Patient Information Leaflet

Ancotil, 10 mg/ml, infusion solution
Flucytosinum
Please read the entire leaflet carefully before use, as it contains important information for the patient.

Keep this leaflet for future reference.
If you have any questions, please consult your doctor, pharmacist, or nurse.
This medicine has been prescribed for a specific individual. Do not share it with others. This medicine may harm others, even if their symptoms are similar.
If the patient experiences any adverse reactions, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse immediately. See section 4.

Table of Contents

What Ancotil is and what it is used for
Important information before using Ancotil
How to use Ancotil
Possible side effects
How to store Ancotil
Contents of the pack and other information

1. What Ancotil is and what it is used for

Ancotil is an antifungal medicine. It acts against specific types of fungi, particularly Candida species and Cryptococcus neoformans, as well as fungi causing chromoblastomycosis (a chronic, subcutaneous fungal infection).
Most strains of yeast isolated in Europe from previously untreated patients are sensitive to flucytosine – the active substance in Ancotil.
Ancotil is used in the treatment of fungal infections: systemic candidiasis, cryptococcosis, and chromoblastomycosis in adults, as well as systemic cryptococcosis and chromoblastomycosis in children.
Ancotil is often used concomitantly with amphotericin B, as the combined effect of these two medicines against many fungi is significantly greater than the sum of their individual effects.
Combination therapy with amphotericin B is recommended in the treatment of cryptococcal meningitis and severe systemic candidiasis. Ancotil may be used in patients both with normal and impaired immune function.

2. Important information before using Ancotil

When not to use Ancotil

If the patient is allergic (hypersensitive) to flucytosine or any of the other ingredients of this medicine (listed in section 6).
If the patient is taking any antiviral medicine belonging to the group of so-called nucleosides, e.g. ganciclovir, valganciclovir, brivudine, sorivudine or their analogues (see below: "Ancotil and other medicines").
If the patient has no activity of the enzyme dihydropyrimidine dehydrogenase (DPD) (complete DPD deficiency).
In breastfeeding women (see below: "Pregnancy, breastfeeding and fertility").

When to be cautious when using Ancotil

If the patient has kidney impairment.
If the patient has liver function disorders.
If the patient has blood disorders or bone marrow dysfunction. Before starting and during treatment with Ancotil, the doctor will recommend blood tests to monitor kidney, liver and bone marrow function.

Women of childbearing age
If the patient is of childbearing age, she must use an effective method of contraception during
and for one month after stopping treatment with Ancotil. This medicine may cause birth defects.
In case of any further doubts, please discuss this with the doctor.
Men
The patient (and his partner of childbearing age) must use an effective method of contraception
during and for three months after stopping treatment with Ancotil. This medicine may
cause birth defects.
In case of any further doubts, please discuss this with the doctor.

Ancotil and other medicines
Tell your doctor about all medicines currently or recently taken, or which the patient plans to take. This especially concerns the medicines listed below.

Concomitant use of antiviral nucleoside analogues such as ganciclovir, valganciclovir, brivudine, sorivudine and their derivatives is contraindicated, as it may increase the risk of adverse effects associated with the use of Ancotil (see also section "When not to use Ancotil").
Cytostatic agents (anticancer drugs). Leukopenia (reduced number of white blood cells in peripheral blood) may occur during Ancotil treatment. Therefore, careful and frequent (even daily) monitoring of the peripheral blood count is required when cytostatics are administered concomitantly.
Medicines that reduce glomerular filtration in the kidneys. These may increase the blood concentration of flucytosine. If such medicines are used together with flucytosine, regular monitoring of kidney function and appropriate dose adjustment of the medicine are necessary.
Cytosine arabinoside (an anticancer drug) abolishes the antifungal activity of Ancotil.
Medicines containing phenytoin (used in the treatment of epilepsy). Intravenous fluorouracil administered concomitantly with phenytoin may increase phenytoin plasma concentrations in some patients, leading to symptoms of phenytoin toxicity. This is also relevant during Ancotil treatment, as flucytosine is metabolized to fluorouracil.

Pregnancy, breastfeeding and fertility
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a
child, she should consult her doctor or pharmacist before using this medicine.
Ancotil may cause birth defects. For this reason, it should not be used in pregnant women or in women of childbearing age who are not using an effective method of contraception. However, in life-threatening situations, the doctor may decide to administer Ancotil during pregnancy. In such cases, both the mother and the fetus or newborn will undergo additional monitoring during pregnancy and after delivery.
Breastfeeding during treatment with Ancotil is absolutely contraindicated. The doctor will decide whether to discontinue breastfeeding or to stop treatment with Ancotil, taking into account the benefits of breastfeeding for the child and the benefits of treatment for the mother.

Contraception in men and women
Ancotil may cause birth defects. Therefore, an effective method of contraception must be used during treatment with Ancotil to prevent pregnancy in the patient taking Ancotil or in the female partner of a man being treated with this medicine.
Women of childbearing age must use an effective method of contraception during and for one month after stopping Ancotil. Men (and their partners of childbearing age) must use an effective method of contraception both during and for three months after stopping Ancotil.

