Calcium Folinate 10 Mg/Ml Solution For Injection

Document: leaflet MAH GENERIC_PL 01502-0094 change

PACKAGE LEAFLET: INFORMATION FOR THE USER

Calcium Folinate 10 mg/ml Solution for Injection Important information about your medicine

> Your doctor or nurse will give you the injection.

> If this injection causes you any problems talk to your doctor, nurse or pharmacist.

> Please tell your doctor or pharmacist, if you have any other medical conditions or have an allergy to any of the ingredients of this medicine.

> Please tell your doctor or pharmacist, if you are taking any other medicines.

Read all of this leaflet carefully before you start using this medicine.

- Keep this leaflet. You may need to read it again.

- If you have any further questions, ask your doctor or pharmacist.

- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

- If any of the side effects becomes serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

The name of your medicine is Calcium Folinate 10 mg/ml Solution for Injection, which will be referred to as Calcium Folinate throughout this leaflet.

In this leaflet:

1. What Calcium Folinate is and what it is used for

2. Before you receive Calcium Folinate

3. How to use Calcium Folinate

4. Possible side effects

5. How to store Calcium Folinate

6. Further information

1. WHAT CALCIUM FOLINATE IS AND WHAT IT IS USED FOR

Calcium Folinate belongs to a group of medicines called detoxifying agents that are used in cancer treatment to reduce the toxic side effects of some medications such as methotrexate.

Calcium Folinate is used

- to reduce the harmful effects of some antiancer drugs such as methotrexate.

- to increase the effectiveness of the anticancer drug 5-fluorouracil.

2. BEFORE YOU RECEIVE CALCIUM FOLINATE You should NOT be given Calcium Folinate

• if you are allergic (hypersensitive) to Calcium Folinate or any of its ingredients. An allergic reaction may include rash, itching, difficulty of breathing or swelling of the face, lips, throat or tongue.

• if you have a blood disease called anaemia that is caused by too little vitamin B12 in the body.

Take special care with Calcium Folinate

• if you are taking medication for treatment of epilepsy.

• If you are currently suffering from diarrhoea.

• If elderly patients and weak patients are receiving combination therapy with the anticancer drug 5-fluorouracil, the toxicity risk of 5-fluorouracil is enhanced (especially with gastrointestinal disorders).

• if you are receiving anticancer drugs such as hydroxycarbamine, cytarabine, mercaptopurine and thioguanine because Calcium Folinate will not reduce their harmful effects.

• if your kidney function is impaired because higher doses or prolonged use of Calcium Folinate may be necessary.

Using other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines you can get without a prescription.

This is especially important with the following medicines as Calcium Folinate can influence their effect:

• Calcium Folinate may reduce the effect of medications for the treatment of epilepsy such as phenobarbital, primidone, phenytoin, or succinimides and may increase the frequency of seizures in susceptible patients.

• Calcium Folinate given together with some anticancer drugs such as cotrimoxazole and pyrimethamine may reduce or completely neutralise the effect of the cancer drug.

• Calcium Folinate may enhance the effect of 5-fluorouracil.

It may still be all right for you to receive Calcium Folinate and your doctor will be able to decide what is suitable for you.

Important information about some of the ingredients of Calcium Folinate

Calcium Folinate contains 3.1 mg sodium per ml solution for injection. That has to be taken into account, if you are on a controlled sodium diet.

Children

For the treatment with Calcium Folinate in combination with 5-fluorouracil there are no data available on the use in children.

Ask your doctor if you have any further questions.

Pregnancy and breast-feeding

This medicine should only be used during pregnancy where the advantages to the individual outweigh the potential risks. Always inform your doctor if you are pregnant or planning a pregnancy before using any medicine.

It is not known if this medicine passes into breast milk. It should be used with caution in nursing mothers, and only if the benefits to the mother outweigh any risks to the nursing infant. Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

There is no evidence that calcium folinate has an effect on the ability to drive or use machines.

3. HOW TO USE CALCIUM FOLINATE

Calcium Folinate must only be given by a doctor or nurse. It can be given

- as slow injection into a vein

- as injection into a large muscle

- as continuous infusion into a vein.

It must not be given as an injection into your spine.

