Ancotil

Leaflet accompanying the packaging: information for the user

Ancotil, 10 mg/ml, solution for infusion

Flucytosine

You should read the contents of the leaflet before using the medicine, as it contains important information for the patient.

• You should keep this leaflet, so that you can read it again if you need to.
• If you have any further questions, you should 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 symptoms 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. See section 4.

Contents of the leaflet

• 1. What Ancotil is and what it is used for
• 2. Important information before you use Ancotil
• 3. How to use Ancotil
• 4. Possible side effects
• 5. How to store Ancotil
• 6. Contents of the pack and other information

1. What Ancotil is and what it is used for

Ancotil is an antifungal medicine. It works against certain types of fungi, especially yeast of the genus Candidaand Cryptococcus neoformans, as well as fungi that cause chromoblastomycosis (a chronic, subcutaneous fungal infection). Most yeast strains isolated in Europe from previously untreated patients are sensitive to flucytosine, the active substance of Ancotil. Ancotil is used to treat fungal infections: generalized candidiasis, cryptococcosis, and chromoblastomycosis in adults, and generalized cryptococcosis and chromoblastomycosis in children. Ancotil is often used in combination with amphotericin B, as the combined effect of these medicines against many fungi is much stronger than the sum of their individual effects. In the treatment of cryptococcal meningitis and severe systemic candidiasis, combination therapy with amphotericin B is recommended. Ancotil can be used in patients with normal or reduced immunity.

2. Important information before you use Ancotil

When not to use Ancotil

• If you are allergic (hypersensitive) to flucytosine or any of the other ingredients of this medicine (listed in section 6).
• If you are taking any antiviral medicines from the group of so-called nucleosides, such as ganciclovir, valganciclovir, brivudine, sorivudine, or their analogs (see also "Ancotil and other medicines").
• If you have not been detected to have dihydropyrimidine dehydrogenase (DPD) enzyme activity (complete DPD deficiency).
• In breastfeeding women (see below: "Pregnancy, breastfeeding, and fertility").

When to be careful when using Ancotil

• If you have kidney failure.
• If you have liver function disorders.
• If you have blood composition disorders or bone marrow function disorders. Before starting and during treatment with Ancotil, your doctor will recommend blood tests to monitor kidney, liver, and bone marrow function.

Women of childbearing age
If you are of childbearing age, you must use effective contraception during and for one monthafter stopping Ancotil treatment. This medicine can cause birth defects.
If you have any further questions, you should discuss them with your doctor.
Men
The patient (and his partner of childbearing age) must use effective contraception during and for three monthsafter stopping Ancotil treatment. This medicine can cause birth defects.
If you have any further questions, you should discuss them with your doctor.

Ancotil and other medicines

You should tell your doctor about all medicines you are taking or have recently taken, as well as any medicines you plan to take. This is especially important for the following medicines.

• Concomitant use of antiviral medicines from the group of so-called nucleosides, such as ganciclovir, valganciclovir, brivudine, sorivudine, and their analogs, is contraindicated because it may increase the risk of adverse reactions associated with Ancotil (see also "When not to use Ancotil").
• Cytostatics (anticancer medicines). During Ancotil treatment, leukopenia (decrease in white blood cell count) may occur, so careful and frequent (even daily) monitoring of peripheral blood counts is necessary when concomitantly administering cytostatics.
• Medicines that reduce renal glomerular filtration. They may cause an increase in flucytosine plasma concentrations. If these medicines are used concomitantly with flucytosine, regular monitoring of renal function and appropriate dose adjustment of the medicine are necessary.
• Cytarabine (an anticancer medicine) causes the loss of the antifungal effect of Ancotil.
• Medicines containing phenytoin (used to treat epilepsy). Fluorouracil administered intravenously simultaneously with phenytoin can cause an increase in its plasma concentration, leading to phenytoin toxicity in some patients. This is also important when using Ancotil, as flucytosine is metabolized to fluorouracil.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or plan to have a child, you should consult your doctor or pharmacist before using this medicine.
Ancotil may cause birth defects. Therefore, it should not be used in pregnant women or women of childbearing age who do not use effective contraception. In life-threatening situations, the doctor may decide to use the medicine in pregnant women. The patient, as well as the fetus or newborn, will then be subject to additional tests during and after pregnancy.
Using the medicine during breastfeeding is contraindicated. The doctor will decide whether to stop breastfeeding or discontinue 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, during Ancotil treatment, effective contraception should be used to prevent pregnancy in the patient taking Ancotil or the partner of a male patient treated with this medicine.
Women of childbearing age during and for one monthafter stopping Ancotil treatment must use effective contraception. Men (and their partners of childbearing age) must use effective contraception during and for three monthsafter stopping Ancotil treatment.