Driving and using machines
No studies on the effect of the medicine on the ability to drive vehicles and operate machinery have been conducted.

Ancotil contains sodium
The medicine contains 34.5 mmol (794 mg) of sodium (the main component of table salt) in one bottle (250 ml) of the medicine. This corresponds to 40% of the maximum recommended daily dietary sodium intake for adults.
The medicine contains 96.6 mmol (2220 mg) of sodium (the main component of table salt) in each maximum daily dose (700 ml of infusion solution for an adult weighing 70 kg). This corresponds to 111% of the maximum recommended daily dietary sodium intake for adults.
If 700 ml or more of infusion solution per day is administered to an adult weighing 70 kg, patients should contact their doctor or pharmacist. This applies to patients receiving Ancotil daily and long-term, especially those on a low-sodium diet.
When calculating water and electrolyte intake, particularly in patients with impaired kidney function, heart failure or electrolyte imbalances, the amount of water and sodium administered with Ancotil must be taken into account.

3. How to use Ancotil

Ancotil should always be used as directed by the physician.
The Ancotil medication is administered exclusively by qualified medical personnel under the supervision of a physician. Detailed information regarding dosage and method of administration of Ancotil is provided at the end of this leaflet, in the section entitled "Information for healthcare professionals".

Use in children and adolescents
Clinical data on the use of Ancotil in children are available but insufficient to establish dosage recommendations for this age group. If a physician prescribes Ancotil for a child, they will also determine the optimal dosage.
Due to the longer elimination period of flucytosine in pediatric patients, especially in the youngest ones, blood concentrations of flucytosine may exceed recommended levels during treatment. Therefore, flucytosine blood levels will be regularly monitored during treatment of children.

Overdose of Ancotil
If an excessive amount of Ancotil is administered, adverse reactions may become more severe, particularly disturbances in peripheral blood composition. If excessively high doses are administered for prolonged periods, diarrhea, nausea, vomiting, and liver function disorders may occur. These symptoms usually resolve quickly after dose reduction or discontinuation of the drug.

Missed dose of Ancotil
If a dose of Ancotil is missed at the scheduled time, medical personnel should administer it as soon as possible. However, if the time for the next dose is approaching, the missed dose should be skipped. Do not administer a double dose to make up for the missed dose.

Discontinuation of Ancotil
Discontinuing treatment with Ancotil may lead to worsening of the disease for which the medication is being used.

If you have any further questions concerning the use of this medicine, consult your physician or pharmacist.

4. Possible adverse reactions

Like all medicines, Ancotil may cause adverse reactions, although not everyone experiences them.
Below is a list of adverse reactions that may occur during treatment with Ancotil.
The exact frequency of these reactions is unknown (cannot be determined based on available data).

Transient nausea, vomiting, and diarrhea.
Transient rash.
Hepatitis, hepatic cell necrosis; in individual cases acute liver damage has been observed, which may lead to death in some patients.
Seizures, headache, dizziness, excessive sedation.
Hallucinations, confusion.
Myocardial damage.
Allergic reactions, Lyell's syndrome (characterized by the occurrence of flaccid, large blisters on the skin).
Transient disturbances in liver enzyme activity (dose-dependent).
Changes in peripheral blood count due to bone marrow suppression, primarily leukopenia (reduced concentration of white blood cells in peripheral blood) and thrombocytopenia (reduced number of platelets) – these changes occur mainly in patients with renal impairment, in whom flucytosine may reach high serum concentrations, and in patients concurrently receiving amphotericin B; in rare cases, bone marrow suppression may be irreversible and lead to death in patients who previously had impaired immune system function.

If any of the following symptoms occur in a patient: hallucinations, seizures, excessive sedation, confusion, jaundice, increased susceptibility to infections, poor wound healing, tendency to bleed, swelling, shortness of breath, or formation of large blisters on the skin, treatment with Ancotil should be discontinued and medical advice should be sought immediately.

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform a doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring of Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products,
Al. Jerozolimskie 181C, 02-222 Warsaw
Tel.: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.zdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps to gather more information on the safety of the medicine.

5. How to store Ancotil

Store at a temperature of 18°C-25°C.
Storage below 18°C may cause precipitation of the product. The precipitate dissolves by heating to a maximum temperature of 80°C for 30 minutes.
Prolonged storage above 25°C may lead to transformation of the product into the cytostatic agent - 5-fluorouracil (this phenomenon is not visible).
Keep out of sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging. The expiry date refers to the last day of the stated month.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. Such measures will help protect the environment.

6. Contents of the package and other information

What Ancotil contains

The active substance is flucytosine. 1 ml of solution contains 10 mg of flucytosine.
Other components of the medicine are: sodium chloride, tromethamine, hydrochloric acid 25%, water for injections.

