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LEVOFOLINIC ACID 50 MG/ML SOLUTION FOR INJECTION OR INFUSION

Active substance(s): LEVOFOLINIC ACID

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Levofolinic acid 50 mg/ml · 90200-VBGB · CB · 07.15 · Pharma-Code: 701
Format: 486 x 252 mm · HKS 44 · Corrective action: KV01_jem_16.07.15

Package leaflet: Information for the user

Levofolinic acid 50 mg/ml
solution for injection or infusion
(Levofolinic acid)

Read all of this leaflet carefully before you start using this medicine
because it contains important information for you.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist or
nurse.
• This medicine has been prescribed for you only. Do not pass it on to
others. It may harm them, even if their signs of illness are the same
as yours.
• If you get any side effects, talk to your doctor, pharmacist or nurse.
This includes any possible side effects not listed in this leaflet.

Levofolinic acid
50 mg/ml
90200-VBGB
CB

What is in this leaflet:
1. What Levofolinic acid 50 mg/ml is and what it is used for
2. What you need to know before you use Levofolinic acid 50 mg/ml
3. How to use Levofolinic acid 50 mg/ml
4. Possible side effects
5. How to store Levofolinic acid 50 mg/ml
6. Contents of the pack and other information

1. What Levofolinic acid 50 mg/ml is and what it is used for

Levofolinic acid
50 mg/ml
90200-VBGB
CB

Use of Levofolinic acid 50 mg/ml in combination with methotrexate
Levofolinic acid 50 mg/ml Solution for injection or infusion belongs to
the group of drug products called antidotes. These are substances
which are used during cancer therapy (cytostatic therapy) to counteract
the toxicity of cytostatics.
Levofolinic acid 50 mg/ml is used in cancer therapy in adults and
children to diminish the toxicity and counteract the action of substances
such as methotrexate which inhibit the action of endogenous folic acid
(so called folic acid antagonists). An overdose of folic acid antagonists
can be treated with Levofolinic acid 50 mg/ml as well.
Use of Levofolinic acid 50 mg/ml in combination with fluorouracil
It has been shown that Levofolinic acid 50 mg/ml increases the
action of certain cytostatics. Thus, it is also used in cancer therapy to
increase the cell-damaging effects of an anticancer medicine called
5-fluorouracil.

2. What you need to know before you use
Levofolinic acid 50 mg/ml
Do not use Levofolinic acid 50 mg/ml
• if you are allergic to levofolinic acid or any of the other ingredients
of this medicine (listed in section 6),
• if you have pernicious anaemia or another anaemia due to
Vitamin B12 deficiency,
• in combination with fluorouracil in case of existing contraindications
against fluorouracil, in particular when you are pregnant or
breast-feeding,
• in combination with fluorouracil if you have severe diarrhoea.
Warnings and precautions
Talk to your doctor, pharmacist or nurse before using
Levofolinic acid 50 mg/ml.

General
Levofolinic acid 50 mg/ml should only be used in combination with
fluorouracil or methotrexate under the direct supervision of a physician
experienced in cancer therapy.
Levofolinic acid should not be administered into the spinal fluid
(intrathecally) because severe side effects have been observed with this
kind of treatment.
If you are administered certain cytotoxic (cell-damaging) substances
such as hydroxycarbamide, cytarabine, mercaptopurin, thioguanine
you may develop macrocytosis (enlarged red blood cells). Such
macrocytosis should not be treated with levofolinic acid.
If you suffer from epilepsy which is treated with certain drug substances
(phenobarbital, phenytoin or primidone), there may be an increased
risk of seizures. This results from a decrease of the concentration
of antiepileptic substances in your blood plasma. Your doctor will
probably carry out blood tests during the administration of levofolinic
acid and after discontinuation. The concentration of your epileptic
medication in your blood plasma may be determined and, if necessary,
the dose will be adapted.
Special precautions for the use of Levofolinic acid 50 mg/ml
in combination with methotrexate
Your doctor will ensure that levofolinic acid is not given simultaneously
with a folic acid antagonist (e.g. methotrexate), as the therapeutic
effects of the antagonist may be reduced.
Your doctor will also avoid excessive levofolinic acid doses since this
might impair the antitumour activity of methotrexate.

