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.

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

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.

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

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

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.

No enhancement of other fluorouracil induced toxicities (e.g. neurotoxicity) was observed.

Weekly reaimen

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

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

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.

Marketing Authorisation Holder and Manufacturer

medac

Gesellschaft fur klinische Spezialpraparate 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 Infusionslosung Denmark:    Levofolininsyre ’’medac” 50 mg/ml

injektions- og infusionsvaeske, oplosning Estonia:    Levofolinic acid medac 50 mg/ml

suste- voi infusioonilahus Levofolic 50 mg/ml injektio/ infuusioneste, liuos Levofolic 50 mg/ml injektions/infusionsvatska, losning Levofolinate de sodium medac 50 mg/ml, solution injectable ou pour perfusion Levofolic 50 mg/ml Injektions- Oder Infusionslosung Sodio Levofolinato medac 50 mg/ml soluzione iniettabile o per infusione Levofolic 50 mg/ml skTdums injekcijam vai infuzijam Levofolino rugstis medac 50 mg/ml injekcinis/infuzinis tirpalas Levofolinsyre medac 50 mg/ml injeksjonsvaeske/infusjonsvaeske, opplosning Levofolic 50 mg/ml roztwor do wstrzykiwan lub infuzji Levofolic 50 mg/ml solugao injectavel ou para perfusao Levofolic 50 mg/ml injekcny alebo infuzny roztok Levofolic 50 mg/ml raztopina za injiciranje ali infundiranje Acido levofolfnico medac 50 mg/ml solucion inyectable o para perfusion Natriumlevofolinat medac, 50 mg/ml injektions- eller infusionsvatska, losning Levofolinic acid 50 mg/ml Solution for injection or infusion

This leaflet was last revised in 07/2015.

The following information is intended for healthcare professionals only:

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

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

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

Only clear solutions without visible particles should be used.

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

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 reaimen: 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 number of repeat cycles used is at the discretion of the clinician.

Disodium levofolinate rescue in methotrexate therapy

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

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. 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 pM).

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 pmol/l, disodium levofolinate dosages should be adapted according to the following table: