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LEVOFOLINIC ACID 50 MG/ML SOLUTION FOR INJECTION OR INFUSION

Active substance(s): LEVOFOLINIC ACID / LEVOFOLINIC ACID / LEVOFOLINIC ACID

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Levofolinic acid 50 mg/ml · 90200-VBGB · DA · 07.17 · Pharma-Code: 551
Format: 486 x 252 mm · HKS 44 · Corrective action: KV01_jte_22.02.16 / KV02_osc_13.12.16 / KV03_osc_29.06.17

Package leaflet: Information for the user

Levofolinic acid 50 mg/ml
solution for injection/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.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This
includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet:
1. What Levofolinic acid is and what it is used for
2. What you need to know before you use Levofolinic acid
3. How to use Levofolinic acid
4. Possible side effects
5. How to store Levofolinic acid
6. Contents of the pack and other information

Levofolinic acid
50 mg/ml
90200-VBGB
DA

Levofolinic acid
50 mg/ml
90200-VBGB
DA

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 medicines
(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 antiepileptic medicine in your blood plasma may
be determined and, if necessary, the dose will be adapted.
Special precautions for the use of Levofolinic acid 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.
However, an accidental overdose of a folic acid antagonist such as
methotrexate will be treated immediately as a medicinal emergency.

1. What Levofolinic acid is and what it is used for
Use of Levofolinic acid in combination with methotrexate
Levofolinic acid 50 mg/ml solution for injection/infusion belongs to the group
of medicines called antidotes. These are substances which are used during
cancer therapy (cytostatic therapy) to counteract the toxicity of cytostatics.
Levofolinic acid 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 as well.
Use of Levofolinic acid in combination with 5-fluorouracil
It has been shown that Levofolinic acid 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
Do not use Levofolinic acid
• 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 5-fluorouracil in case of existing contraindications
against 5-fluorouracil, in particular when you are pregnant or breastfeeding,
• in combination with 5-fluorouracil if you have severe diarrhoea.

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 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 or
the administration period of levofolinic acid may be prolonged.

The effect of one of the following medicinal products may be influenced if
taken together with Levofolinic acid: phenobarbital, primidone, phenytoin,
succinimide (medicines for treatment of epilepsy). Your doctor may
check blood levels of these medicines and change your dose to prevent
increased convulsions (fits).
If Levofolinic acid is given simultaneously with methotrexate it may stop
this medicine from working properly.
Concomitant use of Levofolinic acid with 5-fluorouracil will increase
effectiveness and side effects of 5-fluorouracil.
When Levofolinic acid is given in conjunction with a folic acid antagonist
(e.g. cotrimoxazole, pyrimethamine) the effectiveness of the folic acid
antagonist may either be reduced or completely neutralised.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are
planning to have a baby, ask your doctor for advice before taking this
medicine.
It is unlikely that your doctor will ask you to take/use a folic acid antagonist
or 5-fluorouracil whilst you are pregnant or breast-feeding. However, if you
have taken/used a folic acid antagonist whilst pregnant or breast-feeding,
this medicine (Levofolinic acid) may be used to reduce its side effects.
Pregnancy
There are no indications that Levofolinic acid 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.

Special precautions for the use of Levofolinic acid in combination with
5-fluorouracil
In combined therapy with 5-fluorouracil, levofolinic acid may increase the
risk of toxicity of 5-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

If you are pregnant you must not be administered a combination therapy
with Levofolinic acid and 5-fluorouracil.

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.

Driving and using machines
There is no evidence that Levofolinic acid alone affects the ability to drive
or use machines. Your general condition is more significant than any
effects induced by Levofolinic acid.

General
Levofolinic acid should only be used in combination with 5-fluorouracil or
methotrexate under the direct supervision of a physician experienced in
cancer therapy.

You will neither be administered a combination therapy of 5-fluorouracil
and levofolinic acid nor will a combination therapy be maintained if you
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 5-fluorouracil after the gastrointestinal symptoms
have completely disappeared.