show side effects affecting the gastrointestinal tract regardless of
their severity.
In particular, if you develop diarrhoea the doctor will monitor you very
carefully since your condition may deteriorate rapidly and severe side
effects may occur. Your doctor will initiate or resume combination
therapy of levofolinic acid and fluorouracil after the gastrointestinal
symptoms have completely disappeared.
Elderly or debilitated patients or patients who have undergone
radiotherapy before should take special care as levofolinic acid may
increase the risk of fluorouracil toxicity.

Levofolinic acid 50 mg/ml must not be administered into the spinal
fluid (intrathecally).
Levofolinic acid 50 mg/ml dosage to prevent the manifestations of
intoxication in methotrexate therapy
If you are administered a methotrexate dose of more than 500 mg/m²
body surface in cancer therapy, you must also be administered
Levofolinic acid afterwards. With doses of 100 mg/m² – 500 mg/m²
methotrexate your doctor may consider Levofolinic acid administration.
Your doctor will ensure that the correct dose for your condition is given.

Other medicines and Levofolinic acid 50 mg/ml
Tell your doctor or pharmacist if you are taking, have recently taken or
might take any other medicines.

Levofolinic acid 50 mg/ml dosage to increase the cytotoxic effects
of fluorouracil

The effect of one of the following medicinal products may be influenced if
taken together with Levofolinic acid 50 mg/ml: phenobarbital, primidone,
phenytoin, succinimide (medicinal products for treatment of epilepsy).

There are different regimes for the combination therapy with Levofolinic
acid 50 mg/ml and fluorouracil (weekly regime, bimonthly regime and
monthly regime).

If Levofolinic acid 50 mg/ml is given simultaneously with methotrexate it
may stop this drug from working properly.

Your doctor will ensure that the correct dose for your condition is given
within the appropriate regime.

Concomittant use of Levofolinic acid 50 mg/ml with 5-fluorouracil may
increase the cytotoxic effect of 5-fluorouracil.

If you are given more Levofolinic acid 50 mg/ml than intended
An accidental overdose of Levofolinic acid 50 mg/ml can decrease
the efficacy of folic acid antagonists such as methotrexate. Should
overdosage of the combination of fluorouracil and Levofolinic acid
50 mg/ml occur, overdosage instructions for fluorouracil should be
followed.

When Levofolinic acid 50 mg/ml 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 neutralised.
Pregnancy, breast-feeding and fertility

4. Possible side effects
However, an accidental overdose of a folic acid antagonist such as
methotrexate will be treated immediately as a medicinal emergency.
If you already suffer from impaired kidney function, inadequate
hydration or if you use certain medicines against inflammation or pain
(non steroidal anti-inflammatory agents e.g. ibuprofen, diclofenac
or salicylates such as acetylsalicylate like aspirin) the excretion of
methotrexate may be delayed by fluid accumulation, e.g. in the
peritoneal cavity or in the space between thorax and lung.
Under such circumstances, higher doses of Levofolinic acid 50 mg/ml
or a prolonged administration period may be indicated.
Delayed excretion of methotrexate may in turn affect your kidney
function which increases methotrexate blood levels.
In this case as well you may be given higher doses of Levofolinic
acid 50 mg/ml or the administration period of levofolinic acid may be
prolonged.
Special precautions for the use of Levofolinic acid 50 mg/ml in
combination with fluorouracil
In combined therapy with fluorouracil, levofolinic acid may increase the
risk of toxicity of fluorouracil. The most common manifestations which
may be dose limiting are:
• a reduced number of white blood cells
• inflammation of the mucous membranes (e.g. in the mouth
and/or stomach)
• diarrhoea

