin Calcium therapy is contraindicated in patients with:
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

DBL Leucovorin Calcium injection should be administered only by intramuscular or intravenous injection and must not be administered intrathecally. When DBL Leucovorin Calcium injection has been administered intrathecally following intrathecal overdose of methotrexate, death has been reported (see Section 4.2 Dose and Method of Administration).

General.

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.
Parenteral administration is preferable to oral dosing if there is a possibility that the patient may vomit or not absorb folinic acid.
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. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
Many cytotoxic medicinal products - direct or indirect DNA synthesis inhibitors - lead to macrocytosis (hydroxycarbamide, cytarabine, mercaptopurine, thioguanine). Such macrocytosis should not be treated with folinic acid.
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. See Section 4.8 Adverse Effects (Undesirable Effects), Nervous system disorders.
Since three patients had recurrent neurological symptoms on rechallenge with folinic acid further treatment with folinic acid is not recommended in these circumstances.
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 folinic acid administration and after discontinuation is recommended. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

Folinic acid/methotrexate.

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.
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. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure and all toxicities associated with methotrexate (please refer to 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.
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.

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.

No data available.

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 oral, 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 neutralised.
Concurrent administration of chloramphenicol and folic acid in folate deficient patients may result in antagonism of haematopoietic response to folic acid. Folinic acid 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)
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 folinic acid 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 both oral and parenteral administration of folinic 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: Hypersensitivity.
Very rare (< 0.1%): Anaphylactoid/anaphylactic reactions, and anaphylactic shock.

Psychiatric disorders.

Rare (0.01-0.1%): Insomnia, agitation and depression after high doses.

Nervous system disorders.

Rare (0.01-0.1%): Increase in the frequency of attacks in epileptic patients (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), seizures and/or syncope.

Skin and subcutaneous tissue disorders.

Frequency undetermined: Urticaria.

Gastrointestinal disorders.

Rare (0.01-0.1%): Gastrointestinal disorders after high doses: abdominal pain.

General disorders and administrations site conditions.

Uncommon (0.1-1%): Pyrexia after administration of DBL Leucovorin Calcium 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 flurouracil.

Generally the safety profile of folinic acid depends on the applied regimen of fluorouracil due to enhancement of fluorouracil-induced toxicities.
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:

Metabolism and nutrition disorders.

Frequency undetermined: Hyperammonaemia.

Blood and lymphatic system disorders.

Very common (> 10%): bone marrow failure, including fatal cases.

General disorders and administration site condition.

Very common (> 10%): Mucositis. Fatalities have occurred as a result of mucositis.

Skin and subcutaneous tissue disorders.

Common (1-10%): Palmar-Palmar Erythrodysaesthesia syndrome (hand-foot syndrome).

Gastrointestinal disorders.

Very common(> 10%): Nausea and vomiting, diarrhoea, stomatitis, cheilitis.
The most common dose limiting adverse reaction occurring in patients receiving a 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).

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

Absorption.

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.

Distribution.

Folate is concentrated in the cerebrospinal fluid and liver although distribution occurs to all body tissues. The bioavailability of an oral dose is almost the same as an equivalent intramuscular dose.

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 half-life 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. Following a 15 mg dose given either orally or intramuscularly, peak serum folate concentrations of 0.268 microgram/mL and 0.241 microgram/mL were detected.

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

Tablet.

Lactose monohydrate, microcrystalline cellulose, magnesium stearate.

Solution for injection.

Sodium chloride and water for injections.
Sodium hydroxide and/or hydrochloric acid (used to adjust pH of 300 mg/30 mL only).

6.2 Incompatibilities

Folinic acid has been reported to be incompatible with injectable forms of methotrexate, fluorouracil, droperidol, foscarnet 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

Tablets.

Store below 25°C.

Solution for injection.

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

6.5 Nature and Contents of Container

DBL Leucovorin Calcium tablets is available in bottles of 10 tablets. DBL Leucovorin Calcium tablets are supplied in a high density polyethylene (HDPE) bottle with HDPE cap closure.
DBL Leucovorin Calcium injection 15 mg/2 mL is available in 2 mL amber, Type I glass ampoules in packs of 5 ampoules.
DBL Leucovorin Calcium injection 50 mg/5 mL is supplied in a 5 mL Type I clear glass vial with a chlorobutyl rubber stopper in packs of one vial per pack.
DBL Leucovorin Calcium injection 300 mg/30 mL is supplied in a 30 mL Type 1 clear glass vial with a chlorobutyl rubber stopper in packs of one 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.

Chemical structure.


Chemical name: Calcium (2S)-2-[[4-[[[(6RS)-2-amino-5-formyl-4-oxo1,4,5,6,7,8-hexahydropteridin-6-yl]methyl]amino]benzoyl]amino]pentanedioate.
The chemical formula is C20H21CaN7O7,xH2O and the molecular weight of anhydrous calcium folinate is 511.5.

CAS number.

2060570-47-8.

7 Medicine Schedule (Poisons Standard)

Tablets.

Schedule 2, Pharmacy Only Medicine.

Solution for injection.

Schedule 4, Prescription Only Medicine.

Summary Table of Changes