Levofolinic acid should not be administered into the spinal fluid
(intrathecally) because severe side effects, including death, have been
observed with this kind of treatment.

Elderly or debilitated patients or patients who have undergone radiotherapy
before should take special care as levofolinic acid may increase the risk of
5-fluorouracil toxicity.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before using Levofolinic acid.

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

Breast-feeding
You must stop breast-feeding before treatment with methotrexate or
5-fluorouracil is started.
Levofolinic acid alone can be used during breast-feeding when considered
necessary.

3. How to use Levofolinic acid
The preparation and administration of Levofolinic acid must only be
carried out by trained healthcare professionals.
Levofolinic acid should always be administered into a vein, either undiluted
by injection or by infusion after dilution.
Levofolinic acid must not be administered into the spinal fluid
(intrathecally).

Levofolinic acid dose 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.
Levofolinic acid dose to increase the cytotoxic effects of 5-fluorouracil
There are different regimes for the combination therapy with Levofolinic
acid and 5-fluorouracil (weekly regime, bimonthly regime and monthly
regime).
Your doctor will ensure that the correct dose for your condition is given
within the appropriate regime.
If you are given more Levofolinic acid than intended
Excessive amounts of Levofolinic acid may nullify the efficacy of folic acid
antagonists such as methotrexate. Should overdose of the combination
of 5-fluorouracil and Levofolinic acid occur, overdose instructions for
5-fluorouracil should be followed.
If you have any further questions on the use of this medicine, ask your
doctor, pharmacist or nurse.

4. Possible side effects
Like all medicines, this medicine can cause side effects, although not
everybody gets them.
Stop taking Levofolinic acid and contact a doctor or go to your nearest
emercency department immediately if you experience any of the following
symptoms:
Very rare (may affect up to 1 in 10,000 people):
• Severe allergic reaction – you may experience a sudden itchy rash
(hives), swelling of the hands, feet, ankles, face, lips, mouth or throat
(which may cause difficulty in swallowing or breathing), and you may
feel you are going to faint.
This is a serious side effect. You may need urgent medical attention.
Other side effects that may occur:
Uncommon (may affect up to 1 in 100 people):
• fever
Rare (may affect up to 1 in 1,000 people):
• difficulty sleeping (insomnia), agitation and depression after high doses
• problems with the digestive system (after high doses)
• increase in the frequency of convulsions (fits) in patients with epilepsy
Sodium levofolinate in combination with 5-fluorouracil
If you receive levofolinic acid in combination with an anticancer medicine
containing fluoropyrimidines, it is more likely that you experience the
following side effects of this other medicine.
Very common (may affect more than 1 in 10 people):
• reduction in the number of blood cells (including life-threatening conditions)
• inflammation (painful swelling and reddening) of the lining of the gut and
mouth (life-threatening conditions have occurred)
Common (may affect up to 1 in 10 people):
• redness and swelling of the palms of the hands or the soles of the feet
which may cause the skin to peel (hand-foot-syndrome)

Levofolinic acid 50 mg/ml · 90200-VBGB · DA · 07.17 · Pharma-Code: 551
Format: 486 x 252 mm · HKS 44 · Corrective action: KV01_jte_22.02.16 / KV02_osc_13.12.16 / KV03_osc_29.06.17

Not known (frequency cannot be estimated from the available data):
• higher than normal level of ammonia in the blood (a waste product the
body makes)

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

Generally, the safety profile depends on the applied regimen of
5-fluorouracil due to enhancement of the 5-fluorouracil induced toxicities.

Marketing Authorisation Holder and Manufacturer
medac
Gesellschaft für klinische Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany

Monthly regimen
Very common (may affect more than 1 in 10 people):
• vomiting, nausea
No enhancement of other 5-fluorouracil induced toxicities
(e.g. neurotoxicity) was observed.
Weekly regimen
Very common (may affect more than 1 in 10 people):
• severe diarrhoea and drying out, which may be due to diarrhoea,
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
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).

