Ancotil 2.5g/250 mL Solution for Infusion – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Ancotil 2.5g/250 mL Solution for Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Flucytosine Ph. Eur. 2.5 g in 250 ml.

Excipient with known effect: sodium

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Infusion bottles containing 2.5g flucytosine Ph.Eur in 250 mL isotonic sodium chloride solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Ancotil is indicated for the treatment of systemic yeast and fungal infections due to sensitive organisms: such infections include:

• Cryptococcosis
• Candidiasis
• Chromomycosis
• infections due to Candida glabrata and Hansenula

In the treatment of cryptococcal meningitis and severe systemic candidiasis it is recommended that Ancotil should be given in combination with amphotericin-B. Amphotericin-B may also be given in combination with Ancotil in severe or long-standing infections due to other organisms. In cases of cryptococcal meningitis, where toxicity of amphotericin B, or a combination of flucytosine with amphotericin B is dose limiting, a combination of flucytosine with fluconazole has demonstrated successful cure, but at a lower rate than in combination with amphotericin B.

4.2 Posology and method of administration

Adults

Ancotil for Infusion should be administered using a giving set. It may be administered directly into a vein, through a central venous catheter, or by intra-peritoneal infusion. The recommended daily dosage is 200 mg/kg body-weight divided into four doses over 24 hours. In patients harbouring extremely sensitive organisms a total daily dose of 100 to 150 mg/kg body-weight may be sufficient. Adequate effects can, however, often be obtained with a lower dose.

It is suggested that the duration of the infusion should be of the order of 20 to 40 minutes provided this is balanced with the fluid requirements of the patient. As a rule, treatment with Ancotil for Infusion should rarely be required for periods of more than one week.

Ancotil for Infusion may be given concurrently with other infusions of normal saline, glucose or glucose/saline. No other agent should be added to or mixed with Ancotil for Infusion.

Use in patients with renal insufficiency

Since Ancotil is excreted primarily by the kidneys, smaller doses should be administered with extended intervals in patients with renal impairment based on creatinine clearance. The following is suggested as a guide for dosage in patients with severe infection associated with renal impairment:

In patients with:

Creatinine clearance > 40 ml /min: 25-50 mg/kg every 6 hours.

Creatinine clearance <40 to >20 ml /min: 25-50 mg/kg every 12 hours.

Creatinine clearance <20 to >10 ml /min: 25-50 mg/kg every 24 hours.

Creatinine clearance <10 ml /min: an initial single dose of 25-50 mg/kg; subsequent doses should be calculated according to the results of regular monitoring of the serum concentration of the drug, which should not be allowed to exceed 80 micrograms/ml. Blood levels of 25 to 50 micrograms/ml are normally effective.

Patients under haemodialysis

Flucytosine is filtered and excreted during the haemodialysis therefore the dosage of Ancotil must be repeated after the session of haemodialysis.

In anuric or nephrectomized haemodialysis patients, under no circumstances should the initial single dose be repeated prior to performing the next dialysis session.

Use in patients with liver impairment

Patients with impaired liver function may be treated with flucytosine, but they require particularly careful monitoring.

Paediatric populations

Available data are not sufficient to support evidence-based dosing recommendations in paediatric patients, including term and preterm neonates.

Flucytosine should not be used as first line or monotherapy in paediatric patients. Flucytosine should be used in combination with other appropriate anti-fungal agents when other suitable drugs are not available and are not likely to be effective.

Elderly

Although no specific studies have been performed to establish the use of Ancotil in the elderly, documented use indicated that the dosage requirements and side effects profile are similar to those of younger patients. Particular attention should be paid to renal function in this group.

Antifungal combinations and Amphotericin B

The combination therapy of Ancotil plus amphotericin B has a synergistic effect and therefore it is sometimes possible to reduce the dosage and thus diminish the risk of secondary resistance to flucytosine. This combination is indicated in certain sub-acute and chronic fungal infections, especially with meningo-encephalitides, endocarditides and aspergilloses. The recommended dose of flucytosine for this combination therapy is 100-150 mg/kg Ancotil daily. Particularly careful monitoring of renal function is necessary when flucytosine is combined with amphotericin B. The Summary of Product Characteristics of amphotericin B and international accepted guidelines of infectious diseases should be considered.

Duration of treatment

The duration of treatment should be determined on an individual basis.

