GMP Calcium Levofolinate injection treat for diminishing the
toxicity and counteract the action of folic acid antagonis
1. Name of the medicinal product
Calcium Levofolinate powder for Injection
2. Qualitative and quantitative composition
Calcium levofolinate equivalent to 1.00% w/v (10 mg/ml) of
levoleucovorin (levofolinic acid).
Vials contain 25 mg, 50 mg or 175 mg of levofolinic acid (as
calcium levofolinate) in 2.5 ml, 5 ml or 17.5 ml of solution
For the full list of excipients, see section 6.1
3. Pharmaceutical form
Lypholized powder for injection
4. Clinical particulars
4.1 Therapeutic indications
Calcium Levofolinate Rescue
Calcium levofolinate is used to diminish the toxicity and
counteract the action of folic acid antagonists such as
methotrexate in cytotoxic therapy. This procedure is known as
Calcium Levofolinate Rescue.
Advanced Colorectal Cancer - Enhancement of 5-Fluorouracil (5-FU)
Calcium levofolinate increases the thymine depleting effects of
5-FU resulting in enhanced cytotoxic activity. Combination regimens
of 5-fluorouracil and levofolinate give greater efficacy compared
to 5-FU given alone.
4.2 Posology and method of administration
Calcium Levofolinate Rescue
Adults, Children and the Elderly:
Calcium Levofolinate Rescue therapy should commence 24 hours after
the beginning of methotrexate infusion. Dosage regimes vary
depending upon the dose of methotrexate administered. In general,
the calcium levofolinate should be administered at a dose of 7.5 mg
(approximately 5 mg/m2) every 6 hours for 10 doses by intramuscular
injection, bolus intravenous injection or intravenous infusion,
(see section below, for information concerning use of calcium
levofolinate with infusion fluids). Do not administer calcium levofolinate intrathecally.
Where overdose of methotrexate is suspected, the dose of calcium
levofolinate should be at least 50% of the offending dose of
methotrexate and should be administered in the first hour. In the
case of intravenous administration, no more than 160 mg of calcium
levofolinate should be injected per minute due to the calcium
content of the solution.
In addition to calcium levofolinate administration, measures to
ensure the prompt excretion of methotrexate are important as part
of Calcium Levofolinate Rescue therapy. These measures include:
a. Alkalinisation of urine so that the urinary pH is greater than
7.0 before methotrexate infusion (to increase solubility of
methotrexate and its metabolites).
b. Maintenance of urine output of 1800-2000 cc/m2/24 hr by
increased oral or intravenous fluids on days 2, 3 and 4 following
c. Plasma methotrexate concentration, BUN and creatinine should be
measured on days 2, 3 and 4.
These measures must be continued until the plasma methotrexate
level is less than 10-7 molar (0.1 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. Under such circumstances, higher doses of calcium
levofolinate or prolonged administration may be indicated. Dosage
and administration guidelines for these patients are given in Table
1. Patients who experience delayed early methotrexate elimination
are likely to develop reversible renal failure.
Dosage and Administration Guidelines for Calcium Levofolinate
|Clinical Situation||Laboratory Findings||Levofolinate Dosage and Duration|
|Normal Methotrexate Elimination||Serum methotrexate level approximately 10 μM at 24 hours after
administration, 1 μM at 48 hours and less than 0.2 μM at 72 hours.||7.5 mg IM or IV every 6 hours for 60 hours (10 doses starting at 24
hours after start of methotrexate infusion).|
|Delayed Late Methotrexate Elimination||Serum methotrexate level remaining above 0.2 μM at 72 hours, and
more than 0.05 μM at 96 hours after administration.||Continue 7.5 mg IM or IV every 6 hours, until methotrexate level is
less than 0.05 μM.|
|Delayed Early Methotrexate Elimination and/or Evidence of Acute
Renal Injury||Serum methotrexate level of 50 μM or more at 24 hours or 5 μM or
more at 48 hours after administration, OR; a 100% or greater
increase in serum creatinine level at 24 hours after methotrexate
administration.||75 mg IV every 3 hours, until methotrexate level is less than 1 μM;
then 7.5 mg IV every 3 hours until methotrexate level is less than
Colorectal Cancer: Enhancement of 5-FU Cytotoxicity
Adults and the Elderly:
Administration: The 175 mg in 17.5 ml vial of Calcium Levofolinate Solution for
Injection should be used to administer the high doses of calcium
levofolinate required in combination regimens.
When used in combination regimens with 5-FU, calcium levofolinate
should only be given by the intravenous route. The agents should
not be mixed together. Each vial of calcium levofolinate 175 mg
contains 0.7 mEq (0.35 mmol) of calcium per vial and it is
recommended that the solution is administered over not less than 3
For intravenous infusion, the 175 mg in 17.5 ml Solution for
Injection may be diluted with any of the following infusion fluids
before use: Sodium Chloride 0.9%; Glucose 5%; Glucose 10%; Glucose
10% and Sodium Chloride 0.9% Injection; Compound Sodium Lactate
Calcium levofolinate should not be mixed together with 5-FU in the
same infusion and, because of the risk of degradation, the giving
set should be protected from light.