For intravenous infusion, Calcium Folinate may be diluted according to directions with the recommended infusion fluids, 0.9% w/v Sodium Chloride Intravenous Infusion or

5% w/v Glucose Intravenous Infusion, before administration. Prior to administration, the sterile solution for injection should be visually inspected for clarity, particulate matter, discolouration and the integrity of the container. The solution should only be used if it is clear and the container is undamaged.

Dosage

Your doctor will decide your correct dose of Calcium Folinate. It can be different from patient to patient (depending for example on body size and patient condition). When used in combination with anticancer drugs, the dose depends on the dose of the anticancer drug you received.

What to do if you have received too much Calcium Folinate (overdose)

As a doctor or nurse will be giving you your medicine, it is unlikely that you will receive an overdose. However, if you suspect an overdosage warn a doctor immediately.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Calcium Folinate can cause side effects, although not everybody gets them.

The following side effects have been reported:

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.

Uncommon: may affect up to 1 in 100 people

- fever

Rare: may affect up to 1 in 1,000 people

- difficulty sleeping (insomnia)

- agitation

- depression

- symptoms of the gastrointestinal tract (such as loss in appetite, nausea, distension, flatulence, bad taste in the mouth)

- an increase in convulsions (fits) in patients with epilepsy

Possible side effects if you are taking Calcium Folinate to increase the effectiveness of 5-fluorouracil:

If you receive Calcium Folinate 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

- vomiting

- nausea (being or feeling sick)

- severe diarrhoea

- dehydration which may be due to diarrhoea

- inflammation of the lining of the intestine and mouth (life-threatening conditions have occurred)

- reduction in the number of blood cells (including life-threatening conditions) Common

- 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)

Not known: frequency cannot be estimated from the available data

- elevated ammonia level in the blood

The above side effects may require medical intervention and some may be life-threatening or fatal.

If any of the side effects becomes serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

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 CALCIUM FOLINATE

Keep out of the reach and sight of children.

Your doctor and pharmacist are responsible for the correct storage, use and disposal of Calcium Folinate.

The medicine should be stored in a refrigerator (2°C - 8°C).

Keep the vial in the outer carton in order to protect from light.

The medicine is for single use only. Any unused solution has to be discarded immediately after initial use.

For intravenous infusion, when diluted with the recommended infusion fluids, the solution should be used immediately.

This medicine must not be used after the expiry date which is stated on the packaging after "EXP”. The expiry date refers to the last day of that month.

What Calcium Folinate contains

Each 1 ml of Calcium Folinate contains 10.8 mg calcium folinate, equivalent to 10 mg folinic acid.

The other ingredients are water for injections, sodium hydroxide, sodium chloride, and nitrogen.

What Calcium Folinate looks like and contents of the pack

Calcium Folinate is a sterile, clear yellow solution, practically free from particles. It is supplied in colourless glass vials.

Each single-dose vial contains either 54 mg, 108 mg, 216 mg, 378 mg, 540 mg or 1080 mg of calcium folinate equivalent to 50 mg in 5 ml, 100 mg in 10 ml, 200 mg in 20 ml, 350 mg in 35 ml, 500 mg in 50 ml and 1000 mg in 100 ml of folinic acid, respectively.

Pack sizes:

1 (5 / 10) vial(s) containing 5 ml, 10 ml, 20 ml, 35 ml, 50 ml, or 100 ml.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

hameln pharmaceuticals ltd, Gloucester, United Kingdom Manufacturer

Haupt Pharma Wolfratshausen GmbH, Pfaffenrieder Str. 5, 82515 Wolfratshausen, Germany

hameln rds a.s., Horna 36, 900 01 Modra, Slovak Republic

This leaflet was last revised in 06/2016.

The following information is intended for medical or healthcare professionals only: Calcium Folinate 10 mg/ml Solution for Injection Instructions for use, handling

1. For intravenous and intramuscular administration only. In the case of intravenous administration, no more than 160 mg of calcium folinate should be injected per minute due to the calcium content of the solution.

Calcium Folinate must not be administered intrathecally. ¹

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 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

3. Calcium folinate solutions should not be mixed with any other drug, unless compatibility has been satisfactorily demonstrated. Due to chemical incompatibilities calcium folinate solutions should not be mixed with injectable forms of droperidol, fluorouracil, foscarnet or methotrexate and sodium bicarbonate.