The outcome of therapy will be affected by variations in the sensitivity of the infection organism, its accessibility and its susceptibility to Ancotil, as well as by differences in the response of individual patients. In cases of cryptococcal meningitis, treatment should last for at least four months. The following is a guide;

• systemic candidosis 2 - 4 weeks
• cryptococcus meningitis 6 - 10 weeks
• chromoblastomycosis 6 - 12 months

4.3 Contraindications

Ancotil is contra-indicated:

• in patients who have shown hypersensitivity to flucytosine or any of the excipients.
• in co-administration with antiviral nucleoside drugs e.g. ganciclovir and valganciclovir, brivudine, sorivudine and their analogues (irreversible inhibitors of the dihydropyrimidine dehydrogenase enzyme [DPD] (see section 4.4; Special warnings and precautions for use)
• in known complete dihydropyrimidine dehydrogenase (DPD) deficiency
• Concomitant administration of flucytosine and tegafur/gimeracil/oteracil (of which tegafur is a prodrug of 5-FU, and gimeracil a reversible DPD-inhibitor) (see section 4.4 and 4.5).
• in breastfeeding women (see section 4.6; Fertility, pregnancy and lactation).

4.4 Special warnings and precautions for use

Haematological status and liver function

The haematological status and the liver function (SGOT, SGPT and alkaline phosphatase) should be determined before commencement of treatment and further regular monitoring is advised, especially at the beginning of the treatment (recommended daily during the first week of treatment and twice weekly thereafter).

Patients with impaired liver function may be treated with flucytosine; however, they require particularly careful monitoring.

The product should be used with great caution in patients with depression of bone marrow function or blood dyscrasias. In patients undergoing cytostatic or immunosuppressive therapy blood counts must be monitored more frequently because of high risk of haematological damage.

Renal function and haemodialysis

The excretion of flucytosine drug takes place exclusively at kidney level. Therefore, before and during treatment with Ancotil renal function of the patient should be determined (preferably by determining the endogenous creatinine clearance). If necessary, the dose should be adjusted (see section 4.2 Posology and method of administration).

Creatinine Measurement: Flucytosine may interfere with the two-stage enzymatic measurement of creatinine used with the manual desk top Vitros DT 60 analyser, giving the false impression of azetomia. Other suitable methods should be used for creatinine assessment. The current creatinine method used with automated Vitros analysers is not affected by flucytosine. Flucytosine has no impact on a Jaffe's reaction test.

Ancotil should not be used in patients with impaired renal function in the absence of facilities for monitoring blood levels of the drug.

65 to 75 % of Ancotil is excreted by haemodialysis. Consequently, for patients undergoing haemodialysis, the dose of Ancotil must be administered again after each haemodialysis or purification session.

Flucytosin serum levels

Steady-state serum level should average 35 to 70 μg/ml. Lower levels may be sufficient for more sensitive strains. In vitro sensitivity of most of the susceptible strains lies at minimum inhibitory doses between 10 and 25 μg/ml. However, the dosage should ensure that serum levels greater than 25 μg/ml are maintained due to the increased risk of development of resistance at low concentrations. Prolonged existence of serum levels above 100 μg/ml should be avoided because of increased haematological toxicity at high levels.

Moreover, the 5-FC levels should be monitored in order to adjust the dosage accordingly. When measuring drug serum levels, it should be noted that levels of the drug in blood samples, taken during or immediately after administration of Ancotil for Infusion, are not a reliable guide to subsequent levels; it is advisable to remove blood for monitoring of blood levels of Ancotil shortly before starting the next infusion.

In calculating the fluid and electrolyte intake of patients with impaired renal function, cardiac failure or electrolyte imbalance, due allowance should be made for the volume and sodium content (138 millimole/litre) of Ancotil for Infusion.

Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency

5-Fluorouracil is a metabolite of flucytosine. DPD is a key enzyme involved in the metabolism and elimination of 5-fluorouracil. Therefore, the risk of severe drug toxicity is increased when Ancotil is used in individuals with deficiency in dihydropyrimidine dehydrogenase (DPD).

Nucleoside analogues such as brivudine and sorivudine are potent inhibitors of the DPD enzyme and may therefore cause an abrupt rise in the plasma concentration of 5-fluorouracil and/or other fluoropyrimidines. An interval of at least four weeks should elapse between treatment with brivudine, sorivudine or analogues and subsequent administration of Ancotil.

An interval of at least 7 days should be observed when taking

tegafur/gimeracil/oteracil and subsequent use of flucytosine.

Determination of DPD activity may be considered where drug toxicity is confirmed or suspected. In the event of suspected drug toxicity, consideration should be given to stopping Ancotil treatment.

Drug toxicity

In the event of suspected drug toxicity, consideration should be given to stopping Ancotil treatment and suitable measures taken.

Phenytoin serum levels

Patients receiving phenytoin and Ancotil concomitantly should be checked regularly for increased phenytoin plasma levels (refer to Section 4.5 for further details).