Dosage: Based on the available clinical evidence, the following regimen is
effective in advanced colorectal carcinoma:
Calcium levofolinate given at a dose of 100 mg/m2 by slow
intravenous injection, followed immediately by 5-FU at an initial
dose of 370 mg/m2 by intravenous injection. The injection of
levofolinate should not be given more rapidly than over 3 minutes
because of the calcium content of the solution. This treatment is
repeated daily for 5 consecutive days. Subsequent courses may be
given after a treatment-free interval of 21-28 days.
For the above regimen, modification of the 5-FU dosage and the
treatment-free interval may be necessary depending on patient
condition, clinical response and dose limiting toxicity. A
reduction of calcium levofolinate dosage is not required. The
number of repeat cycles used is at the discretion of the clinician.
On the basis of the available data, no specific dosage
modifications are recommended in the use of the combination regimen
with 5-FU in the elderly. However, particular care should be taken
when treating elderly or debilitated patients as these patients are
at increased risk of severe toxicity with this therapy (see section
There are no data available on the use of this combination in
Method of administration
For single use only.
Hypersensitivity to calcium levofolinate or to any of the
excipients listed in section 6.1.
Calcium levofolinate should not be used for the treatment of
pernicious anaemia or other megaloblastic anaemias due to vitamin
Regarding the use of calcium levofolinate with methotrexate or 5-FU
during pregnancy and lactation, (section 4.6), and the Summaries of
Product Characteristics for methotrexate and 5-FU-containing
4.4 Special warnings and precautions for use
Calcium levofolinate must not be administered intrathecally. When
levofolinic acid has been administered intrathecally, following
intrathecal overdose of methotrexate, death has been reported.
Calcium levofolinate treatment may mask pernicious anaemia and
other megaloblastic anaemias resulting from vitamin B12deficiency.
Calcium levofolinate should only be used with 5-FU or methotrexate
under the direct supervision of a clinician experienced in the use
of cancer chemotherapeutic agents.
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.
Calcium levofolinate / 5-FU
Calcium levofolinate may enhance the toxicity profile of 5-FU,
particularly in elderly or debilitated patients. The most common
manifestations are leucopoenia, mucositis, stomatitis and / or
diarrhoea, which may be dose limiting.
Combined 5-FU / calcium levofolinate treatment should neither be
initiated nor maintained in patients with symptoms of GI toxicity,
regardless of the severity, until all of these symptoms have
Patients presenting with diarrhoea must be carefully monitored
until the symptoms have disappeared completely, since a rapid
clinical deterioration leading to death can occur. If diarrhoea and
/ or stomatitis occur, it is advisable to reduce the dose of 5-FU.
The elderly and patients with a low physical performance due to
their illness are especially prone to these toxicities. Therefore,
particular care should be taken when treating these patients.
In elderly patients and patients who have undergone preliminary
radiotherapy, it is recommended to begin with a reduced dosage of
Calcium levofolinate must not be mixed with 5-FU in the same IV
injection or infusion.
Calcium levofolinate / 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 calcium
levofolinate rescue increases, calcium levofolinate effectiveness
in counteracting toxicity decreases.
Calcium levofolinate has no effect on non-haematological toxicities
of methotrexate such as the nephrotoxicity resulting from
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. 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 calcium levofolinate.
The possibility that the patient is taking other medications that
interact with methotrexate (e.g. medications which may interfere
with methotrexate elimination or binding to serum albumin) should
always be considered when laboratory abnormalities or clinical
toxicities are observed.
Excessive calcium levofolinate doses must be avoided since this
might impair the anti-tumour activity of methotrexate, especially
in CNS tumours where calcium levofolinate accumulates after
Resistance to methotrexate as a result of decreased membrane
transport implies also resistance to folinic acid rescue as both
medicinal products share the same transport system.
4.5 Interaction with other medicinal products and other forms of
When calcium levofolinate is given in conjunction with a folic acid
antagonist (e.g. cotrimoxazole, pyrimethamine) the efficacy of the
folic acid antagonist may either be reduced or completely
Calcium levofolinate may diminish the antiepileptic effect of
phenobarbital, phenytoin, primidone and succinimides, and may
increase the frequency of seizures in susceptible patients.
Clinical monitoring is therefore recommended.
4.6. Fertility, pregnancy and lactation
Pregnancy and Breast-feeding
There are no adequate and well-controlled clinical studies
conducted in pregnant or breast-feeding women.
Calcium levofolinate may be excreted in human milk and should only
be administered where the benefits of the drug to the mother
outweigh possible hazards to the infant. Calcium levofolinate can
be used during breast-feeding when considered necessary according
to the therapeutic indications.
4.7 Effects on ability to drive and use machines
There is no evidence that calcium levofolinate has an effect on the
ability to drive or use machines.