Pregnancy
There are no indications that Levofolinic acid 50 mg/ml induces harmful
effects if administered alone during pregnancy.
If you are pregnant, you should only be administered methotrexate if the
benefits of your treatment outweigh the possible risks for your child.
If you are given methotrexate although you are pregnant, there are
no limitations as to the use of disodium levofolinate to diminish or
counteract the effects of methotrexate.
If you are pregnant you must not be administered a combination therapy
with Levofolinic acid 50 mg/ml and fluorouracil.
Breast-feeding
You must stop breast-feeding before initiation of treatment with
methotrexate or fluorouracil.
Levofolinic acid 50 mg/ml alone can be used during breast-feeding when
considered necessary.
Driving and using machines
There is no evidence that Levofolinic acid 50 mg/ml alone affects the
ability to drive or operate machines. Your general condition is more
significant than any effects induced by Levofolinic acid 50 mg/ml.

Like all medicines, this medicine can cause side effects, although not
everybody gets them.
The following frequencies form the basis of the evaluation of side
effects:
Very common: may affect more than 1 in 10 people
Common: may affect up to 1 in 10 people
Uncommon: may affect up to 1 in 100 people
Rare: may affect up to 1 in 1,000 people
Very rare: may affect up to 1 in 10,000 people
Not known: frequency cannot be estimated from the available data
Please tell your doctor immediately if you notice any side effects and
discuss any further actions with him.
Uncommon

• General disorders (Fever)

Rare

• Psychiatric disorders (Insomnia, agitation and
depression after high doses)

3. How to use Levofolinic acid 50 mg/ml
• Gastrointestinal disorders (after high doses)

If you suffer from watery stools two times per day and/or
inflammation of the mucous membrane of the stomach (mild to
moderate ulcers), you should consult your physician immediately.
You will neither be administered a combination therapy of fluorouracil
and levofolinic acid nor will a combination therapy be maintained if you

The preparation and administration of Levofolinic acid 50 mg/ml must
only be carried out by trained healthcare professionals.
Levofolinic acid 50 mg/ml Solution for injection or infusion should always
be administered into a vein, either undiluted by injection or by infusion
after dilution.

• Nervous system disorders (increase in the frequency
of attacks in epileptics)
Very rare

• Immune system disorders (allergic reactions including
anaphylactoid reactions and urticaria)

Levofolinic acid 50 mg/ml · 90200-VBGB · CB · 07.15 · Pharma-Code: 701
Format: 486 x 252 mm · HKS 44 · Corrective action: KV01_jem_16.07.15

Sodium levofolinate in combination with fluorouracil
Generally, the safety profile depends on the applied regimen of
fluorouracil due to enhancement of the fluorouracil induced toxicities.

Pack sizes:
Vials with 1 ml, 4 ml, or 9 ml solution for injection or infusion in packs
of 1 or 5 vials. Not all pack sizes may be marketed.

Monthly regimen
Very common

Levofolinic acid 50 mg/ml is compatible with fluorouracil.

posology and method of administration of disodium levofolinate.

Only clear solutions without visible particles should be used.

The following guidelines may serve as an illustration of regimens used
in adults, elderly and children:

For single use only; any unused product should be disposed of in
accordance with local requirements.

• Gastrointestinal disorders (vomiting, nausea)
• General disorders (mucosal toxicities, which can
be severe)

No enhancement of other fluorouracil induced toxicities (e.g.
neurotoxicity) was observed.
Weekly regimen
Very common

vials type I with bromobutyl rubber stoppers and aluminium
flip-off caps.

• Gastrointestinal disorders (diarrhoea with higher
grades of toxicity, and dehydration resulting in
hospital admission for treatment and even death)