This medicinal product is authorised in the member states of the EEA
under the following names:
Belgium:
Levofolic 50 mg/ml solution injectable/pour perfusion
Levofolic 50 mg/ml oplossing voor injectie / infusie
Levofolic 50 mg/ml Injektions-/Infusionslösung
Denmark:
Levofolininsyre ”medac” 50 mg/ml
injektions-/infusionsvæske, opløsning
Estonia:
Levofolinic acid medac 50 mg/ml süste-/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/pour perfusion
Germany:
Levofolic 50 mg/ml Injektions-/Infusionslösung
Italy:
Sodio Levofolinato medac 50 mg/ml
soluzione iniettabile o per infusione
Latvia:
Levofolic 50 mg/ml šķīdums injekcijai/infūzijai
Lithuania:
Levofolino rūgštis medac 50 mg/ml
injekcinis ar infuzinis tirpalas
Norway:
Levofolinsyre medac 50 mg/ml
injeksjons-/infusjonsvæske, oppløsning
Poland:
Levofolic 50 mg/ml roztwór do wstrzykiwań / do infuzji
Portugal:
Levofolic 50 mg/ml solução injetável ou para perfusão
Slovakia:
Levofolic 50 mg/ml injekčný/infúzny roztok
Slovenia:
Levofolic 50 mg/ml raztopina za injiciranje/infundiranje
Spain:
Ácido levofolínico medac 50 mg/ml
solución inyectable y para perfusión
Sweden:
Natriumlevofolinat medac
United Kingdom: Levofolinic acid 50 mg/ml solution for injection/infusion

Shelf life after first opening or dilution
After mixing with 5-fluorouracil or dilution with sodium chloride 9 mg/ml
(0.9 %) solution or 5 % glucose solution:
Chemical and physical in-use stability has been demonstrated for 72 hours
at 20 – 25 °C.
From a microbiological point of view the product should be used
immediately. If not used immediately, in-use storage times and conditions
prior to use are the responsibility of the user and would normally not be
longer than 24 hours at 2 °C – 8 °C, unless dilution has taken place in
controlled and validated aseptic conditions.
Posology and method of administration
Increasing the cytotoxicity of 5-fluorouracil
Different regimes and different doses are used, without any dose 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.
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.

The following information is intended for healthcare professionals only:

For the combination therapy with 5-fluorouracil, modification of the
5-fluorouracil dose 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 dose is not required.

Instructions for use and handling of Levofolinic acid

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

Preparation of solution for infusion must take place in aseptic conditions.

Paediatric population
No data on the use of these combinations are available.

Keep the vial in the outer carton in order to protect from light.
This leaflet was last revised in 07/2017.
6. Contents of the pack and other information

Doses above 12.5 – 25 mg levofolinic acid 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.
Dose and duration of disodium levofolinate rescue primarily depend on
the type and dose 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 disodium levofolinate 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 doses should be adapted according
to the following table:

What Levofolinic acid contains
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:

Disodium levofolinate rescue in methotrexate therapy

≥ 0.5 μmol/l

7.5 mg/m²

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

≥ 1.0 μmol/l

50 mg/m²

≥ 2.0 μmol/l

100 mg/m²

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 looks like and contents of the pack
Levofolinic acid is a clear, colourless to slightly yellow solution for
injection/infusion. It is marketed in colourless glass vials type I with
bromobutyl rubber stoppers and aluminium flip-off caps.

The solution for injection/infusion may be diluted with sodium chloride
9 mg/ml (0.9 %) solution or 5 % glucose solution.
Levofolinic acid is compatible with 5-fluorouracil.
Only clear solutions without visible particles should be used.
For single use only. Any unused product or waste material should be
disposed of in accordance with local requirements.
For intravenous use.

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

Expand Transcript

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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