4.8 Undesirable effects
Within the organ system classes, adverse reactions are listed under
the headings of frequency (number of patients expected to
experience the reaction), using the following categories: very
common (>1/10); common (>1/100, <1/10); uncommon
(>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare
(<1/10,000); not known (frequency cannot be estimated from the
Immune system disorders:
|Very rare:||Anaphylactoid / anaphylactic reactions (including shock)|
|Not known:||Allergic reactions, urticaria|
Nervous system disorders:
|Rare:||Seizures and syncope|
General disorders and administration site conditions:
Cases of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal
Necrolysis (TEN), some fatal, have been reported in patients
receiving calcium levofolinate in combination with other agents
known to be associated with these disorders. A contributory role of
calcium levofolinate in these cases cannot be excluded.
Calcium levofolinate may enhance 5-FU induced toxicities depending
on the applied regimen. Additional undesirable effects when used in
combination with 5-FU:
|Very common:||Nausea, vomiting, diarrhoea|
Skin and subcutaneous tissue disorders:
|Not known:||Palmer-Plantar Erythrodysaesthesia|
General disorders and administration site conditions:
|Not known:||Mucositis, including stomatitis and chelitis|
Fatalities have occurred as a result of gastrointestinal toxicity
(predominantly mucositis and diarrhoea) and myelosuppression.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the
medicinal product is important. It allows continued monitoring of
the benefit/risk balance of the medicinal product.
There have been no reported sequelae in patients who have received
significantly more calcium levofolinate than the recommended
dosage. However, excessive amounts of calcium levofolinate may
nullify the chemotherapeutic effect of folic acid antagonists.
Should overdose of the combination of 5-FU with calcium
levofolinate occur, the overdose instructions for 5-FU should be
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment .ATC Code: V03AF04
Levofolinate is the pharmacologically active isomer of
5-formyltetrahydrofolic acid. Levofolinate does not require
reduction by the enzyme dihydrofolate reductase in order to
participate in reactions utilising folates as a source of "one
carbon" moieties. Levofolinate is actively and passively
transported across cell membranes.
Administration of levofolinate can "rescue" normal cells and
thereby prevent toxicity of folic acid antagonists such as
methotrexate which act by inhibiting dihydrofolate reductase.
Levofolinate can enhance the therapeutic and toxic effects of
fluoropyrimidines used in cancer therapy such as 5-fluorouracil.
5-fluorouracil is metabolised to
5-fluoro-2'-deoxyuridine-5'-monophosphate (FDUMP), which binds to
and inhibits thymidylate synthase. Levofolinate is readily
converted to another reduced folate, 5,
10-methylenetetrahydrofolate, which acts to stabilise the binding
of FDUMP to thymidylate synthase and thereby enhances the
inhibition of this enzyme.
Levofolinate is also effective in the treatment of megaloblastic
anaemias due to folate deficiencies.
5.2 Pharmacokinetic properties
When levofolinate is injected intravenously it is 100%
The pharmacokinetics of levofolinate after intravenous
administration of a 15 mg dose were studied in healthy male
volunteers. After rapid intravenous administration, serum total
tetrahydrofolate (total-THF) concentrations reached a mean peak of
1722 ng/ml. Serum levo-5-methyl-THF concentrations reached a mean
peak of 275 ng/ml and the mean time to peak concentration was 0.9
hours. The mean half-life for total-THF and levo-5-methyl-THF was
5.1 and 6.8 hours respectively.
The distribution and plasma levels of levofolinate following
intramuscular administration have not been established.
The distribution in tissue and body fluids and protein binding have
not been determined.
In vivo, levofolinate is converted to levo-5-methyltetrahydrofolic acid
(levo-5-methyl-THF), the primary circulating form of active reduced
folate. Levofolinate and levo-5-methyl-THF are polyglutamated
intracellularly by the enzyme folylpolyglutamate synthetase.
Folylpolyglutamates are active and participate in biochemical
pathways that require reduced folate.
Levofolinate and levo-5-methyl-THF are excreted renally.
Due to the inherent lack of levofolinate toxicity, the influence of
impaired renal or hepatic function on levofolinate disposition was
5.3 Preclinical safety data
The pre-clinical data raises no concerns for the clinical uses
6. Pharmaceutical particulars
6.1 List of excipients
Water for Injection
Calcium levofolinate should not be mixed together with 5-FU in the
same intravenous injection or infusion.
In addition to 5-FU, incompatibilities have also been reported
between injectable forms of calcium levofolinate and injectable
forms of droperidol, foscarnet and methotrexate.
6.3 Shelf life
6.4 Special precautions for storage
Store and transport refrigerated (2°C – 8°C)
Keep vial in the outer carton in order to protect from light.
6.5 Nature and contents of container
Type I amber glass vials each containing the equivalent of 25 mg,
50 mg or 175 mg of calcium levofolinate in 2.5 ml, 5 ml or 17.5 ml
of solution respectively. Isovorin Solution for Injection is packed
in boxes of 1 vial.
Not all pack sizes may be marketed.