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse.
This includes any possible side effects not listed in this leaflet. You can
also report side effects directly via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard
By reporting side effects you can help provide more information on the
safety of this medicine.
5. How to store Levofolinic acid 50 mg/ml
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the
label and the carton after “EXP”. The expiry date refers to the last day
of that month.
Store in a refrigerator (2 °C – 8 °C).
Keep the vial in the outer carton in order to protect from light.
6. Contents of the pack and other information
What Levofolinic acid 50 mg/ml contains
The active substance is levofolinic acid.
Each ml of solution contains 54.65 mg disodium levofolinate, equivalent
to 50 mg levofolinic acid.
Each 1 ml vial contains 54.65 mg disodium levofolinate, equivalent
to 50 mg levofolinic acid.
Each 4 ml vial contains 218.6 mg disodium levofolinate, equivalent
to 200 mg levofolinic acid.
Each 9 ml vial contains 491.85 mg disodium levofolinate, equivalent
to 450 mg levofolinic acid.
The other ingredients are:
• sodium hydroxide
• hydrochloric acid
• water for injections
What Levofolinic acid 50 mg/ml looks like and contents of the pack
Levofolinic acid 50 mg/ml is a clear, colourless to slightly yellow
solution for injection or infusion. It is marketed in colourless glass

Marketing Authorisation Holder and Manufacturer
medac
Gesellschaft für klinische Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany
This medicinal product is authorised in the member states of the
EEA under the following names:
Belgium:
Levofolic 50 mg/ml
solution injectable ou pour perfusion
Levofolic 50 mg/ml
oplossing voor injectie of infusie
Levofolic 50 mg/ml
Injektions- oder Infusionslösung
Denmark:
Levofolininsyre ”medac” 50 mg/ml
injektions- og infusionsvæske, opløsning
Estonia:
Levofolinic acid medac 50 mg/ml
süste- või infusioonilahus
Finland:
Levofolic 50 mg/ml injektio/ infuusioneste, liuos
Levofolic 50 mg/ml
injektions/infusionsvätska, lösning
France:
Levofolinate de sodium medac 50 mg/ml,
solution injectable ou pour perfusion
Germany:
Levofolic 50 mg/ml Injektions- oder Infusionslösung
Italy:
Sodio Levofolinato medac 50 mg/ml
soluzione iniettabile o per infusione
Latvia:
Levofolic 50 mg/ml šķīdums injekcijām vai infūzijām
Lithuania:
Levofolino rūgštis medac 50 mg/ml
injekcinis/infuzinis tirpalas
Norway:
Levofolinsyre medac 50 mg/ml
injeksjonsvæske/infusjonsvæske, oppløsning
Poland:
Levofolic 50 mg/ml roztwór do wstrzykiwań lub infuzji
Portugal:
Levofolic 50 mg/ml
solução injectável ou para perfusão
Slovakia:
Levofolic 50 mg/ml injekčný alebo infúzny roztok
Slovenia:
Levofolic 50 mg/ml
raztopina za injiciranje ali infundiranje
Spain:
Ácido levofolínico medac 50 mg/ml
solución inyectable o para perfusión
Sweden:
Natriumlevofolinat medac, 50 mg/ml
injektions- eller infusionsvätska, lösning
United Kingdom: Levofolinic acid 50 mg/ml
Solution for injection or infusion

For intravenous use.
Shelf life after first opening or dilution
After dilution with 0.9 % sodium chloride solution or 5 % glucose solution:
The in-use stability of the ready for use solution is 72 hours when
stored at 20 – 25 °C.
However, from a microbiological point of view the product should be
used immediately. If not used immediately, your doctor will ensure the
correct in-use storage times and conditions prior to use in order to
preserve the quality of the solution. Normally, this would be not longer
than 24 hours at 2 °C – 8 °C, unless opening and preparation have
taken place in controlled and sterile conditions.
Dosage and method of administration
Increasing the cytotoxicity of fluorouracil
Different regimes and different dosages are used, without any dosage
having been proven to be the optimal one.
The following regimes have been used in adults and elderly in the
treatment of advanced or metastatic colorectal cancer and are given as
examples.
There are no data on the use of these combinations in children.
Bimonthly regimen: 100 mg/m² levofolinic acid (= 109.3 mg/m² disodium
levofolinate) by intravenous infusion over two hours, followed by bolus
400 mg/m² of 5-fluorouracil and 22-hour infusion of 5-fluorouracil
(600 mg/m²) for 2 consecutive days, every 2 weeks on days 1 and 2.
Weekly regimen: 10 mg/m² levofolinic acid (= 10.93 mg/m² disodium
levofolinate) by bolus injection or 100 to 250 mg/m² levofolinic acid
(= 109.3 mg/m² to 273.25 mg/m² disodium levofolinate) as i.v. infusion
over a period of 2 hours plus 500 mg/m² 5-fluorouracil as i.v. bolus
injection in the middle or at the end of the disodium levofolinate infusion.
Monthly regimen: 10 mg/m² levofolinic acid (= 10.93 mg/m² disodium
levofolinate) by bolus i.v. injection or 100 to 250 mg/m² levofolinic acid
(= 109.3 mg/m² to 273.25 mg/m² disodium levofolinate) as i.v. infusion
over a period of 2 hours immediately followed by 425 or 370 mg/m²
5-fluorouracil as i.v. bolus injection during 5 consecutive days.