Driving and using machines

No studies have been conducted on the effect of the medicine on the ability to drive and use machines.

Ancotil contains sodium

The medicine contains 34.5 mmol (794 mg) of sodium (the main component of common salt) in one vial (250 ml) of the medicine. This corresponds to 40% of the maximum recommended daily sodium intake in the diet for adults.
The medicine contains 96.6 mmol (2220 mg) of sodium (the main component of common salt) in each maximum daily dose of the medicine (700 ml of infusion solution for an adult weighing 70 kg). This corresponds to 111% of the maximum recommended daily sodium intake in the diet for adults.
In the case of taking 700 ml of infusion solution per day or more for an adult weighing 70 kg, patients should contact their doctor or pharmacist. This applies to patients who take Ancotil daily and for a long time, especially patients on a low-sodium diet.
When calculating water and electrolyte intake, especially in patients with impaired renal function, heart failure, and electrolyte disorders, the amount of water and sodium received with Ancotil should be taken into account.

3. How to use Ancotil

Ancotil should always be used as directed by your doctor.
Ancotil is administered only by qualified medical personnel under the supervision of a doctor. Detailed information on dosing and administration of Ancotil is provided at the end of this leaflet, in the section "Information for healthcare professionals".

Use in children and adolescents

Clinical data on the use of Ancotil in children are available, but they are insufficient to determine dosing recommendations for this age group. If the doctor prescribes Ancotil to a child, they will also determine the best dosage.
Due to the longer elimination period of flucytosine in pediatric patients, especially the youngest ones, during flucytosine treatment, plasma concentrations may exceed the recommended levels. Therefore, during treatment, the child's plasma flucytosine concentration will be regularly monitored.

Using a higher dose of Ancotil than recommended

In the event of using too much Ancotil, side effects may worsen, especially blood composition disorders, and when using high doses for a long time, diarrhea, nausea, vomiting, and liver function disorders may occur. These symptoms usually disappear quickly after reducing the dose or discontinuing the medicine.

Missing a dose of Ancotil

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

Stopping Ancotil treatment

Stopping Ancotil treatment may lead to worsening of the disease for which it is being used.
If you have any further questions about using the medicine, you should ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, Ancotil can cause side effects, although not everybody gets them.
The following side effects may occur when using Ancotil. The exact frequency of their occurrence is unknown (cannot be determined based on available data).

• Transient nausea, vomiting, and diarrhea.
• Transient rash.
• Hepatitis, liver cell necrosis; in single cases, acute liver damage has been observed, which can lead to death in some patients.
• Seizures, headaches, and dizziness, excessive sedation.
• Hallucinations, confusion.
• Heart muscle damage.
• Allergic reactions, Lyell's syndrome (characterized by the occurrence of soft, large blisters on the skin).
• Transient disorders of liver enzyme activity (dose-dependent).
• Changes in peripheral blood counts, related to bone marrow suppression, primarily leukopenia (decrease in white blood cell count) and thrombocytopenia (decrease in platelet count) - these changes occur mainly in patients with renal failure, in whom flucytosine may reach high plasma concentrations, as well as in patients taking amphotericin B concomitantly; in single cases, bone marrow suppression may be irreversible and lead to death in patients who have previously had immune system suppression.

If you experience the following symptoms: hallucinations, seizures, excessive sedation, confusion, yellowing of the skin, frequent colds, and difficulty healing wounds, tendency to bleed, swelling, shortness of breath, formation of large blisters on the skin, you should stop using Ancotil and immediately consult your doctor.

Reporting side effects

If you experience any side effects, including any not listed in this leaflet, you should tell your doctor or pharmacist. Side effects can be reported directly to the Department of Monitoring of Adverse Reactions to Medicinal Products, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products,
Jerozolimskie Avenue 181C, 02-222 Warsaw
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
website: https://smz.zdrowie.gov.pl.
Side effects can also be reported to the marketing authorization holder.
Reporting side effects will help 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 at temperatures below 18°C may cause the product to precipitate. The sediment dissolves when heated to a maximum temperature of 80°C for 30 minutes.
Long-term storage at temperatures above 25°C may cause the product to transform into a cytostatic - 5-fluorouracil (this phenomenon is invisible).
Store in a place 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 specified month.
Medicines should not be disposed of via wastewater or household waste. You should ask your pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

6. Contents of the pack and other information

What Ancotil contains

• The active substance of the medicine is flucytosine. 1 ml of the solution contains 10 mg of flucytosine.
• The other ingredients of the medicine are: sodium chloride, trometamol, 25% hydrochloric acid, water for injections.