What Ancotil looks like and contents of the pack
The cardboard box contains 5 vials made of colourless glass, closed with a rubber stopper and sealed with an aluminium cap, each containing 250 ml of solution.
Marketing Authorisation Holder
Bausch Health Ireland Limited
3013 Lake Drive
Citywest Business Campus
Dublin 24, D24PPT3
Ireland
Manufacturer
ICN Polfa Rzeszów S.A.
Przemysłowa 2 Street
35-959 Rzeszów, Poland
(logo of the marketing authorisation holder)
Information for healthcare professionals
Medicinal product for intravenous administration
Flucytosine should be administered as a rapid infusion (20 to 40 minutes) four times daily, at exactly six-hour intervals.
Official recommendations on appropriate use of antifungal agents should be taken into account.
Sodium content
One litre of Ancotil product contains 138 mmol of sodium. When calculating fluid and electrolyte intake in patients with impaired renal function, heart failure, or electrolyte disturbances, the amount of water and sodium administered with Ancotil should be considered.
Dosing in adult patients with normal renal function
The standard single dose of flucytosine is 25 mg/kg body weight administered four times daily. The daily dose is 100 mg/kg body weight. The induction phase of treatment should last for 2–4 weeks. In subacute and chronic infections, treatment usually lasts longer. Antifungal therapy (maintenance) should then be continued, e.g. using systemic azole antifungals. In urinary tract candidiasis, treatment usually lasts 7–10 days.
During flucytosine therapy, monitoring of its serum concentration is recommended, and the dose should be adjusted, if necessary, to maintain maximum serum concentrations within the range of 40–60 μg/ml.
Due to the risk of resistance development, flucytosine is usually administered concomitantly with amphotericin B.
Dosing in patients with renal impairment
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Creatinine clearance Interval between administration of single doses of 25 mg/kg body weight
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40–20 ml/min 12 hours
20–10 ml/min 24 hours
Below 10 ml/min 12 hours after the first dose, serum flucytosine concentration should be measured. Subsequent doses should be administered at intervals ensuring maintenance of a therapeutic serum flucytosine concentration of 25 to 50 μg/ml.
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Combination therapy with amphotericin B
Experimental studies have shown that flucytosine in combination with amphotericin B exhibits synergistic or at least additive effects.
Clinical studies have also confirmed higher efficacy of combination therapy.
This may allow reduction of amphotericin B dose and its adverse effects, as well as shortening of treatment duration. The combination of these two substances prevents or delays the emergence of secondary resistance, which may occur during flucytosine monotherapy.
Combination therapy is particularly important in cryptococcosis and in subacute and chronic fungal infections (meningitis and encephalitis, myocarditis, Candida endophthalmitis, etc.).
Administration of amphotericin B may lead to reduced creatinine clearance and consequently decreased flucytosine elimination. In such cases, flucytosine dosage should be adjusted according to the scheme (see: “Dosing in patients with renal impairment”).
When using lipid formulations of amphotericin B, dosing depends on the indication and the specific medicinal product. Dosing of lipid formulations of amphotericin B should also follow recommendations provided in the product characteristics of those medicinal products.
Dosing in immunocompromised adult patients
In adult patients with acquired immunodeficiency syndrome and cryptococcal meningitis and encephalitis, flucytosine is recommended at a daily dose of 100 mg/kg body weight given in four divided doses, in combination with conventional amphotericin B (0.7–1.0 mg/kg body weight per day) for at least 2 weeks.
In organ transplant recipients with cryptococcal meningitis, flucytosine is recommended at a daily dose of 100 mg/kg body weight given in four divided doses, in combination with liposomal amphotericin B at a dose of 3–4 mg/kg body weight per day or with lipid-complex amphotericin B at a dose of 5 mg/kg body weight per day, for at least 2 weeks.
Dosing in paediatric patients with normal renal function
In paediatric patients with cryptococcal meningitis, flucytosine is recommended at a daily dose of 100 mg/kg body weight given in four divided doses, in combination with conventional amphotericin B (1.0 mg/kg body weight per day) for at least 2 weeks.
Dosing in immunocompromised paediatric patients
In paediatric patients with acquired immunodeficiency syndrome or undergoing immunosuppressive therapy after organ transplantation and suffering from cryptococcosis, flucytosine is recommended at a daily dose of 100 mg/kg body weight given in four divided doses for at least 2 weeks, in combination with amphotericin B.
In central nervous system infections, concomitantly administered doses of liposomal amphotericin B should be 4–6 mg/kg body weight/day in patients with acquired immunodeficiency syndrome and 3–4 mg/kg body weight/day in organ transplant recipients.
Flucytosine is not recommended for the treatment of systemic candidiasis in paediatric patients.
During treatment, blood counts should be monitored and renal function should be regularly assessed to determine creatinine concentration and creatinine clearance. Standard contraindications and amphotericin B treatment regimens should also be taken into account.