Sensitivity testing:

It is recommended that cultures for sensitivity testing be taken before treatment and repeated at regular intervals during therapy. However, it is not necessary to delay treatment until results of these tests are known.

To determine sensitivities, the methods of Shadomy (Appl. Microbiol., 1969, 17, 871) and Scholer (Mykosen, 1970, 13, 179) are recommended. For sensitivity testing it is essential that culture media are free of antagonists to flucytosine.

Combination therapy

The combination therapy of Ancotil plus amphotericin B has a synergistic effect. However, it should be remembered that this combination increases the risk of side-effects.

Contraception in males and females:

Flucytosine is partially metabolised into 5-fluorouracil, which is genotoxic and considered as a potential human teratogen.

Females of childbearing potential under treatment must use effective contraception during treatment and for one 6 months after treatment. In case of renal impairment, the contraception period should be prolonged for an additional two months.

Male patients (or their female partners of childbearing potential) must use effective contraception during treatment and for three months after treatment (see section 4.6; Fertility, pregnancy and lactation). In case of renal impairment, the contraception period should be prolonged for an additional two months.

Paediatric populations:

Flucytosine has a narrow therapeutic window and there is a risk of its potential toxicity at high systemic concentrations.

Because of prolonged elimination of flucytosine in paediatric patients, especially in term and preterm neonates, flucytosine administration may lead to exceeding the optimum serum levels. Monitoring of plasma flucytosine levels based on local (or national) antifungal treatment guidelines and dose adjustments, as needed, are necessary to avoid excessive exposure to flucytosine.

The blood count and kidney function should be regularly controlled in paediatric patients during the treatment to monitor creatinine concentration and clearance.

Excipients

The medicinal product contains 34.5 mmol (or 0.8g) sodium/250ml solution for infusion, equivalent to 40% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

The maximum daily dose of this product (14 g flucytosine, calculated with 200 mg/kg flucytosine and a body weight of 70 kg) contains 4.4 g sodium, equivalent to approximately 220% of the WHO recommended maximum daily intake for sodium for an adult,

Ancotil is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

4.5 Interaction with other medicinal products and other forms of interaction

There is contradictory evidence concerning a drug interaction between flucytosine and cytarabine (cytostatic cytosine). The antimycotic effect of flucytosine might be impaired by cytarabine. Strict monitoring of blood levels is required if the two medicines are given concurrently.

Brivudine, sorivudine and analogues are potent inhibitors of DPD, a fluorouracil metabolising enzyme (see section 4.4). As fluorouracil is a metabolite of flucytosine, concomitant administration of these drugs with Ancotil is contraindicated (see section 4.3).

Concomitant use of the combination tegafur/gimeracil/oteracil (of which tegafur is a prodrug of 5-FU and gimeracil a reversible DPD inhibitor) and flucytosine is contraindicated (see section 4.3) as it may lead to additional toxicities

Caution should be applied when myelosuppressive agents are co-administered, because of a potential risk of increased toxicity.

Increased phenytoin plasma levels have been reported with concomitant administration of phenytoin and intravenous fluorouracil, leading to symptoms of phenytoin intoxication (see section 4.4). This is relevant to Ancotil as flucytosine is metabolised to fluorouracil. Although administration of Ancotil results in much lower plasma concentrations of fluorouracil, this interaction cannot be entirely excluded. Therefore, patients receiving co-administered phenytoin and Ancotil should be regularly monitored for increased plasma concentrations of phenytoin.

Concomitant administration of flucytosine and nephrotoxic substances require extremely careful monitoring of renal function. Medicines which affect glomerular filtration prolong the half-life of flucytosine.

4.6 Fertility, pregnancy and lactation

Contraception in males and females:

Flucytosine is partially metabolised into 5-fluorouracil, which is genotoxic and considered as a potential human teratogen (see section 5.3, Preclinical safety data). Females of childbearing potential under treatment must use effective contraceptive during treatment and for 6 months after treatment. In case of renal impairment, the contraception period should be prolonged for an additional two months. Male patients (or their female partners of childbearing potential) must use effective contraception during treatment and for three months after treatment. In case of renal impairment, the contraception period should be prolonged for an additional two months.

Pregnancy

In animal studies, flucytosine and one of its metabolites (5-fluorouracil) showed reproductive toxicity (teratogenicity and embyrotoxicity) (see section 5.3; Preclinical safety data).

In humans, flucytosine crosses the placenta. There are very limited data on use of flucytosine in pregnant women. Therefore, harmful impact on the embryo/foetus cannot be excluded, especially during the first trimester. Consequently, Ancotil should not be used during pregnancy and in women of childbearing potential not using contraception unless strictly necessary in case of life-threatening infections and lack of an effective alternative treatment.