What Ancotil looks like and contents of the pack

The carton contains 5 glass vials, closed with a rubber stopper and protected with an aluminum cap, containing 250 ml of solution each.

Marketing authorization 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

Date of last revision of the leaflet:

(logo of the marketing authorization holder)

Information for healthcare professionals

Medicine for intravenous administration

Flucytosine is administered in a rapid infusion (20 to 40 minutes) four times a day, exactly every six hours.
Official recommendations for the proper use of antifungal medicines should be taken into account.
Sodium content
One liter of Ancotil contains 138 mmol of sodium. When calculating water and electrolyte intake in patients with impaired renal function, heart failure, and electrolyte disorders, the amount of water and sodium received with Ancotil should be taken into account.
Dosing in adult patients with normal renal function
The standard single dose of flucytosine is 25 mg/kg body weight, administered four times a day.
The daily dose is 100 mg/kg body weight. The induction phase of treatment should last for 2-4 weeks.
In acute and chronic infections, treatment usually lasts longer. Antifungal treatment (maintenance) should then be continued, for example, using systemic azole antifungals. In candidiasis of the urinary tract, treatment usually lasts for 7-10 days.
During flucytosine treatment, it is recommended to measure its plasma concentration and, if necessary, adjust the dose to ensure maximum plasma concentrations in the range of 40-60 μg/ml.
Due to the risk of resistance, 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 the product, amounting to 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 administration of the first dose, the flucytosine concentration in plasma is determined. Subsequent doses are administered at such a frequency that the therapeutic flucytosine concentration in plasma is maintained, ranging from 25 to 50 μg/ml.
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Combination therapy with amphotericin B
Based on experimental studies, it has been found that flucytosine with amphotericin B has a synergistic effect, at least additive.
Clinical studies have also confirmed the greater efficacy of combination therapy.
In this case, it is possible to reduce the dose and side effects of amphotericin B, as well as shorten the treatment time. The combined effect of these two substances prevents or delays the onset of secondary resistance, observed during monotherapy with flucytosine.
Combination therapy is especially important in cryptococcosis and in acute and chronic fungal infections (meningitis and brain abscess, endocarditis, and fungal eye infections, etc.).
Administration of amphotericin B may lead to a decrease in creatinine clearance, and consequently, a decrease in flucytosine elimination. In such a situation, the flucytosine dose should be modified according to the scheme (see "Dosing in patients with renal impairment").
In the case of using lipid forms of amphotericin B, its dosing depends on the indication and the specific medicinal product. When selecting the dose of lipid forms of amphotericin B, the instructions in the characteristics of these medicinal products should also be followed.
Dosing in adult patients with reduced immunity
In adult patients with acquired immune deficiency syndrome and cryptococcal meningitis, it is recommended to administer flucytosine in a daily dose of 100 mg/kg body weight in four divided doses, together with amphotericin B in a conventional form (0.7-1.0 mg/kg body weight per day) for at least 2 weeks.
In patients after organ transplantation and cryptococcal meningitis, it is recommended to administer flucytosine in a daily dose of 100 mg/kg body weight in four divided doses, together with amphotericin B in a liposomal form in a dose of 3-4 mg/kg body weight per day or amphotericin B in a lipid complex form in a dose of 5 mg/kg body weight per day for at least 2 weeks.
Dosing in pediatric patients with normal renal function
In pediatric patients with cryptococcal meningitis, it is recommended to administer flucytosine in a daily dose of 100 mg/kg body weight in four divided doses, together with amphotericin B in a conventional form (1.0 mg/kg body weight per day) for at least 2 weeks.
Dosing in pediatric patients with reduced immunity
In pediatric patients with acquired immune deficiency syndrome or during immunosuppressive therapy after organ transplantation and cryptococcosis, it is recommended to administer flucytosine in a daily dose of 100 mg/kg body weight in four divided doses for at least 2 weeks, together with amphotericin B.
In the case of central nervous system infections, the doses of amphotericin B administered concomitantly in a liposomal form should be 4-6 mg/kg body weight per day in patients with acquired immune deficiency syndrome and 3-4 mg/kg body weight per day in patients after organ transplantation.
Flucytosine is not recommended for the treatment of generalized candidiasis in pediatric patients.
During treatment, blood counts and renal function should be regularly monitored to assess creatinine concentration and clearance. The typical contraindications and treatment schedules for amphotericin B should also be taken into account.