----------------------------------------------------------------------------------

For the combination therapy with 5-fluorouracil, modification of the
5-fluorouracil dosage and the treatment-free interval may be necessary
depending on patient condition, clinical response and dose limiting
toxicity as stated in the product information of 5-fluorouracil.
A reduction of disodium levofolinate dosage is not required.

The following information is intended for healthcare professionals only:

The number of repeat cycles used is at the discretion of the clinician.

Instructions for use and handling of Levofolinic acid 50 mg/ml

Disodium levofolinate rescue in methotrexate therapy

Preparation of the ready to use solution for infusion must take place in
aseptic conditions.

Since the disodium levofolinate rescue dosage regimen depends
heavily on the posology and method of the intermediate- or high-dose
methotrexate administration, the methotrexate protocol will dictate the
dosage regimen of disodium levofolinate rescue. Therefore, it is best to
refer to the applied intermediate or high dose methotrexate protocol for

This leaflet was last revised in 07/2015.

Levofolinic acid 50 mg/ml Solution for injection or infusion may be
diluted with 0.9 % sodium chloride solution or 5 % glucose solution.

Disodium levofolinate rescue has to be performed by parenteral
administration in patients with malabsorption syndromes or other
gastrointestinal disorders where enteral absorption is not assured.
Dosages above 12.5 – 25 mg should be given parenterally due to
saturable enteral absorption of disodium levofolinate.
Disodium levofolinate rescue is necessary when methotrexate is given
at doses exceeding 500 mg/m² body surface and should be considered
with doses of 100 mg – 500 mg/m² body surface.
Dosage and duration of disodium levofolinate rescue primarily depend
on the type and dosage of methotrexate therapy, the occurrence
of toxicity symptoms, and the individual excretion capacity for
methotrexate. As a rule, the first dose of levofolinic acid is 7.5 mg
(3 – 6 mg/m²) to be given 12 – 24 hours (24 hours at the latest) after
the beginning of methotrexate infusion. The same dose is given every
6 hours throughout a period of 72 hours. After several parenteral doses
treatment can be switched over to the oral form.
In addition to levofolinic acid administration, measures to ensure the
prompt excretion of methotrexate are important.
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 1,800 – 2,000 cc/m²/24 hr by
increased oral or intravenous fluids on days 2, 3 and 4 following
methotrexate therapy.
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 levofolinic acid or prolonged
administration may be indicated. Patients who experience delayed early
methotrexate elimination are likely to develop reversible renal failure.
Forty-eight hours after the start of the methotrexate infusion, the
residual methotrexate-level should be measured. If the residual
methotrexate-level is > 0.5 μmol/l, disodium levofolinate dosages
should be adapted according to the following table:
Residual methotrexate blood level
48 hours after the start of the
methotrexate administration:

Additional levofolinic acid to
be administered every 6 hours
for 48 hours or until levels of
methotrexate are lower than
0.05 μmol/l:

≥ 0.5 μmol/l

7.5 mg/m²

≥ 1.0 μmol/l

50 mg/m²

≥ 2.0 μmol/l

100 mg/m²

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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