If Ancotil is administered in pregnancy, the patient should be advised of the teratogenic risk of Ancotil, and careful prenatal and postnatal monitoring should be performed. In case of administration up to delivery, in view of the safety profile in flucytosine, a neonatal monitoring (haematologic and hepatic) should be performed.

Breast-feeding

There are no data on the excretion of flucytosine in human milk. Breastfeeding is contraindicated during flucytosine treatment (see section 4.3, Contraindications).

4.7 Effects on ability to drive and use machines

Not applicable.

4.8 Undesirable effects

Undesirable effects of flucytosine primarily affect the gastrointestinal tract, liver and bone marrow. Serious side effects may occur with elevated serum concentrations of flucytosine (e.g. in renal insufficiency, if the dose is not adjusted to the reduced renal excretion capacity).

Assessment of undesirable effects is based on the following frequency categories:

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1 000 to < 1/100)

Rare (≥ 1/10 000 to < 1/1 000)

Very rare (<1/10 000)

Not known (Frequency cannot be estimated from the available data)

The following undesirable effects have been observed:

In the majority of the cases, these disorders occur within the first 2 to 3 weeks of treatment.

Undesirable effects may occur more frequently with combination therapy with amphotericin B and other potentially nephrotoxic compounds. Thus, flucytosine serum levels may be increased if the dose is not adjusted in accordance with the reduced renal function.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Signs and symptoms

Likely symptoms of overdose include nausea, vomiting, diarrhoea and abdominal pain, blood count changes, especially leukopenia and thrombocytopenia, and elevated liver enzyme levels in serum.

Management

There is no specific antidote. Milder toxic effects such as nausea, vomiting, diarrhea, bone marrow damage and elevated liver transaminases are usually completely reversible after discontinuation of treatment.

After ingestion, further absorption may be prevented by inducing vomiting or gastric lavage and then administration of activated charcoal and sodium sulphate as a laxative.

Forced diuresis is indicated as soon as possible.

Haemodialysis may be considered and will produces a rapid fall in the serum concentration of Ancotil.

Further treatment is symptomatic.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotic agent ATC Code: J02AX01

Flucytosine is a fluorinated pyrimidine derivative. It is an antimycotic agent exerting fungistatic and fungicidal activity by interfering with protein and DNA synthesis. Fungal cells absorb flucytosine selectively via cytosine permease. It is desaminated to 5-fluorouracil which is then incorporated into fungal RNA, leading to faulty protein biosynthesis. 5-Fluorouracil is also converted to fluorodeoxyuridine monophosphate by uracil phosphoribosyltransferase (UPRTase). Fluorodeoxyuridine interferes with the enzyme thymidylate synthase. Inhibition of thymidylate synthase subsequently causes disruption of DNA synthesis.

Flucytosine has fungistatic and fungicidal activity in systemic and local infections against yeasts such as Candida, Torulopsis and Cryptococcosis as well as in chromomycosis. In aspergilli, it shows exclusively fungistatic activity.

Antimycotic activity

An in vitro study on susceptibility of approximately 8,800 clinical isolates (yeasts and filamentous fungi) to flucytosine according to NCCLS (The National Committee for Clinical Laboratory Standards) guidelines demonstrated that the four most common Candida species are extremely sensitive (the minimal inhibitory concentration for Candida species varied from 0.12 μg/ml to 1 μg/ml for 90% of the tested strains).

Mechanism of resistance:

Two major mechanisms of resistance have been described:

• decreased activity of the cytosine permease or deaminase, leading to a decreased uptake or conversion of the drug. This mechanism is responsible for primary and intrinsic resistance.
• loss of activity of UPRTase

Resistance may also result from increased synthesis of pyrimidines, which compete with the fluorinated antimetabolites of 5-FC and thus diminish its antimycotic activity. Other mechanisms of flucytosine resistance include the up-regulated expression of a vacuolar glutathione S-conjugate pump that pumps flucytosine out of cells as well as the induced expression of a multi-drug resistance gene that permeates flucytosine out of cells.

Primary resistance has been observed in some fungi. However, it occurs only very rarely with Candida spp. (95% susceptible, 2% intermediary, 3% resistant), except for C. krusei (5% susceptible, 67% intermediary, 28% resistant), while resistance is common in C. lusitaniae. Intermediately susceptible or resistant strains are also not uncommon in C. tropicalis.

Resistance to C. neoformans is rare but around 30 % of strains show intermediate susceptibility.