4. Prior to administration, Calcium Folinate Injection should be visually inspected. The solution for injection or infusion should be a clear and yellowish solution. If cloudy in appearance or particles are observed, the solution should be discarded.

5. Calcium Folinate solution is for single dose use only. Discard any unused solution immediately after initial use and also if precipitation occurs following dilution.

6. Store the unopened vial at 2 °C - 8 °C in a refrigerator. Keep it in the outer carton in order to protect from light.

Dosage

Calcium folinate rescue in methotrexate therapy:

Since the calcium folinate 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 calcium folinate rescue.

Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of calcium folinate.

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

Calcium folinate 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 25-50 mg should be given parenterally due to saturable enteral absorption of calcium folinate.

Calcium folinate rescue is necessary when methotrexate is given at doses exceeding 500 mg/m¹ body surface and should be considered with doses of 100 mg - 500 mg/m¹ body surface.

Dosage and duration of calcium folinate 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 calcium folinate is 15 mg (6 - 12 mg/m¹) 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 calcium folinate administration, measures to ensure the prompt excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the calcium folinate rescue treatment. Renal function should be monitored through daily measurements of serum creatinine.

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, calcium folinate dosages should be adapted according to the following table:

Residual methotrexate blood level 48 hours after the start of methotrexate administration	Additional calcium folinate to be administered every 6 hours for 48 hours or until levels of methotrexate are lower than 0.05 pmol/l
> 0.5 pmol/l	15 mg/m²
> 1.0 pmol/l	100 mg/m²
> 2.0 pmol/l	200 mg/m²

In combination with 5-fluorouracil in cytotoxic therapy:

Different regimens and different dosages are used, without any dosage having been proven to be the optimal one.

The following regimens 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: Calcium folinate 200 mg/m² by intravenous infusion over two hours, followed by bolus 400 mg/m² of 5-fluorouracil and 22-hour infusion of 5-FU (600 mg/m²) for 2 consecutive days, every 2 weeks on days 1 and 2.

Weekly regimen: Calcium folinate 20 mg/m² by bolus i.v. injection or 200 to 500 mg/m² 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 calcium folinate infusion.

Monthly regimen: Calcium folinate 20 mg/m2 by bolus i.v. injection or 200 to 500 mg/m2 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 five consecutive days.

For the combination therapy with 5-fluorouracil, modification of 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 calcium folinate dosage is not required.

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

Antidote to the folic acid antagonists trimetrexate, trimethoprime, and pyrimethamine: Trimetrexate toxicity:

• Prevention: Calcium folinate should be administered every day during treatment with trimetrexate and for 72 hours after the last dose of trimetrexate. Calcium folinate can be administered either by the intravenous route at a dose of 20 mg/m2 for 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m2, or by oral route with four doses of 20 mg/m² administered at equal time intervals. Daily doses of calcium folinate should be adjusted depending on the haematological toxicity of trimetrexate.

• Overdosage (possibly occurring with trimetrexate doses above 90 mg/m² without concomitant administration of calcium folinate): after stopping trimetrexate, calcium folinate 40 mg/m² IV every 6 hours for 3 days.

Trimethoprime toxicity:

• After stopping trimethoprime, 3-10 mg/day calcium folinate until recovery of a normal blood count.

Pyrimethamine toxicity:

• In case of high dose pyrimethamine or prolonged treatment with low doses, calcium folinate 5 to 50 mg/day should be simultaneously administered, based on the results of the peripheral blood counts.

Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

For intravenous infusion, calcium folinate may be diluted with 0.9 % Sodium Chloride or 5 % Glucose Injection before use.

Chemical and physical in-use stability of Calcium Folinate after dilution to 1.5 mg/ml with either 0.9 % Sodium Chloride Injection or 5 % Glucose Injection was demonstrated for up to 96 hours, at both room temperature and 2-8°C, when protected from light.

Chemical and physical in-use stability of Calcium Folinate after dilution to 0.2 mg/ml was demonstrated with 0.9 % Sodium Chloride Injection over an in-use shelf life of 24 hours at 2-8°C, when protected from light.