Secondary resistance may develop, in particular with flucytosine monotherapy. Strains initially susceptible to Ancotil may become resistant during therapy. It is thus recommended to estimate the susceptibility of the strains before and during therapy. Combination of flucytosine and other antimycotic agents such as amphotericin B and triazoles often result in a synergistic effect; the MIC value achieved with the combination is less than the MIC values of the individual substances.

5.2 Pharmacokinetic properties

Absorption:

Bioavailability after an oral dose of 2 g varies between individuals and ranges from 76 – 98 %. Peak plasma concentrations are reached within 1 – 2 hours after oral administration but may be delayed in subjects with renal impairment to 4 - 6 hours. Food and antacids decrease the absorption rate, but the total extent absorbed is not relevantly affected.

Distribution:

Ancotil is widely distributed in body tissues and fluids (including cerebrospinal fluid). The volume of distribution is between 0.5 and 1.0 l/kg.

Binding to plasma proteins is minimal (< 5%). Typical maximum serum concentrations are between 30 and 50 ug/ml after oral intake or intravenous administration of 2 g flucytosine. Flucytosine concentrations in cerebrospinal fluid, saliva and peritoneal fluid are slightly lower.

Flucytosine crosses the human placenta. Accumulation of flucytosine in amniotic fluid has been observed.

The urinary concentrations of Ancotil may be up to 100 times higher than plasma concentrations, in patients with a normal renal function.

Metabolism:

Only a small proportion of flucytosine is metabolised. Enteric bacteria may be responsible for some metabolism of flucytosine to 5-fluorouracil (5-FU). Additionally 5-FU is released from killed fungi cells. The 5-FU/5-FC ratio of plasma concentrations is low (4%).

Excretion:

The plasma half-life is 3-6 hours in patients with normal renal function but this value increases in renal failure (30-250 hours). Excretion is almost exclusively through glomerular filtration. About 90 % of the dose administered is excreted unchanged in the urine.

Flucytosine is readily removed by haemodialysis. Virtually the total amount of a single dose is removed by haemodialysis. Consequently, a full dose must be administered again after each haemodialysis session.

Elimination via peritoneal dialysis is possible

Paediatric populations:

The limited data available on flucytosine pharmacokinetic properties in paediatric patients suggest that in children, especially neonates flucytosine half-life is longer than in adults (4 vs 7 h). One neonatal pharmacokinetic study demonstrated that flucytosine half-life was twice as that reported in adults, although peak concentrations were comparable. Additionally, the volume of distribution of flucytosine approximates the volume of total body water due to its high solubility. In a retrospective study of 391 paediatric patients, 65 % of flucytosine trough concentrations exceeded the normal reference range.

5.3 Preclinical safety data

In vitro investigations on mutagenic potential of flucytosine were negative. No studies are available on the carcinogenic potential of Ancotil.

Flucytosine has been shown to be teratogenic and embryotoxic in rats when given in oral or parenteral doses of 40 mg/kg body weight per day onwards (240 mg/m² or 0.043 times the human daily dose).

The flucytosine metabolite 5-fluorouracil is genotoxic in mice and in vitro, embryotoxic and teratogenic in mice and rats, and is classified as possible human teratogen.

Malformations occurred (defects in the nervous system, palate, skeleton, tails, limbs) in several species (including rat and Syrian Golden hamsters). Embryotoxic effects (small foetus, resorption) are also observed in monkeys treated with 5-fluorouracil.

Both flucytosine and 5-fluorouracil cross the placenta.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride Ph. Eur., tromethamine USP, hydrochloride acid 25% and water for injections Ph. Eur.

6.2 Incompatibilities

Ancotil for Infusion may be given concurrently with other infusions of Sodium Chloride Intravenous infusion (0.9% w/v) BP, Glucose Intravenous Infusion (5% w/v) BP, or Sodium Chloride (0.18% w/v) and Glucose (4% w/v) Intravenous infusion BP. No other agent should be added to or mixed with Ancotil for Infusion.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Ancotil for Infusion should be stored between 18ºC and 25ºC. If stored below 18ºC, precipitation of Ancotil substance may occur.

Prolonged storage above 25ºC could lead to the decomposition of Ancotil resulting in the formation of 5-fluorouracil.

6.5 Nature and contents of container

250 ml neutral glass bottle (DIN 58363) with a teflon coated butyl rubber stopper and aluminium crimping cap. Bottles are in packs of 5.

6.6 Special precautions for disposal

Ancotil for Infusion is available to hospitals only.

7. MARKETING AUTHORISATION HOLDER

Viatris Products Limited

20 Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 46302/0116

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

27/02/2009

10 DATE OF REVISION OF THE TEXT

06/11/2025